Orlando, G: Transplantation, Bioengineering, and Regeneratio 0128148330, 9780128148334

Table of contents :
Cover
TRANSPLANTATION,
BIOENGINEERING,
AND
REGENERATION
OF THE ENDOCRINE
PANCREAS,
VOLUME 1
Copyright
Dedication
Contributors
Preface
Part A: Whole pancreas allo-transplantation
Section I: Introduction
1 History of pancreas transplantation
The first attempt at transplantation of pancreatic tissue
The nature of the pancreas
Discoveries about the pancreas
Discoveries about the relationship between pancreas and diabetes
Discoveries about insulin and diabetes etiology
Early animal models of diabetes and pancreas transplantation
Modern animal models of pancreas transplantation and surgical techniques
Modern animal models of pancreas transplant immunology
History of pancreas transplantation in humans
Acknowledgments
References
2
How to build a pancreas transplant program
Introduction
Leadership commitment to growth in pancreas transplantation
Growing the pancreas transplant waitlist through reevaluation of diabetic kidney waitlist patients
Growing the pancreas transplant waitlist through expanded recipient eligibility criteria
Modification of kidney transplant evaluation of new patients
Promotion of pancreas transplant for diabetic kidney transplant recipients (PAK)
Promotion of solitary pancreas transplants for hypoglycemic unawareness
Modification of clinical outreach to promote pancreas transplantation
Modification of donor call to promote pancreas transplant
Modification of donor pancreas acceptance rates
Simplifying pancreas transplant management through use of protocols
Conclusions
References
3
Pathophysiology of diabetes
Introduction
Insulin structure, secretion, and action
Structure
Secretion
Action
Effects of insulin on glucose and lipid metabolism
Vascular actions of insulin
Pathogenesis of diabetes
Genetic factors
Environmental factors
Type 1 diabetes
Autoimmunity and cellular immunity
Type 2 diabetes
Insulin resistance
Adipokines and insulin resistance
Peripheral glucose uptake
Hepatic glucose production
β -Cell dysfunction
Glucotoxicity
Lipotoxicity
References
4
Epidemiology of diabetes mellitus
History/classic definitions
Special populations
Descriptive epidemiology
Risk factors
Diabetes complications
Treatment
References
Section II: The donor
5
Pancreas donor selection
Introduction
The ideal pancreas donor
Extending the age range of viable pancreas donors
Donor body mass index
Abnormal laboratory values
Infection
Local vs imported organs
Donation after cardiac death donors
Pancreas donor quality assessment scales
Graft selection
Logistical aspects to optimize organ viability
Conclusion
References
6
Deceased donor pancreas procurement
Donor selection
Assessment of the potential pancreas donor
Evolution of practice
Preoperative preparation
Surgical technique
Warm phase dissection
Cross clamping and initiation of cold perfusion
Cold phase dissection
Pancreas preservation
En bloc technique for pancreas-liver procurement
DCD procurement
Arterial variations in combined pancreas and liver procurement
Procurement with small bowel
Procurement without liver
Summary
References
7
Surgical techniques for living donor pancreas transplantation
Introduction
Selection criteria for donors
Donor operation
Open standard procurement of the distal pancreas from a living donor
Open simultaneous procurement of left kidney/distal pancreas
Laparoscopic/robotic procurement of the distal pancreas from a living donor
Variations
Laparoscopic/robotic procurement of the distal pancreas with the left kidney
Laparoscopic/robotic procurement of the distal pancreas with the right kidney
Postoperative management
Donor complications
Recipient operation
Bladder drainage
Enteric drainage
Variations in operative technique
Diversion of exocrine pancreatic secretions
Positional variations
Posttransplant management
Anticoagulation
Immunosuppression
Blood glucose control and octreotide
Complications
Outcomes
Conclusions
References
8
Pancreas preservation
Introduction
Organ damage after death
Cold storage and its effects
Development of UW
Clinical results
Pancreas preservation going forward
References
9
Pancreas graft back-table surgery technique
Introduction
Anatomical variations
Classical technique with sutures/ties
Vascular reconstruction
Gastroduodenal reconstruction
Dorsal pancreatic artery
Venous reconstruction
Tieless technique with bipolar device
Methods (description of technique)
Conclusion
References
Further reading
Section III: The recipient
10
Pancreas transplant alone
Introduction
Indications
Pretransplant evaluation
Cardiovascular assessment
Peripheral vascular disease
Assessment of insulin requirements, C-peptide, and autoimmunity
Assessment of hypoglycemia
Assessment of complications related to hyperglycemia
Kidney function evaluation
Donor selection: Avenues to increase pancreas utilization
Preoperative transplant assessment
Recipient operation
Immunosuppression
Postoperative management
Complications
Rejection
Outcomes
Summary
References
11
Pancreas after kidney transplantation
Introduction
Indications and options for uremic diabetes
General indications for PAK
Availability of a living donor kidney and avoiding dialysis
Determining appropriateness for PAK
Timing of PAK
Deciding between SPK and PAK
Operative concerns and immunologic challenges for PAK
Outcomes: Graft and patient survival
Patient-reported outcomes
Future directions and challenges
References
12
Simultaneous pancreas-kidney transplantation
Introduction
History
Epidemiology
Indications
IDDM patients with renal failure: Treatment options (SPK, KTA, PAK, and re-transplantation)
Recipient selection
Donor characteristics
Donor/recipient compatibility
Outcomes
Patient survival
Pancreas graft survival
Kidney graft survival
Effects on long-term diabetes complications
Immunosuppression
Induction
Biological agents
Corticosteroids
Maintenance
Calcineurin-inhibitors (CNI)
Rapamycin inhibitors
Antiproliferative agents
Corticosteroids
Surgical techniques
Back-table surgery
Implantation
Exocrine drainage
Endocrine drainage
Complications
Early technical failure
Medical postoperative complications
Cardiovascular complications
Immunological complications
Rejection
Recurrent autoimmune disease
Infections
Cancer
Surgical late complications
SPK and pregnancy
References
Further reading
13
Surgical techniques for deceased donor pancreas transplantation
Introduction
Management of exocrine pancreatic secretions: Bladder vs enteric drainage
Surgical procedure: Intraoperative management
Surgical procedure: Recipient operation (1)
Enteric drainage
Bladder drainage
Surgical procedure: Recipient operation (2)
Venous outflow: Systemic vs portal drainage
Graft size: Whole organ vs segmental transplants
Graft placement: Intraperitoneal vs extraperitoneal implantation
Surgical variations and technical modifications
Systemic vein and bladder exocrine drainage
Whole organ pancreaticoduodenal transplants with systemic vein and bladder exocrine drainage on the right side
Whole organ pancreaticoduodenal transplants with systemic vein and bladder exocrine drainage on the left side
Segmental pancreas transplant with systemic vein and bladder drainage
Systemic vein and enteric drainage
Whole organ pancreaticoduodenal transplant with systemic vein and enteric drainage: Right side
Caudad position
Cephalad position
Whole organ pancreaticoduodenal transplant with systemic vein and enteric drainage: Left side
Segmental pancreas transplants with systemic vein and enteric drainage
Portal vein and enteric drainage
Whole organ pancreaticoduodenal transplant with portal vein and enteric drainage
Segmental pancreas transplants with portal vein and enteric drainage
Other drainage options
Other types of pancreas transplants
Robotic techniques
Surgical technique
Conclusion
References
14
Robotic pancreas transplantation
Introduction
Why to pursue robotic PTx
Practical issues with robotic PTx
Graft rewarming/cooling
Pneumoperitoneum
Graft bleeding at the time of reperfusion
What is needed to perform robotic PTx
Operative team
Operating room
Donor procedure
Recipient procedure
Other techniques for robotic PTx
Conclusions
References
15
Pancreas transplantation in the setting of multivisceral transplantation
Introduction
Indications and types of grafts
Contraindications
Donor selection
Donor surgery
Recipient surgery
Immunosuppression
Postoperative management
Monitoring of the pancreas graft
Outcomes and complications
Ischemia-reperfusion injury
Technical complications
Pancreaticobiliary complications
Infections
Rejection
Mechanisms of allograft rejection
Acute rejection
Chronic rejection
Gvhd
Chronic kidney disease
References
16
Imaging in pancreas transplantation
Preoperative planning: Imaging of potential recipient
Preoperative planning: Imaging of donor
Postoperative imaging
Sonography
Computed tomography and magnetic resonance imaging
Interventional imaging
Complications
Vascular complications
Nonvascular complications
Postoperative hematoma
Postoperative abscess
Pancreatitis
Rejection
Bowel complications
Posttransplant lymphoid proliferative disorders
Conclusion
References
17
Postoperative care of the pancreas transplant patient
Introduction
Perioperative care
General postoperative care
Antibioprophylaxis
Glycemic control
DVT prophylaxis
Nutrition
Somatostatin and analogues
Immunosuppression
Prevention of vascular graft vein thrombosis
Other specific surveillance
Conclusion
References
18
Immunosuppression for pancreas allo-transplantation
Introduction
Induction therapy
Induction immunosuppression agents
Evidence for induction therapy
Maintenance therapy
Maintenance immunosuppression agents
Evidence for maintenance regimens
Antirejection treatment
Infections and immunosuppression
Immunosuppression and malignancy in PTX
Immunosuppressive therapy and pregnancy
Conclusion
References
Section IV: Complications after pancreas allo-transplantation
19
Infectious complications after pancreas allotransplantation
Introduction
Evaluation for infection before transplantation
Perioperative prophylaxis
Surgical site infections
Urinary tract infections
Bacteremia
Cytomegalovirus infection
BK virus infection
Donor-derived infections
Pancreas transplantation in HIV-infected individuals
Conclusions
References
Further reading
20
Medical complications after pancreas transplantation
Hyperglycemia
Early posttransplant hyperglycemia
Primary nonfunction
Delayed endocrine graft function
Late posttransplant hyperglycemia
Hypoglycemia
Early posttransplant hypoglycemia
Late posttransplant hypoglycemia
Pancreatitis
Pancreatitis in enteric-drained and bladder-drained grafts
Pancreatitis specific to bladder-drained grafts
Gastrointestinal bleeding
Gastrointestinal bleeding in enteric-drained pancreas graft recipients
Gastrointestinal bleeding in bladder-drained pancreas graft recipients
Loss of native kidney function (pancreas transplant alone recipients only)
Other medical complications specific to bladder-drained grafts
Urinary tract infection
Urethral complications and dysuria
Hematuria
Metabolic acidosis and dehydration
References
21
Technical complications of pancreas allotransplantation
Introduction
Surgical techniques/considerations
Current pancreas transplant procedure
Exocrine drainage
Endocrine drainage
Pretransplant complications
Intraoperative complications
Posttransplant complications
Early posttransplant pancreas graft thrombosis
Late posttransplant pancreas graft thrombosis
Posttransplant bleeding
Intra-abdominal bleeding
Gastrointestinal (GI) bleeding
Genitourinary (GU) bleeding
Other potential causes of bleeding and vascular compromise
Intra-abdominal infection
Anastomotic leak
Graft pancreatitis
Transplant pancreatic pseudocysts and fistulas
Urologic complications of bladder-drained grafts
Kidney vascular torsion
Conclusion
References
22
Pancreas transplantation, bioengineering, and regeneration
Introduction: Clinical presentation of pancreas rejection through the evolution of surgical techniques and immunosuppressiv ...
The early segmental pancreas transplant period
Return to the whole organ technique for transplantation
Epidemiology and risk factors for pancreas rejection
The early beneficial role of HLA matching in pancreas transplantation
Recurrence of autoimmunity in pancreas recipients
Evaluation means of diagnosing rejection
Clinical manifestations
Laboratory monitoring for rejection
Urinary markers
Urine markers of exocrine rejection
Urine amylase
Other urine markers
Urine markers of endocrine rejection
Serum markers
Serum markers of exocrine rejection
Serum amylase and serum lipase
Other serum markers of exocrine rejection
Serum markers of endocrine rejection
Plasma glucose
Glucose disappearance rate
First-phase insulin release
Immunological markers
Imaging techniques
US, CT, and magnetic resonance imaging
Other imaging techniques
Cell and tissue diagnosis of allograft rejection
Fine-needle aspiration biopsy
Cytology
Needle core biopsy
Graft biopsy: Cystoscopic transduodenal
Graft biopsy: Percutaneous
Graft biopsy: Laparoscopic
Graft biopsy: Endoscopic gastroduodenal and enteric biopsies
Biopsy algorithm
Clinical presentation of pancreas graft dysfunction and rejection
Recipients of a solitary pancreas transplant (PAK or PTA)
Recipients of a SPK transplant
Confirming the diagnosis of pancreas allograft rejection
Acute cellular rejection
Antibody-mediated rejection
Mixed AR
Treatment of pancreas transplant rejection
Summary and recommendations
References
Section V: Natural history
23
Reversal of secondary complications of type 1 diabetes (nephropathy, neuropathy, retinopathy, and cardiopathy)
Introduction
Nephropathy
Effect of PTx alone on native kidney function
Effect of simultaneous pancreas-kidney or pancreas after kidney on preservation of kidney graft
Impact of immunosuppression
Neuropathy
Effect of PT on peripheral DN
Effect of PT on autonomic DN
Impact of immunosuppression
Retinopathy
Effect of PTx on DR
Cardiopathy
Effect of PTx on diabetic cardiopathy
Effect of PTx cardiovascular risk factors and ischemic heart disease
Summary
References
24
Recurrence of type 1 diabetes following simultaneous pancreas-kidney transplantation
Preamble
Introduction
Diagnosis of T1D recurrence (T1DR)
Remodeling/transdifferentiation in pancreas transplant of T1DR
Treatment of T1DR: Evidence for return of memory T cells in T1DR
Cell-mediated responses in T1DR
Autoreactive T cell-mediated beta cell destruction experimentally in vivo
A possible case of incipient T1DR
Re-transplantation of the pancreas for T1DR
Longitudinal study of T1DR at the University of Miami
Therapy for T1D
T1DR therapy at the Miami Transplant Institute
Theoretical considerations
CXCR3 as a potential target in T1DR
CXCR3 in alopecia areata and AA as a model of T1DR
Combination therapies
Future considerations
Network for the pancreas organ donors with diabetes
Conclusions
Acknowledgment
References
25
Pathological evaluation of whole pancreas transplants
Introduction
Types of Biopsies for Evaluation of WPnTx
Pathological guidelines for processing pancreas allograft biopsies
Concordance between the pancreas and kidney rejection in SPK
Surveillance (protocol) biopsies
Acute rejection in the duodenal cuff
Features of acute rejection
Concordance of rejection in the duodenal cuff and the pancreas
Enteroscopic duodenal cuff biopsies
Histological diagnosis and grading of acute allograft rejection—Banff schema
Diagnostic categories specific considerations
Mixed ACMR and ABMR
Other (nonrejection) histological diagnoses
Graft thrombosis
Posttransplantation (ischemic) pancreatitis
Posttransplant infectious pancreatitis/peripancreatitis/fluid collection/peripancreatic abscess
Anastomotic leak
Viral infections
Cytomegalovirus infection
EBV-related posttransplant lymphoproliferative disorder
Correlation between pathological findings and time and type of WPnTx dysfunction
References
26
Failure of the pancreas allograft
Definition of pancreas allograft failure
Epidemiology of pancreas allograft failure
Causes of pancreas allograft failure
Histological findings
Causes of pancreas allograft failure
Early graft failure
Late graft failure
Diagnostic strategy
Risk factors of pancreas allograft failure
Risk factors of early pancreas allograft failure
Risk factors of long-term allograft failure
Evaluation of glucose homeostasis to predict long-term allograft failure
Therapeutic issues
Indications of transplantectomy
Conclusions and prospects
References
27
Pancreas retransplantation
Introduction
Historical perspective
Indications and considerations
Retransplant type and outcomes
Recipient evaluation
Donor selection
Timing
Surgical approaches
Postoperative care
Summary
References
Section VI: State of the art of pancreas transplantation
28
The current state of pancreas transplantation in the United States—A registry report
Introduction
Statistical methods
Patient population
Recipient characteristics
Donor characteristics
Transplant characteristics
Transplant outcomes
Discussion
References
29
Trends in pancreas transplantation in the United States
Introduction
Number of pancreas transplant recipients
Demographic characteristics of pancreas transplant recipients and donors over time
Transplant volume by center
Outcomes following transplantation
Summary
References
30
Experimental pancreas transplantation
Introduction
Small animal models
Surgical techniques
Immunogenicity
Organ preservation
Xenotransplantation
Rejection
Pharmacology
Summary
Large animal models
Surgical techniques
Canine model
Swine model
Systemic vs portal venous drainage
Graft pancreatitis
Preservation
Rejection
Summary
References
31
Pancreas transplantation: Current issues, unmet needs, and future perspectives
Introduction
Improving outcomes in the setting of fewer transplants being performed
Donor, recovery, and preservation issues
Pancreas allocation and donor risk indices
Surgical techniques
Recipient selection and waiting list considerations
Immunosuppression and immunological outcomes
Pancreas vs islet transplantation
Summary and conclusions
References
Part B: Islet allo-transplantation
Section I: Introduction and indications
32
Treatment of type 1 diabetes complicated by problematic hypoglycemia
Introduction
What is problematic hypoglycemia?
How common is problematic hypoglycemia in type 1 diabetes?
Risk factors for problematic hypoglycemia
Patient-related factors
Secondary causes
Approach to a patient with problematic hypoglycemia
Identifying patients with problematic hypoglycemia or at high risk of SH
Review risk factors for hypoglycemia
Structured education
Psychologically based educational interventions
Hypoglycemia and the role of different insulins
The balance between basal and bolus insulin
Basal Insulins
Prandial Insulins
Use of technology
Bolus advisors
Continuous subcutaneous insulin infusion
Continuous glucose monitoring
SAP therapy
Closed loop
Continuous intraperitoneal insulin infusion
Transplantation
Summary
References
33
Eligibility of patients with type 1 diabetes for islet transplantation alone
Introduction: Current status of islet transplantation alone
Indications for beta-cell replacement in the absence of renal insufficiency
Assessment of “problematic hypoglycemia” as an indication for ITA
Management of problematic hypoglycemia
Clinical efficacy of ITA in problematic hypoglycemia
Eligibility criteria for ITA
Age
Metabolic demand
HLA sensitization
Autoimmunity
Coagulation disorders
Hepatic disorders
Retinopathy
HbA1c
Nephropathy
Inclusion and exclusion criteria in recent multicenter clinical trials
Selection for PTA vs ITA
A word on IAK transplantation
Perspectives
References
34
Islet vs pancreas transplantation in nonuremic patients with type 1 diabetes
Introduction
β -Cell replacement
Solid organ pancreas transplant
Islet transplantation
Recommendations for pancreas vs islet transplantation
References
35
Simultaneous islet-kidney and islet-after-kidney transplantation
Introduction
Treatment strategy in patients with end-stage kidney disease with and without a history of severe hypoglycemia
Treatment algorithm for beta-cell replacement therapy depends on kidney function
Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/PAK, or ITA/PTA)
Conclusions
References
36
Pancreatic islet transplantation in cystic fibrosis: Lung and islet transplantation
Introduction
Techniques
Combined islet-lung transplantation
Islet after lung transplantation
Immunosuppression
Indications
Results
Complications
Perspectives
Acknowledgments
References
37
Combined liver and islet transplantation in hepatogenous diabetes, cluster exenteration, and cirrhosis with type 1 diabetes
Introduction
Epidemiology, diagnosis, and prognosis of HD
Pathophysiology of HD
Treatment of HD
Liver transplantation
Combined liver and islet transplantation after upper abdominal exenteration
Combined liver and islet transplantation in patients with HD/T2DM
Combined liver and islet transplantation in patients with cirrhosis and T1DM
Combined liver and pancreas transplantation in cirrhotic patients with T1DM or HD/T2DM
Concluding remarks
References
Section II: Donor selection
38
Evolving approaches to organ allocation for the whole pancreas vs islet transplantation
Introduction
Indications and definition of success after β -replacement
Edmonton protocol
Donor risk stratification
Impact of donor age
Impact of donor obesity
Allocation scheme in the United Kingdom
Allocation scheme in the United States
Cost and reimbursement implications
Forging ahead toward insulin-independence
References
39
Living donors
Introduction
Background of living donor islet transplantation
First report of living donor islet transplantation
Can we expand living donor islet transplantation?
Possible disadvantage to be concerned
Donor safety
Efficacy to ameliorate diabetes mellitus
Ethical considerations of donors
Possible advantages
Conclusion
Conflicts of interest
References
40
Pancreatic islet isolation from donation after circulatory death pancreas
Introduction
History
Donation after brain death
Donation after circulatory death
Ischemic time intervals
Controlled DCD perfusion technique
Prevalence of DCD
Graft outcomes in DCD kidney and liver transplantation
DCD vascularized pancreas transplantation
Donor selection for pancreas retrieval in DCD donors
Clinical outcome of vascularized DCD pancreas transplantation
Donor selection for DCD pancreatic islet isolation
Pancreatic islet isolation from DCD pancreas
Islet in vitro function after islet isolation from DCD pancreas
Clinical outcome of islet transplantation using DCD pancreas
Future perspectives
Conclusion
References
Section III: Islet isolation
41
Factors related to successful clinical islet isolation
Introduction
Clean rooms, equipment, and essentials for islet isolation
Donor and pancreas impacts
Donor retrieval and perfusion of the pancreas
Donor factor effects
Processing effects
Receipt and pancreas preparation
Minimization of potential contaminants
Distension and digestion of the pancreas
Density separation
Postisolation culture and quality assurance
Discussion
Acknowledgments
References
42
Pancreas and islet preservation
Introduction
Key determinants of islet yield, function and viability during preservation
Impact of ischemia time during pancreas procurement, storage and transportation on transplantation outcomes
Ischemia/reperfusion injury
Hypoxia/cold ischemia
Ionic disturbances
ROS-mediated injury
Effects of hypoxia during islet isolation, culture and distribution
Pancreas preservation prior to islet isolation
Static methods/pancreas immersion
Static cold storage
Preservation solutions
Perfluorocarbons (PFCs)
Additives
Dynamic methods/pancreas perfusion
Liquid perfusion
Hypothermic machine perfusion
Normothermic machine perfusion
Gaseous perfusion
Persufflation
Islet preservation during isolation and purification
Isolation of human islets
Pancreas distension, tissue dissociation, and islet collection
Islet purification
Islet preservation during culture and distribution
Culture ware and culture methods
Islet culture supplements
Cryopreservation
Outlook
References
43
Collagenases in pancreatic islet isolation
Introduction
Basic structure
Collagenases
Neutral proteases
Clostripain
ECM of the pancreas with emphasis on the peri-insular region
Role of different enzyme fractions in pancreatic digestion
Pancreatic dissociation enzymes in clinical islet isolation: Evolution, safety, and overview of commercial products
Exogenous parameters affecting collagenase digestion
Tailored approach to islet isolation
Conclusions
References
44
Predicting the function of islets after transplantation
Introduction
Glucose tolerance and stimulation tests
Oral glucose tolerance test
Glucose clamp techniques
Intravenous glucose tolerance test
Mixed-meal tolerance test
Indices for solitary transplantation
HYPO score and lability index
MAGE index
SUITO index
Clarke score
C-peptide-to-glucose ratio
β -Score
Transplant estimated function
Transplanted functional islet mass
Biomarkers of graft failure
Measurements of alloimmune response
Soluble CD30
Cytotoxic lymphocyte genes
Microparticles in peripheral blood
Autoimmune recurrence
Proteins
C-peptide
Gad65
Doublecortin
Ppp1r1a
Uch-L1
Hmgb1
Cxcl10
Ccl2
Nucleic acids
Circulating cell-free DNA
Ratio of unmethylated to methylated insulin DNA
Micro RNAs
Long noncoding RNAs
Circular RNAs
Current noninvasive imaging techniques for pancreatic islet transplantation
Bioluminescence imaging
Fluorescence imaging
Ultrasonography
Positron emission tomography
Single-photon emission computed tomography
Magnetic resonance imaging
Summary
References
Section IV: Outcomes after allogeneic pancreatic islet transplantation
45
Metabolic and endocrine evaluation of islet transplant function
Introduction
Glycemic control
Glucose tolerance
β -Cell function
β -Cell secretory capacity
β -Cell stress
Insulin-dependent glucose disposal (insulin sensitivity)
Insulin-independent glucose disposal (glucose effectiveness)
α -Cell function and glucose counterregulation
Conclusion
Acknowledgments
References
46
Procedure-related and medical complications in and after intraportal islet transplantation
Introduction
General overview of complication incidence related to intraportal ICT
Differences in complication rates between allogeneic and autologous islet cell transplantation
Complications related to percutaneous islet cell transplantation
Bleeding
Risk factors for bleeding complications
Antiplatelet therapy and anticoagulation
Portal venous pressure
Coagulopathy
Technical aspects of procedure
Diagnosis of bleeding complications
Preventative measures against bleeding complications
Treatment of bleeding complications related to islet cell transplantation
Portal vein thrombosis
Risk factors for portal vein thrombosis related to islet cell transplantation
Purity of islet preparations
Infusion volume
Increased portal venous pressure
Thrombophilic disorders
Diagnosis of portal vein thrombosis after islet cell transplantation
Preventative measures against PVT Complications
Treatment of PVT complications
Noninvasive management
Invasive management
Rare procedure-related complications associated with percutaneous transhepatic islet cell transplantation
Procedure-related complications pertaining to the percutaneous transjugular approach
Procedure-related complications pertaining to the surgical (transmesenteric) approach to islet cell transplantation
Medical complications of islet cell transplantation
Hepatic steatosis
Risk factors for hepatic steatosis
Diagnosis of hepatic steatosis
Management of hepatic steatosis
Chronic portal hypertension
Complications related to immunosuppression
Closing remarks
References
47
Secondary complications of diabetes
Introduction
Nephropathy
Retinopathy
Neuropathy
Cardiovascular disease
Conclusion
References
Section V: Current clinical results
48
Treating diabetes with islet transplantation: Lessons learnt from the Nordic network for clinical islet transplantation
Introduction
The development of networks
How can we better serve our patients by working in networks?
The islet isolation facilities within the NNCIT
Standard operational procedures
CoE for type 1 diabetes
Allocation of pancreas
Patient selection and allocation
Our current practice in islet transplantation in brief
Concomitant medication
Follow-up
Metabolic and functional follow-up post-islet transplantation
Safety
A selection of NNCIT studies or reports
Visualizing islets with positron-emission tomography combined with computed tomography
Amyloid deposition in transplanted human pancreatic islets
Clinical and experimental pancreatic islet transplantation to striated muscle, an establishment of a vascular system simila ...
Encapsulation of the insulin-producing cells with the bioartificial pancreas β Air
Inhibition of IBMIR with heparin or low molecular weight sulfated dextran in clinical islet transplantation
Insulin independence after conversion from tacrolimus to cyclosporine in islet transplantation
Predict patient outcome in IAK
Islet graft function 1 year after pregnancy
Cost and clinical outcome of clinical islet transplantation in Norway 2010–2015
Conclusion
Acknowledgments
References
49
UK’s nationally funded integrated islet transplant program
Demonstration of successful steroid-free islet transplantation in the UK
Validation of islet transport protocol
National Institute for Health and Care Excellence assessment
National Health Service funding of an integrated program
Listing criteria/recipient assessment
Product release and transplantation
Posttransplant follow-up
Attainment of metabolic goals within the integrated UK program with locally isolated and transported islets
The UK Pancreas Allocation Scheme for whole organ and islet transplantation
Islet graft survival and metabolic outcomes within the integrated Pancreas Allocation Scheme
UKITC biomedical and psychosocial outcomes of islet transplant research
To determine and implement congruent protocols for rigorous clinical, metabolic, and psychosocial assessment and follow-up ...
To determine and implement congruent protocols for rigorous recording of donor pancreas quality in addition to islet number ...
To validate a new approach to transplantation across UK incorporating separate isolation and transplant centers ensuring co ...
To develop/validate two new instruments for psychosocial evaluation enabling robust assessment of satisfaction/impact on qu ...
To establish an external quality assurance (QA) system and UK database for collation of all patient, islet, transplantation ...
Next steps for the UKITC/NHS program
Concluding comments
References
50
Type 1 diabetes transplanted with allogenic islets within the Swiss-French GRAGIL network
Introduction
Rationale for the Swiss-French GRAGIL network
Cost analysis of islet transplantation in the GRAGIL network
Organisation of the GRAGIL network
Patient wait-listing and pancreas allocation
Logistics and coordination
Islet processing and transplantation
Evolution of islet transplantation protocols in the GRAGIL network and outcomes
The initial Geneva experience
GRAGIL-1 clinical trial and the initial GRAGIL experience
GRAGIL-1b clinical trial
GRAGIL-1c clinical trial
GRAGIL-2 clinical trial
TRIMECO clinical trial
STABILOT clinical trial
Current ITA protocol
Current IAK/SIK protocol
Activity in the GRAGIL network
QoL after islet transplantation in the GRAGIL network
Islet transplantation in diabetic patients with cystic fibrosis within the GRAGIL network
Lessons learned from 20 years of the GRAGIL network—Conclusion
Acknowledgments
References
51
Optimizing primary graft function in islet allotransplantation: T he Lille experience
Introduction
Methods
Patients
Transplantation
Sequential multiple infusions in Lille
Results
Patient and graft characteristics
Primary graft function
Discussion and perspectives
References
52
Treating diabetes with islet transplantation: Lessons from the Milan experience
Introduction
Indication for beta-cell replacement in Italy
Pancreas transplantation activity in Italy
Pancreas transplantation cost
Islet transplantation in Italy
Pancreas allocation system
Islet isolation and transplantation activity in Italy
Islet transplantation cost
The Milan pioneering activity during the early 1990s
Major achievement of Milan experience
Main ongoing projects
Future plans
References
53
Treating diabetes with islet transplantation: Lessons from the University of Miami
Introduction
Clinical islet transplantation experience at the University of Miami
Adjuvant therapies
Patient management
Psychosocial outcomes
Potential risks and complications
Conclusion
Acknowledgment
References
54
Treating diabetes with islet cell transplantation: Lessons from the Edmonton experience
Introduction
The history of islet transplantation
The Edmonton protocol
Indication for islet transplantation
Islet isolation and transplantation
Donor selection
Pancreas procurement
Islet isolation
Intraportal infusion
Risks of islet transplantation
Immunosuppresion
Induction immunosuppression
Maintenance immunosuppression
Adjunct peri-transplant anti-inflammatory agents
Outcomes
Future directions
References
Section VI: Monitoring of allogeneic islet grafts
55
Immune monitoring of allogeneic islets
Introduction
Mechanism of rejection of pancreatic islet grafts
Innate immunity
Humoral immunity
Cell-mediated immunity
Nonimmune monitoring of pancreatic islet grafts
Clinical monitoring
Urine markers
Serum markers
Imaging modalities
Immune monitoring of pancreatic islet grafts ( Table 1)
Islet graft biopsy
Innate response
Humoral response
Cellular response
Conclusion
References
56
Markers for beta-cell loss
Introduction
Beta-cell loss after islet transplantation
Indirect markers of beta-cell loss
Imaging techniques
Functional beta-cell mass
Choice of the function marker
Choice of the stimulation test
Hyperglycemic clamp test
Validation in (a)symptomatic type 1 diabetes
Validation in islet transplantation
Direct markers of beta-cell loss
Protein markers
The 65 kDa isoform of glutamate decarboxylase (GAD65)
Validation in vitro and in animal models
Validation in islet transplantation
Other candidate protein markers
Validation in vitro and in animal models
Nucleic acid markers
Differentially methylated DNA
Validation in vitro, in animal models and in type 1 diabetes
Validation in islet transplantation
Differentially expressed RNA
Coding RNA
Noncoding RNA: The example of miR-375
Validation in vitro, in animal models and in type 1 diabetes
Validation in islet transplantation
Comparison of protein- and nucleic acid markers in islet transplantation
Conclusions and perspectives
References
57
In vivo quality control of human islets in the immunodeficient mouse to predict islet function in man: A retrospec
Introduction
Methods
Islet isolation, transplantation, and quality controls
Animal follow-up
Transplant morphology
Statistical analysis
Results
Our in vivo model is potentially a good model to predict islet function in man after transplantation
Involvement of transplant aspect, purity, and vascularization in transplanted islet function
Determining the functional islet mass required in 1–3 transplants to achieve optimal long-term islet function (beta score  ...
Discussion
Conclusion
Perspectives
Acknowledgments
References
Further reading
Section VII: Immunomodulatory technologies applied to islet transplantation
58 Progress toward islet transplantation tolerance
Introduction—Rationale for tolerance in islet transplantation
History of tolerance in solid organ transplantation
Tolerance strategies for islet transplantation
T-cell-focused immune tolerance strategies
B cell-focused immune tolerance strategies
Dendritic cells and myeloid-derived suppressor cells in tolerance
Nonimmune and stromal cell-mediated tolerance
Advanced islet transplantation technologies and immune tolerance
Conclusion and future directions
References
59
Filling the gap to improve islet engraftment and survival using anti-inflammatory approaches
Introduction
Inflammation prior islet isolation
The pancreas donor
The cold ischemia injury
Inflammation and isolation procedure
Inflammatory status during islet culture
Peri-transplant inflammation
The ischemia–reperfusion injury
The instant blood-mediated inflammatory reaction
Posttransplant inflammation
Hypoxia
Innate immune reaction
Conclusion
References
60
Islet immunoisolation by macroencapsulation
Introduction
Key aspects in islet macroencapsulation
Structural approaches
Encapsulation materials
Protection from immune rejection and inflammation
Oxygen requirements
Kinetics of glucose and insulin release
Transplantation site
Recent and current clinical trials
Future perspectives
Conclusions
References
61
Islet immunoisolation by microencapsulation
Introduction
Brief pre-insulin history of diabetes
Brief review of medical treatment for diabetes
Brief history of pancreas research
Human islet transplants
Decline of pancreas transplants
Limitations with islet transplant
Alternative therapies
Newer glucose-lowering agents
Gene therapy with attempts at modifying gene expression utilizing gene vectors or gene vaccines
Regenerative therapy of pancreatic β cells
Induction of graft tolerance by utilizing bone marrow transplantation or foreign antigen recognition blocking agents
Xenotransplantation
Genetic modification of porcine cells
Islet immunoisolation
Extravascular diffusion devices
Sheet- and pouch-type macroencapsulation devices
Polymer scaffolds
Various implantation sites have been evaluated
Intravascular diffusion devices
Extravascular micro-devices
Microencapsulation
Oxygen supply to immunoisolated islets
Other factors that affect pancreatic islet function and viability
Alginate-based microcapsules
Conformal coatings
Alternative micro-coating techniques
Nanoencapsulation or layer-by-layer approaches
Other nanotechniques
Professional opinion
References
62
Recurrence of type 1 diabetes after beta-cell replacement
Introduction
The persistence of autoreactive memory T cells and B cells after the onset of T1D
The presence of autoreactive memory T cells and autoantibodies before islet transplant
Autoimmunity recurrence after islet or pancreas transplantation
Pancreas transplantation
Islet transplantation
References
Section VIII: Cellular therapies in preclinical and clinical islet transplantation
63
T regulatory cell therapy in preclinical and clinical pancreatic islet transplantation
Introduction
Types of regulatory T cells and mechanisms of suppression
CD4 + regulatory T cells
tTreg
iTreg
Tfr
Tr1
CD8 + regulatory T cells
CD4 − CD8 − regulatory T cells
NKT cells
γ δ T cells
Non-T regulatory cells
Breg
Tolerogenic DCs
Regulatory macrophages
MSCs
MAPCs
MDSCs
ILCs
Treg isolation and expansion protocols
Treg stability and how to improve it
Treg cell dose to meet the therapeutic target
Approaches to generate (allo)antigen-specific Tregs
FOXP3 Tregs
Tr1 cells
Location of Treg infusion and function
Tregs alone or in combination with immunotherapy?
Timing of Treg infusion
Safety and survival in vivo
Ongoing Treg therapies in solid organ transplantation
Barriers and other logistics
Conclusions
References
64
Cellular therapies in preclinical and clinical islet transplantation: Mesenchymal stem cells
Introduction
Clinical islet transplantation
Mesenchymal stem cells (MSCs)
Understanding the mechanisms of MSCs
MSCs mediator secretion, immunogenicity, and immunomodulation
MSCs administration in vivo
MSCs in chronic clinical settings
Treating type 1 diabetes with MSC-based therapy
Ex vivo processing of MSCs. How to minimize the confounding artefacts?
Donor variability
Manufacturing of clinical grade MSCs
MSCs and islets
Co-culture of MSCs and islets
Co-transplantation of MSCs and islets
Systemic administration of MSCs to restore or repair islet damage
The use of MSCs in clinical islet transplantation
The potential of MSCs for islet transplantation
Conclusion
References
65
Alternative transplantation sites for islet transplantation
Introduction
The pancreas
The spleen
The kidney
The adrenal glands
Immunoprivileged sites
The brain
The testis
The thymus
The anterior chamber of the eye
The bone marrow
The gastrointestinal tract
The gastric submucosa
The duodenal submucosa
The small bowel
The urinary tract
The muscle
The subcutaneous space
The peritoneum
The omentum
Conclusions
References
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Z
Back Cover

Citation preview

TRANSPLANTATION, BIOENGINEERING, AND REGENERATION OF THE ENDOCRINE PANCREAS

TRANSPLANTATION, BIOENGINEERING, AND REGENERATION OF THE ENDOCRINE PANCREAS VOLUME 1 Edited by

Giuseppe Orlando Lorenzo Piemonti Camillo Ricordi Robert J. Stratta Rainer W.G. Gruessner

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-814833-4 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisition Editor: Elizabeth Brown Editorial Project Manager: Kristi Anderson Production Project Manager: Stalin Viswanathan Cover Designer: Matthew Limbert Typeset by SPi Global, India

Dedications

To our patients who entrust us with their lives for the prevention and cure of diabetes mellitus. The secret of the care of the patient is in caring for the patient. Francis Peabody, American Physician, 1927

To the pioneers of transplant and regenerative medicine who laid the foundations of our work. If I have seen further, it is by standing on the shoulders of giants. Sir Isaac Newton, 1676

Contributors

Peter Abrams  MedStar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, United States

Alain Gerald Bertoni  Wake Forest School of Medicine, Department of Epidemiology & Prevention, Winston-Salem, NC, United States

Joel T. Adler  Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States

Federico Bertuzzi  Diabetology Unit, Niguarda Hospital, Milano, Italy

Rodolfo Alejandro  Diabetes Research Institute; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, FL, United States Mohamed Alibashe-Ahmed  Division of Transplantation, Department of Surgery, Cell Isolation and Transplantation Center, University of Geneva Hospitals and School of Medicine, Geneva, Switzerland Ana Alvarez  Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States Takayuki Anazawa  Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, University of Kyoto, Kyoto, Japan Axel Andres  Division of Transplantation, Department of Surgery, Cell Isolation and Transplantation Center, University of Geneva Hospitals and School of Medicine, Geneva, Switzerland Barbara Antonioli  Tissue Therapy Unit, Niguarda Hospital, Milano, Italy Alan Apete  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine, Lille, France David A. Axelrod  University of Iowa, Iowa City, IA, United States Lionel Badet  Service d’urologie et de chirurgie de la transplantation, Hospices Civils de Lyon, Lyon, France David Baidal  Diabetes Research Institute; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, FL, United States Kaylene Barrera  Department of Surgery, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States Pierre-Yves Benhamou  Department of Endocrinology, Grenoble University Hospital, Grenoble, France Thierry Berney  Division of Transplantation, Department of Surgery, Cell Isolation and Transplantation Center, University of Geneva Hospitals and School of Medicine, Geneva, Switzerland

Ugo Boggi  Division of General and Transplant Surgery, University of Pisa, Pisa, Italy Caroline Bonner  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine; Institut Pasteur de Lille, Lille, France Adel Bozorgzadeh  Department of Surgery, Division of Transplant, University of Massachusetts, Worcester, MA, United States Julien Branchereau  Centre de Recherche en Transplantation et Immunologie (CRTI), Inserm, Université de Nantes; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France Jonathan Bromberg  Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States George W. Burke, III  Miami Transplant Institute, Jackson Memorial Hospital; Department of Surgery, Division of Transplantation; Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States Fanny Buron  Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, Lyon, France Robert Caiazzo  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine; Department of General and Endocrine Surgery, CHU Lille, Lille, France Rossana Caldara  Department of Internal Medicine, Transplant Medicine Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy Stephanie S. Camhi  University of Miami Miller School of Medicine, MD/MPH Program, Miami, FL, United States Diego Cantarovich  Centre de Recherche en Transplantation et Immunologie (CRTI), Inserm, Université de Nantes; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France Massimo Cardillo  UOC Coordinamento Trapianti, Milano, Italy D. Castanares-Zapatero  Critical Care Department, Cliniques universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium

xvii

xviii Contributors Pierre Cattan  Department of Digestive Surgery, University Hospital Saint-Louis, Paris, France Suresh Rama Chandran  Department of Diabetes Research (Denmark Hill), King’s College London, London, United Kingdom; Department of Endocrinology, Level III, Academia, Singapore General Hospital, Singapore, Singapore Erin Chang  Department of Surgery, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States Linda Chen  Miami Transplant Institute Jackson Memorial Hospital; Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine, Miami, FL, United States Mikael Chetboun  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine; Department of General and Endocrine Surgery, CHU Lille; Service de Chirurgie de l’Obésité, Centre Hospitalier Universitaire de Lille, Lille, France

Hector De Leon  University of Arizona, Department of Surgery, Institute of Cellular Transplantation, Tucson, AZ, United States Nathalie Delalleau  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine, Lille, France Laura DiChiacchio  Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States Jason B. Doppenberg  Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands Cinthia B. Drachenberg  Department of Pathology; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States Erica Dugnani  IRCCS Ospedale San Raffaele, San Raffaele Diabetes Research Institute, Milan, Italy Ty B. Dunn  University of Pennsylvania, Philadephia, PA, USA

Pratik Choudhary  Department of Diabetes Research (Denmark Hill), King’s College London, London, United Kingdom

Marten A. Engelse  Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands

Gaetano Ciancio  Miami Transplant Institute, Jackson Memorial Hospital; Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine, Miami, FL, United States

Ahmed Farag  Miami Transplant Institute, Jackson Memorial Hospital, University of Miami Miller School of Medicine, Miami, FL, United States

Maria Pia Cicalese  San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET); Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Alan Farney  Department of Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States Anne Elizabeth Farrow  Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, United States

Antonio Citro  IRCCS Ospedale San Raffaele, San Raffaele Diabetes Research Institute, Milan, Italy

Ibrahim Fathi  Division of Transplantation and Regenerative Medicine, Tohoku University, Sendai, Japan

C. Collienne  Critical Care Department, Cliniques universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium

Jose Figueiro  Miami Transplant Institute, Jackson Memorial Hospital; Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine, Miami, FL, United States

Caterina Conte  Vita-Salute San Raffaele University; Clinical Transplant Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy Claire Counter  Statistics and Clinical Studies, NHS Blood and Transplant, Bristol, United Kingdom Khaled Z. Dajani  Department of Surgery and Clinical islet Transplant Program, University of Alberta, Edmonton, AB, Canada Carly M. Darden  Institute of Biomedical Studies, Baylor University, Waco; Islet Cell Laboratory, Baylor University Medical Center, Baylor Scott and White Research Institute, Dallas, TX, United States Francesco De Cobelli  Department of Radiology and Center for Experimental Imaging, IRCCS San Raffaele Scientific Institute, Milano, Italy Eelco J.P. de Koning  Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands

Anneliese Flatt  Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom Georgia Fousteri  Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI) IRCCS San Raffaele Scientific Institute, Milan, Italy Jonathan A. Fridell  Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States Peter J. Friend  Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom Giacomo Gastaldi  Division of Diabetes/Endocrinology, Department of Internal Medicine, University of Geneva Hospitals, Geneva, Switzerland Valery Gmyr  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine, Lille, France

Contributors xix

Javier Gonzalez  Servicio de Urología, Hospital General Universitario Gregorio Marañón, Madrid, Spain Jeevan Prakash Gopal  West London Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom Frans K. Gorus  Diabetes Research Center, Vrije Universiteit Brussel; Department of Clinical Chemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium Masafumi Goto  Division of Transplantation and Regenerative Medicine, Tohoku University, Sendai, Japan Mitsukazu Gotoh  Osaka General Medical Center, Osaka, Japan Michel Greget  Department of Radiology, University Hospital, Strasbourg, France Dominique Grenet  Department of Pneumology, Foch Hospital, Suresnes, France Paolo Antonio Grossi  Infectious Diseases Section, Department of Medicine and Surgery, University of Insubria, Varese; ID Consultant National Center for Transplantation, Rome, Italy Rainer W.G. Gruessner  Department of Surgery, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States Angelika C. Gruessner  Department of Nephrology, SUNY Downstate Medical Center, New York, NY; School of Public Health, University of Arizona, Tucson, AZ, United States David I. Harriman  Department of Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States Wayne J. Hawthorne  National Pancreas and Islet Transplant Laboratories, The Westmead Institute for Medical Research; Department of Surgery, Westmead Clinical School, University of Sydney, Westmead Hospital, Westmead, NSW, Australia

Raja Kandaswamy  Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, United States Georges Karam  Centre de Recherche en Transplantation et Immunologie (CRTI), Inserm, Université de Nantes; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France Dixon B. Kaufman  Department of Surgery, UW School of Medicine and Public Health, UW-Madison SMPH, Madison, WI, United States WF Kendall Jr  University of Florida-Halifax Health Center for Transplant Services, Daytona Beach, FL, United States Clark D. Kensinger  Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States Norma S. Kenyon  Diabetes Research Institute; Department of Surgery, Division of Cellular Transplantation, University of Miami Miller School of Medicine, Miami, FL, United States Julie Kerr-Conte  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine, Lille, France Delphine Kervella  Centre de Recherche en Transplantation et Immunologie (CRTI), Inserm, Université de Nantes; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France Laurence Kessler  Department of Diabetology, University Hospital; INSERM–UMR 1260, Regenerative Nanomedicine, Federation of Translational Medicine, University of Strasbourg; Service d’Endocrinologie Diabète et Maladies Métaboliques, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

Jarl Hellman  Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Romain Kessler  INSERM–UMR 1260, Regenerative Nanomedicine, Federation of Translational Medicine, University of Strasbourg; Department of Pneumology, University Hospital, Strasbourg, France

Brenda Lee Holbert  Wake Forest School of Medicine, Department of Radiology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, United States

Bart Keymeulen  Diabetes Research Center, Vrije Universiteit Brussel; Department of Diabetology, Universitair Ziekenhuis Brussel, Brussels, Belgium

Thomas Hubert  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine, Lille, France

Olle Korsgren  Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala; Department of Biomedicine, University of Gothenburg, Gothenburg, Sweden

Sara Iacopi  Division of General and Transplant Surgery, University of Pisa, Pisa, Italy

Sandrine Lablanche  Department of Endocrinology, Grenoble University Hospital, Grenoble, France

Marco Infante  Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy

Muhaib Lakhani  Islet Cell Laboratory, Baylor University Medical Center, Baylor Scott and White Research Institute, Dallas, TX, United States

Peter Jacob  Department of Diabetes Research (Denmark Hill), King’s College London, London, United Kingdom

Neeraj Lalwani  Wake Forest School of Medicine, Department of Radiology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, United States

Paul Johnson  Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Oxford, United Kingdom

P.F. Laterre  Critical Care Department, Cliniques universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium

xx Contributors Michael C. Lawrence  Islet Cell Laboratory, Baylor University Medical Center, Baylor Scott and White Research Institute, Dallas, TX, United States Frances Tangherlini Lee  Department of Surgery, Northwestern University; McGaw Medical Center, Evanston, IL, United States Roger Lehmann  Department of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, Zürich, Switzerland Elina Linetsky  Diabetes Research Institute; Department of Surgery, Division of Cellular Transplantation, University of Miami Miller School of Medicine, Miami, FL, United States Barbara Ludwig  Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany Torbjörn Lundgren  Department of Transplantation Surgery, Karolinska University Hospital; Department of Clinical Science, Intervention and Technology, Karolinska Institute, Solna, Sweden Xunrong Luo  Department of Nephrology and Hypertension, Northwestern University; McGaw Medical Center, Evanston, IL, United States SriGita Madiraju  Florida Atlantic University, Charles E. Schmidt School of Medicine, Boca Raton, FL, United States Paola Maffi  Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy Paola Magistretti  Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy Kristell Le Mapihan  Department of Endocrinology Diabetology and Metabolism, CHU Lille, Lille, France James F. Markmann  Division of Transplantation, Department of Surgery, Massachusetts General Hospital; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Geert Martens  Diabetes Research Center, Vrije Universiteit Brussel, Brussels; Department of Laboratory Medicine, Algemeen Ziekenhuis Delta, Roeselare, Belgium Paulo N. Martins  Department of Surgery, Division of Transplant, University of Massachusetts, Worcester, MA, United States Francesco Antonio Mazzotta  Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy Kavya Chitra Mekala  Wake Forest School of Medicine, Section on Endocrinology & Metabolism, Winston-Salem, NC, United States Raffaella Melzi  Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy Alessia Mercalli  Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy Paolo Monti  Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy Mahmoud Morsi  Miami Transplant Institute, Jackson Memorial Hospital; Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine, Miami, FL, United States

Irene Mosca  Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom M. Mourad  Surgery and Abdominal Transplantation Department, Cliniques universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium Anand S. Rathnasamy Muthusamy  West London Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust; Academic Department of Surgery, Imperial College, London, United Kingdom Rita Nano  Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy Bashoo Naziruddin  Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, United States Christian Noel  Department of Nephrology, CHU Lille, Lille, France John O’Callaghan  Oxford Transplant Centre, Oxford University Hospitals, Oxford, United Kingdom Jon S. Odorico  Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, United States Anne Olland  INSERM–UMR 1260, Regenerative Nanomedicine, Federation of Translational Medicine, University of Strasbourg; Department of Thoracic Surgery, University Hospital, Strasbourg, France EC Opara  Institute for Regenerative Medicine, Biomedical Engineering, Wake Forest Medical School, Winston Salem, NC, United States Giuseppe Orlando  Department of Surgery, Division of Transplant, Wake Forest University School of Medicine, Wiston Salem, NC, United States Nathalia Padilla  Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States John C. Papadimitriou  Department of Pathology; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States Vassilios E. Papalois  West London Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust; Academic Department of Surgery, Imperial College, London, United Kingdom Klearchos K. Papas  University of Arizona, Department of Surgery, Institute of Cellular Transplantation, Tucson, AZ, United States Gianni Pasquetti  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine, Lille, France François Pattou  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine; Department of General and Endocrine Surgery, CHU Lille; Service de Chirurgie de l’Obésité, Centre Hospitalier Universitaire de Lille, Lille, France Silvia Pellegrini  Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy

Contributors xxi

Nadine Pernin  Division of Transplantation, Department of Surgery, Cell Isolation and Transplantation Center, University of Geneva Hospitals and School of Medicine, Geneva, Switzerland

Hanne Scholz  HTH Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo; Department of Transplant Medicine and Institute for Surgical Research, Oslo University Hospital, Oslo, Norway

Vittorio Grazio Perrone  Division of General and Transplant Surgery, University of Pisa, Pisa, Italy

Antonio Secchi  Vita-Salute San Raffaele University; Clinical Transplant Unit, Division of Immunology, Transplantation and Infectious Diseases; Department of Internal Medicine, Transplant Medicine Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy

Lorenzo Piemonti  Diabetes Research Institute, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University, Milano, Italy Rutger Ploeg  Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom John A. Powelson  Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States Alberto Pugliese  Diabetes Research Institute; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism; Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States Shanthini K. Rajan  Islet Cell Laboratory, Baylor University Medical Center, Baylor Scott and White Research Institute, Dallas, TX, United States Karthik V. Ramanathan  Department of Surgery, University of Minnesota, Minneapolis, MN, United States Violeta Raverdy  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine; Department of General and Endocrine Surgery, CHU Lille, Lille, France Robert R. Redfield  Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States John Renz  Department of Surgery, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States Michael R. Rickels  Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States Charles G. Rickert  Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Camillo Ricordi  Diabetes Research Institute; Department of Surgery, Division of Cellular Transplantation, University of Miami Miller School of Medicine, Miami, FL, United States Jeffrey Rogers  Department of Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States Joseph R. Scalea  Department of Pathology; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States Jesse D. Schold  Department of Quantitative Health Sciences; Center for Populations Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States

Oscar K. Serrano  Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, United States A.M. James Shapiro  Department of Surgery and Clinical islet Transplant Program, University of Alberta, Edmonton, AB, Canada Sidharth Sharma  Department of Surgery, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States Edward Sharples  Oxford University Hospitals NHS Trust, University of Oxford, Oxford, United Kingdom James A.M. Shaw  Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom Sanjay Sinha  Oxford University Hospitals NHS Trust, University of Oxford, Oxford, United Kingdom Carlo Socci  Department of Surgery, IRCCS San Raffaele Scientific Institute, Milano, Italy Jean-Paul G. Squifflet  Department of Abdominal Surgery and Transplantation, University of Liege, Liege, Belgium Peter G. Stock  Department of Transplant Surgery, UC San Francisco, San Francisco, CA, United States Robert J. Stratta  Department of Surgery, Section of Transplantation, Wake Forest School of Medicine, WinstonSalem, NC, United States David E.R. Sutherland  Department of Surgery, University of Minnesota, MN, United States Manfredi Tesauro  Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy Olivier Thaunat  Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology; Claude Bernard University (Lyon 1); French National Institute of Health and Medical Research (Inserm) Unit 1111, Lyon, France Julien Thévenet  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine, Lille, France Christoph Troppmann  Department of Surgery, School of Medicine, University of California, Davis, CA, United States Marie-Christine Vantyghem  Université de Lille, INSERM U1190, Translational Research for Diabetes, EGID (European Genomic Institute for Diabetes), Faculté de Médecine; Department of Endocrinology Diabetology and Metabolism, CHU Lille; Service d’Endocrinologie, Centre Hospitalier Universitaire de Lille, Lille, France

xxii Contributors Francesco Vendrame  Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, FL, United States Massimo Venturini  Department of Radiology and Center for Experimental Imaging, IRCCS San Raffaele Scientific Institute, Milano, Italy Rodrigo Vianna  Miami Transplant Institute, Jackson Memorial Hospital; Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine, Miami, FL, United States Fabio Vistoli  Division of General and Transplant Surgery, University of Pisa, Pisa, Italy

Bengt von Zur-Mühlen  Department of Surgical Sciences, Uppsala University, Uppsala, Sweden X. Wittebole  Critical Care Department, Cliniques universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium Anne Wojtusciszyn  Department of Endocrinology, Diabetes and Nutrition, Montpellier University Hospital, Montpellier, France Arya Zarinsefat  Department of Transplant Surgery, UC San Francisco, San Francisco, CA, United States Asha Zimmerman  MedStar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, United States

Preface

The idea for this book spawned from the observation that the challenges in cellular and organ transplantation are steadily evolving toward solutions that can be found in the burgeoning field of regenerative medicine. Although not immediately apparent to the neophyte, this transition began many years ago, somehow “ante litteram,” before the term, “regenerative medicine” was even created, with the development of the field of organ preservation. In fact, when we preserve organs immediately after procurement, we try to minimize damage by slowing metabolism through hypothermia and providing substrates to prevent cellular edema and membrane destabilization in order to facilitate the intrinsic ability of tissues to repair, recover, and regenerate following reperfusion. If we agree with the definition of the term regenerative medicine formulated by the National Institutes of Health—“regenerative medicine is the process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects” (https://report.nih.gov/­nihfactsheets/ ViewFactSheet.aspx?csid=62 [nam01.safelinks.protection.outlook.com])—and we focus on the word replace, we could even contend that, inherently, transplantation is synonymous with regenerative medicine. Formidable progress in biomaterial sciences and tissue engineering has been made in the past few decades, concomitant with the stem cell revolution. These new advances are offering alternative strategies for the identification of a potentially inexhaustible source of organs as well as immunosuppression-free transplantation. In this

context, beta-cell replacement to treat diabetes mellitus offers a unique platform for the application of regenerative medicine strategies. In the regenerative medicine era, the scenario envisioned is that islet (cell) transplantation will become the preferred therapeutic procedure for beta-cell replacement secondary to its metabolic efficiency compared to the “artificial or bionic pancreas” and superior safety profile (less invasive) compared to pancreas transplantation. With this book, we intend to capture the remarkable changes that are about to revolutionize the field of beta-cell replacement, while depicting the current and future status of pancreas and islet transplantation, as well as groundbreaking research pertinent to the application of regenerative medicine and bioengineering technologies to beta-cell replacement. We intend to provide state-of-the-art information to anyone who has interest in the newest and most exciting concepts as applied to the management of the epidemic of diabetes mellitus through beta-cell replacement in the regenerative medicine era and on how regenerative medicine is shaping modern transplantation. The present book follows two previous tomes, Regenerative Medicine Applications in Organ Transplantation and Kidney Transplantation, Bioengineering, and Regeneration proposing a new paradigm for transplantation literature. The study of organ bioengineering, regeneration, and repair (namely, regenerative medicine) should now be referred to as the new Holy Grail of modern transplantation because both fields crossover with respect to their genesis, clinical challenges, and ultimate goals.

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C H A P T E R

1 History of pancreas transplantation David E.R. Sutherland*, Rainer W.G. Gruessner† *

Department of Surgery, University of Minnesota, MN, United States, †Department of Surgery, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States

O U T L I N E The first attempt at transplantation of pancreatic tissue 5 The nature of the pancreas

6

Discoveries about the pancreas

6

Modern animal models of pancreas transplantation and surgical techniques 10

Discoveries about the relationship between pancreas and diabetes 6 Discoveries about insulin and diabetes etiology Early animal models of diabetes and pancreas transplantation

8

12

History of pancreas transplantation in humans

12

Acknowledgments

21

References

21

9

The first attempt at transplantation of pancreatic tissue

all cases of diabetes are secondary to an abnormality of the pancreas. His article conveyed the widespread confusion at both a microscopic and gross level over the relation of the pancreas to diabetes. The separate concept of external and internal secretion was not yet understood at the time.3–14 In Williams’ day, the clinical classification of diabetes was little more than a general recognition of mild and severe forms. The mild forms were seen more commonly in adults and associated with obesity (diabetes gras); the severe form was more common in children and associated with leanness (diabetes maigre).15 However, at the end of the 19th century, it was clear that there was a form of diabetes that should be amenable to treatment by pancreatic extracts or transplants. Both extracts and transplants were successfully applied in the 20th century16, 17 and remain as treatments in the early part of the 21st century. The development of both these ­treatments—exogenous insulin and transplants (b-cell replacement)—depended on the persistent efforts of individuals who built on the cumulative knowledge and technical advances of preceding generations in multiple disciplines.

On December 20, 1893, 3  years after von Mering and Minkowski had shown that total pancreatectomy in dogs resulted in diabetes mellitus,1 Dr. Watson Williams in Bristol, England, grafted three fragments of a pancreas obtained from a freshly slaughtered sheep into the subcutaneous tissue of a 15-year-old diabetic boy in extremis.2 The recipient died 3 days later from unrelenting acidosis, a consequence of untreated diabetes. At autopsy, the recipient’s own pancreas was shriveled and sections showed little but fibrous stroma. According to Williams, the case “presented all the conditions that might lead one to hope for beneficial result from successful grafting of the pancreas, if anything can he hoped for in this direction at all.” He was not discouraged, and stated further that “If ever I felt justified again in resorting to pancreatic grafts in a similar case, I should obtain them from a living animal.” Williams’ used the term “pancreatic diabetes” for describing his patient’s condition which reflected the prevailing attempts at classification by etiology and the concept that not

Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas, Volume 1 https://doi.org/10.1016/B978-0-12-814833-4.00001-0

Modern animal models of pancreas transplant immunology

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© 2020 Elsevier Inc. All rights reserved.

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1.  History of pancreas transplantation

The nature of the pancreas It took centuries to understand that the pancreas is a nearly unique organ with dual components that function more or less independently: (1) the exocrine portion (98% of the gland), connected by a ductal system to the intestine, excretes lytic enzymes to aid in digestion; and (2) the endocrine portion, comprised of about 1 million separate cellular spheres scattered throughout the gland—called islets because of their appearance when sliced in histological section. The islets secrete hormones into the bloodstream, of which one, insulin, is essential to sustain life by its promotion of carbohydrate metabolism in nearly all tissues of the body. The end-stage disease can occur simultaneously in both components of the pancreas (endocrine or exocrine), but more often one component is affected and the other is not. Given its dual nature, the entire pancreas can be transplanted as an immediately vascularized graft to correct endocrine deficiency alone (most common), exocrine deficiency alone (relatively rare), or both. Or, the endocrine portion (islets) can be isolated and transplanted as a free graft to an ectopic site in a diabetic recipient, restoring autoregulated insulin secretion after neovascularization occurs. Within the islets, β-cells synthesize and secrete insulin. Insulin acts at the cell membrane level, facilitating the entry of glucose into the cell for metabolism. The role of the β-cell is to maintain blood sugar levels within a narrow range. The brain does not require insulin to drive glucose into the cells but does require a sufficient level of glucose in the blood so that enough is constantly available for metabolism. Thus, β-cells are not only synthesizers and secreters but also glucostats (analogous to mechanical thermostats or humidistats). They turn on to secrete insulin when the blood sugar rises above the threshold level (about 83 mg/dL) and shut off when the blood sugar reaches or is below this level.18 The β-cell is the ultimate in a close-looped insulin pump.

Discoveries about the pancreas The highlights of discoveries about pancreatic anatomy and physiology were described by Busnardo,19 by Child in his history of pancreatic surgery, 20 and by Wellman and Volk in their historical review of the diabetic pancreas.8 Landmarks in the evolution of our understanding of the diabetes were summarized by Papaspyros21 and Levine22 and put in perspective by Gale.23 In early England writings, the pancreas was called “sweet-bread”24 and the term has persisted in the language of the abattoir. The pancreas was grossly described by the anatomist Herophilus of Chalcedon around 300 BC. It took another two centuries until it was given its name (pan = all; creas = flesh) by Ruphos of Ephesus.

Galen (ca. AD 130–201) referred to the pancreas in his writings but without an understanding of its function.20 The exocrine function of the pancreas was not understood until Claude Bernard performed his experiments in the mid-19th century.25 However, the realization that the pancreas must have a dual nature, with both external and internal secretions did not occur until the end of the 19th century.26 Diabetes mellitus, as a syndrome with clinical characteristics, was described in ancient medical writings of several cultures.21 Yet, it was centuries before an association with pancreas pathology was described— sketchily in the 18th century but not definitively until the 19th century.8 From the time Galen described the pancreas as a cushion for the stomach, virtually no reference to the organ was recorded until the Middle Ages.8, 18, 20 The fact that the pancreas had a duct was mentioned by Luzzi in 1275. But, the first accurate description of the pancreas and its anatomic relations was not published until 1543, in the monumental De Humani Corporus Fabrica Libri Septem by Vesalius and his student Fallopio. In the 17th century, Thomas Wharton noticed the structural similarity of the pancreas and salivary glands. The main pancreatic duct was described by Wirsung in 1642, the accessory duct by Santorini in 1724, the termination of the main duct in a papilla by Vater in 1728, the vascular relationships by Walther in 1729, and the musculature surrounding the papilla by Oddi in 1887.26 The descriptions of anatomy were paralleled by physiologic studies.20 The earliest experimental observation was by de Graf in 1664. He cannulated the pancreatic duct of a dog with a quill, collected secretions, and noted their corrosive action. However, it was nearly two more centuries before the function of the pancreatic secretions were described. In the mid-19th century, Claude Bernard, in Lyon, demonstrated that the secretions could emulsify fat, convert starch to sugars, and dissolve protein.25 Bernard dismissed hints linking the pancreas to diabetes when the disease did not ensue in animals after atrophy of the pancreas was induced by duct injection of paraffin. In 1875, Heidenhain described the effect of vagal nerve stimulation on pancreatic secretions.27 The very beginning of the 20th century was a fermentative period in the conceptualization of the hormonal and endocrine systems. The contemporary understanding of pancreatic exocrine sections and their interactions with the gut via secretin was provided by Bayliss and Starling in 1902.28

Discoveries about the relationship between pancreas and diabetes The quest to understand the function of a specific organ, the pancreas, and the quest to understand diabetes were not fully joined until the serendipitous experiment

A.  Whole pancreas allo-transplantation



Discoveries about the relationship between pancreas and diabetes

of von Mering and Minkowski in 1889.1 This experiment, originally designed to study digestion, 29, 30 definitively showed that total extirpation of the pancreas resulted in diabetes. Until then, the quests had been on different pathways that only on occasion touched. But, after von Mering and Minkowski’s experiment, understanding the anatomy, function, and pathology of the endocrine pancreas became synonymous with understanding diabetes. It is easiest to describe each pathway separately, with a comment on where they bumped together before joining. Regarding the quest to understand diabetes, the pathway was tortuous, because there are so many forms of the disease. Today’s classification of diabetes is complex, according to etiology, pathogenesis, or treatment:31 type 1 or insulin-dependent DM due to β-cell destruction, usually leading to absolute insulin deficiency; type 2, so-called non-insulin-dependent (but some will need exogenous insulin) due to a progressive insulin secretory defect on the background of insulin resistance; gestational diabetes mellitus diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes; and specific types of diabetes due to other causes. The latter include a wide variety of other conditions and disorders: pancreatic diabetes (e.g., cystic fibrosis or secondary to pancreatectomy or pancreatitis); monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]); extrapancreatic or endocrine diabetes (e.g., with hyperadrenalism); and drug- or chemical-induced diabetes (e.g., steroids or calcineurin inhibitors). The complexities of the current diabetes classification are also evident by the fact that assigning a type of diabetes to an individual often depends on the circumstances present at the time of diagnosis, with individuals not necessarily fitting clearly into a single category. For example, some patients cannot be clearly classified as having type 1 or type 2 diabetes. Clinical presentation and disease progression may vary considerably in both types of diabetes. In addition, the traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both cohorts.31 The term diabetes was coined by the Greek physician Aretaeus of Cappadocia in the second century AD.21 It means “to run through a siphone.” Aretaeus described the clinical syndrome of diabetes “as a melting down of flesh and limbs into urine.” However, at that time, the word diabetes was essentially synonymous with polyuria. Polyuria has many causes. Polyuric syndromes are described in ancient literature, including the Egyptian papyrus Ebers from around 1500 BC. Japanese and Chinese physicians of second and third centuries and Indian physicians of the 6th century describe cases of polyuria associated with a sweet taste to the urine, almost c­ ertainly

7

diabetes mellitus, as we know it today. Avicenna, the famous Arabic physician also described around AD 1000, a syndrome consistent with diabetes that was associated with the sweetness of urine. Few European references to diabetes were recorded until Paracelsus described a case in the early 16th century.21 Indeed, he evaporated urine from a diabetic patient and obtained a white powdery residue that he thought was salt. In the 17th century, Thomas Willis rediscovered the sweetness of the urine in some individuals with diabetes (polyuria).32 Willis even stated that sugar first appeared in the blood and then the urine. Dobson in the 18th century also linked glycosuria to elevated sugar in the blood.33 In 1815, the French chemist Michel Chevreul (1787–1882) showed that the sugar in the urine of diabetics was not the sugar of the cane but of the grape (glucose).34 Willis makes clear that there are two forms of diabetes: with glycosuria and without.35 The qualifying adjective mellitus (Latin for “sweetened with honey”) was added to diabetes (Ionic Greek) by William Cullen in 1787 to distinguish it from polyuria of other causes, or what he termed diabetes insipidus (urine with no taste, i.e., insipid).36 Attempts to classify diabetes mellitus into subtypes began in the 19th century, primarily as a guide to the only treatment available, dietary.37 The class we recognize today as insulin-dependent type 1 diabetes would have been rapidly fatal then, no matter what the diet. Thus, most of the descriptions of success in the literature of the late 18th and 19th centuries probably reflect the response of individuals with type 2 diabetes.38, 39 In 1887, Lancereaux first introduced the terms diabetes maigre (lean diabetes) and diabetes gras (obese diabetes).15 He,40 along with his contemporary Frerichs,41 also described diabetes associated with gross pancreatic pathology that they considered etiologic. But, they were not first to note gross pancreatic pathology associated with diabetes mellitus. This honor belongs to Thomas Cawley in 1788,42 but from his article, it is apparent that he believed that the association was fortuitous and that it was the kidney that was diseased in diabetes mellitus, a logical assumption based on polyuria. An understanding of the secondary nature of the polyuria of diabetes was provided by the 19th-century French physician Bouchardat,43 a prodigy of Chevreul. He developed reliable techniques for quantitation of the sugar in blood and urine. Bouchardat was also one of the first physicians to demonstrate truly good results with dietary therapy. He observed that during the food shortage of the Franco-Prussian war of 1870 and 1871, his patients with diabetes improved.14 Later, dietary therapy was carried to the extreme of starvation for patients with type 1 diabetes, juvenile onset, rapidly lethal severe diabetes.44

A.  Whole pancreas allo-transplantation

8

1.  History of pancreas transplantation

In the 19th century, hints that the pancreas was involved in diabetes were dismissed by Claude Bernard and Moritz Schiff (in Italy) because of the result of experiments with an injection of paraffin into the pancreatic duct of animals; despite the atrophy induced in the gland, diabetes did not appear.22, 25 However, Bernard was a pioneer in understanding the action of pancreatic secretions as well as the physiology of carbohydrate metabolism (and thus diabetes) through his discovery of glycogen.25 Others had studied pancreatic secretions, including Brunner in the 17th century (who also observed polyuria in pancreatectomized dogs but did not deduce that they were diabetic).19, 20 However, Bernard was the first to quantify their action in breaking starch into sugar, emulsifying fat, and dissolving protein.25 Indeed, Bernard began the modern studies of the physiology of the exocrine pancreas. Before Paul Langerhans described the clusters of pancreatic cells (Zelhaufen) in his doctoral thesis at the University of Berlin in 1869, there was little reason for Bernard or anyone else to suspect that the pancreas was anything other than an exocrine organ. The significance of Langerhans’ findings was not appreciated until after the observation of von Mering and Minkowski. Diabetes had rarely been associated with the gross or microscopic pathology induced by duct occlusion, as described by several groups during the 19th century (reviewed by Minkowski himself29, 30). But, with von Mering and Minkowski’s experiment,1 everything changed. One of the first questions asked was how the absence of the pancreas induced diabetes. Minkowski proposed that the pancreas secreted a substance into the vascular system that lowered blood sugar (so-called internal secretion, although not a term he coined). In 1893, he published the results of an experiment in which he transposed a segment of the canine pancreas to the subcutaneous tissue on a vascular pedicle, did a completion pancreatectomy, and later severed the pedicle. Diabetes did not ensue, apparently prevented by neovascularization of the pancreatic fragment.3 Hedon, in 1892, described a similar experiment. He did a partial pancreatectomy of the tail and body of the pancreas while transposing the descending portion (equivalent to the uncinate process in humans, but basically a second tail in dogs) to the subcutaneous tissue on a vascular pedicle.4 Diabetes did not ensue until the pancreatic remnant was removed. With the exocrine secretions collected externally via a fistula, there could be no doubt that the internal section had to exist. In 1893, Laguesse postulated that the clusters of pancreatic cells described by Langerhans were the organelles that secreted the substance that lowered blood glucose in the vascular system.5 Laguesse named the nonacidic clusters of cells scattered throughout the pancreas the “islets of Langerhans.” He later showed (along with

others) that duct ligation of animal pancreases induced exocrine atrophy while leaving islets intact. Pathologists then swung into full gear. By the beginning of the 20th century, Opie,12 among others, described hyalinization of islets in association with diabetes. The observations were not clean. Shortly thereafter pathologists also described hyalinization of islets in autopsy material in individuals who did not have diabetes, and cases of diabetes were also described in which no obvious pathology of the islets was present (referenced in Wellman and Volk).8 Yet, histologic techniques were being refined. In 1907, Lane labeled the two types of islets cell as α and β.13 In 1931, Δ-cells were described by Bloom.45 Meanwhile, pancreatic duct ligation experiments continued. In 1902, Ssobolew,46 emphasized that the anatomic isolation of the islets by duct ligation “will permit the testing, in a rational way, of an organotheraphy for diabetes.” MacCallum, in 1909 at John Hopkins University,47 confirmed that pancreatic duct ligation was followed by atrophy of the exocrine parenchyma with the survival of the islets. He showed that diabetes occurred after removal of the duct-ligated pancreas, adding a nuance to the original observations of von Mering and Minkowski.

Discoveries about insulin and diabetes etiology The new information fueled intense efforts to extract the internal secretion of the pancreas to use for exogenous therapy.48 The name insulin was first given to this theoretical substance by DeMayer in 1909 49 and was used by Sharpey-Shafer, of Edinburgh, in 1916;50 this name is what fellow Scotsman Richard Macleod, chairman of the Department of Physiology at the University of Toronto, insisted21 be used for the internal pancreatic secretion isolated in his laboratory by Banting and Best in 1921.51 Banting’s quest was sparked by reading the 1920 article by Moses Barron on pancreatic lithiasis. Barron described pancreatic atrophy with preservation of the islets of Langerhans.52 The acid-alcohol extraction process was used by Banting and Best on duct-ligated canine pancreases. It was further refined by Collip so it would work with normal pancreases without duct ligation and was effective for insulin extraction from cow and pig as well as dog pancreases.53 Thus, the modern therapy for what is now called type 1 diabetes mellitus began. A description of the history of classification of diabetes and the terms type 1 and type 2 was provided by Gale.23 The paradigm shift to view type 1 diabetes as an autoimmune disorder did not occur until the 1970s.23 Nonetheless, islet inflammation was described as early as 1901 by Opie,12 and the term insulitis was coined by von Meyenberg in 1940.54 The autoimmune nature of

A.  Whole pancreas allo-transplantation



Early animal models of diabetes and pancreas transplantation

type 1 diabetes was further hinted at in the 1950s and 1960s by the pathologic observations of LeCompte55 and Gepts. 56 In the 1970s, the demonstration of cell- 57 and humoral-58 mediated autoimmunity, of an HLA association,59 and of spontaneous animal models60, 61 made autoimmunity the most compelling hypothesis to explain the pathogenesis of type 1 diabetes. Autoimmunity must be overcome for clinical pancreas and islet transplants to succeed.62, 63

Early animal models of diabetes and pancreas transplantation Although Carrel transplanted several different organs in animal models in the early 1900s, the pancreas was not one of them (although he did mention that it should be done for functional studies).64 The first reported attempt at transplantation of the pancreas as an immediately vascularized graft was by Hedon in 1913.65 He placed an allograft in the neck of pancreatectomized dogs and did not observe even temporary correction of diabetes, probably a failure for technical reasons. He also did somewhat complicated cross-circulation experiments66 between normal and panceatectomized dogs and temporarily correcting diabetes in the latter with both systemic and portal connections. He erroneously concluded that the innervation is necessary for proper function, ever thought that would have required reinnervation of the transposed neovascularized pancreatic segment auto-graft in his severed vascular pedicle experiments reported earlier and discussed by him until 1920.67 The vascular pedicled/delayed severed neovascularized canine segmental pancreatic autograph model with technical variations was described in detail in 1926 by Ivy at Northwestern University in Chicago,68 with a hint that both exocrine and endocrine function were retained (removal of the rest of the pancreas was not described) and a promise that the details would be reported in later articles (the articles never appeared). After Hedon,65 the next reported attempt of an immediately vascularized pancreas transplant was by Houssay and Molinelli in 1927,69 also to the neck in pancreatectomized dogs and also without correction of diabetes, again probably for technical reasons and again leading to the erroneous conclusion that extrinsic innervation was necessary for the endocrine pancreas to function. That same year, Gayet and Guillaumie reported immediate correction of diabetes by pancreas allotransplantation to the neck of pancreatectomized dogs,70 concluded that extrinsic innervation was not necessary for the endocrine function of the pancreas, and was certain that the Hedon65 and Houssay69 had failed for a technical reason. Houssay et al. then repeated their experiments71, 72 and duplicated the results of Gayet and

9

Guillaumie with correction of diabetes by a pancreas allograft to the neck of pancreatectomized dogs. They described in great detail the technical aspects of the operation71 (they used the 1900 Payr vascular anastomosis technique, connecting vessels by eversion through and over a metal tube,73 ignoring Carrel’s technique). They also studied the effect of at least partial denervation of native pancreases in comparison to grafted pancreases on glucose tolerance and concluded that the effect was minor.72, 74 Gayet et al.75–77 largely used the canine neck vascularized pancreas-duodenal transplant model to do physiologic studies of exocrine function and the role of extrinsic and intrinsic nervous function on the secretin response to various stimuli, concluding that the intestine does not need extrinsic innervation to perform its endocrine function any more than the pancreas. Perhaps the most interesting pancreas transplant experiment in the series performed by the French investigators is that of Houssay et  al.,78 in which multiple pancreases (four) were transplanted simultaneously into normal dogs, one to each side of the neck (carotid-­ jugular) and groin (femoral vessels). Hypoglycemia did not ensue despite five pancreases, showing to their satisfaction that glucose homeostasis was not a function of the islet mass, but of the regulation of insulin secretion by glucose itself, perhaps the first articulation of the concept that the β-cell acts as its own glucostat. All the French groups doing pancreas transplants for physiologic studies used the Payr technique for their vascular anastomoses but mention neither Payr nor Carrel. The only other article on pancreas transplants from this era, by Bottin of Liege in 1936,79 does refer to both Carrel and Payr and flatly states that the Payr technique is better because the ischemia time is less. However, the world was not convinced and all subsequent descriptions of immediately revascularized pancreas transplants clearly use the Carrel technique. However, after Bottin (who simply did allografts to the neck in non-­pancreatectomized canine recipients and followed the unmodified course of the graft-death from the toxicity of rejection necrosis within 8 days) no articles appeared on the topic until the 1950s. After a 20-year hiatus, the first article on pancreas transplantation is a resurrection of the Hedon ­vascular-pedicle transposition autograft but is at least a confirmation that neovascularization occurs and even carries the experiment a step further by free-grafting the neovascularized tissue component.80 Rundles and Swan, as reported in 1956,80 transposed the splenic tail of the pancreas, based on the splenic vessels, to the subcutaneous tissue. In 6–8  weeks, a completion pancreatectomy was made of the remaining intra-abdominal pancreas, and the vascular pedicle to the transposed portion was ligated. Seven of the 15 dogs did not become diabetic, indicating that the autograft was neovascularized and

A.  Whole pancreas allo-transplantation

10

1.  History of pancreas transplantation

producing insulin. Subsequently, the neovascularized graft was excised, minced, and then reimplanted intramuscularly. All recipients initially became hyperglycemic but were treated with insulin for 1–2 months; insulin was then withdrawn and two of the dogs remained euglycemic. Following excision of the transplanted pancreatic fragments, the dogs again became diabetic. Thus, Rundles and Swan clearly showed the ability of pancreatic fragments to become neovascularized, confirming the outcomes reported by Hedon and Minkowski more than a half-century earlier. Brooks, in 1959,81 published a brief description of similar experiments and cited Ivy (apparently unaware of the 19th-century experiments or the more recent ones of Rundels and Swan). He also excised the neovascularized fragment, but exchanged it between dogs (allograft) and observed no evidence of function or survival. Brooks also did vascularize pancreas allografts to nonpancreatectomized recipients; he described technical problems or allograft rejection in less than 1 week in all cases and was not able to perform functional studies. Interestingly, Brooks also described transplantation of human pancreas allograft using fragments of neonatal tissue, again without any evidence of success in the diabetic recipients.81

Modern animal models of pancreas transplantation and surgical techniques The first description that can be found in the literature of an intra-abdominal immediately vascularized pancreas transplant is by Irving Lichtenstein (of hernia fame) and Richard Barschak in 1957.82 They placed pancreas allografts to the iliac vessels of nonpancreatectomized dogs, described the techniques in great detail, and simply killed the dogs at 6–8 weeks, finding no residual pancreatic tissue at the graft site. They seemed completely unaware of any preceding attempts, failing to reference the French work or the Rundles and Swan work, and obviously believed that they were the first to ever have done an immediately vascularized pancreas allograft in any model. They mentioned theoretical reasons for why an allograft might be successful in humans, referring to successful kidney transplants between monozygotic twins (but not referencing the obvious source of this information—Murray and associates in Boston). They also mentioned that homografting of skin had been successful in patients with agammaglobulinemia (again not referencing the work by Varco et al. at Minnesota,83 work that was cited by Rundles and Swan). However, the canine pancreas allograft technique described by Lichtenstein and Barschak79 was modern and similar to that described in pancreatomized recipients by the subsequent investigators in the 1960s who set the stage

for clinical application, namely, Lucas et al.,84 DeJode and Howard,85 Reemtsma et  al.,86 Bergan et  al.,87 Teixeira et  al.,88 Seddon and Howard,89 Ota et  al.,90 and, most critically, in Kelly et al.’s 91 laboratory (segmental), Merkel et al.,92 and in Lillehei et al.’s17 laboratory (whole pancreaticoduodenal), Largiader et  al.,93 and Idezuki et al.,94 experiments well summarized in the classic article by Lillehei et al., in 1970.17 The numerous pancreas transplant experiments in animal models from 1970 to the mid-1990s have been summarized in detail in previous reviews.95–100 The segmental pancreas allograft technique in dogs described by Merkel et al.92, 101 was similar to that used in the first human.91 Merkel, working in Kelly’s laboratory, interposed the graft superior mesenteric-splenic-portal vein complex and the celiac-splenic complex to the iliac vein and artery of the recipient dog, to reduce the risk of thrombosis by maximizing the flow through the graft vessels. In the first clinical case, the vein complex was interposed (side to side with the intervening recipient iliac vein ligated, a departure from the dog model where the interposition was end to end) but the arterial complex was not.91 The point of Merkel’s experiment was to reduce exocrine function by irradiation,101 but the strategy was not effective, at least clinically.91 Largiager et  al.93 was the first to describe completely orthototic all transplantation of the pancreas in dogs with exocrine drainage, via a Roux-en-Y duodenojejunostomy, which was the technique used for the 6th through 13th pancreas transplants in the early Minnesota series.17, 102 The 14th transplant, the last done by Lillehei, was performed with only the papilla of Vater anastomosed to a Roux-en-Y limb of recipient jejunum, after the technique developed in Lillehei’s laboratory of Acquino et al.103 Because of the perception that many of the early complications of pancreas transplantation were related to the duodenum, segmental transplantation was clinically popular from at least the mid-1970s to the mid-1980s.104 Accordingly, segmental grafts were used in animal experiments to develop methods of duct management.96 Gold, in 1972, reported on segmental pancreas transplants in dogs with ductoureterostomy,105 a technique applied clinically by his mentor, Marvin Gliedman, at Montefiore Hospital in New York beginning in the early 1970s.106 Similarly, Cook, in 1983, reported on segmental pancreas transplants in dogs with ductocystostomy,107 a technique applied clinically by his mentor, Hans Sollinger, at the University of Wisconsin beginning in the early 1980s.108 Gold et  al.105 and Cook et  al.107 both hinted that urine amylase might be a marker for rejection. Prieto et al., in canine experiments at the University of Minnesota in the mid-1980s,109 formally showed that a decline in urine amylase preceded hyperglycemia as a

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Modern animal models of pancreas transplantation and surgical techniques

manifestation of rejection of bladder-drained segmental pancreas allografts. Shortly thereafter, Marsh et al. at the Mayo Clinic demonstrated the utility of transcystoscopic biopsy for pathologic diagnosis in bladder-drained canine pancreaticoduodenal allografts,110 followed by clinical application.111 Between the development of the two techniques of urinary drainage, and as an alternative to the hazardous enteric drainage of segmental grafts,112 Dubernard, in the mid-1970s in Lyon, applied the technique of duct injection with an occlusive and locally toxic polymer (his choice, neoprene) to suppress and induce fibrosis of the exocrine tissue of segmental pancreatic allografts in dogs and humans.113 Dubernard refers to the use of acrylate glue for occlusion of the pancreatic duct of native canine and human pancreases by the American surgeon J.M Little,114 but it is of interest to note the pancreatic duct injection began at Lyon in the 19th century in the experiments of Bernard (paraffin)25 and Thiroloix (oil and lampblack)115, 116 (as discussed by Hedon117). Following the publication of Dubernard’s work, several groups used duct injection experimentally and clinically with a variety of polymers: by Land et al. at Munich118; polyisoprene by McMaster et al. at Cambridge,119 and silicone at University of Minnesota.120, 121 The Dubernard experience at Lyon was a stimulus to resume pancreas transplant experimentally and clinically at the University of Minnesota. We did a series of segmental pancreas transplants in dogs and pigs, comparing the outcome with neoprene injection to that of simply leaving the duct open to drain freely into the peritoneal cavity.122–125 To our surprise, the animals tolerated the open duct very well, absorbing the pancreatic secretions with only an occasional case of enzyme activation and activation and chemical peritonitis. Although not as successful clinically as other methods of duct management,126 the open-duct technique was used routinely in our animal laboratory127, 128 for a variety of investigations on the site of venous drainage (systemic vs portal),129, 130 preservation,131–133 metabolism,134–136 and immunosuppression.137–139 The metabolic effect of the site of pancreas venous drainage, systemic or portal, has been the subject of experiments since the initial attempts by Hedon.69 Idezuki et al.94 were the first to drain pancreas graft venous effluent into the portal system, but no formal metabolic studies were carried out. Ruiz et  al.140 were the first to do studies comparing glucose metabolism for systemicvs portal-drained canine pancreas transplants, and at least as far as glucose tolerance, no differences were discerned. Florak et  al.130 and Hanks,141 in segmental pancreas autograft experiments, found that both denervation and site contribute to the hyperinsulinism associated with systemic venous drainage. In canine pancreas allografts experiments, despite the theoretical reasons

11

as to why the immune response should be dampened, rejection has been similar to systemic and portal drainage.130, 142 (Clinically, less rejection with portal drainage of pancreas allografts has been reported.143) Large-animal experiments have been critical for the development of methods for ex vivo organ preservation prior to transplantation. Idezuki et  al.94 in 1968 first reported on pancreas preservation prior to transplantation and demonstrated the function of canine allografts after 22 h of hyperbaric chamber storage in 5% dextran-balanced salt solution. Westbroek et al.,144 in 1974, were the first to report on pulsatile pump machine preservation of pancreas grafts and were able to successfully preserve some for 24 h. Machine preservation longer than 24 h has not been achieved,133 but Florak et  al.,132 in 1982, showed that canine pancreas grafts could be cold-stored for 48 h in a silica gel-filtered plasma solution, a solution that provide satisfactory to routinely preserve human pancreas allografts for >24 h at the University of Minnesota145 until superseded by nonbiologic (thus eliminating the risk of disease transmission) hyperosmolar solution developed at the University of Wisconsin (UW) by Fred Belzer in the late 1980s.146 The UW solution was first shown to be effective for preservation for up to 72 h by Wahlberg in a canine pancreas transplant model.147 In 1994, Kuroda in Kobe, Japan, showed that by using a two-layer method with UW solution and perfluorochemical, canine pancreas graft preservation could be extended beyond 72 h.148 The two-layer technique was applied clinically for pancreas preservation beyond 30 h by Matsumoto et  al.149 Tanioka et  al.150 also showed that the two-layer technique allowed the canine pancreas to be stored significantly longer prior to islet isolation for transplantation. Most of the clinically relevant experiments on pancreas transplant surgical techniques and preservation were in large-animal models, but the rat model has been used as well to address certain questions of clinical interest. Lee et al.151 from University of California at San Diego first reported pancreas-duodenal transplants in rats in 1972, and the model was used by Orloff et al.152 at the same institution to study the long-term (and favorable) effect of pancreas transplantation on secondary complications of diabetes. Metabolic problems have also been addressed in the rat model. For example, Schang et  al. did bladder-drained pancreaticoduodenal transplants in rats and showed that the metabolic acidosis that ensued was mainly due to the duodenal secretions rather than the pancreatic secretions.153 A technique for segmental pancreas transplantation in rats was developed by Squifflet et al.154 and has been used to address several questions,128 e.g., the manifestation of rejection in relation to β-cell mass engrafted for pancreas vs islet allografts.155

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1.  History of pancreas transplantation

Modern animal models of pancreas transplant immunology Immunologic questions have been addressed in both the rat and large-animal models. Lillehei was the first to suggest that a pancreas transplant alone (PTA) was more likely to stimulate a rejection response in an immunosuppressed host than a combined kidney and pancreas transplant alone.17 One possible explanation was that uremia itself is immunosuppressive. We tested this hypothesis in both rat and pig models.156–159 Nakai et  al.156 made rats uremic by removal of all of one and part of the remaining kidney or diabetic by administering streptozotocin or both, and then did simultaneous pancreas and kidney (SPK) transplants, kidney transplants alone (KTA), or PTA allografts in rats with one or the other or both afflictions. Uremia was found to delay pancreas graft rejection independent of whether the kidney and pancreas grafts were transplanted together or separately, but this was not the whole explanation for the greater rejection risk for PTA transplants: even without uremia, an SPK pancreas graft was less likely to be rejected. In nephrectomized, or pancreatectomized, or nephrectomized/pancreatectomized pigs (unlike the rat model, done at the time of the transplant, so they were not uremic prior to transplant), the outcome was nearly the same as in the experiments in nonuremic rats: SPK pancreas grafts were rejected later than PTA grafts.157, 158 The original notion of Lillehei et al.102 that there was a hierarchy of rejection susceptibility was confirmed in our series of porcine allograft experiments, with the pancreas being more susceptible to rejection than the kidney.159 Correlative pathology in the porcine allograft model by Nakhleh et al.160 showed that rejection in the pancreas and duodenum is usually but not always concordant, consistent with the clinical observations in dual same-donor transplants that rejection of one organ is not always associated with the rejection of the other organ.100 A historical review of experimental pancreas and islet transplantation in animal models, encompassing a period from the end of the 19th to the beginning of the 21st century, as one section in a single book chapter, cannot do justice to the unique contributions of so many investigators.

History of pancreas transplantation in humans Insulin independence in type 1 diabetic was first achieved on December 17, 1966, when William Kelly and Richard Lillehei (Fig. 1) transplanted a duct-ligated segmental pancreas graft simultaneously with a kidney from a deceased donor into a 28-year-old uremic woman at the University of Minnesota (Fig. 2). The pancreas segment (body and tail) was transplanted extraperitoneally

to the left iliac fossa, with anastomosis of the graft celiac axis to the left common iliac artery. The graft splenic vein was left attached to its junction with the superior mesenteric and portal vein; each was anastomosed end to side to the recipient’s iliac vein with ligation of the intervening segment, converting the donor venous conduit into a bypass graft (Fig. 2), a technique devised by Fred Merkel (also a member of the surgical team) in experiments in dogs to reduce the risk of thrombosis.92 Posttransplant immunosuppression consisted of azathioprine (8 mg/ kg/day tapered to 4 mg/kg/day by day 3) and prednisone slowly tapered from 150 mg/day. Cobalt60 950 rad (300, 200, and 150 rad on consecutive days) was administered to the pancreas graft in an attempt to suppress exocrine function, again based on the experiments of Merkel.101 The objective of the irradiation was not achieved and the recipient’s postoperative course was complicated by a pancreatic fistula requiring open drainage of a­ mylaserich peripancratic fluid at 7  days’ posttransplant. At relaparotomy, the pancreas graft was swollen, and a graft biopsy consisted pancreatitis. The recipient was insulin-free for only 6  days and then needed increasing doses of insulin. On February 14, 1967, the pancreas (along with kidney) was removed. During graft removal, a longitudinal tear in the side of the iliac vein occurred that was repaired but resulted in narrowing of the vessel. Postoperative anticoagulation had to be discontinued because of bleeding, but swelling of the leg improved progressively with bed rest and elevation. However, the recipient died from pulmonary embolism 13  days after pancreas graft removal. Histologically, the pancreas graft was noted to show a moderate mononuclear cell infiltration between lobules of acinar tissue, on occasion within acinar (but not in islet) tissue. Islets also appeared normal in the configuration. This first case exemplified many of the problems that were associated with pancreas transplantation over the following two decades: surgical complications, wound infections, and graft rejection. In that first pancreas transplant, Kelly was the lead surgeon, Lillehei his assistant.91 However, in the second pancreas transplant, on New Year’s Eve 1966, Lillehei was the lead surgeon.91, 161 In that 32-year-old recipient, the donor’s whole pancreas and attached duodenum were transplanted extraperitoneally to the left iliac fossa. (As with the first transplant, the kidney was transplanted extraperitoneally to the recipient’s right iliac fossa.) The donor’s celiac axis and superior mesenteric artery on a small cuff of the aorta were anastomosed end-to-side to the left common iliac artery, and the portal vein was anastomosed end-to-side to left common iliac vein. The proximal duodenal end was closed blindly and the distal end (duodenum with the first portion of the jejunum) was brought out as a cutaneous graft duodenostomy-jejunostomy.

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History of pancreas transplantation in humans

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FIG. 1  First page of the original article on the first two pancreas transplants performed by William Kelly and Richard Lillehei at the University of Minnesota.91

Immunosuppressive therapy consisted of azathioprine and prednisone (as for the first recipient), but no posttransplant graft irradiation was administered. The second time, a more prolonged state of pancreas graft function was achieved. But, rejection treatment (consisting of prednisone boluses and graft irradiation) had to be instituted 3 and 8 weeks posttransplant. During both rejection episodes, the graft duodenum was affected: It showed superficial erosions, with some intermittent bleeding; histologically, the tips of the villi were sloughed, but they regrew with recovery from rejection. The recipient was on insulin when she died 4.5 months posttransplant from sepsis. Of interest, between the first and

second transplants, significant changes in surgical technique had been made pertaining to graft size (segmental vs whole organ) and duct management (duct ligation vs cutaneous duodenostomy). In part, these changes were based on the experimental work conducted in Kelly‘s and Lillehei’s laboratories at the time. Kelly was the senior author on the publication describing these two first recipients.91 The second case (pancreaticoduodenal) was redescribed separately, with Lillehei as the lead author, in the next volume of the same journal within the context of pancreas and bowel transplantation.161 Lillehei performed a total of 13 pancreas transplants,17, 102 the last on January 11, 1973.102 In publications on his

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1.  History of pancreas transplantation

FIG. 2  Schematic drawing of the first pancreas transplant.91

personal series, he numbered his cases 1–13 and gave the 0 to the first institutional case (done by Kelly). This first series addressed most aspects of pancreas transplantation that were still discussed until the turn of the millennium, such as the management of the exocrine secretions and type of graft. In his first four transplants, Lillehei managed the exocrine secretion with a cutaneous graft duodestomy; in the next 8, with internal exocrine drainage using a Roux-en-Y duodeno-jejunostomy (Fig.  3); and the 13th and last, with only the papilla of Vater retained for anastomosis to the recipient’s bowel.102 He initially chose external (over internal) drainage, to enable early detection of graft rejection (by direct observation of the duodenal mucosa and measurements of the volume of exocrine secretion) and to avoid the risk of an anastomotic leak. After experimental studies in his laboratory using the

FIG. 3  Technique of pancreaticoduodenal transplant via Roux-en-Y loop according to Lillehei.17

dog model showed that internal drainage could be done safely, he clinically introduced enteric drainage via a Roux-en-Y loop.17 Regarding graft size, both Kelly and Lillehei thought that transplanting a segment (body and tail) was simpler and faster, but associated it with a higher risk of leakage of pancreatic juice and a reduction in the number of islets. Transplantation of the whole pancreas and duodenum was perceived as technically more difficult and associated with a higher output of exocrine secretions. Other technical aspects of that first series of 13 pancreas transplants are still valid today. Lillehei anastomosed the whole pancreaticoduodenal allograft in the recipients iliac fossa and restored the blood supply by anastomosing the donor aortic cuff (containing the celiac axis and superior mesenteric artery of the graft) to the side of the recipient’s common or external iliac artery and anastomosing the end of the donor’s portal vein to the recipient’s common iliac vein. Indeed, the technique he employed in his 5th through 12th cases is nearly identical to contemporary methods of pancreaticoduodenal transplantation with enteric drainage. Regarding the recipient category, of those first 13 pancreas transplants, 9 were done with a simultaneous kidney transplant (SPK category); 4 were done without a kidney (PTA category). Interestingly, most complications were associated with the kidney graft: First, kidney rejection occurred in almost all SPK recipients without evidence of pancreas graft rejection. This issue of synchronous vs dyssynchronous rejection episodes was later studied extensively, both experimentally and clinically.159, 162–165 Yet, Lillehei had already proposed a “hierarchy” of rejection, according to which the pancreas was less antigenic than the kidney and also less antigenic than the duodenum.17 Second, most of the recipient deaths in this series resulted from problems with the kidney graft; in only one recipient was the pancreaticoduodenal graft the cause of death. Because most of the complications in the SPK group were associated with the kidney graft, Lillehei postulated that doing PTA would greatly reduce morbidity and mortality. He further postulated that PTA would allow researchers to study whether or not a normally functioning pancreas can “influence the course of the characteristic vascular lesions of diabetes mellitus.”17 None of the pancreas graft in this early series functioned for more than 1 year and only three grafts functioned for 5–12  months. But, Kelly and Lillehei had proven the technical feasibility of the procedure. And, insulin independence had been established and maintained for up to 1 year. Worldwide after those first four pancreas transplants at the University of Minnesota, the next four transplants (May through September 1968) were performed in South America,104, 166, 167 three in Brazil (one at the University

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History of pancreas transplantation in humans

of Rio de Janeiro, two at the University of Sao Paulo) and one in Argentina (Buenos Aires Hospital). Of those four South American solitary pancreas grafts, only one functioned for 4 months, but it was subsequently lost to rejection.104 In 1969, two other US institutions performed one SPK transplant each: one at the University of Colorado (Merkel and Starzl) and one at the University of California, Irvine Medical Center (Connolly).104, 168 The first pancreas transplant in Europe (along with a kidney transplant) was performed in 1972 at Guys Hospital in London.10 Until December 31, 1970, only 25 pancreas transplants had been performed at six institutions worldwide. Twothirds of that early pancreas transplant experience was done along with a simultaneous kidney transplant and one-third (in nonnumeric patients) without. Exocrine secretions had been handled by duct ligation, cutaneous duodenostomy, or enteric drainage using a Roux-en-Y loop. Of these 25 grafts, only one (from Lillehei’s original series) functioned for almost 1 year and none for more than 1  year. Of the 25 recipients (9 PTA, 16 SPK), only six (5 PTA, 1 SPK) survived for more than 1 year. Thus, morbidity was significantly higher for SPK recipients. During the 1970s, however, SPK mortality rates began to steadily decrease, but lower rates remained associated with the PTA (vs SPK) category.169 On November 24, 1971, the first pancreas transplant using urinary drainage via the native ureter was performed by Marvin Gliedman at Montefiore Hospital in New York. In 1973, Gliedman et al. published the results of four segmental pancreas transplants in which the pancreatic duct had been anastomosed to the recipient’s ipsilateral native ureter.106 Gliedman introduced this technique “to avoid an intraperitoneal procedure, transplantation of the duodenum, a small-bowel anastomosis, or a continuing external pancreatic fistula.” Gliedman and associates performed a total of 11 ureteral-drained pancreas transplants in the early1970s,170 8 in uremic patients: three received SPK transplants; in five, the pancreas was grafted prior to a kidney transplant. Of this series, one graft functioned for 22  months, another for 50 months until then, the longest pancreas graft survival recorded.171 However, ureteral drainage did not find widespread application because of the tenuous ­leakage-prone duct-to-ureter anastomosis, leakage from the pancreas cut surface, and the need for ipsilateral native nephrectomy in some cases. Interestingly, Merkel et al. in 1973 reported a segmental PTA with end-to-side ductoureterostomy without the need to sacrifice the kidney in a nonnumeric diabetic recipient.172 By the mid-1970s, it was recognized that the management of exocrine pancreatic secretions with the drainage techniques of that time remained a major cause of graft failure from leakage. Thus, two new techniques were

15

i­ ntroduced in the mid and late 1970s: open drainage and duct injection. As with duct ligation, enteric drainage, and ureteral drainage before, the two new techniques had been extensively studied in large-animal models and appeared promising, Open-duct drainage (in contrast to duct ligation) preserves the function of exocrine pancreatic tissue, and pancreatic secretions are absorbed by the peritoneum if the enzymes are not activated (without opening the bowel there is no exposure to the main activating enzyme, enterokinase; although tissue thromboplastin is a weak activator, once activated the enzymes are autocatalytic). Key to a successful outcome is preventing intra-abdominal contamination at the time of the transplant. The first two open-drained pancreas transplants were performed on February 3, 1976, by Bewick at Guys Hospital in London104 and on July 25, 1978, at the University of Minnesota.123 The latter recipient lived for 18 years until she was thrown off a horse and died with a functioning graft.173 In 1978, Dubernard et al. reported on a technique in which the pancreatic duct of the segmental pancreas graft was injected with neoprene, a synthetic polymer (Fig. 4). Various synonyms such as duct obstruction and duct occlusion have subsequently been used, but duct injection best describes the purpose of this technique. Before its clinical use, duct injection was studied in dogs: Progressive fibrosis of the pancreatic tissue was demonstrated, yet the islets usually remained vascularized and functioned for prolonged periods of time. The first transplant using duct injection was performed on October 22, 1976, fittingly in Lyon, the city of Claude Bernard, who more than a century earlier had injected paraffin into animal pancreases and showed that diabetes did not occur despite the glandular atrophy induced.2 By the end of the 1970s and during the early 1980s, duct injection became the most common technique for drainage of exocrine secretions, in particular in Europe. Yet, the number of pancreas transplants remained small. One of the most important workshops facilitating the development of pancreas and islet transplantation was held in Lyon in March 1980. The workshop was organized by Max Dubernard and Jules Traeger,174 and virtually every pancreas or islet transplant done to date was scrutinized. It was also the beginning of the International Pancreas and Islet Transplant Registry (IPTR). By the time of the first report of the IPTR summarizing the results of the Lyon meeting in March 1980, only 105 pancreas transplants had been performed worldwide: 53 in the United States and 52 outside of the United States (mainly in Europe).175 The most active centers at that time in the United States were the University of Minnesota in Minneapolis and Montefiore Hospital of the Albert Einstein College of Medicine in New York; in Europe, Huddinge Hospital in Stockholm, Sweden, and the Hospital Edouard Herriot in Lyon, France. After the

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1.  History of pancreas transplantation

FIG. 4  First page of the original article by Dubernard et al. on the use of duct-injection for segmental transplants.113

Lyon meeting, pancreas transplant activity rapidly increased.104 The ongoing debate on the optimal surgical technique for managing pancreatic exocrine secretions was exemplified by those institutions: In the late 1970s, the technique being used at the University of Minnesota was open drainage; at Montefiore Hospital, ureteral drainage; at Huddinge Hospital, enteric drainage; and at the Hospital Eduard Herroit, duct injection.101 Clearly, the most suitable technique had not been identified, and the quest for a less complications-prone technique continued. Segmental grafts were favored by most at the time, based on the perception that the complications Lillehei described were related to the duodenum, although a critical examination of his cases showed that the majority of complications were related to the kidney graft.102 In 1983, Hans Sollinger at the UW reported on a technique that over the next decade in one variation or another became the most used method for managing pancreatic exocrine secretions: bladder drainage176 (Fig.  4). In essence, it is an extension of the concept of urinary drainage originally introduced by Gliedman,106 but using the bladder for direct anastomosis of a segmental graft was technically easier.176 After developing

the technique in dogs,107 Sollinger et al. reported an initial series of 10 bladder-drained pancreas transplants (9 SPK) in 1984.108 The first clinical pancreaticocystostomy was performed at the UW on June 30, 1982 (according to IPTR data, the 225th documented pancreas transplant).169 Sollinger and others later incorporated the modification of Nghiem and Corry177 of whole ­pancreaticoduodenal transplantation with a secure duodenocystotomy. Sollinger et al. rapidly accumulated a large experience and in 1988 reported an extremely low incidence of surgical complications (in particular a low leak rate) with bladder drainage.178 In the initial clinical publication on the technique in 1984, Sollinger et al. stated that “a significant decrease in urinary amylase might be a sensitive indicator for earlier pancreatic rejection,”108 and Prieto et al. later showed his hypothesis to be correct.179 Urinary drainage began with segmental pancreas transplants, first to the ureter106 and then to the bladder,108 and was further modified for whole-pancreas transplants. In 1985, Gil-Vernet et  al., from Barcelona, described a urinary drainage technique in which the papilla of Vater of a whole-organ graft was anastomosed to the recipient’s ipsilateral ureter (pancreaticoureterostomy),180 preparing the graft as described by Lillehei

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History of pancreas transplantation in humans

for his last clinical case (enteric drainage).102 The technique did not become popular, probably for the same reasons that Gliedman’s ureteral drainage had not been adopted as a routine procedure by other transplant centers. In 1987, Nghiem and Corry177 at the University of Iowa described the technique of bladder drainage via a graft-to-recipient duodenostomy for whole pancreaticoduodenal grafts (Fig.  5), preparing the donor organ as described by Lillehei for his first 12 cases.17, 102 They pointed out that the “anastomosis from the duodenum to

17

the bladder is safer than the duodenojejunostomy, since the leak can easily be controlled by reoperation, whereas a gastrointestinal leak would be catastrophic”177 They also noted that the use of the duodenum (instead of the duct of Wirsung) for anastomosis would avoid stenosis. Bladder drainage via the graft duodenum was quickly adopted by most US centers; it was the predominant surgical technique for managing pancreatic exocrine secretions well into the mid-1990s, as documented by annual IPTR reports.181 For SPK transplants, the dominant

FIG. 5  First page of the original article of bladder drainage for pancreaticoduodenal transplants by Nghiem and Corry.178

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1.  History of pancreas transplantation

r­ eason to use bladder drainage was for safety, since rejection could be monitored by serum creatinine levels. But, for solitary pancreas transplants, bladder drainage had the advantage of urine amylase monitoring for rejection. The IPTR analyses consistently showed a significantly lower graft loss rate from rejection for bladder-than ­nonbladder-drained solitary pancreas transplants in the late 1980s and early 1990s.181 In Europe, duct injection and enteric drainage remained the predominant surgical techniques in the late 1980s, in part because nearly all transplants were SPK and the surgical techniques were refined. The Stockholm group reported that for segmental grafts, using a Roux-en-Y loop for the pancreaticoenteric anastomosis and a pancreatic duct catheter for temporary protection, the complication rate was lowered.182, 183 Nevertheless, a pancreatic ductoenterostomy is an inherently complication-prone procedure, and every surgeon recognizes that an enteroenterostomy is technically easier and more secure. Thus, in 1984, Starzl et  al.184 reintroduced the technique of enteric-drained whole-organ pancreaticoduodenal transplants as originally described by Lillehei.17 Nearly everyone was convinced that whole-organ pancreaticoduodenal transplants were preferable for transplants from deceased donors, and methods for reconstructing the vasculature to both organs after liver and pancreas procurement were devised by the community of transplant surgeons and a pancreatic duct catheter for temporary protection, the complication rate was lowered.185–187 The Stockholm group continued to do enteric drainage but by direct duodenoenterostomy.188 The Lyon group also adopted the whole-organ pancreaticoduodenal technique,189 comparing bladder drainage as described by Nghiem and Corry with enteric drainage as described by Lillehei and Starzl. At the University of Minnesota, whole pancreaticoduodenal transplants were also resumed after the Starzl report,190 with bladder drainage preferred for solitary and enteric drainage for SPK transplants.173, 191 From the mid-1980s to the mid-1990s, bladder drainage became the most common technique worldwide, for SPK transplants because of its safety, for PTA for this reason and because a decrease in urine amylase activity could be used as a sensitive, if nonspecific, marker of rejection that preceded hyperglycemia by several days.192–194 IPTR analyses consistently showed higher survival rates or a lower incidence of rejection failure for bladder than for enteric-drained solitary pancreas transplants. As a result of the improvements in pancreas transplantation and renewed interest in islet transplantation in the early 1990s, the International Pancreas and Islet Transplantation Association (IPITA) was incorporated in 1993, formed as the result of successive congresses held in Stockholm in 1988,195 Minneapolis in 1989,196 and Lyon in 1991.197

The late 1990s then saw a shift again from bladder to enteric drainage, in particular, for SPK transplants.181 Enteric drainage is a more physiologic way to drain pancreatic exocrine secretions, and improvements in antimicrobial and immunosuppressive therapy reduced the risks of complications as well as rejection. In addition, the chronic complications of bladder drainage (e.g., urinary tract infections, hematuria, acidosis, and dehydration) led to the need for enteric conversion in 10%–15% of bladder-drained recipients.181 The first successful conversion from the bladder to enteric drainage was reported by Tom et al.198 from the University of Cincinnati in 1987. Either enteric or bladder drainage is now done for virtually all pancreas transplants. The other techniques whose historical account is given above—in order applied, duct ligation, graft duodenostomy, ureteral drainage, duct injection, and open duct-drainage—are virtually never used unless for salvage of a technical situation (e.g., duct injection might be used to manage a leak). Other techniques that were used in only a few cases should also be mentioned: gastric drainage as described by Calne et al.199 in 1984 and used in a few cases by Tyden et  al.200; and drainage via the recipient gallbladder as reported by Helmut Wolfe from Berlin in the 1980s (personal communication). In regard to venous drainage of pancreas grafts, the portal would be the most physiological but from the first cases of Kelly and Lillehei91 until Calne reported using the recipient splenic vein as the outflow for a gastric-duct-drained segmental pancreas graft venous effluent in 1984,200 the systemic venous system was accessed. Following Calne’s case,199 other groups drained segmental grafts into the portal system, specifically the superior mesenteric vein in Stockholm,200 the splenic vein in Barcelona,180 and the inferior mesenteric vein at the University of Minnesota.201 The first whole-organ pancreaticoduodenal transplant drained via the portal circulation was reported by Mühlbacher from the University of Vienna, Austria, in 1989.202 He described a unique technical modification in which the distal end of the donor splenic vein was anastomosed to the recipient portal vein. Using the distal end of the donor’s splenic vein allowed drainage of the pancreas via the duodenum into the bladder. Like many other creative surgical modifications in pancreas transplantation, the combination of portal venous and bladder drainage never found widespread application. In 1992, Rosenlof et  al. from the University of Virginia203 and Shokou-Amri et  al. from the University of Tennessee204 described the use of portal drainage at the junction of the recipient’s superior and splenic veins in recipients of enteric-drained whole-organ pancreaticoduodenal transplants. Subsequently, Gaber et  al. reported on a large series of cases from the University of

A.  Whole pancreas allo-transplantation



History of pancreas transplantation in humans

Tennessee,205 touting its metabolic and possible immunologic advantages, features also noted at the University of Maryland, another large program that at the time converted to doing portal drainage almost exclusively.143 By the end of the 1990s ~20% of pancreas transplants in the United States were being done with portal drainage but the proportion did not increase nearly as much as the proportion of pancreas grafts that are enteric drained, to over 50% for solitary and over 70% for SPK transplants.206 As the 20th century came to an end, enteric and systemic venous drainage were the most commonly used techniques worldwide. The issue of whether to use a segmental or a whole-organ pancreas graft has also evolved over time. Most transplants in the late 1960s and early 1970s were whole-organ grafts. Segmental transplants became more common in the late 1970s and early 1980s. Since the mid1980s, whole-organ transplants with a duodenal segment (rather than a duodenal button or patch) have been standard. Segmental transplants have not completely disappeared but are primarily used with living donors (LDs). Pancreas transplants with LDs began at the University of Minnesota in the late 1970s207 and have been done in all three recipient categories.121, 208 The first LD pancreas after kidney (PAK) transplant was performed on June 20, 1979, the first LD PTA on May 14, 1980, and the first LD SPK transplant on March 10, 1994. All three firsts were at the University of Minnesota, the same institution where LD laparoscopic distal pancreatectomy was introduced in 2001.209 As an aside, recurrence of autoimmune isletitis in pancreas grafts with selective destruction of β-cells in the absence of rejection was first described at the University of Minnesota in 1984 for segmental transplants from LDs,210 either from an HLA-identical sibling to a minimally immunosuppressed recipient or from an identical twin to a nonimmunosuppressed recipient.211 These seminal transplants provided critical evidence that type 1 diabetes is an autoimmune disease. In subsequent identical twin segmental pancreas transplants, isletitis were prevented by immunosuppression.212 These subsequent twin and HLA-identical transplants were equally pivotal not only to our understanding of the autoimmune nature of the disease but also to its potential prevention. The level of immunosuppression to prevent autoimmune recurrence of disease is probably less than that necessary to prevent rejection in most pancreas allograft recipients, but not in all, as demonstrated by the occurrence of selective total loss of β-cells in two allografts removed by Tyden et  al. in Stockholm, long after recurrence of diabetes.213 Most likely, isletitis had been present but resolved once the antigenic stimulant (β-cells) had been eliminated. When it becomes possible to induce specific immune tolerance to donor alloantigens and eliminate immunosuppression to prevent

19

rejection, it may still be necessary to immunosuppress to prevent recurrence of disease, unless the strategy to induce allo-tolerance also restores self-tolerance. The Tyden213 observation was subsequently confirmed by George Burke214 who found that with over 25  years of follow-up, 6%–8% of SPK recipients developed autoimmune recurrence of disease and conversion of type 1 diabetes associated autoantibodies such as GAD65, IA-2, and ZnT8. Burke also noted that no therapeutic regimen so far has controlled the progression of islet autoimmunity, even when additional immunosuppression was added to the ongoing chronic regimens. One other technical modification that relies on transplanting segmental grafts is the split pancreas procedure. In 1988, a cadaver pancreas graft was split into two segments (head and body-tail) and successfully transplanted in two recipients with negative cross-matches to the donor despite high panel-reactive alloantibody levels.215 The split-pancreas procedure preceded the now common split-liver procedures by 1 year. Besides the use of LDs for SPK transplants to facilitate achievement of insulin independence as well as a dialysis-free state in a nephropathic diabetic, for a recipient whose LD can or is willing only to give a kidney, an SPK transplant can still be done. Each organ would come from different donors, either fortuitously having a deceased donor pancreas available at the time of a scheduled LD kidney transplant, as was first done at the University of Minnesota in the 1980s,191 or with the LD kidney donor on call to come in when a deceased donor pancreas becomes available for the recipient. A relatively large series in the latter category was reported by Farney et al. from the University of Maryland in 2000.216 Refinements in surgical techniques have been critical not only to the development of pancreas transplantation but also to improved outcome. Unlikely in kidneys transplantation, discussion of surgical techniques in pancreas transplantation dominated the seminars organized to forward the field in the first decades that followed the first case. After standardization of surgical techniques in the 1980s and 1990s, robotic procedures were introduced to the field of pancreas transplantation after the new millennium. Following the first report of a laparoscopically performed simultaneous distal pancreatectomy and nephrectomy in a LD,209 the same procedure was performed in 2007 using the DaVinci robotic system.217 Boggi subsequently reported on the first robotic-assisted pancreas transplant.218 But aside from the progress in refining the surgical procedures, progress in the field of multiorgan donor procurement was critical as were improvements in the diagnosis and treatment of rejection, advances in immunosuppressive protocols for induction and maintenance therapy, and antimicrobial prophylaxis and treatment, all of which evolved over time.

A.  Whole pancreas allo-transplantation

20

1.  History of pancreas transplantation

Early diagnosis of pancreas rejection had been difficult from the beginning, in particular for solitary pancreas transplants where serum creatinine could not be used as a surrogate marker. In SPK same-donor transplants, serum creatinine could be used as a marker, because rejection usually (there were exceptions219) involved both organs and usually manifested in the kidney first. For solitary pancreas transplants, rejection was more difficult to diagnose because hyperglycemia was such a late event, occurring only after a substantial proportion of β-cells were destroyed. Clinical parameters in pancreas rejection (e.g., fever and graft tenderness) were no more specific or likely to occur than in kidney rejection, where many rejection episodes are silent and manifested solely biochemically until advanced. The ordinary laboratory tests were either late indicators of rejection (e.g., plasma glucose) or nonspecific and not always manifest (e.g., serum amylase and lipase). The introduction of bladder drainage resulted in a better marker for rejection: urine amylase. Both experimental and clinical models showed that hypoamylasuria preceded hyperglycemia by several days, thus creating a therapeutic window to successfully reverse the rejection episode.100, 179 In fact, 85% of rejection episodes were reversible when based on the occurrence of hypoamylasuria. As for other solid-organ transplants, graft biopsy has been the gold standard for diagnosing rejection right from the beginning. But, in pancreas transplantation, graft biopsies when they began to be done at the University of Minnesota in the early 1980s were by laparotomy,220 a deterrent to an aggressive pursuit of tissue sampling. The use of imaging techniques and other maneuvers largely eliminated the need for laparotomy to obtain pancreas graft tissue. In 1990, James Perkins from the Mayo Clinic described a cystoscopic transduodenal biopsy technique.111 In 1991, Richard Allen from Westmead Hospital, Sydney, Australia, described an ultrasound-guided percutaneous biopsy technique for bladder-drained pancreas transplants.221 In 1992, Osama Gaber at the University of Tennessee described computed tomography (CT)-guided percutaneous biopsy for bladder- or enteric-drained pancreas transplants,222 a procedure now used routinely.223 On occasion, these maneuvers fail. Thus, in 1996 a laparoscopic pancreas graft biopsy technique was described at the University of Minnesota.224 Percutaneous ultrasound or CT-guided biopsies have now become the gold standard for tissue diagnosis in pancreas transplantation. Both the cytoscopic approach (limited to bladder-drained transplants and now rarely done) and the laparoscopic approach require general (or regional) anesthesia and shortterm hospitalization. Following the lead in kidney transplantation, standardized guidelines for the diagnosis and grading of pancreas allograft rejection were introduced as Banff criteria in 2008225 and further refined in 2011.226

Advances in immunosuppressive protocols and the introduction of new immunosuppressants have had a major impact on improved outcome after pancreas transplants. The introduction of the calcineurin inhibitors (cyclosporine in the 1980s and tacrolimus in the 1990s) significantly increased the number of pancreas transplants. In 1979, Calne et  al. first reported the successful use of cyclosporine in two pancreas recipients (one simultaneously received a kidney and the other one a liver).227 In the early 1980s, maintenance immunosuppressive regimens were shifted from dual (azathioprine and steroids) to triple (cyclosporine-based) drug therapy.228 Triple-drug therapy was the most common according to IPTR analyses until tacrolimus and mycopehenolate mofetil were Food and Drug Administration (FDA)-licensed in the mid-1990s.181 Starzl et al. first reported the use of tacrolimus in pancreas allograft recipients during the investigative period in 1989.229 After FDA approval, the first report on the use of tacrolimus for pancreas transplantation was by Shaffer et  al., successfully receiving ongoing acute rejection in two SPK recipients.230 Perceived as having greater potency and better absorption in diabetic recipients, tacrolimus has been the predominant calcineurin inhibitor used in pancreas transplants. By the late 1990s, over 80% of all pancreas recipients worldwide were on tacrolimus-based maintenance immunosuppressive regimens.181, 231 Likewise, in the mid-1990s mycophenolate mofetil replaced azathioprine (the mainstay immunosuppressant or coimmunosupressent for more than three decades).232 The combination of tacrolimus and mycophenolate motefil became the most popular maintenance therapy regimen for pancreas transplant recipients,233 but sirolimus, albeit much less commonly, is also being used in pancreas recipients.206 Induction therapy with anti-T-cell preparations to prevent early pancreas rejection was used in some of the first cases according to information in the IPTR database.169 Polyclonal antibodies were first used for US pancreas recipients in 1970 and outside the United States (Argentina) in 1968. Monoclonal antibody therapy (OKT3) was first used for US pancreas recipients in 1985 and outside the United States (Czechoslovakia) in 1983. After the advent of cyclosporine, quadruple immunosuppression (induction therapy plus three-drug maintenance) quickly became popular worldwide.169 In the late 1990s, the spectrum of antibody induction therapy for pancreas recipients was expanded to those directed against the interleukin-2 receptor and the CD 52 antigen marker. The last decade saw the introduction of new antibodies in pancreas transplantation such as alemtuzumab (for induction therapy and calcineurin inhibitor-free maintenance therapy),234 belatacept (to avoid calcineurin inhibitor toxicity),235 rituximab,236 and bortezomib237 (for the treatment of antibody-mediated

A.  Whole pancreas allo-transplantation



References

rejection), and eculizumab (for the treatment of calcineurin inhibitor-induced hemolytic syndrome and ABOincompatible transplants).238, 239 The history of pancreas transplantation is also intertwined with the study of secondary complications of diabetes. Before the diabetes control and complications trial (DCCT) was completed,240 a favorable impact of successful pancreas transplantation (euglycemia) on diabetic complication was shown, including on neuropathy,241–246 to a lesser extent retinopathy,247 nephropathy in both transplanted,248–250 and native251 kidneys, microcirculatory disorders,252 and atherosclerotic risk factors.253, 254 Several groups found that addition of a pancreas improves survival probabilities of uremic diabetes over and above that of transplanting a kidney alone,255–258 and a successful PTA was also associated with improved survival probabilities in neuropathic diabetics,246, 259 Studies in the 1980s showed that the pancreas recipients perceived the quality of their lives to be better when nondiabetic on immunosuppression than when they were nonimmunosuppressed but diabetic.260, 261 As of 2018, more than 50,000 pancreas transplants worldwide have been reported to the IPTR244 and >30,000 from the United States alone.262–265 The most recent IPTR data also show that since the beginning of the new millennium, enteric and systemic venous drainage are the most commonly used surgical techniques. Bladder drainage, portal venous drainage and segmental transplants are rarely performed procedures.266 Likewise, HLA typing has lost its importance and most pancreas transplants are actually performed without HLA consideration with the exception of donor-specific antibodies.262–266 The concept of quadruple immunosuppression for induction therapy and triple immunosuppression for maintenance therapy has not changed since the introduction of tacrolimus and mycophenolate mofetil. The initial excitement about using steroid-free protocols and the use of sirolimus has waned.262–264 The greatest challenge nowadays for pancreas transplantation is the lack of support for the procedure itself.267, 268 Since 2004, the number of pancreas transplants has decreased despite significant improvements in outcome specifically for solitary pancreas transplants.269–272 Despite the overall declining numbers, pancreas transplants have seen an increase in type 2 diabetic patients with end-stage renal disease and in African Americans.264–266, 273 Except for a small number of transplants with good long-term function in very selected recipients, the results of islet transplantation still continue to significantly trail those of pancreas transplantation.266 Moreover, pancreas transplantation has become a viable treatment option for recipients of a failed islet transplant with excellent longterm outcome.274 Pancreas transplantation is also an option for diabetic patients after total pancreatectomy for

21

chronic pancreatitis to cure both endocrine and exocrine deficiency.275 Modern devices for exogenous insulin administration have seen progress, but establishing normoglycemia and cessation of the progression of secondary diabetic complications still remain elusive goals. At the time of this writing, pancreas transplantation is the only cure for insulin-dependent diabetes mellitus with excellent longterm results.

Acknowledgments Parts of this chapter were previously published in Transplantation of the Pancreas. Gruessner RWG, Sutherland DER (editors). Chapter  4, pp. 39–68. Springer, New York, 2004. The authors thank Mrs Paula Lopez for transcription services.

References 1. von Mering  J, Minkowski  O. Diabetes mellitus nach Pancreasextirpation. Arch Exp Pathol Pharmakol. 1890;26:371–387. 2. Willams  PW. Notes on diabetes treated with grafts of sheep’s pancreas. Br N Med J. 1894;19:1303–1304. 3. Minkowski  O. Weitere Mitteilung über den Diabetes Mellitus nach Exstirpation des Pankreas. Berl Klin Wchnshr. 1892;29:90–94. 4. Hedon E. Greff sous-cutanee du pancreas: ses resultants au point de vue de la theorie du diabete pancreatique. C R Soc Biol (Paris). 1892;44:678–680. 5. Laguesse  GE. Sur la formation des ilots de Langerhans dans le pancréas. Comp Rend Soc Biol. 1893;5:819. 6. Langerhans  P. Beiträge zur Mikroskopischen Anatomie der Bauchspeicheldrüse, Inaugural Dissertation. Berlin: G Lange; 1869. 7. Laguesse E, de la Roche AG. Les ilots de Langerhans dans le pancreas du cobaye âpre. C R Sos Biol. 1902;54:854. 8. Wellman KF, Volk BW. In: Volk BW, Wellman KF, eds. The Diabetic Pancreas. New York: Plenum Press; 1977:1–14. 9. Diamare V. Studii comparativi sulle isole di Langerhans del pancreas. Int Machr Anat Physiol. 1899;16:155–209. 10. Schulze  W. Die Bedeutung der Langerhans’schen Inseln im Pankreas. Arch Mikros Anat Entwick. 1900;56:491. 11. Ssoblowe LW. Zbl Allg Path Path Anat. 1900;11:202. 12. Opie EL. The relation of diabetes mellitus to lesions of the pancreas. Hyline degeneration of the islands of Langerhans. J Exp Med NY. 1900;1:527–540. 13. Lane WA. The cytological characters of the areas of Langerhans. Am J Anat. 1907;7:409–421. 14. Homans J. Proc Roy Sos London B. 1913;86:73. 15. Lancereaux E. Le diabete maigre: Ses symptoms son evolution, son protonic et son traitment. Union Med Paris. 1880;3(29):161–167. 205–211. 16. Banting  FG, Best  CH, Collip  JB, et  al. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assos J. 1922;12:141. 17. Lillehei RC, Simmons RL, Najarian JS, et al. Pancreatico-duodenal allotransplantation: experimental and clinical experience. Ann Surg. 1970;172:405–436. 18. Cryer PE. Banting lecture. Hypoglycemia; The limiting factor in the management of IDDM. Diabetes. 1994;43:1378–1389. 19. Busnardo  AC. History of the pancreas. Am J Surg. 1983; 146:539–550. 20. Child CC. History of pancreatic surgery. In: Toledo-Pereyra LH, ed. The Pancreas. Principles of Medical and Surgical Practice. New York: John Wiley & Sons; 1985:1–29. 21. Papaspyros  NS. Bibliography on the History of Diabetes. 2nd ed. Stuttgart: Georg Thieme Verlag; 1964.

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51. Banting FG, Best CH. The internal secretion of the pancreas. J Lab Clin Med. 1922;7:251. 52. Barron  M. The relation of the islets of Langerhans to diabetes with special reference to cases of pancreatic lithiasis. Surg Gynecol Obstet. 1920;31:438–448. 53. Collip J. The original method as used for the isolation of insulin semipure form for the treatment of the first clinical case. J Biol Chem. 1923;55:40–41. 54. Von Meyenburg  H. Über “Insulitis” bei Diabetes. Schweiz Med Wochenschr. 1940;24:554–556. 55. Le Compte PM. “Insulitis” in early juvenile diabetes. Arch Pathol. 1958;66:450–457. 56. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965;14:619–633. 57. Nerup J, Andersen OO, Bendixen G, et al. Cell-mediated autoimmunity in diabetes mellitus. Proc Roy Soc Med. 1974;67:506–513. 58. Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974;2:1280–1283. 59. Nerup J, Andersen O, Christy M, et al. HL-A antigens and diabetes mellitus. Lancet. 1974;2:1280–1283. 60. Nakhooda AF, Like AA, Chappel DVM, Murray FT, Marliss EB. The spontaneously diabetic Wistar rat. Diabetes. 1976;26:100–111. 61. Makino  S, Kunimoto  K, Muraoka  Y, Mizushima  Y, Katagiri  K, Tochino Y. Breeding of a non-obese diabetic strain of mice. Jikken Dobutsu. 1980;29:1–13. 62. Naji  A, Bellgrau  D, Anderson  AO, Silvers  WK, Barker  CF. Transplant of islets and bone marrow cells to animals with immune insulitis. Diabetes. 1990;31(suppl 4):84–89. 63. Sutherland  DER, Sibley  RK. Recurrence of disease in pancreas transplants. In: Van Schilfgaarde  R, Hardy  MA, eds. Transplantation of the Endocrine Pancreas. Amsterdam: Elsevier Science; 1988:60–66. 64. Carrel A. The transplantation of organs: a preliminary communication. JAMA. 1905;45:1645–1646. 65. Hedon E. Arch Int Physiol. 1913;13:255–257. 66. Hedon  E. Sur la secretion interne du pancreas. C R Soc Biol. 1911;71:124–127. 67. Hedon  E, Giraud  G. La course de la glycemie dans les premieres heures qui suivent la pancreatectomie. C R Soc Biol Paris. 1920;83:330–335. 68. Ivy AA, Farrel JI. Contribution to the physiology of the pancreas: I. Method for subcutaneous auto-transplantation of the tail of the pancreas. Am J Physiol. 1926;77:474–479. 69. Houssay  BA, Molinelli  F-A. La greffe duodeno-pancreatique et son employ pour deceler les descharges d’adrenaline et de secretine dans le sang. C R Soc Biol Paris. 1927;97:1032–1034. 70. Gayet  RC, Guillamie  M. La regulation de la secretion interne pancreatique par un processus humoral, demonstree par des transplantations de pancreas. Experiences sue des animaux depancreates. CR Soc Biol. 1927;97:1615–1618. 71. Houssay  BA. Technique de la greffe pancreaticoduodenale aucou. C R Soc Biol Paris. 1929;100:138–140. 72. Houssay  BA, Lewis  JT, Foglia  VG. Action de la greffe pancreatique sur les variations de la glycemie phoduites par l’injection de glucose. C R Soc Biol. 1920;100:140–142. 73. Payr  E. Beitrage zur technik der blutgefass- und nervennaht nebst mitteilungen uber die verwendung eines resorbirbaren metalles in der chirurgie. Arch Klin Chir. 1900;62:67–93. 74. Houssay BA, Lewis JT, Fogila VG. Influence de l’enervation du pancreas sur les variations de la glycemiei produites par l’injection de glucose. C R Soc Biol. 1929;100:144–145. 75. Gayet R, Guilanmie M. La regulation de la secretion interne pancreatique par un processus humoral, demonstree par des transplantations de pancreas. Experiences sur des animaux normaux. C R Soc Biol Paris. 1927;97:1613–1620.

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125. Baumgartner D, Sutherland D, Heil JE, Kyriakides GK, Najarian JS. Long-term canine segmental pancreas transplants with the duct left open, neoprene-injected duct, and pancreatico-­ureterostomy. A comparative study. Transplant Proc. 1981;13:812–814. 126. Sutherland  DER, Goetz  FC, Elick  BA, Najarian  JS. Experience with 49 segmental pancreas transplants in 45 diabetic patients. Transplantation. 1982;34:330–338. 127. Florak G, Sutherland DER, Cavallini M, Najarians JS. Technical aspects of segmental pancreatic autotransplantation in dogs. Am J Surg. 1983;146:565–574. 128. Sutherland DER, Kaufman D, Nakai I, RWG G. Pancreas and islet allo- and autografts in large and small animal models. Minerva Chir. 1991;46(suppl 1):29–36. 129. Baumgartner D, Illig R, Sutherland DER. Effect of venous drainage to the vena cava and denervation on endocrine function of pancreatic segments in dogs. Transplant Proc. 1984;16:769–772. 130. Florak  G, Sutherland  DER, Heil  JE, Zweber  BA, Najarian  JS. Effect of graft denervation, systemic venous drainage, and reduction of beta cell mass on insulin levels after heterotopic pancreas transplantation in dogs. Surg Forum. 1982;33:351–353. 131. Kanenko G, Barneo L, Toda S, et al. Comparison of allograft survival between orthotopic (portal drained) and heterotopic (systemic drained) segmental pancreas transplants. Transplant Proc. 1989;21:2806–2808. 132. Baumgartner D, Sutherland DER, Heil JE, Squifflet JP, Najarian JS. Long-term preservation of segmental pancreas autographs. Surgery. 1982;92:260–269. 133. Florak  G, Sutherland  DER, Heil  JE, Squifflet  JP, Najarian  JS. Preservation of canine segmental pancreatic autografts: cold storage versus pulsatile machine perfusion. J Surge Res. 1983;34:493–504. 134. Baumgartner D, Hanson SL, Sutherland DER. Endocrine function pancreatic segmental transplants. Eur Surg Res. 1981;13:33–34. 135. Florak  G, Sutherland  DER, Ward  SL, Najarian  JS. Vascularized pancreatic graft: effects of different techniques on endocrine function. Surg Forum. 1984;35:377–379. 136. Florak  G, Sutherland  DER, Hesse  UJ, Ward  SL, Squifflet  JP. Metabolic studies after heterotopic segmental pancreas and intrasplenic islets cell transplantation: a comparison. Transplant Proc. 1986;18:1164–1166. 137. Squifflet JP, Sutherland DER, Ryanasiewicz JJ, Heil JE, Najarian JS. Synergistic immunosuppressive therapy with cyclosporine A and azathioprine. Transplantation. 1982;34:315–318. 138. Squifflet JP, Sutherland DER, Field MHJ, RyanasiewicZ JJ, Heil JE, Najarian JS. Synergistic immunosuppressive effects of cyclosporine A and Azathioprine. Transplant Proc. 1983;15:520–522. 139. Florak  G, Sutherland  DER, Sibley  RK, Najarian  JS, Squifflet  JP. Combined kidney and segmental allotranplantation in dogs. Transplant Proc. 1985;17:374–377. 140. Ruiz JQ, Uchida J, Schultz LS, Lillehei RC. Function studies after auto- and allotransplantation and denervation of pancreaticoduodenal segments in dogs. Am J Surg. 1972;123:236–242. 141. Hanks J, Portal vs systemic venous drainage of the pancreas, Personal communication, Minneapolis, 1983. 142. Martin X, Faure JL, Amiel J, Eloy R, Margonari J, Dubernard JM. Systemic versus portal vein drainage of segmental pancreas transplants in dogs. Transplant Proc. 1980;12(4, suppl 2): 138–140. 143. Philosophe  B, Farney  AC, Schweitzer  E, Colonna  J, Jarrell  BE, Bartlett  S. The superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: a retrospective study. Ann Surg. 2000;234:689–695. 144. Westbroek DL, de Gruyl J, Dkjkhis CM, Hulmans HAM. Twentyfour hour hypothermic preservation perfusion and storage of the duct-ligated canine pancreas with transplantation. Transplant Proc. 1974;6:319–322.

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1.  History of pancreas transplantation

209. Gruessner RWG, Kandaswamy R, Denny R. Laparoscopic simultaneous nephrectomy and distal pancreatectomy from a live donor. J Am Col Surg. 2001;193:333–337. 210. Sutherland DER, Sibley RK, Xu XZ, et al. Twin-to-twin pancreas transplantation: reversal and reenactment of the pathogenesis of type 1 diabetes. Trans Assoc Am Physicians. 1984;97:80–87. 211. Sibley  RK, Sutherland  DER, Goetz  FC, Michael  AF. Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest. 1985;53:132–144. 212. Sutherland DER, Goetz FC, Sibley RK. Recurrence of disease in pancreas transplants. Diabetes. 1989;38:85–87. 213. Tyden G, Reinholt FP, Sundkvist G, Bolinger J. Reoccurrence of autoimmune diabetes mellitus in recipients of cadaveric pancreatic grafts [see comments][published erratum appears in N Engl Med 1996;335(23):1778.] N Engl J Med. 1996;335:860–863. 214. Burke  GW, Vendrame  F, Virdi  SK, et  al. Lessons from pancreas transplantation in type 1 diabetes: recurrence of islet autoimmunity. Curr Diab Rep. 2015 Dec;15(12):121. 215. Sutherland  DER, Morel  P, Gruessner  RW. Transplantation of two diabetic patients with one divided cadaver donor pancreas. Transplant Proc. 1990;22:585. 216. Farney  AC, Cho  E, Schweitzer  EJ. et  al. Simultaneous cadaver pancreas living-donor kidney transplantation: a new approach for the type 1 diabetic uremic patient. Ann Surg. 2000;232:696–700. 217. Horgan S, Galvani C, Gorodner V, et al. Robotic distal pancreatectomy and nephrectomy for living donor pancreas-kidney transplantation. Transplantation. 2007 Oct 15;84(7):934–936. 218. Boggi  U, Signori  S, Vistoli  F, et  al. Laparoscopic robot-assisted pancreas transplantation: first world experience. Transplantation. 2012 Jan 27;93(2):201–206. 219. Gruessner  RWG, Dunn  DL, Tzardis  J, et  al. An immunologic comparison of pancreas transplants alone in nonnumeric patients versus simultaneous pancreas/kidney transplants in uremic diabetic patients. Transplant Proc. 1990;22(4):1581–1584. 220. Sutherland DER, Casanova D, Sibley RK. Role of pancreas graft biopsies in the diagnosis and treatment of rejection after pancreas transplantation. Transplant Proc. 1987;19:2329–2331. 221. Allen RDM, Wilson TG, Grierson JM, et al. Percutaneous biopsy of the bladder-drained pancreas transplants. Transplantation. 1991;51:1213–1216. 222. Gaber  AO, Gaber  L, Shokouh-Amiri  MH, Hathway  D. Percutaneous biopsy of pancreas transplants. Transplantation. 1992;54:548–550. 223. Lafavi MR, Gruessner A, Bland BJ, et al. Diagnosis of pancreas rejection. Transplantation. 1998;30:642–644. 224. West  M, Gruessner  RWG. Laparoscopic biopsy after pancreaticoduodenal transplantation. Transplantation. 1996;62:1684–1687. 225. Drachenberg  CB, Odorico  J, Demetris  AJ, et  al. Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel. Am J Transplant. 2008 Jun;8(6):1237–1249. 226. Drachenberg  CB, Torrealba  JR, Nankivell  BJ, et  al. Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema. Am J Transplant. 2011 Sep;11(9):1792–1802. 227. Calne RY, Rolles K, White DJG, et al. Cyclosporine A initially as the only immunosuppressant in 36 recipients of cadaveric organs: 32 kidney, 2 pancreas, and 2 livers. Lancet. 1979;2:1033. 228. Sutherland  DER, Goetz  FC, Wlick  BA, Najarian  JS. Experience with cyclosporine versus azathioprine for pancreas transplantation. Transplant Proc. 1983;15:2881–2888. 229. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989;2:1000–1004.

230. Shaffer  D, Simpson  MA, Conway  P, et  al. Normal pancreas allograft function following simultaneous pancreas-kidney transplantation after rescuer therapy with tacrolimus (FK506). Transplantation. 1995;59:1063–1066. 231. Gruessner RWG. Tacrolimus in pancreas transplantation: a multicenter analysis. Tarcolimus Pancreas Transplant Study Group. Clin Transplant. 1997;11:229–312. 232. Rayhill  SC, Kirk  AD, Odorico  JS, et  al. Simultaneous pancreas-­ kidney transplantation at the University of Wisconsin. Clin Transplant. 1995;261–269. 233. Gruessner  RWG, Sutherland  DER, Drangstveit  MB, West  M, Gruessner  A. Mycophenolate nofetil and tacrolimus for induction and maintenance therapy after pancreas transplantation. Transplant Proc. 1998;30:518–520. 234. Gruessner  RWG, Kandaswamy  R, Humar  A, Gruessner  AC, Sutherland DE. Calcineurin inhibitor- and steroid-free immunosuppression in pancreas-kidney and solitary pancreas transplantation. Transplantation. 2005;79(9):1184–1189. 235. Mujtaba  MA, Sharfuddin  AA, Taber  T, et  al. Conversion from tacrolimus to belatacept to prevent the progression of chronic kidney disease in pancreas transplantation: case report of two patients. Am J Transplant. 2014 Nov;14(11):2657–2661. 236. Melcher ML, Olson JL, Baxter-Lowe LA, Stock PG, Posselt AM. Antibody-mediated rejection of a pancreas allograft. Am J Transplant. 2006 Feb;6(2):423–428. 237. Govil A, Walsh RC, Tevar A, et al. Bortezomib-based treatment of antibody mediated rejection in pancreas allograft recipients. Clin Transpl. 2009;443–453. 238. Chandran S, Baxter-Lowe L, Olson JL, Tomlanovich SJ, Webber A. Eculizumab for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas-kidney transplantation--a case report. Transplant Proc. 2011 Jun;43(5):2097–2101. 239. Biglarnia  AR, Nilsson  B, Nilsson  T, et  al. Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation. Transpl Int. 2011 Aug;24(8):e61–e66. 240. Diabetes Control and Complications Trial Research Group (DCCT). The effect of intensive diabetes treatment in long term complications in IDDM. N Engl J Med. 1993;329:977–986. 241. Solders  G, Wilczek  H, Gunnarsson  R, Tyden  G, Persson  A, Groth CG. Effects of combined pancreatic and renal transplantation on diabetic neuropathy: a two-year follow-up study. Lancet. 1987;2:1232–1235. 242. Van der Vliet JA, Navarro X, Kennedy WR, Goetz FC, Najarian JS, Sutherland  DER. The effect of pancreas transplantation on diabetic polyneuropathy. Transplantation. 1988;45:368–370. 243. Kennedy WR, Navarro X, Goetz FC, Sutherland DER, Najarian JS. Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med. 1990;322:1031–1037. 244. Navarro X, Kennedy WR, Loewensen RB, Sutherland DER. Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction, and mortality in diabetes mellitus. Diabetes 1990;39:802–806. 245. Solders G, Tyden G, Persson A, Groth CG. Improvement of nerve conduction in diabetic neuropathy: a follow-up study 4  years after combined pancreatic and renal transplantation. Diabetes. 1992;41:946. 246. Navarro X, Sutherland DER, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol. 1997;42:727–736. 247. Ramsay  RC, Goetz  FC, Sutherland  DER, et  al. Progression of diabetic retinopathy after pancreas transplantation for insulin-­ dependent diabetes mellitus. N Engl Med. 1988;208–214. 248. Bohman  SO, Tyden  G, Wilczek  H, et  al. Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man. Diabetes. 1985;4:306–308.

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References

249. Bilous RW, Mauer SM, Sutherland DER, Najarian JS, Goetz FC, Steffes  MW. The effects of pancreas transplantation on the glomerular structure of renal allografts in pancreas with insulin-­ dependent diabetes. N Engl Med. 1989;321:80–85. 250. Wilczek H, Jaremko G, Tyden G, Groth CG. Pancreas graft protects a simultaneously transplanted kidney from developing diabetic nephropathy: a 1 to 6 year follow-up study. Transplant Proc. 1993;25:1314–1315. 251. Fioretto  P, Steffes  MW, Sutherland  DER, Goetz  FC, Mauer  SM. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl Med. 1998;339:69–75. 252. Cheung  AT, Chen  PC, Leshchinsky  TV, et  al. Improvement in conjunctival microangiopathy after simultaneous pancreas-­ kidney transplants. Transplant Proc. 1997;29:660–662. 253. Königsrainer  A, Foger  BH, Miesenbock  G, et  al. Pancreas transplantation with systemic endocrine drainage leads to improvement in lipid metabolism. Transplant Proc. 1994;26: 501–503. 254. Fiorina  P, La Rocca  E, Venturini  M, et  al. Effects of kidney-­ pancreas transplantation on atherosclerosis risk factors and endothelial function in patients with uremia and type 1 diabetes. Diabetes. 2001;50:496–500. 255. Tyden  G, Bolinger  J, Solders  G, et  al. Improved survival in patients with insulin-independent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation. 1999;67:645–648. 256. Smets  YF, Westendorp  RG, van der Pijl  JW, et  al. Effects of simultaneous pancreas-kidney transplantation on mortalily in type 1 diabetic patients with end-stage renal failure. Lancet. 1999;353:1915–1917. 257. Rayhill  SC, D’Alessandro  AM, Odorico  JS, et  al. Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: is there a difference in survival? Ann Surg. 2000;231:417–421. 258. Becker  BN, Brazy  PC, Becker  YT, et  al. Simultaneous pancreas-­ kidney transplantation reduces excess mortality in type 1 diabetic patients with end-stage renal disease. Kidney Int. 2000;57:2129–2133. 259. Navarro X, Kennedy WR, Aeppli D, et al. Neuropathy and mortality in diabetes: influence of pancreas transplantation. Muscle Nerve. 1996;19:1009–1012. 260. Nakache  R, Tyden  G, Groth  CG. Quality of life in diabetic patients after combined pancreas-kidney or kidney transplantation. Diabetes. 1989;38(suppl 1):40–42. 261. Zehrer CL, Gross CR. Quality of life of pancreas transplant recipients. Diabetologia. 1991;34(suppl 1):S145–S149. 262. Gruessner  AC, Gruessner  RW. Pancreas transplant outcomes for United States and non-United States cases as reported to the United Network for Organ Sharing and the International Pancreas Transplant Registry as of December 2011. Clin Transpl. 2012;23–40.

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263. Gruessner  AC, Gruessner  RW. Pancreas Transplantation of US and Non-US Cases from 2005 to 2014 as Reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud. 2016;13(1):35–58. 264. Gruessner AC, Gruessner RW. Long-term outcome after pancreas transplantation: a registry analysis. Curr Opin Organ Transplant. 2016 Aug;21(4):377–385. 265. Gruessner AC, Gruessner RWG. Pancreas transplantation for patients with type 1 and type 2 diabetes mellitus in the united states: a registry Report. Gastroenterol Clin North Am. 2018;47(2):417–441. 266. Gruessner  RW, Gruessner  AC. The current state of pancreas transplantation. Nat Rev Endocrinol. 2013;9(9):555–562. 267. Stratta RJ, Fridell JA, Gruessner AC, Odorico JS, Gruessner RW. Pancreas transplantation: a decade of decline. Curr Opin Organ Transplant. 2016;21(4):386–392. 268. Stratta RJ, Gruessner AC, Odorico JS, Fridell JA, Gruessner RW. Pancreas transplantation: an alarming crisis in confidence. Am J Transplant. 2016 Sep;16(9):2556–2562. 269. Gruessner  AC, Gruessner  RWG. Declining numbers of pancreas transplantations but significant improvements in outcome. Transplant Proc. 2014;46(6):1936–1937. 270. Gruessner RWG, Gruessner AC. Pancreas transplant alone: a procedure coming of age. Diabetes Care. 2013;36(8):2440–2447. 271. Rana  A, Gruessner  A, Agopian  VG, et  al. Survival benefit of solid-­organ transplant in the United States. JAMA Surg. 2015 Mar 1;150(3):252–259. 272. Gruessner  RWG, Sutherland  DER, Gruessner  AC. Mortality assessment for pancreas transplants. Am J Transplant. 2004;4(12):2018–2026. 273. Gruessner  AC, Laftavi  MR, Pankewycz  O, Gruessner  RWG. simultaneous pancreas and kidney transplantation-is it a treatment option for patients with type 2 diabetes mellitus? an analysis of the international pancreas transplant registry. Curr Diab Rep. 2017;17(6):44. 274. Gruessner RWG, Gruessner AC. Pancreas after islet transplantation: a first report of the international pancreas transplant registry. Am J Transplant. 2016;16(2):688–693. 275. Gruessner  RWG, Sutherland  DE, Drangstveit  MB, Kandaswamy R, Gruessner AC. Pancreas allotransplants in patients with a previous total pancreatectomy for chronic pancreatitis. J Am Coll Surg. 2008;206(3):458–465.

A.  Whole pancreas allo-transplantation

C H A P T E R

2 How to build a pancreas transplant program Peter Abrams⁎, Asha Zimmerman⁎, John A. Powelson†, Jonathan A. Fridell† ⁎

MedStar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, United States † Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States O U T L I N E Introduction

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Promotion of solitary pancreas transplants for hypoglycemic unawareness

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Leadership commitment to growth in pancreas transplantation

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Growing the pancreas transplant waitlist through reevaluation of diabetic kidney waitlist patients

Modification of clinical outreach to promote pancreas transplantation

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Growing the pancreas transplant waitlist through expanded recipient eligibility criteria

Modification of donor call to promote pancreas transplant

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Modification of donor pancreas acceptance rates

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Simplifying pancreas transplant management through use of protocols

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Conclusions

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References

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Modification of kidney transplant evaluation of new patients Promotion of pancreas transplant for diabetic kidney transplant recipients (PAK)

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KEY POINTS • Leadership: Transformative change in a pancreas

• Consolidated donor call and protocol-based donor organ

transplant program begins only after the transplant executive director decides that pancreas transplantation is a high priority, empowering transplant faculty members to invest time and energy into program growth.

• Protocol-based patient evaluations for pancreas transplant

evaluation: Increased rates of pancreas organ acceptance will occur after on-call clinicians are personally motivated to perform more pancreas transplants and overly stringent exclusion criteria are modified according to evidence-based guidelines.

• Protocol-based management: High-volume pancreas

and “internal conversion” of kidney-only waitlist patients: The number of pancreas transplant evaluations and listings can be significantly increased as a result of protocol-based consideration of pancreas transplantation in diabetic patients either referred for kidney transplant alone or already waitlisted for kidney transplant.

Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas, Volume 1 https://doi.org/10.1016/B978-0-12-814833-4.00002-2

transplant programs achieve sustainable success using a multidisciplinary, protocol-based team approach that can similarly be used by developing programs to facilitate their own growth and maintain excellent outcomes.

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© 2020 Elsevier Inc. All rights reserved.

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2.  How to build a pancreas transplant program

Introduction The steady decline in pancreas transplants performed in the United States and the multiple causes of this unfortunate trend have been comprehensively documented.1, 2 This myriad of different negative factors resulting in a progressive downward spiral of fewer and fewer pancreas transplants being performed has also caused a decrement in fellowship training and deterioration of the surgical skills of pancreas transplant teams, ultimately leading to a further decline in pancreas transplants nationally due to the collective decline at a large number of pancreas transplant centers. As reported to the United Network of Organ Sharing (UNOS), of the 131 approved pancreas transplant programs in the United States, 11% of centers did not perform a single pancreas transplant during fiscal year 2016, another 15% performed only 1 transplant, and 11% performed only 2 pancreas transplants. As the results of modern-day pancreas transplantation are excellent and continue to improve, achieving durable restoration of normal glucose homeostasis in over 90% of patients suffering from complications of diabetes mellitus (DM), it is concerning that pancreas transplant programs as a whole are significantly decreasing access to pancreas transplantation for the precarious end-stage diabetic communities that they serve. In this context, it is interesting to note that two recent studies, one based on US data from the Scientific Registry of Transplant Recipients (SRTRs) and the other based on Eurotransplant data, correlate lower volume pancreas transplant centers with worse outcomes.3, 4 Our chapter focuses on efforts being made at certain pancreas transplant programs to buck this trend and grow their pancreas transplant volumes through easily accomplished changes to their existing programmatic structure and function.

Leadership commitment to growth in pancreas transplantation The most critical element of initiating transformative change in a pancreas transplant program comes from the transplant executive director deciding that pancreas transplant growth is a high priority. Once the director of the transplant program commits to pancreas transplantation, it becomes important for the hospital administration to recognize the needs of the pancreas transplant program on an operational basis. This administrative support translates into many small but significant accommodations by the hospital including availability of operating rooms and staff for pancreas transplants at all hours including in the middle of the night and during a busy weekday operating schedule despite possible opposition from other surgical services. The director can

also empower the medical and surgical directors within the transplant faculty to dedicate time and energy to the development of a vibrant and busy program. Equally important, the leadership of the pancreas program must not be divided between pancreas and kidney transplantation alone. To do the job well requires steadfast commitment to one organ, as the significant amount of work involved in running a successful kidney program limits the amount of time available to successfully build a pancreas program. Growth of a pancreas transplant program should not be expected to be associated with suboptimal initial outcomes. Experience from the Barcelona group suggests that the “learning curve” associated with changing from low volume to higher volume does not mean that outcomes will suffer as a result. Several other anecdotal examples of US transplant surgeons assuming leadership positions in pancreas transplant programs and safely and responsibly growing transplant volumes at their institutions should allay any fears of a potential “learning curve” effect on patient outcomes.5, 6 The remainder of this chapter describes ways in which the pancreas transplant leadership, once empowered to grow and expand to meet the needs of their diabetic patient population, can rebuild their program into a high-volume center.

Growing the pancreas transplant waitlist through reevaluation of diabetic kidney waitlist patients In a program that has not historically performed a high volume of pancreas transplants each year, there will invariably be a significant number of kidney alone-­ waitlist patients with DM who could significantly benefit from a pancreas transplant. In appropriately selected candidates, it is now well established that receiving both a pancreas and a kidney transplant improves life expectancy over kidney transplant alone.7, 8 This survival advantage is particularly true for preemptive transplants. Compared to deceased donor kidney transplant alone, diabetic patients considering preemptive transplant derive greater benefit from either pancreas after living donor kidney (PALK) transplant or simultaneous pancreas and kidney transplant (SPK).9–11 If no living donor kidney is available for the diabetic patient with end-stage renal disease (ESRD) patient, then the available options include an SPK or cadaver kidney alone transplant. As the allocation for an SPK transplant is often associated with much shorter waiting times than a cadaver kidney alone, it affords a very desirable option and can significantly reduce mortality while waiting for a kidney transplant. Accordingly, failure to offer pancreas transplantation to appropriately selected diabetic ESRD patients who are listed for a cadaver kidney not only

A. Whole pancreas allo-transplantation



Growing the pancreas transplant waitlist through expanded recipient eligibility criteria

results from excessively strict selection criteria and/or a lack of enthusiasm for pancreas transplantation, but also misses an opportunity to provide eligible patients a life-extending SPK transplant and achieve institutional growth. A growing US transplant program has recently described their own novel process as an “internal conversion” of diabetics listed for kidney transplant alone to being listed for SPK or PALK.12 From their kidney alone transplant list of over 1100 patients, this program found nearly 25% met criteria for SPK evaluation. Furthermore, in a program that is developing or renewing their commitment to pancreas transplantation, one great opportunity is to review the prior kidney alone recipients in order to identify recipients that should have been offered pancreas transplantation. Pancreas transplantation after prior cadaveric kidney transplantation, even if remote, can still be performed with excellent long-term results.11

Growing the pancreas transplant waitlist through expanded recipient eligibility criteria Recent literature now demonstrates excellent outcomes after pancreas transplantation at programs that have expanded recipient eligibility criteria in several different ways. Multiple pancreas transplant centers have now achieved acceptable pancreas transplant outcomes in recipients exceeding 60 years of age, suggesting that chronological age may be a less relevant factor than careful, physiological age assessment, and cardiac evaluation.13, 14 Furthermore, it has been observed by these centers that older pancreas transplant recipients are relatively less likely to experience allograft rejection, making it possible to offset the risks incurred by major surgery with minimization of immunosuppression and its attendant morbidity. As patients with diabetes live longer, it is worthwhile judiciously considering pancreas transplantation in this older population. A growing body of literature exists that supports the role of pancreas transplantation for selected Type 2 DM (T2D) patients with an acceptable major-surgery risk profile.15, 16 According to the International Pancreas Transplant Registry (IPTR), nearly 13% of SPK transplants occurring in the United States are performed for T2D, a number that has steadily risen over the last several years. For example, located in an urban center with high rates of T2D, the pancreas program at Medstar Georgetown transplants a disproportionately large cohort (approximately 18.5% of total number of pancreas transplants) of highly selected pancreas transplant candidates with T2D and achieves comparable postoperative glycemic control despite varying degrees of insulin resistance.17 In more rural Wisconsin, an even greater percentage of SPK transplants in 2017 at the University of Wisconsin Transplant Program (12 of 38, 31.6%) were

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in patients with T2D. Although historical evidence had suggested that recipient obesity (BMI >30) was associated with increased risk of perioperative complications, graft failure, and death, more recent single-center case studies seem to suggest that careful recipient and donor selection along with high-volume center experience may allow for successful pancreas transplantation in the obese T2D patient with comparable outcomes.18–20 Al-Qaoud et al. also showed that T2D recipients of SPK transplants performed between 2004 and 2014 (prior to the new UNOS pancreas allocation system implementation) had similar patient, kidney graft, and pancreas graft survival in recipients with a BMI >30 compared to those with a BMI 30 recipients was also similar to that of T2D LDK BMI >30 recipients, and superior to that of DDKT BMI >30 recipients.21 Given the obesity epidemic seen across the United States over the last couple of decades, it is safe to anticipate increasing BMIs will be encountered during pancreas transplant evaluations. Of course, clinical judgment in assessing operative risk is essential for this cohort of patients, and not all T2D ESRD recipients should undergo SPK transplantation. Patient characteristics that constitute a suitable T2D recipient for SPK transplantation is beyond the scope of this chapter and should be uniquely set by individual transplant programs. Nonetheless, to categorically deny all T2D recipients from receiving an SPK transplant is a missed opportunity to provide a potentially life-saving transplant to a patient population who may benefit while also losing an opportunity for program growth. In order to achieve consensus and “buy-in” from program personnel, it is advisable to develop criteria for pancreas transplant listing by first embracing the wisdom and skill sets of the transplant program’s existing multidisciplinary team of surgeons, nephrologists, transplant waitlist coordinators, and nutritionists. Expanding listing criteria is best achieved by first demonstrating excellent outcomes using more conservative criteria and earning the respect and confidence of the transplant center personnel. After institutional personnel witness the improved quality of life (QoL) following pancreas transplant and once it is recognized that the ultimate goal is to maximize access to pancreas transplant for the sake of patient welfare, enthusiasm for expanding pancreas transplant listing criteria is more likely to be shared by others. “Buy-in” from institutional personnel to improve the health of their patients will increase volume more than any attempt to increase volume for its own sake. Suitable criteria for pancreas transplantation would include T1D or select T2D candidates that either meet UNOS listing criteria for renal transplantation (creatinine clearance 15 kg), and DCD donors. None of these factors predictably leads to suboptimal pancreas transplant outcomes, and therefore should not be used as exclusion criteria. Similarly, simultaneous retrieval of a small intestine allograft is not a contraindication to pancreas retrieval for transplant, although it is highly recommended that a representative from the pancreas transplant program participate in the procurement procedure.33 Validated risk factors of technical failure include donor history of pancreatitis, age >50 years old, creatinine >2.5, BMI >30, and CIT >20 h,34 but even these factors are not absolute contraindications to transplantation. Several indices including the pancreas donor risk index (PDRI),34 the preprocurement pancreas suitability score (P-PASS)35 and a third composite model proposed by the University of Minnesota36 have been proposed to assist with pancreas donor evaluation, but ultimately all of these fall short of providing an absolute answer. As tools, they help with decision-making but do not replace clinical judgment. Ideally, all potentially suitable local pancreas donors, particularly if there is already a team retrieving the liver and kidneys, should be

assessed with an intention of transplantation. The final decision should be based on the organ appearance. If the pancreas appears normal, meaning not excessively fat, firm, edematous or injured, consideration should be made for transplantation. In the current era, one of the important issues is that with declining numbers of pancreas transplants, fellowship training in retrieval and transplantation has become inadequate in many centers and there are fewer trained transplant surgeons that are experienced enough to assess and retrieve a pancreas allograft. When considering an import offer, training and experience of the procuring surgeon should be evaluated and there may be occasions where the transplanting center may want to send a team. Specific reasons worthy of declining an offer would include: trauma, hematoma, infiltrating fat, hard nodular pancreas, and significant edema. With short ischemia times through chartered vs commercial air transportation and with expedited or virtual cross matches, it is possible to achieve similar results for imported pancreas allografts compared to locally procured grafts.37, 38 The use of young donors involves the careful consideration of US Public Health Service (PHS) increased risk organ donors, as a large percentage of young donors fall into this category. We consider these young and otherwise ideal donors on a case-by-case basis; but in almost every scenario, especially for uremic TD1 candidates with a high waitlist mortality, the risk of declining a high-quality donor pancreas clearly outweighs the risk (around 1% for highest risk behavior, but usually much less than 1%) of transmission of HIV, HBV, or HCV from a NAT-negative donor. For PTA candidates, the risk of declining is weighed against the history of life-threatening SHEs.

Simplifying pancreas transplant management through use of protocols To optimize efficiency and achieve a team-based approach to growing a pancreas transplant program, we recommend a protocol-based system. The best way to develop protocols is to visit and observe pancreas transplantation at an already high-volume center. Protocols for all phases of care should be developed, including pretransplant evaluation, intraoperative management such as anticoagulation and immunosuppression, and postoperative care. Ideally, patients should be followed indefinitely and specifically by surgeons and nephrologists or endocrinologist familiar with pancreas transplantation. To optimize pancreas allograft longevity, we believe that it is wise to establish a plan for doing pancreas transplant biopsies, either with interventional radiology or with physicians in the transplant division.

A. Whole pancreas allo-transplantation



References

Conclusions It is within the grasp of every pancreas transplant program in the United States to make programmatic and personnel modifications without substantial increases in capital investment to achieve a significant and sustainable volume growth without compromising clinical outcomes. If only a fraction of the 131 pancreas transplant programs were to commit themselves to these changes on behalf of the local diabetic communities that they serve, the transplant community might finally turn the tide and bring about a significant upward trend in ­pancreas transplant volume nationally.

References 1. Stratta RJ, Gruessner AC, Odorico JS, Fridell JA, Gruessner RWG. Pancreas transplantation: an alarming crisis in confidence. Am J Transplant. 2016;16(9):2556–2562. 2. Kandaswamy  R, Stock  PG, Gustafson  SK, et  al. OPTN/SRTR 2016 annual data report: pancreas. Am J Transplant. 2018;18(suppl 1):114–171. 3. Kopp W, van Meel M, Putter H, et al. Center volume is associated with outcome after pancreas transplantation within the eurotransplant region. Transplantation. 2017;101(6):1247–1253. 4. Alhamad  T, Malone  AF, Brennan  DC, et  al. Transplant center volume and the risk of pancreas allograft failure. Transplantation. 2017;101(11):2757–2764. 5. Fridell  JA, Mangus  RS, Powelson  JA, Mujtaba  MA, Chen  JM, Taber  TE. Pancreas transplantation in the new millennium: the Indiana University experience. Clin Transpl. 2011;145–156. 6. Fridell  JA, Agarwal  A, Powelson  JA. Pancreas transplantation at Indiana University: a brief overview of recent progress. In: Pancreatic Transplantation. New York: Informa Healthcare; 2007:421–426. 7. Morath C, Zeier M, Döhler B, et al. Transplantation of the type 1 diabetic patient: the long-term benefit of a functioning pancreas allograft. Clin J Am Soc Nephrol. 2010;5(3):549–552. 8. Sollinger  HW, Odorico  JS, Becker  YT, D’Alessandro  AM, Pirsch  JD. One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg. 2009;250(4):618–630. 9. Huang  E, Wiseman  A, Okumura  S, Kuo  H-T, Bunnapradist  S. Outcomes of preemptive kidney with or without subsequent pancreas transplant compared with preemptive simultaneous pancreas/kidney transplantation. Transplantation. 2011;92(10):1115–1122. 10. Fridell  JA, Powelson  JA. Pancreas after kidney transplantation: why is the most logical option the least popular? Curr Opin Organ Transplant. 2015;20(1):108–114. 11. Fridell JA, Mangus RS, Hollinger EF, et al. The case for pancreas after kidney transplantation. Clin Transpl. 2009;23(4):447–453. 12. Scalea  JR, Sultan  S, Lamos  EM, Bartlett  ST, Barth  RN. Improvement in pancreas transplant evaluation and surgical volume using a multidisciplinary approach. Am J Transplant. 2018;18(5):1295–1296. 13. Shah  AP, Mangus  RS, Powelson  JA, et  al. Impact of recipient age on whole organ pancreas transplantation. Clin Transpl. 2013;27(1):E49–E55. 14. Scalea JR, Redfield RR, Arpali E, et al. Pancreas transplantation in older patients is safe, but patient selection is paramount. Transpl Int. 2016;29(7):810–818.

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15. Redfield RR, Scalea JR, Odorico JS. Simultaneous pancreas and kidney transplantation: current trends and future directions. Curr Opin Organ Transplant. 2015;20(1):94–102. 16. Margreiter  C, Resch  T, Oberhuber  R, et  al. Combined ­pancreas-kidney transplantation for patients with end-stage nephropathy caused by type-2 diabetes mellitus. Transplantation. 2013;95(8):1030–1036. 17. Murthy  A, Abrams  PL, Verbesey  J, et  al. Glycemic Control After Pancreas Transplantation in Non-Obese, Insulin-Dependent Type 2 Diabetes Patients. Oxford: International Pancreas and Islet Transplant Association (IPITA); 2017. 18. Laurence  JM, Marquez  MA, Bazerbachi  F, et  al. Optimizing pancreas transplantation outcomes in obese recipients. Transplantation. 2015;99(6):1282–1287. 19. Yeh  CC, Spaggiari  M, Tzvetanov  I, Oberholzer  J. Robotic pancreas transplantation in a type 1 diabetic patient with morbid obesity: a case report. Medicine (Baltimore). 2017;96(6):e5847. 20. Fridell JA, Mangus RS, Taber TE, et al. Growth of a nation part II: impact of recipient obesity on whole-organ pancreas transplantation. Clin Transpl. 2011;25(4):E366–E374. 21. Al-Qaoud T, Redfield R, Leverson G, Welch B, Odorico J. The Case for Simultaneous Pancreas Kidney (SPK) Transplantation for Obese T2D Patients. Oxford: International Pancreas and Islet Transplant Association (IPITA); 2017. 22. Porubsky M, Powelson JA, Selzer DJ, et al. Pancreas transplantation after bariatric surgery. Clin Transpl. 2012;26(1):E1–E6. 23. Kleinclauss  F, Fauda  M, Sutherland  DER, et  al. Pancreas after living donor kidney transplants in diabetic patients: impact on long-term kidney graft function. Clin Transpl. 2009;23(4):437–446. 24. Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned from more than 1000 pancreas transplants at a single institution. Ann Surg. 2001;233(4):463–501. 25. Poommipanit  N, Sampaio  MS, Cho  Y, et  al. Pancreas after living donor kidney versus simultaneous pancreas-kidney transplant: an analysis of the organ procurement transplant network/ united network of organ sharing database. Transplantation. 2010;89(12):1496–1503. 26. Weiss AS, Smits G, Wiseman AC. Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation. Clin J Am Soc Nephrol. 2009;4(5):988–995. 27. Choudhary  P, Rickels  MR, Senior  PA, et  al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care. 2015;38(6):1016–1029. 28. Fridell  JA, Mangus  RS, Chen  JM, et  al. Steroid-free three-drug maintenance regimen for pancreas transplant alone: comparison of induction with rabbit antithymocyte globulin +/− rituximab. Am J Transplant. 2018;18(12):3000–3006. 29. Gross CR, Limwattananon C, Matthees BJ. Quality of life after pancreas transplantation: a review. Clin Transpl. 1998;12(4):351–361. 30. Adang  EM, Engel  GL, van Hooff  JP, Kootstra  G. Comparison before and after transplantation of pancreas-kidney and ­pancreas-kidney with loss of pancreas–a prospective controlled quality of life study. Transplantation. 1996;62(6):754–758. 31. Salonia A, D’Addio F, Gremizzi C, et al. Kidney-pancreas transplantation is associated with near-normal sexual function in uremic type 1 diabetic patients. Transplantation. 2011;92(7):802–808. 32. Fridell  JA, Rogers  J, Stratta  RJ. The pancreas allograft donor: current status, controversies, and challenges for the future. Clin Transpl. 2010;24(4):433–449. 33. Fridell  JA, Mangus  RS, Powelson  JA, Vianna  RM, Tector  AJ. Outcomes of pancreas allografts procured simultaneously with an isolated intestine allograft: single-center and national data. Transplantation. 2012;94(1):84–88.

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2.  How to build a pancreas transplant program

34. Axelrod DA, Sung RS, Meyer KH, Wolfe RA, Kaufman DB. Systematic evaluation of pancreas allograft quality, outcomes and geographic variation in utilization. Am J Transplant. 2010;10(4):837–845. 35. Vinkers MT, Rahmel AO, Slot MC, Smits JM, Schareck WD. How to recognize a suitable pancreas donor: a eurotransplant study of preprocurement factors. Transplant Proc. 2008;40(5):1275–1278. 36. Finger  EB, Radosevich  DM, Dunn  TB, et  al. A composite risk model for predicting technical failure in pancreas transplantation. Am J Transplant. 2013;13(7):1840–1849.

37. Fridell  JA, Mangus  RS, Hollinger  EF, et  al. No difference in transplant outcomes for local and import pancreas allografts. Transplantation. 2009;88(5):723–728. 38. Eby  BC, Redfield  RR, Ellis  TM, Leverson  GE, Schenian  AR, Odorico JS. Virtual HLA crossmatching as a means to safely expedite transplantation of imported pancreata. Transplantation. 2016;100(5):1103–1110.

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C H A P T E R

3 Pathophysiology of diabetes Manfredi Tesauro, Francesco Antonio Mazzotta Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy O U T L I N E Introduction

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Insulin structure, secretion, and action Structure Secretion Action Pathogenesis of diabetes

38 38 38 39 39

Type 1 diabetes Autoimmunity and cellular immunity

42 42

Introduction Diabetes mellitus (DM) is a group of metabolic disorders characterized by chronic hyperglycemia caused by alterations in insulin secretion, by the ineffectiveness of the insulin produced or both. Diabetes can be classified into the following general categories (1) type 1 diabetes (T1D) due to autoimmune β-cell destruction, leading to absolute insulin deficiency, (2) type 2 diabetes (T2D) due to a progressive loss of insulin sensitivity and β-cell insulin secretion, (3) gestational diabetes which is diagnosed in the second or third trimester of pregnancy that was not clearly present prior to gestation, and (4) diabetes due to other causes such us pancreatectomy and pancreatitis, drugs, or chemical-induced diabetes (such as glucocorticoids which reduce insulin sensitivity, immunosuppressive therapies required after organ transplants which inhibit insulin secretion, use of pentamidine in patients with pneumonia caused by Pneumocystis carinii by damaging β cells, and the use of β blockers that can cause a reduction in peripheral glucose uptake and decreased insulin secretion), endocrine diseases (such as ­ pheochromocytoma-causing excess catecholamine

Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas, Volume 1 https://doi.org/10.1016/B978-0-12-814833-4.00003-4

Type 2 diabetes Insulin resistance Peripheral glucose uptake Hepatic glucose production β-Cell dysfunction

43 43 44 44 45

References

46

r­elease, leading to an increase in glucose production by glycogenolysis, acromegaly, and Cushing’s syndrome which are characterized by increased levels of growth hormone (GH) and cortisol, respectively, which cause hyperglycemia by acting as insulin antagonists and promoting gluconeogenesis) and monogenic diabetes syndromes (such as neonatal diabetes, maturity onset diabetes of the young (MODY), maternally inherited diabetes and deafness (MIDD), and autosomal recessive forms of DM). T1D is a multifactorial disease in which genetic predispositions are associated with a triggering event that promotes autoimmune mechanisms in the β cells of the pancreas which results in the lack of insulin secretion. Despite the peak incidence occurring during childhood and adolescence, the disease can develop at any age. Less frequently, it can manifest in adulthood where it is known as latent autoimmune diabetes of adults (LADAs). The most commonly associated genetic predisposition in T1D is the major histocompatibility complex (MHC). An unknown environmental stimulus triggers β-cell-specific autoimmunity where viruses, bacteria, diet, and incorrect life style have all been implicated and are considered the most important environmental factors.

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© 2020 Elsevier Inc. All rights reserved.

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3.  Pathophysiology of diabetes

T2D is the most common form of the disease and is characterized by reduced peripheral insulin sensitivity, lack of efficient glucose uptake in target tissues such as skeletal muscle, liver and adipose tissue, impaired regulation of hepatic glucose production, and declining β-cell function. These metabolic defects ultimately lead to βcell failure. Hyperglycemia occurs when insulin secretion is unable to compensate for insulin resistance. T2D has a strong genetic component that is amplified by environmental factors such as age, obesity, diet, and lack of physical activity.1 Both T1D and T2D are associated with an increased risk of vascular and metabolic disorders. In this chapter, we discuss the main mechanisms underlying DM. We believe that understanding the pathophysiology of diabetes is crucial as it can lead to the development of new targeted therapies.

Insulin structure, secretion, and action Structure Insulin is a peptide hormone synthesized by the pancreatic β cells in the islets of Langerhans. It is composed of 51 amino acids and has a molecular weight of 5808 Da. The gene coding for human insulin is located on the short arm of chromosome 11. Insulin is produced as a precursor known as pre-pro-insulin. Initially, fmigrates to the rough endoplasmic reticulum where it is converted into pro-insulin by signal peptidases, which remove its signal peptide from the N-terminal. Proinsulin is subsequently cleaved, and this removes the connecting strand (c-peptide) to form the double-chain insulin molecule. One chain has 21 amino acids while the other has 30, and the two chains are linked together by two disulfide bonds which connect with cysteine on both chains. Both the C peptide and insulin are stored in membrane-bound storage granules and they are released upon stimulation in the portal circulation in the same concentration. Considering the reduced hepatic metabolism, the C peptide levels represent a precise endogenous marker for insulin production.2

Secretion Insulin secretion follows a circadian rhythm, with an elevated release in the morning postprandially, and decreased levels in the evening. In the hepatic portal vein, insulin secretion shows an oscillatory pulsatile pattern, with alternations of rapid, low amplitude secretions and slow, high amplitude secretions.3 Glucose concentration is the most important stimulator for insulin production. Insulin secretion requires the transport of glucose into the β cell by the glucose

transporter 2 (GLUT2) protein, which is subsequently phosphorylated by glucokinase and then metabolized to produce adenosine triphosphate (ATP). The resultant increase in the ATP:ADP (adenosine diphosphate) ratio closes the K+ATP channel, which causes depolarization due to intracellular K+ entrapment. This opens the ­voltage-gated Ca2+ channel, which causes insulin release.4 Even a moderate increase in glucose levels induces the secretion of insulin. Initially, insulin is released by the storage granules present in the β cells and then by de novo insulin synthesis. Importantly, the administration route of glucose regulates the production of insulin whereby increased insulin levels are produced when glucose is administered orally because of the simultaneous stimulation of several gut-peptides such as glucagonlike-­peptide 1 (GLP-1) and gastric-inhibitory polypeptide (GIP). This is defined as the incretin effect and it is the basis of some of the new pharmacological therapies for the treatment of T2D. GLP-1 is secreted by the small intestinal L cells in response to food intake thereby stimulating insulin secretion. GLP-1 binds to its receptor which activates adenylyl cyclase allowing the production of cyclic adenosine monophosphate (cAMP) thus potentiating glucose-mediated insulin secretion. The insulinotropic effect of GLP-1 depends on glucose concentration. Accordingly, during fasting periods GLP-1 does not stimulate insulin secretion. Intravenously administered insulin does not directly enter the gastrointestinal tract and therefore, is not subject to gastrointestinal hormone effects, leading to insulin synthesis at a lower rate compared to oral administration. Some amino acids under appropriate conditions can stimulate glucose-mediated insulin secretion. For example, the combination of glutamine and leucine increase the production of insulin. In addition, arginine stimulates insulin secretion if acting in conjunction with glucose. Furthermore, some amino acids can indirectly influence insulin secretion. Accordingly, during fasting periods, energy is produced by proteolysis occurring in skeletal muscle which leads to an accumulation of free amino acids such as alanine and glutamine which stimulate glucagon production, with a consequent increase in glucose levels, thereby promoting insulin secretion. Moreover, it has been demonstrated that some amino acids can induce insulin secretion through incretin-­ dependent mechanisms. Glucose and amino acids orally assumed together stimulate the production of GLP-1 and GIP by intestinal cells which causes increased insulin secretion when binding to their receptors. Furthermore, it has been shown that β cells have free fatty acid receptors (FFARs). The stimulation of FFAR-1 stimulates insulin secretion by the production of long-chain acyl coenzyme A (CoA) and diacylglycerol (DAG). DAG promotes insulin secretion by activating protein kinase C (PKC) while long-chain acyl CoA

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Insulin structure, secretion, and action

contributes to insulin secretion by acetylating proteins involved in granule fusion to the cell membrane, such as synaptosomal-associated protein 25 (SNAP25). Several other hormones regulate the secretion of insulin and these include estrogens, GH, and leptin. 17-β estradiol can stimulate β cells to produce insulin. When 17-β estradiol binds to its receptors in β cells it decreases K+ATP channel activity, thus allowing membrane depolarization. This causes an increase in the opening of voltage-gated Ca2+ channels, which promotes insulin secretion. On the contrary, GH reduces insulin secretion by the production of insulin-like growth factor-1 (IGF1) and its binding proteins. IGF-1 activates phosphodiesterase 3B (PDE3B) which degrades cAMP in β cells. Finally, leptin, an adipokine produced by adipose tissue, plays an inhibitory role on insulin secretion by having an antagonistic effect on cAMP.2

Action Insulin binds to the insulin receptor (IR) with high affinity and to the insulin-like growth factor-1 receptor (IGF-1R) with low affinity. The IR is structurally composed of 2α and 2β subunits linked by disulfide bonds in a hetero-tetrameric pattern. The α subunits mediate mechanical insulin binding while the β subunits are important for autophosphorylation to promote tyrosine kinase activity, which is required for downstream signaling initiation by the activation of insulin receptor substrate (IRS). Insulin exerts its actions by two major pathways. The first involves phosphoinositide-3-kinase (PI3K) which acts downstream by phosphorylation of multistep signaling intermediates to activate protein kinase B (AKT/ PKB). In this pathway, insulin stimulates protein anabolism via mammalian target of rapamycin (mTOR), increases glycogen synthesis by glycogen synthase kinase 3 (GSK3), promotes cell survival by the inhibition of antiapoptotic proteins, upregulates gluconeogenesis by increased expression phosphoenolpyruvate carboxykinase (PEPCK) by forkhead box protein O1 (FOXO1), and increases GLUT4 translocation to the plasma membrane. The second pathway involves the activation of two mitogen-activated protein kinases (MAPK) known as MEK1 and MEK2. These consequently phosphorylate the Elk-1 transcription factor which expresses genes which have a pro-mitogenic function.5 Effects of insulin on glucose and lipid metabolism One of the main actions of insulin is to stimulate Na+independent GLUT channels to the plasma membrane, permitting glucose uptake into the cells. The main GLUT channels translocated are the GLUT4 (which are present in adipose tissue and skeletal muscle). However, in states

39

of elevated insulin concentrations, GLUT1 has also been shown to be translocated by the MAPK pathway, despite GLUT1 transporters permanently residing on the plasma membrane. Furthermore, insulin promotes glucose uptake by upregulating the glycolytic enzymes hexokinase and 6-phosphofructokinase to accelerate the rate of glycolysis. This permits more glucose internalization in the cell by the reestablishment of a concentration gradient across the GLUT transporters. Insulin action also promotes glycogen synthesis directly by the upregulation of the glycogen synthase enzyme and indirectly by the increased amount of glyconeogenic precursors available. In addition, insulin decreases hormone-sensitive lipase activity. This causes a decrease in the rate of free fatty acid (FFA) mobilization in the blood and indirectly allows increased glucose internalization. Insulin also promotes upexpression of malonyl-CoA in skeletal muscle. Malonyl-CoA inhibits carnitine ­palmitoyltransferase-1, thereby causing decreased mitochondrial shuttling and consequently decreased β oxidation.6 Vascular actions of insulin Insulin plays an important role in endothelial cells by producing nitric oxide (NO), thereby causing vasodilatation. This vasodilatory action permits the delivery of both the hormone and the substrate to metabolically active tissues, promoting an enhanced insulin sensitivity. Abnormalities in insulin-mediated vasodilatation in conditions of endothelial dysfunction, such as obesity and diabetes, may contribute to insulin resistance. Insulin also stimulates endothelin-1 (ET-1) in endothelial cells by the activation of MAPK signaling pathway after the activation of signal-regulated kinase-1/2 (ERK1/2). In healthy physiological conditions, there is an equilibrium between insulin-mediated release of ET-1 and NO, causing a neutral vascular response to the hormone due to the balance between these two opposing forces. Obese and T2D patients with insulin resistance have impaired PI3K-dependent signaling, while the MAPK signaling pathway is conserved. The compensatory increased insulin concentration causes an upregulation of MAPK signaling which causes an increased production of ET-1 and decreased synthesis of NO, causing endothelial dysfunction. Indeed, these notions are supported by the fact that insulin-resistant patients show increased ET-1mediated vascular tone.7

Pathogenesis of diabetes T1D is an autoimmune disease characterized by the selective loss of β cells in the pancreatic islets which occurs in genetically susceptible subjects. T1D is associated with other autoimmune diseases such as Graves’ disease, Hashimoto’s thyroiditis, celiac disease, and

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3.  Pathophysiology of diabetes

autoimmune gastritis/pernicious anemia. Moreover, Addison’s disease and vitiligo are also associated with T1D. The diagnosis of T1D usually occurs in early childhood or adolescent stages, nevertheless, it may have any age of onset including during adulthood.8 T2D is characterized prevalently by three metabolic defects acting in synergy: increased hepatic production, impaired insulin secretion, and lack of peripheral glucose uptake (particularly in skeletal muscle) which all contribute to β-cell dysfunction. Genetic predispositions are also thought to be crucial to the development of T2D. If a member of a twin pair has T2D, the other member is more likely to develop the disease or acquire impaired glucose tolerance. There is no obvious correlation between single susceptibility genes and the risk of developing diabetes, therefore T2D is considered a polygenic disease. Insulin resistance can be genetically inherited or acquired, and the former is thought to prevail in the pathogenesis. Acquired factors are thought to be contributory and these include: sedentary lifestyle, aging, and obesity. Usually after a variable amount of time of insulin-resistance/compensatory hyperinsulinemia and normal glucose level, subjects exhibit impaired glucose tolerance due to the insulin-resistance aggravation. After this phase, most patients become diabetic. Overtime, the insulin levels begin to decrease since the β cells become stressed from the excessive secretion of insulin and the β cells undergo apoptosis with consequent further deterioration of glucose levels (Fig. 1).9 Genetic factors T1D and T2D are both considered to be polygenic diseases with many variants which have a low influence on the development of the disease. There is a high risk (approximately 40%) of developing T2D if one parent is affected (with a higher risk if the mother is affected)10 while the risk of developing T1D is about 12% if the father is affected and 6% if the mother is affected. Since T1D is a multifactorial disease, there is no clear correlation between a single genotype and phenotype. Accordingly, many factors are involved, each of which cause an increased risk of developing the disease. Indeed, each single factor causes decreased penetrance and there-

FIG. 1  Main hallmarks of type 1 and type 2 diabetes.

fore makes it extremely difficult to map genes involved in T1D. First-degree relatives have a much higher risk of being affected by T1D compared to the general population. Studies on monozygous twins have suggested that the concordance rate between the two individuals is approximately 50%. However, in 85% of cases T1D occurs in patients with no family history. Almost 50 genetic loci are known to be associated with the susceptibility of T1D. The class II human leukocyte antigen (HLA) genes, which are present on the short arm of chromosome 6, have shown the highest susceptibility of developing the disease. Specifically, these include the HLA-DR3 and HLA-DR4 haplotypes. These susceptibility alleles are thought to contribute to about 50% of developing T1D. On the contrary, the HLA DQB1 class II is very rarely found in patients with T1D (200 mg/dL (11.1 mmol/L) with associated symptoms of hyperglycemia, or a plasma glucose >200 mg/dL after a 75 g glucose load on an OGTT.5

Special populations Gestational DM is diagnosed between the second and third trimester of pregnancy with OGTT testing and is due to progressive insulin resistance. Of note, women with gestational DM are at increased risk of developing T2DM in the future. Neonatal diabetes is diagnosed within the first 6 months of life. The term “maturity-­onset type diabetes of childhood or of the young” was first coined at the Fifth Congress of the International Diabetes Federation in 1964 based on pedigree studies showing a distinct type of diabetes with strong familial basis. Since then, at least 13 genes have been identified and they have a monogenic autosomal dominant pattern of inheritance of DM related to specific gene defects (HNF-1a, HNF-1b, HNF-4a, GCK). It is typically diagnosed before age 25 in nonobese individuals, but it can be diagnosed later in life as well if mild, asymptomatic course. They typically have a strong family history of DM involving at least 2–3 generations. It is important to recognize these individuals with gene testing to tailor therapeutic options. Patients with GCK MODY have mild hyperglycemia and do not usually require therapy. Those with HNF 1a and 1b mutations respond to sulfonylurea therapy.5

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The term posttransplant diabetes mellitus (PTDM) has been described by the presence of DM after solid organ transplantation.13 It is very common to see elevated blood sugars in the immediate posttransplant period owing to stress and steroid-induced hyperglycemia. A number of these patients have preexisting diabetes or prediabetes. A small subset can develop new posttransplant hyperglycemia and various mechanisms have been proposed including immunosuppressant agents, stress, and inflammation as well as genetic predisposition.14 Calcineurin inhibitors (CNIs) are commonly used in posttransplant immunosuppressive therapy and have reduced the need for steroid therapy. The introduction of tacrolimus therapy confirmed the increased propensity of glucose intolerance and hyperglycemia with CNI therapy, more so than cyclosporine. The continuation of immunosuppressive therapy for the long term often results in persistent hyperglycemia requiring therapy. The traditional risk factors for diabetes also can play a role in increasing risk of PTDM. The standard ADA/WHO criteria for diagnosis of DM can be applied to making the diagnosis of PTDM, although given comorbid conditions, HbA1c may be unreliable and an OGTT may be preferred. It is recommended that the diagnosis not be made in the immediate postoperative period, but rather after the transplant recipient is on a stable immunosuppressant regimen, in the absence of any active infection. It is important to recognize and treat PTDM given the increased risk of complications including higher rates of rejection.13, 14 Other rarer forms of diabetes exist, including syndromes of severe insulin resistance such as lipodystrophy and Wolfram syndrome. Diabetes is relatively common among persons with cystic fibrosis (5%–6% prevalence) and is typically labeled cystic fibrosisrelated diabetes. It is manifested by insulin deficiency and altered glucose metabolism related to cystic fibrosis disease features, including chronic infection, malnutrition caused by malabsorption, abnormal intestinal function, and liver dysfunction.15 Several classes of medications have been linked to incident diabetes mellitus. These include corticosteroids,16 certain antipsychotics,17 and antiretroviral drugs (for HIV infection).18 A meta-analysis has also shown a small increase (9%) in new onset diabetes among statin (lipid lowering) drugs compared to placebo, however the absolute risk was low and felt to be acceptable when compared to the substantial risk reduction for cardiovascular disease.19 Beta blockers and thiazide diuretics for hypertension have also been linked to diabetes.20 The mechanisms for druginduced diabetes are not known for all the implicated drugs but may involve promoting insulin resistance or causing insulin deficiency, or may be indirect such

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4.  Epidemiology of diabetes mellitus

as promoting weight gain. Cessation of the offending agent may cause remission of diabetes in some cases.20 There is often times an overlap in presentations of T1DM and T2DM leading to the use of confusing nomenclature such as “type 1.5.” Also, there are circumstances where individuals present in ketosis, but without necessarily remaining insulin dependent (ketosis-prone DM or “Flatbush DM”). There is a growing push toward using antibody testing (to establish autoimmune basis) and c-peptide levels (to determine beta-cell reserve); however, high costs remain a concern. Newer nomenclature such as the Aß classification may become more a commonplace as we head in the direction of precision medicine with personalized therapeutic options.

Descriptive epidemiology Globally, the prevalence of diabetes has increased substantially since 1980. The World Health Organization has estimated that in 1980, there were 108 million adults living with diabetes in the world; by 2014 there were 422 million persons with diabetes. The prevalence of adults with diabetes rose from 4.7% to 8.5%; increasing prevalence was noted in all regions. Perhaps most striking was the increase in diabetes in poorer and middle-income countries observed during this epoch. Estimates of diabetes prevalence across Africa was 3.1% in 1980 and 7.1% in 2014.21 The largest numbers of people with diabetes are found in China (114.4 million), India (72.9 million), the United States (30.2 million), Brazil (12.4 million), Mexico (12.0 million), and Indonesia (10.3 million).22 However with respect to the age-adjusted prevalence of diabetes, the greatest burden of the disease is found in several Pacific Island nations (e.g., 30.5% of adults in the Marshall Islands, 22% in Mauritius, 17.7% in Papua-New Guinea), followed by several nations in the Middle East (Saudi Arabia, Egypt, United Arab Emirates—17%–18% of adults). It is difficult to quantify precisely the prevalence of diabetes subtypes, as in most global data sources there is a lack of differentiation between T1DM and T2DM owing to the costs of additional testing. It is estimated that the overwhelming proportion of people with diabetes have T2DM, whereas about 5% of people with diabetes have T1DM.23 Estimates of the burden of diabetes in the United States are based on varied data sources. Those that rely solely on self-report—such as the Behavioral Risk Factor Surveillance System (which is a phone-based interview) or the National Health Interview Survey (which is an in-person interview) typically inquire if a doctor has told the person they have diabetes and produce statistics on diagnosed diabetes. In 1980 the prevalence of diagnosed diabetes among adults aged ≥20 years was 4%; by 2000 it

was 6%, and by 2012 was 8%, a doubling in disease prevalence in approximately 30 years.24 More recently, these data demonstrate marked differences in the geographic distribution of diabetes—for example, recent estimates ranging from 11.2% of adults ≥45 years in Colorado to 26.8% in Puerto Rico.25 Similarly, self-reported data have consistently shown race/ethnic differences in the prevalence of diabetes in the United States. In 2010, compared to the White, non-Hispanic population (prevalence 6.8%), the age-adjusted prevalence of diagnosed diabetes in the United States was higher among Asians (7.8%) non-Hispanic blacks (11.3%), Hispanics (11.5%), and mixed race/other racial groups (14.0%).26 Others surveys such as NHANES, which include an examination of participants (including obtaining biomarkers) allow for the determination of the total prevalence of diabetes (those that are diagnosed) plus additionally those testing positive for diabetes who were unaware of their diagnosis. Based on the National Diabetes Statistic Report, an estimated 30 million people had diabetes mellitus in the year 2015; approximately 23% of this total was estimated to be undiagnosed.23 The prevalence of any disease is proportional to the incidence and the duration of living with the disease. Changes in prevalence can occur if there is increased screening for a disease as well (particularly if there is a lag between onset of disease and significant clinical manifestations). There is evidence from a variety of sources, including prospective cohort studies, that the incidence of diabetes (primarily type 2) has been increasing in the past 30 years.24, 27–29 The Centers for Disease Control and Prevention’s Division of Diabetes Translation (which publishes the National Diabetes Statistics Report) estimated that in 2015 there were approximately 1.5 million new cases of diabetes in the US adult population aged 18 and older.23 Table 1 describes the prevalence of diabetes as well as the incidence of diabetes in the total population, as well as by gender and race/ethnicity. TABLE 1  US diabetes statistics by demographic characteristics

Characteristic

US prevalence of diabetes 2011–2014 Incidence (diagnosed + undiagnosed), rate in 2015 adults ≥18, (%) (per 1000)

Total population

11.5

6.7

Men

12.2

6.7

Women

10.8

6.8

Asian

16.0

6.0

Non-Hispanic black

17.7

9.0

Non-Hispanic white

 9.3

5.7

Hispanic

16.4

8.4

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Risk factors

For the 2016 US National Health Interview Survey, participants who responded that they had diabetes were asked if they had T1DM, T2DM, or another type of diabetes, and also what medications were being used. Only those who reported both type 1 and current insulin use were considered to have T1DM; estimates based on these data is that 0.55% of the US population had diagnosed T1DM, 8.58% had T2DM, and 0.31% another type of diabetes.30 Among those with any type of diabetes, 6% had T1DM and 91% T2DM. There is substantial variability in the incidence of T1DM globally, for example, one study reported incidence ranges from 0.1/100,000 per year in China to 36.5/100,000 in Finland.31 More recent (2010–2013) data from China still indicates an extremely low incidence rate of 0.93/100,000.32 The best estimates on current trends in diabetes among youth in the United States come from the SEARCH for Diabetes in Youth study. The SEARCH study is a large multicenter observational study looking at the incidence and prevalence of nongestational diabetes among youths aged 0–19. Based on this study, the incidence of T1DM in children was 21.7/100,000 in 2012 in the study sample. The incidences of both T1DM and T2DM among youths increased significantly between 2002 and 2012, especially among racial/ethnic minority children.33

Risk factors The major clinical factors associated with diabetes are listed in Table 2. Although persons are at higher risk above the age of 45 (primarily for T2DM), the prevalence is particularly high among those aged 65 and above. Having a family history of diabetes is a risk factor for both T1DM and T2DM. Genetic susceptibility is not due to single genes, however. Multiple genetic loci have been implicated using modern “GWAS” techniques for both T1DM and T2DM.34, 35 Studies are consistent that lifestyle characteristics, including being overweight, having insufficient physical activity, smoking, and poor dietary patterns are potent risk factors for diabetes, either via direct effects or their effects on obesity.36–39 There is also clinical trial evidence that weight-loss focused lifestyle interventions reduce the risk of T2DM among people at high risk for the disease.40, 41 Diabetes prevention studies typically focus on people with prediabetes or impaired glucose tolerance. These individuals have intermediate levels of glucose (below the threshold to diagnose diabetes, but higher than optimal) either in the fasting state or post-OGTT. Prediabetes can be considered a risk factor for diabetes, or an indication of the earliest manifestation of insulin resistance, a key physiological abnormality in T2DM. It is very common—an estimated 84 million people or 34% of the US adult population had prediabetes

TABLE 2  Risk factors for diabetes mellitus Clinical risk factors

Type 1

Type 2

Family history

Y

Y

Age >45

Y

Overweight or obesity

Y

Insufficient physical activity

Y

High blood pressure

Y

Dyslipidemia (high triglycerides, low HDL)

Y

Lower socioeconomic status

Y

European ancestry

?

African ancestry

Y

Hispanic ethnicity

Y

Asian ancestry

Y

Native American ancestry

Y

Environmental factors

Y

Y

History of gestational diabetes

Y

Polycystic ovary syndrome

Y

Putative risk factors/mechanisms Sugar sweetened beverages

?/Y

Dietary pattern

?

Early exposure to cow’s milk

?

Early expose to gluten

?

Microbiome

?

Vitamin D

?

Viral infections

Y

Autoimmunity

Y

Steroids/transplant drugs

?

?

Y

in 2015.23 Hypertension and abnormal serum lipids are frequently present before diabetes incidence. The constellation of obesity, hypertension, dyslipidemia, and abnormal glucose metabolism has been called “metabolic syndrome”42 and indicates persons with a high absolute risk of developing T2DM. Finally, nonwhite racial/ethnic groups are at increased risk for T2DM, and persons of a lower socioeconomic status are also at higher risk. It is important to note, however, that there is a considerable prevalence of T2DM, particularly in Asia and Africa, among person who are underweight or normal weight,43 highlighting the fact that diabetes mellitus is a complex disorder with multiple factors affecting its etiology. Recent research has focused on novel mechanisms/pathways such as inflammation,44, 45 the gut microbiome,46 and specific dietary factors (such as sugar sweetened beverages47). Studies have also demonstrated

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4.  Epidemiology of diabetes mellitus

the potential role of environmental factors including neighborhood characteristics.48 There is increasing interest in understanding the interplay of genetic susceptibility with lifestyle and environmental factors, however at this point genetic risk scores are not clinically utilized in diabetes prediction.49 T1DM is fairly strongly linked to genetic factors, however environmental contributors to T1DM pathogenesis have long been postulated.50 Environmental risk factors may be the trigger that leads to autoimmune destruction of beta cells, or may be the stress that accelerates the process that is already underway. Viral infections such as enteroviruses, cytomegalovirus, coxsackie virus B, mumps, and rubella have been linked, although definitive causality has not been established. Early exposure to cow’s milk and gluten protein may also increase the risk of T1DM. The aim of trying to understand triggers for T1DM is that interventions could be designed and then offered to those at high genetic risk for T1DM, however thus far this goal has not been achieved. In light of the risk factors outlined in Table 2, potential explanations for the increase in T2DM, both in the United States and globally, lie in the increasing prevalence of overweight and obesity.51 There are also demographic shifts resulting in an increasing proportion of the population that is elderly in many nations. These trends suggest that the number of adults living with diabetes by 2035 may reach 592 million people, a 55% increase over 2013 estimates.52

Diabetes complications The immediate, direct complications of hyperglycemia are serious metabolic states which lead to hospitalization and may cause death, specifically DKA and hyperosmolar nonketotic coma. DKA is characterized by elevated blood sugars (typically ≥250 mg/dL) associated with increased serum ketones and metabolic acidosis. It is typically seen in T1DM and may be the heralding event culminating in the diagnosis.53 It is usually triggered by a precipitating event such as sudden withdrawal of insulin, dehydration, and intercurrent illness such as myocardial ischemia or pneumonia, or surgery. Prompt initiation of therapy with intravenous fluids and insulin is often necessary to prevent complications, coma, and death. It has been estimated that the rate of hospitalization for DKA in the United States between 2000 and 2014 has ranged from 20 to 30 hospitalizations per 1000 persons with diabetes. During this period the case-fatality rate declined from 1% to 0.4%.54 With the advent of newer class of glycemic agents in the category of SGLT2 inhibitors, there is a concern for development of DKA at even lower threshold of blood sugar and the term “euglycemic DKA” has been used to describe this.55, 56

Hyperosmolar hyperglycemic state (HHS) is characterized by blood sugars over 600 mg/dL with elevated effective serum osmolality >320 mosm/kg in the absence of ketoacidosis.53 The incidence of HHS is 80% of PTX patients have maintenance therapy consisting of tacrolimus/mycophenolate with approximately 40% of these patients on steroid-free regimens.1, 10 PTX patients are followed closely postoperatively in transplant clinics

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© 2020 Elsevier Inc. All rights reserved.

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18.  Immunosuppression for pancreas allo-transplantation

with frequent adjustments or changes in immunosuppression medications often necessary. Understanding categories of PTX is paramount, as immunosuppression strategies and follow-up protocols may vary between groups. Three major categories of PTX can be considered: simultaneous pancreas-kidney (SPK) transplant (81% of PTXs), pancreas after deceased or live donor kidney (PAK) transplant (8% of PTXs), and pancreas transplant alone (PTA—11% of PTXs).10 SPK graft survival outcomes are consistently superior compared to solitary pancreas transplants, which includes both PAK and PTA, due to increased early graft loss due to rejection and thrombosis with a trend toward heavier immunosuppression in solitary pancreas transplants to combat these issues.11 Patient survival rates at 1 year following pancreas transplant are >96% with 1-year graft survival rates of 89% for SPK, 84% for PAK, and 83% for PTA.1, 10 In the United States from 2015 to 2016, the incidence of acute rejection within 1 year of transplant was 13.7%, 16.2%, and 16.3% for SPK, PAK, and PTA, respectively.10 The estimated half-life of a pancreas allograft is now 14 years for SPK and 7 years for both categories of solitary pancreas transplant prolonged graft survival is possible in patients who avoid rejection episodes and tolerate their medication regimen.12 This chapter aims to provide an overview of clinically relevant concepts in immunosuppression therapy as it relates to PTX. Islet immunosuppression will not be reviewed as it is covered elsewhere in this textbook.

Induction therapy Induction immunosuppression is intense, prophylactic therapy used in the perioperative transplant setting with the goal of preventing early acute rejection by inducing host immunological hyporesponsiveness to allo-antigen.13 This concept is based on empiric

­ bservations that intensive early immunosuppression o decreases the risk of acute rejection, which is maximal within the first 3  months following PTX. Beyond this time, owing to the body accommodating the new organ, the intensity of maintenance immunosuppression medications can often be lowered. Even in the modern era of induction therapy, rejection rates remain high, with up to 25% of SPK recipients and up to 40% of PTA recipients experiencing rejection episodes within the first year posttransplant.10 Both antibody lymphocyte depleting and non-lymphocyte depleting regimens have been established, with a current trend toward depleting induction in the vast majority of cases. These drugs are administered parenterally, typically given at the time of surgery, and often with a high dose of corticosteroid for added immunosuppressive effect. Some of these drugs need to be continued short term following the transplant. In addition to the potential benefit of avoiding rejection, which is not always guaranteed, maintenance immunosuppression regimens can be started at lower doses and gradually optimized, which may help avoid some of the consequences of higher doses of maintenance immunosuppression. Other possible benefits of induction therapy include delayed introduction of calcineurin inhibitors (CINs), CIN minimization strategies, or even steroid-free regimens in lower immunological risk patients. The trade-off of induction immunosuppression increases the risk of opportunistic infections within the first 3–6  months posttransplant and possibly increases rates of posttransplant lymphoproliferative disorders (PTLDs) due to high cumulative immunosuppression doses for patients. Table 1 highlights common induction immunosuppression agents.

Induction immunosuppression agents Antithymocyte globulin (ATG; Thymoglobulin): ATG is an animal-derived purified polyclonal ­immunoglobulin

TABLE 1  Induction immunosuppression agents Lymphocyte depleting?

MOA

Induction dose

Antithymocyte globulin, horse

a

ATGAM

Yes

Polyclonal antibody

15 mg/kg total in divided doses 1981

Basiliximab

Simulectb

No

IL-2 Antagonism— anti-CD25

20 mg × 2 doses

1998

Antithymocyte globulin, rabbit

Thymoglobulinb

Yes

Polyclonal antibody

6 mg/kg total in divided doses

2017 (FDA approved in 1998 for reversal of acute rejection)

Alemtuzumab

Campathc

Yes

Monoclonal antibody—anti-CD52

30 mg × 1 dose

NA

Drug

a b c

Brand

Discontinued. FDA approved for marketing as an induction agent. Not approved for marketing as an induction agent.

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FDA approval date



Induction therapy

preparation that targets T lymphocytes and has been used in transplantation for decades, with the current clinical preparation deriving from immunizing rabbits with human thymocytes and recovering the antibodies from the rabbit serum. The binding of ATG to mature T-lymphocytes results in complement-dependent and antibody-dependent cytotoxicity resulting in T-cell depletion. Induction dose is typically 6 mg/kg divided into four doses over a 4–7  day period with each dose given over a 6-h period. Most commonly, ATG is administered via central line but peripheral administration is also possible.14 Close clinical monitoring is necessary with thymoglobulin because of risk of cytokine-release syndrome from widespread cell lysis (fever, chills, rashes, nausea, vomiting, diarrhea, and hypotension). In an attempt to avoid this phenomenon, premedication with corticosteroid, antihistamine, and acetaminophen is commonly administered. The risk of the cytokinerelease syndrome decreases with each subsequent dose. Other common side effects include thrombocytopenia, leukopenia, headache, abdominal pain, hypertension, and hyperkalemia. ATG may play a role in mitigating ischemia reperfusion injury owing to anti-inflammatory properties.15 Alemtuzumab (Alem; Campath): Alemtuzumab is a monoclonal humanized depleting antibody against CD-52 receptors expressed by T lymphocytes, B lymphocytes, and natural killer cells. It is used off label as an induction agent in transplant (FDA approval is for the treatment of some hematologic malignancies). It is administered intravenously at the time of transplant, centrally, peripherally, or subcutaneously, with premedication. Typically, a single dose of 30 mg is administered but it has also been given as two divided doses of 20 mg. Cytokine-release syndrome can also occur with the administration of this medication, less so if given subcutaneously, with similar outcomes compared to intravenous administration in SPK recipients.16 The major side effect is lymphopenia, which can be profound and persist for up to 1  year following transplant in some cases. Other common side effects include hypotension, fevers, rigors, chills, rash, bronchospasm, shortness of breath, dizziness, muscle stiffness, joint discomfort, and insomnia.15 Basiliximab (Simulect): Basiliximab is a recombinant murine chimeric nondepleting antibody that prevents T-cell proliferation by blocking CD-25 on the IL-2 receptors of activated T-lymphocytes; in other words it is an IL-2 receptor antagonist. It does not result in lymphopenia and does not cause myelosuppression. It is administered in two 20-mg intravenous doses over 30 min via central or peripheral line. The first dose is typically given within 2 h of organ implantation and the second on postoperative day 3 or 4. The effect of this medication lasts up to 6 weeks after administration. Basiliximab is generally well tolerated, but can cause nausea, stomach

219

discomfort, gastrointestinal issues, cold symptoms, insomnia, headache, and swelling. Anaphylactic reactions are rare.15 Daclizumab is an IL-2 receptor antagonist that has now been discontinued, however, efficacy and safety profiles were similar to basiliximab. Corticosteroids (methylprednisolone, dexamethasone): A high dose of corticosteroid is typically coadministered with all induction agents. It is typically administered prior to antibody induction agents as premedication, however, it also has a synergistic induction immunosuppressive effect that works via incompletely characterized pathways and it is also believed to mitigate the deleterious effects of the ischemic reperfusion cascade.17

Evidence for induction therapy Although widely practiced, the use of induction immunosuppression at the time of PTX is not without controversy. In 2017, more PTXs were performed with no induction (7%) vs IL-2 receptor antagonist therapy (6%).10 Good outcomes in PTX have been achieved with no induction strategies, which typically involve more aggressive maintenance immunosuppression, often with triple therapy including a corticosteroid. No induction strategies are generally employed only for the lowest immunological risk recipients, with more than 90% of current PTXs undergoing some form of antibody induction. In general, PTX patients are felt to be at a relatively high risk of rejection compared to other solid organ transplants based on the autoimmune etiology of many type 1 diabetics, inconsistent maintenance drug regimens, absorption issues in patients with diabetic gastroparesis or enteropathy, and the observed high rates of acute rejection within the first year posttransplant in this population.4 Nondepleting (IL-2 receptor antagonist) antibody induction versus no induction: Two main randomized, prospective, multicenter trials have assessed IL-2 receptor antagonist induction versus no induction with tacrolimus/mycophenolate/steroid maintenance therapy. Kaufman and colleagues randomized 174 low immunological risk SPK recipients [panel reactive antibody (PRA) 30%) of chronic complications of bladder drainage (acidosis, hematuria, dehydration, infections, and high rates of enteric conversion) along with the perception of physiologic exocrine drainage.18, 19 Currently, whole pancreas with donor duodenum grafts are the preferred allograft with duodenal segment drained enterically 90% of the time with bladder drainage in the other 10% of cases.11–20 Table 1 highlights the benefits and drawbacks of enteric vs bladder exocrine drainage.

Endocrine drainage Optimal pancreatic venous drainage has also been controversial owing in large part to the catastrophic effect of vascular complications and metabolic considerations. Initial experience with venous drainage was via systemic circulation, most commonly an iliac vein,

TABLE 1  Enteric vs bladder drainage of the exocrine secretions [13] Enteric drainage

Bladder drainage

Pros

− Physiologic: • Enteric environment tolerates digestive enzymes • Reverses exocrine insufficiency − Technical: • Allows portal venous drainage

− If an anastomotic leak occurs, it is outside the fecal stream − Allows cystoscopic access for biopsy and sampling of urine to monitor for rejection

Cons

− Increased rates of: • Peri-pancreatic fluid collections • Intra-abdominal abscess/sepsis • Peritonitis • Anastomotic leaks • Gastrointestinal (GI) bleeding • Wound infections • Wound healing problems − Selective need for enterolysis or diverting Roux en Y limb − Loss of direct access to anastomosis and allograft for diagnosis and treatment − Inability to directly monitor exocrine secretions as a marker of rejection

− Urologic problems: • Hematuria • Dysuria • Cystitis • Urethritis • Urethral stricture or disruption • Balanitis • Increased lower urinary tract infections • Bladder stone formation • Urine leaks − Metabolic and volume problems: • Dehydration • Orthostatic hypotension • Constipation • Erythrocytosis • Metabolic acidosis − Reflux-associated pancreatitis − Urothelial malignancy/dysplasia − Need for enteric conversion for refractory, persistent, or recurrent problems − Medication burden (massive amounts of bicarbonate supplementation)

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Intraoperative complications

perhaps because of the larger and successful experience with renal transplantation using the same site; comparatively the portal vein is less accessible.21–23 Portal venous drainage, most often via the superior mesenteric vein, was first described in 1992 as a means of allowing physiologic endocrine drainage: to allow the first pass effect of the liver and ameliorate hyperinsulinemia.24 A recent systematic review and meta-analysis by Oliver et  al. found equivalent rates of graft thrombosis and graft survival between these two techniques.25 Currently, the portal vein is implanted systemically (iliac vein or inferior vena cava) in about 80% of SPKTs and about 20% of the time to the recipients portal system depending on the center preference and surgeon experience.20

Pretransplant complications The technical aspects of a pancreas transplant procedure begin at organ procurement. The pancreas is intimately associated with adjacent organs and can often blend into surrounding fat making it a challenging organ to procure. Meticulous dissection, excellent visualization, and gentle handling of tissue are required for optimal organ recovery.26 Visual inspection at the time of procurement by assessing fat content, procurement-related injuries, and vascular assessment remains the single most important step in determining if the organ is suitable for transplantation. Despite procuring surgeons best intentions, injuries to the pancreas vasculature, capsule, parenchyma, and duodenum are often initially unrecognized and vastly underreported.27 In fact, a recent UK registry analysis assessing damage to the deceased donor pancreas during procurement found that 52% of recovered pancreases were injured in some manner. Predisposing risk factors for injury include: concomitant liver donation, procurement team inexperience, variant right hepatic arterial anatomy, increased donor body mass index, and simultaneous small intestine donation.28 Bench preparation of the pancreas-duodenal allograft allows recognition and repair of most procurement-related issues, however, organ discard is undoubtedly increased due to procurement injury, with a single-center study from the Netherlands findings 17.2% of pancreases discarded because of surgical damage following back-table inspection.29 Vascular injuries are by far the most common ­procurement-related issue. In some instances, the injury is purposeful, driven by a concern on the part of the procuring surgeon that anatomy is forcing a choice between adequately recovering the pancreas or another organ (liver or small bowel). A replaced right hepatic artery is often handled by including with it the stump of the superior mesenteric artery. Injury to the inferior pancreaticoduodenal branch can occur in this situation, resulting in a devascularized pancreatic head and duodenum

(failure to recognize this anatomy may result in infarction of the graft and duodenal conduit leaks). Reconstruction of the gastroduodenal artery, which is ligated at the time of liver procurement, has been proposed as a solution to this issue, but is not widely practiced given the current trend to utilize ideal organs without the need for complex reconstruction in hopes of optimizing outcomes.30–32 Direct injection of the superior mesenteric artery and splenic artery can assess for vascular compromise, however, caution should be taken to avoid excessive flushing that can lead to pancreatic edema which predisposes to allograft pancreatitis. Under rare circumstances, methylene blue flush or angiogram can be performed to assess for specific vascular injuries.33 When injuries are identified they can typically be directly repaired. Stretch injury of the Y-graft occurring at the bifurcation of the common iliac artery needs to be recognized. Without repair, an intimal injury of the Y-graft may result in pseudoaneurysm, thrombosis, or posttransplant bleeding. It is the author’s opinion that a stretch injury of the bifurcation of the common iliac artery is best handled by total excision of the involved segment of artery and reanastomosis; an attempt to directly repair the injury may leave injured intima or narrow the lumen. On occasion, donor vessels can be absent when arriving to the transplanting center which can complicate vascular reconstruction. Distal superior mesenteric artery of the pancreas graft, a splenic artery segment from the splenic hilum, recipient inferior mesenteric vein, or saphenous vein reconstruction have been described, as has direct implantation of the splenic artery to the superior mesenteric artery in an end-to-side fashion.34–36 A short portal vein is not in and of itself a deal-breaker for pancreas transplant. It results from competing interests between the liver and pancreas anatomy. Short portal veins can often be sewn in directly to the patient following careful mobilization along with appropriate recipient vein mobilization or, alternatively, dealt with by attaching a venous extension (or interposition) of iliac vein. Use of an interposition venous graft does not appear to increase the rate of pancreas graft loss based on current evidence.12 Injury to the pancreas capsule or parenchyma occurs commonly in the tail region. This type of injury can most often simply be oversewn, however, distal pancreas resection can also be considered in extreme cases. Failure to recognize such injury can lead to enzymatic leaks posttransplant.

Intraoperative complications Recipient arterial (vascular clamp injury, arterial dissection, arterial thrombosis) and venous (hemorrhage from internal iliac vein, venous thrombosis) vascular

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21.  Technical complications of pancreas allotransplantation

events can occur at the time of pancreas transplant. Arterial events mandate immediate repair with a number of techniques including reconstruction with donor iliac vessels, artificial graft placement, or even stenting in the right circumstance.37–39 Atraumatic vascular clamps or Fogarty balloon catheters should be considered on heavily calcified vessels, however, the optimal way to avoid such complications involves meticulous surgical technique and preoperative imaging, most commonly a noncontrast computed tomography scan, which can provide valuable information about recipient arterial calcifications and help plan a safe site for arterial implantation. Common iliac vein mobilization is often necessary for the venous anastomosis from donor portal vein to recipient iliac vein. At times, division of the internal iliac vein can be extremely helpful to improve mobilization, however, care needs to be taken to adequately ligate both sides of this vessel because failure to secure the distal stump can result in life-threatening hemorrhage that is difficult to control. Mechanical thrombectomy and anticoagulation should be considered for recipient venous thrombosis that is recognized intraoperatively. The pancreas allograft can also experience intraoperative issues. Reperfusion hemorrhagic pancreatitis, which may be technical or idiopathic, may necessitate allograft pancreatectomy if hemostasis cannot be achieved. In less severe cases, drainage and close postoperative monitoring can be attempted with low thresholds to reexplore if ongoing transfusion requirements. Intraoperative graft thrombosis can occur and should be treated by thrombectomy, graft flushing, and anticoagulation. Avoidance of hypotension in these diabetic patients with adequate fluid management and vasopressor support as needed are key components of the intraoperative management to avoid thrombotic complications. The pancreas tail can be ischemic upon reperfusion, despite adequate blood flow to the head of the pancreas and duodenum. Splenic arterial thrombectomy can be attempted, however, distal pancreatectomy of ischemic tissue may be necessary.40 Should the tail of the pancreas be perfused with the duodenum and head of the pancreas ischemic, Whipple procedure has been described so long as the splenic artery of the tail is intact.41

Posttransplant complications The risk of mortality, most commonly from cardiovascular or infectious etiologies, and graft loss following pancreas transplantation is maximal within 3 months from transplant. After this time, death rate drops markedly and becomes lower than the risk of death on the waitlist (2.9% with pancreas transplant vs 6.8% on the waitlist).42 Risk factors for mortality post-pancreas transplant include recipient age >45, pancreas or kidney

transplant graft loss, and need for pretransplant dialysis.20 Risk factors for pancreas graft loss include donor factors (donor age > 45, cerebrovascular cause of death), transplant factors (low-volume center, extended cold ischemic time, nondepleting antibody induction, tacrolimus/sirolimus/mycophenolate avoidance), and recipient factors (younger age, female gender, high body mass index, HLA sensitization).20 It is worth reemphasizing that the key to minimizing post-pancreas transplant complications is to select appropriate donors and recipients, inspect the organ for damage or anatomic abnormalities that may predispose to complications (i.e., fatty pancreatic gland), perform meticulous bench and intraoperative surgical work, give appropriate medical management including evidence-based immunosuppression with perioperative antibiotics, and to follow these patients closely postoperatively to address issues in a timely fashion. Table 2 outlines a simple conceptual framework of early complications associated with pancreas transplantation. Radiologic evaluation is often useful in the work-up of pancreatic transplant complications. Duplex Doppler ultrasound is typically the first-line study given its availability, lack of ionizing radiation, and noninvasive nature. It is especially useful to diagnose vascular complications and fluid collections/abscesses. Computed tomography (CT) with intravenous (IV) contrast is the study of choice for most early and late complications, even with renal transplant dysfunction. The majority of pancreas transplant patients are at risk for acute kidney TABLE 2  Early complications of pancreas transplantation Vascular  Thrombosis   Arterial   Venous  Hemorrhage   Pancreatic graft   Vascular anastomosis Infection   Bacterial or fungal   Intraperitoneal   Superficial   Urinary tract Metabolic  Acidosis  Electrolytes   Hyper/hypokalemia   Hypocalcemia   Hypomagnesemia  Dehydration Gastrointestinal (GI)   Enteric leak   Mechanical obstruction Urologic   Bladder anastomotic leak   Bladder outlet obstruction

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Posttransplant complications

injury following contrast administration given that most also received a kidney at the time of pancreas transplant (SPK) or they are on tacrolimus for maintenance immunosuppression which can itself contribute to progressive nephropathy. Renal protective protocols (hydration, N-acetylcysteine, bicarbonate, and withholding nephrotoxic medications agents) are often implemented prior to IV contrast irrespective of kidney function, however, the benefit of these interventions in preventing contrast induced nephropathy, beyond hydration, is debatable.43 Oral contrast can be added to CT scans to rule out enteric leaks in enteric-drained grafts, while retrograde bladder contrast can be added to rule out leaks in ­bladder-drained grafts. Magnetic resonance imaging with IV gadolinium is often contraindicated secondary to renal dysfunction with risk for nephrogenic systemic fibrosis, but could be considered in select circumstances (glomerular filtration rate > 30).44 Angiography, cystography, and nuclear medicine scintigraphy are rarely required. Many transplant surgeons feel the optimal imaging m ­ odality is direct visualization of the pancreas graft at the time of relaparotomy. The following sections will discuss the relevant complications associated with pancreas transplantation. Presentation, workup, and management will be touched upon to keep this section clinically relevant.

Early posttransplant pancreas graft thrombosis Graft thrombosis continues to be the primary reason for early technical failure, although it is important to recognize that immunologic factors (i.e., pancreas allograft rejection) become the prominent etiology of graft thrombosis beyond 2 weeks posttransplant.45, 46 An international pancreas transplant registry report compared complications over two time periods (2005–09 vs 2010–14) and found decreased rates of early graft thrombosis for all categories of pancreas transplant overtime (SPK: 7.4% vs 5.4%, P = .0003; PAK: 10.9% vs 7.1%, P = .03; PTA: 9.1% vs 5.9%, P = 0.08, respectively).20 Reasons for this improvement are likely related to more stringent donor and recipient selection criteria given the current paradigm of optimizing patient outcomes. The pancreas allograft is uniquely predisposed for vascular complications because of complex arterial reconstructions (i.e., Y-graft), low microcirculatory pancreatic blood flow and the typical need to rely on collateral flow via the inferior pancreaticoduodenal artery to vascularize the head of the pancreas and donor duodenum. Approximately 6% of all pancreas transplants in the United States are currently lost secondary to thrombosis, which is most commonly venous in origin.47 Risk factors for thrombosis include donor factors (age > 45, cerebrovascular cause of death, donation after cardiac death, massive volume resuscitation leading to pancreatic edema which predisposes to graft pancreatitis which creates an

251

inflammatory background that promotes platelet aggregation and deposition, fatty infiltration of the pancreas and donor BMI  > 30 kg/m2), recipient factors (hypercoagulable states), surgical factors [suboptimal surgical technique, excessive flush pressure and volume, ­histidine-tryptophan-ketoglutarate (HTK) solution, prolonged preservation time > 12 h, segmental pancreas grafts, and surgeon experience] and postoperative factors (prolonged or severe pancreatitis, oral cyclosporine, intravenous tacrolimus, and intravenous immunoglobulin).18, 20, 36, 48–51 Many sources site portal venous drainage as being a risk factor for graft thrombosis, however, best evidence indicates no increased risk compared to systemic drainage.25 Venous thrombosis can be total or partial with the latter often successfully managed with therapeutic anticoagulation. The former necessitates urgent laparotomy that most often results in graft pancreatectomy. Clinically, venous thrombosis presents with sudden onset of otherwise unexplained hyperglycemia or hyperamylasemia. Occasionally, new onset abdominal pain or graft tenderness can be seen, secondary to inflammation from the ischemic graft. In urinary grafts, dark hematuria and markedly decreased urinary amylase can occur. Duplex Doppler ultrasound is the first-line imaging modality in this scenario, with the diagnosis often being confirmed. In ambiguous cases, CT scan with IV contrast (if renal function allows), conventional angiography or nuclear medicine scintigraphy can be considered, but are usually not necessary. Treatment of early graft thrombosis almost always necessitates relaparotomy with transplant pancreatectomy, with rare case reports of salvage.52, 53 Graft salvage is accomplishable in the setting of partial thrombosis and ischemia, but not when complete thrombosis and infarction have occurred. Urgency is necessary to prevent a partial thrombosis propagating to complete thrombosis. In addition to laparotomy, treatment options include systemic anticoagulation (particularly for partial venous thromboses), percutaneous interventional thrombolysis/thrombectomy, surgical thrombectomy, and partial resection of thrombosed/ischemic region of the pancreas, however, salvage results are universally poor with transplant pancreatectomy often still being required despite these heroic attempts.40, 54, 55 In cases of known pancreas graft thrombosis, delayed transplant pancreatectomy with simultaneous repancreas transplant has been successfully accomplished, however, the likelihood of receiving a timely organ offer must be weighed against the risk of a delay in removing an infarcted graft.56 Prevention of early graft thrombosis involves keen awareness of donor, recipient, and surgical-technical risk factors. There is an absence of high-level evidence for utility of pharmacoprophylaxis, yet many transplant centers believe in perioperative anticoagulation protocols involving daily low-dose aspirin, low-dose heparin drip

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with discontinuation at hospital discharge, and even long-term oral anticoagulation if previous personal history of graft thrombosis or hypercoagulable state.

Late posttransplant pancreas graft thrombosis Chronic allograft failure/rejection leads to progressive pancreas fibrosis with resultant vascular occlusion, often arterial. Presentation is most often asymptomatic, many years following transplant with an insidious history of worsening endocrine graft dysfunction. Intervention is rarely indicated as most cases are asymptomatic and nonsalvageable. Transplant pancreatectomy may be performed for specific indications (i.e., infection, pain, bowel obstruction). Prevention of late graft thrombosis/failure is aimed at optimizing immunosuppression regimens, treating cardiovascular disease aggressively, and close monitoring of pancreatic enzymes and endocrine function. Long-term aspirin may help reduce the incidence of this finding.45

Posttransplant bleeding Early postoperative bleeding is one of the most frequent indications for posttransplant relaparotomy, estimated to occur in up to 16% of cases, fortunately it rarely results in graft loss with less than 0.3% of all pancreas grafts lost to bleeding.8, 20 Clinically, post-pancreas transplant bleeding can occur intra-abdominally, via the gastrointestinal tract (enteric drained) or in the urinary bladder (bladder drained). Late posttransplant bleeding is rare, but potentially catastrophic, particularly if related to a pseudoaneurysm. Late bleeding can also occur due to rejection or cytomegalovirus (CMV) infection and treatments should be directed to these causes. Intra-abdominal bleeding Intra-abdominal bleeding typically occurs very early posttransplant and is often surgical in nature. It is more common in the setting of perioperative anticoagulation, but can also be seen in non-anticoagulated patients. Progressive decline in hemoglobin level on serial laboratory evaluations is often seen, but more brisk postoperative bleeding can present with hemodynamic instability that requires timely relaparotomy. At our center, we place surgical drains around the transplant pancreas and find visual inspection and analysis of drain fluid a useful clinical tool to use in cases of suspected bleeding. Firstline imaging involves Doppler pancreas ultrasound with the goal of ruling out graft thrombosis as a cause of the bleed. Intravenous contrast studies are more sensitive than ultrasound at pinpointing the site of bleeding and can be considered in select cases of suspected intra-abdominal bleed when ultrasound results are ambiguous. Intra-abdominal bleeding can be self-limited with early treatment in hemodynamically stable patients

aimed at supportive care (i.e., reversal of anticoagulation, close monitoring, blood product administration, etc.). Relaparotomy is mandated for hemodynamically unstable patients or patients who fail supportive care, with interventional radiology angiography less commonly utilized. Other causes of hypotension, such as myocardial infarction and sepsis, should be ruled out and managed before relaparotomy. Gastrointestinal (GI) bleeding Enteric drainage of exocrine secretions can lead to GI bleeds, both early and late. The incidence of early GI bleeding was found to occur in 11% of enteric-drained grafts in a recent single-center study from Europe.57 Within the first few weeks post-transplant, GI bleeds typically arise from the enteric anastomotic suture line and manifests with hematochezia.50 Bleeding of this nature is usually self-limited, but warrants correction of any coagulation abnormalities and close monitoring with escalation of investigations if conservative management fails. Diagnosis is typically clinical, with endoscopy and radiology studies only reserved for persistent cases. Rarely, early postoperative GI bleeding can originate from gastric or duodenal ulcers, often from or exacerbated by high-dose steroids administered peritransplant especially in patients not on proton pump inhibitor therapy. Relaparotomy is rarely indicated for this issue. Late GI bleeding is most commonly related to the graft duodenum with ischemia, an ulcer, CMV infection, duodenitis, or transplant rejection being the most likely etiologies. A rare cause for late GI bleeding involves erosion of an arterial mycotic pseudoaneurysm into the intestine (discussed below).58 Imaging is used to rule out vascular compromise and to assess for duodenal graft pathology. Rarely, capsule endoscopy may be beneficial to help with diagnosis. CMV polymerase chain reaction evaluation can readily identify CMV infection. Pancreatic biopsy may be necessary to evaluate for pancreas rejection. Ultimately, once the underlying etiology is found treatment should be aimed at addressing that issue. Transplant duodenectomy is rarely indicated for late GI bleeding, with recent estimates of less than 1.5% of these cases needing this aggressive intervention.59 Genitourinary (GU) bleeding Bladder drainage of exocrine secretions can lead to GU bleeding, both early and late. Early bleeding is often anastomotic and typically self-limited with supportive management including Foley catheter drainage and continuous bladder irrigation as needed. It is important in cases of GU bleeding to perform Doppler ultrasound of the pancreas (and the kidney in SPK transplant recipients) to rule out venous thrombosis of the graft which can also present in this manner.

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Late hematuria is often associated with duodenal pathology including duodenitis, ulceration, transplant rejection, and CMV infection. However, hematuria can also be a result of an endoscopic duodenal biopsy complication, an arterial-venous malformation, a mycotic pseudoaneurysm, chronic irritation of bladder mucosa with pancreas juices, or urinary tract infection. In general, treatment is aimed at addressing the underlying cause with endoscopic management by urology being a consideration. Should recurrent late hematuria prove difficult to manage conversion to enteric exocrine drainage may be mandated or even transplant pancreatectomy in rare cases. Other potential causes of bleeding and vascular compromise Mycotic pseudoaneurysm: Arterial mycotic pseudoaneurysms are rarely encountered post-pancreas transplant.58, 60 They can be bacterial, fungal, or sterile and can originate from any graft or recipient artery. They are generally felt to be a consequence of an early ­intra-abdominal infection, however, they may not manifest until many years later.61 Patients can present with massive ­intra-abdominal, gastrointestinal (erosion into the graft duodenum) or vesicular (bladder-drained grafts) ­bleeding, sepsis, unilateral iliac vein thrombosis with loss of distal pulses of affected extremity, or graft dysfunction. CT scan with intravenous contrast is important in identifying the lesion with positive blood cultures often being present. Infected pseudoaneurysms are typically treated by transplant pancreatectomy with excision and repair of affected vessels. In some cases, direct repair is hazardous and stenting can be life saving. Arteriovenous fistula: Arteriovenous fistulas can spontaneously form between mass-ligated arteries and veins in the graft mesenteric pedicle or can result from a pancreas graft biopsy. Identification can be incidental on imaging performed for other reasons, however, graft dysfunction can also occur and rarely GI, GU, or intra-abdominal bleeding can result.62–64 Diagnosis can be confirmed by auscultating a bruit over the pancreas graft or, more likely via pancreas Doppler ultrasound or CT with IV contrast. Treatment has been successful with interventional radiology angioembolization or surgical ligation, but observation may be an option for small lesions.65 Transplant pancreatectomy is often avoided in these situations, but is always a consideration if the lesion is not manageable with more conservative therapies. Pancreatic graft splenic artery aneurysm: This is usually donor or procurement related and typically treated via percutaneous embolization or surgical ligation. Distal pancreatectomy can also be a consideration if other treatments fail with a high probability of ongoing endocrine function following. Late stenosis of pancreas graft arteries: Pancreas graft vascular stenosis can result due to progression of preexisting

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donor vascular disease, de novo atherosclerosis, arterial injury at the time of surgery, or chronic rejection. Symptoms are typically nonspecific, but slow, progressive graft dysfunction usually results. If transplant pancreas Doppler ultrasound identifies a stenotic artery, interventional radiology involvement may become necessary to perform angiography and endovascular stenting. If the stenosis occurs slowly, collaterals may develop that support the graft. In this case, intervention is not warranted. This scenario is more likely if the stenosis is identified by routine imaging and not accompanied by clinical signs or symptoms.

Intra-abdominal infection Intra-abdominal infections (IAIs) historically led to high rates of graft loss and mortality.66 Owing to improved surgical technique with optimized antimicrobial and immunosuppressive perioperative management, minimizing cold ischemic time, and selective acceptance of donors, current estimates of graft loss due to IAIs are 0.5%, 0.5%, and 0.3% for SPK, PAK, and PTA, respectively.20 It is well established that longer administration of perioperative antibiotics is not better, and simply results in an increased incidence of resistant pathogens including fungal infections. Bacterial infections are most common, typically Staphylococcus species, and present earlier than fungal infection, most commonly Candida albicans, which can be more challenging to diagnose and treat.67 Risk factors for intra-abdominal infection include older donor age, pancreas after kidney transplant, retransplant, pretransplant peritoneal dialysis, extended preservation time, pancreatitis, enteric drainage, aggressive immunosuppression, and sirolimus use.20, 50, 68 Typical timeline for patient presentation is within 1 month following transplant, with fever, leukocytosis, abdominal pain, ileus, or peritonitis potentially being present. Superficial wound infection is frequently also present, with a well-healed skin incision decreasing the likelihood of deep infection. CT with IV and oral contrast (retrograde contrast for bladder-drained grafts) is often obtained to identify any potential sites of infection and to rule out anastomotic leak, which may be found in up to 30% of cases.50 IAIs can be localized abscesses, often treated with antimicrobial agents and percutaneous drainage, or diffuse with widespread ­intra-abdominal contamination. The latter situation mandates broad spectrum antimicrobial coverage and laparotomy for washout and inspection/repair of the pancreas allograft.

Anastomotic leak Anastomotic leaks recognized and managed in a timely fashion rarely impact graft or patient survival with  3,000 U/h) have a higher chance of enjoying a functioning graft for > 10 years according to the University of Minnesota series.30 Several studies have correlated hypoamylasuria with pancreas graft biopsy results.75,76 They show that a ≥ 50% decrease of UA from stable posttransplant baseline on two consecutive measurements are considered consistent with rejection and correlate well with biopsy results. Other urine markers  Other urine markers include: - Urine lipase (no widespread application). - Urine pH, as bladder drainage results in alkalization of urine. Urine pH monitoring is simple but not specific.

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- Experimental markers in animal models. In rejection, urine prostaglandin E2 and urine thromboxane B2 rise and precede a fall in UA. These tests are expensive and not routinely available. Urine markers of endocrine rejection Urine C-peptide determination after bladder-drained pancreas transplants is not reliable due to the fact that the C-peptide molecule may be altered by pH fluctuations and the proteolytic activity of pancreatic enzymes such as trypsin. Serum markers Serum markers of exocrine rejection They can be monitored in all types of pancreas transplants, irrespective of the technique used to manage pancreas exocrine secretions. They detect not only rejection but also pancreatitis, preservation injury, infection, and all types of acinar tissue damage. The latter include cytomegalovirus (CMV) pancreatitis, posttransplant lymphoproliferative disorder (PTLD), and graft biopsy pancreatitis.1 Serum amylase and serum lipase  Both are markers of pancreas inflammation from any cause. Increases in either may occur with rejection, and may even precede a decline in UA in bladder-drained pancreas transplants, but both markers are nonspecific. Levels rise proportionally with the degree of exocrine parenchymal injury. Serum amylase correlates better with histologically proven AR than does serum lipase.77 Other serum markers of exocrine rejection  These markers have shown a significant increase several days before hyperglycemia occurred in experimental and clinical studies. However, none of them is specific for rejection. These markers are: - - - - - - - - -

serum anodal trypsinogen (SAT), plasma pancreatic secretory trypsin inhibitor, pancreas-specific protein, pancreatitis-associated protein, pancreatic elastase, phospholipase A2, amyloid A, prostaglandin E2, and thromboxane B2.

None of these markers, except for SAT, has been showed clinically useful in diagnosing pancreas rejection.78,79 Serum markers of endocrine rejection Already in the early days of pancreas transplantation, serum markers of endocrine rejection were considered late markers of rejection.5 Today, and in addition

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to other markers and imaging techniques, they may be helpful in the decision-making process for considering a graft biopsy. The following are markers of endocrine rejection: Plasma glucose  Persistent hyperglycemia is considered the definitive test of pancreas graft failure. It is usually observed in recipients with severe AR episodes and islet involvement, but also in chronic rejection with persistent low-grade damage to the exocrine and vascular tissues resulting in graft fibrosis.77 Therefore, it is the least sensitive marker of rejection.80 Glucose disappearance rate  The glucose disappearance rate (kG) reflects the first- and second-phase insulin response. In contrast to the first-phase insulin release, a kG value can be quickly determined from serial blood glucose measurements. Modifications of the kG slope during the second-phase insulin response of an intravenous glucose tolerance test (IVGTT) can detect β-cell dysfunction in pancreas recipients.81 It is particularly useful when other markers provide conflicting data or when monitoring those markers is not possible.81 But, the presence of factors that may cause insulin resistance should be avoided. Moreover, the cause of a 20% decline is unidentifiable in almost 9% of pancreas recipients.81

used serum amylase and lipase levels correlate with ­biopsy-proven rejection.85 Over the last decade, the value of HLA antibody and De Novo donor-specific antibody (dn DSA) monitoring has been progressively established. Antibodymediated processes play an important role in pancreas transplantation as they do for other transplant organs.86 Along or in combination with cellular rejection, antibody-mediated rejection (AMR) is not an uncommon cause of graft dysfunction.55 Among early pancreas graft losses which were usually attributed to technical failure (thrombosis) in the past, AMR should be suspected based on DSA monitoring and ruled out.87 In a multivariate analysis by Mittal et al.,88 the development of dn DSA emerged as a strong independent predictor of pancreas graft failure. According to Malheiro et al.,89 emergence of dn DSA increased also the risks of graft failure in SPK recipients. Moreover, the risk of posttransplant dn DSA development correlates with early immunosuppressive management.90 HLA-Ab and dn DSA monitoring might help identify patients at a higher risk for AMR and graft failure and indicate the need for a biopsy and pancreas allograft histology.91

Imaging techniques

US, CT, and magnetic resonance imaging Pancreas grafts have vascular and enteric or bladder connections that vary in their anatomic location. Imaging techniques display the pancreatic transplant arterial and venous vasculature, parenchyma, and intestinal or urinary drainage.92–94 Critical vascular information includes venous thrombosis (partial or complete), arterial occlusion, arterio-enteric fistula, or (pseudo-) aneurysm. Parenchymal abnormalities are nonspecific and occur in pancreatitis, graft rejection, and graft ischemia. Peripancreatic fluid collections include hematoma, seroma, pseudocyst, and abscess. The latter two are related to pancreatitis, duct disruption, Immunological markers or leak from the duodenal anastomosis. Therefore, imRecent advances in posttransplant immunological aging techniques are used to diagnose or exclude graft monitoring have been helpful to transform monitoring complications.92–94 for pancreas transplant rejection. A number of assays US provides high-resolution imaging of the panhave been established to detect markers that identify creas graft but imaging can be obscured by overlying patients at higher risk for rejection including HLAbowel gas. US can be used to detect intrapancreatic and antibodies, antiendothelial antibodies, membrane gluperipancreatic fluid collections or a dilated pancreatic coprotein CD30, chemokines CXC ligand 9 and ligand duct.95,96 Color and spectral Doppler scans can display 10, as well as determination of donor-specific memory venous and arterial anastomotic stenosis, aneurysms, T-cell reactivity.83 In addition, Cashion et al.84 have used reduced pancreatic graft perfusion, and thrombi.97–99 a real-time polymerase chain reaction assay of gene-­ Major advantages of US are: expression levels including granzyme B, perforin, and HLA-Ab. But, these markers are not readily available - first reliable imaging technique utilized; clinically and have not been helpful in detecting AR. Yet, - easily portable; they have been helpful in confirming that the widely - lack of ionizing radiation; First-phase insulin release  The first-phase insulin release can be studied in response to intravenous (IV) glucose or glucagon injection. A blunted response characterizes poor functional reserve, is predicting an impending β-cell failure and, in transplant recipients, potential graft rejection.82 But in clinical practice, measuring first-phase insulin release is depending on logistical problems: drawing C-peptide and insulin levels at 1-min intervals and C-peptide and insulin analyses being readily available and rapidly obtainable is cumbersome.

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Evaluation means of diagnosing rejection

- no use of IV contrast agents; and - real-time vascular flow map for detection of vascular anastomotic stenosis and/or reduced pancreatic graft perfusion. CT imaging with enhanced agents, even in the absence of well-preserved renal function, provides a superior angiographic and parenchymal display of the pancreas graft.92,93 It can be used in patients with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 and with IV hydration (500 mL normal saline 2 h before procedure, and 1 L normal saline 4–6 h after procedure) in patients with an eGFR of 40–60  mL/min/1.73  m2. But magnetic resonance (MR) imaging is preferred in patients with an eGFR  30 mL/min/1.73 m2. Other imaging techniques A variety of tracers for scintigraphy imaging have been studied in pancreas transplant patients.105 Clinically, the most frequently used tracer is 99Tc DPTA (technetium—99  m—diethylenetriamine—pentaacetic acid) because of its excellent visualization of the simultaneously transplanted kidney. Computer analysis can quantitatively measure blood flow to the pancreas (technetium index). However, poor visualization of the pancreas has been reported despite normal allograft function. In general, all scintigraphic methods are not capable of distinguishing subtle changes such as early rejection or mild pancreatitis.105 Another imaging technique that has been evaluated for the diagnosis of pancreas transplant rejection is positron emission tomography (PET) coupled with CT. As AR involves recruitment of leucocytes avid for fluorodeoxyglucose 18F (18F-FDG), PET/CT may ­noninvasively

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distinguish nonrejection from AR. In a series of 31 adult kidney transplant recipients, Lovinfosse et  al.106 have demonstrated that 18F-FDG PET/CT may help, noninvasively, prevent unnecessary transplant biopsies. This imaging technique has yet to be tested in pancreas transplantation.

Cell and tissue diagnosis of allograft rejection Fine-needle aspiration biopsy Before needle core biopsy techniques were successfully developed and safety performed, fine-needle aspiration biopsy (FNAB) was used to monitor the transformation of infiltrating mononuclear cells into blasts.107 AR was defined by an accumulation of immature cells such as lymphoblasts, plasmablasts, and monoblasts while vascular rejection was associated with proliferation of mononuclear phagocytes and tissue macrophages.107 Technical difficulties in recipients with peripancreatic fluid collections or graft fibrosis have been reported resulting in false-positive results and depended on the expertise of the pathologist.108 Therefore, needle core biopsies are preferred for histologic evaluation. Cytology Monitoring of pancreatic juice cytology for rejection was done in conjunction with temporary external drainage of the pancreatic duct in enteric-drained recipients109 and in delayed duct-injected segmental pancreatic grafts.27 Cytology revealed increased cellularity, especially mononuclear cells with lymphoblasts along with a decrease in amylase concentration in the pancreatic juice.109 Needle core biopsy Since the early days, and valid for all solid-organ transplants (e.g., kidney, liver, heart, lung, and intestine), a graft biopsy with histopathologic evaluation was and continues to be the gold standard for diagnosing graft rejection. For pancreas transplants, the use of a graft biopsy was initially deferred for two reasons. First, isolated pancreas graft rejection is a relatively rare event in SPK recipients, who represent the most common recipient category.1 It is common clinical practice that pancreas graft rejection is monitored indirectly by relying on serum creatinine levels and/or on kidney graft biopsies. In solitary pancreas graft recipients, kidney graft function cannot be used as a marker. Second, pancreas graft biopsies were only reluctantly done in the past given potential complications such as intra-abdominal bleeding, pancreatitis, pancreatic fistulas, and abscesses with subsequent graft loss. Before the introduction of imaging techniques (US, CT, and MRI) and before the availability of special biopsy needles, tissue diagnosis required open

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laparotomy.110 With the subsequent development of cystoscopic biopsies for bladder-drained pancreas transplants, and of percutaneous or laparoscopic biopsies for all other types of exocrine drainage, open biopsies are now rarely performed.1 Routine use of various biopsy techniques is now considered one of the main reasons for improvement in pancreas transplant outcome, in particular in recipients of solitary pancreas transplants in whom laboratory and clinical diagnosis of rejection can be difficult. The relatively late introduction of routine graft biopsies has also delayed the development of standardized grading systems for acute and chronic rejection111 (see Section V). Graft biopsy: Cystoscopic transduodenal The cystoscopic transduodenal pancreas biopsy technique was developed by Perkins et al. for the monitoring of bladder-drained pancreatic grafts.112 For improving the technique, other groups introduced a modification of the Menghini needle, proposed biopsy under US guidance and the use of modified core-cut needles (18-gauge, 40-cm needles) mounted on a regular biopsy gun (Bard Inc., Covington, GA).113,114 Another advantage of the cystoscopic biopsy technique is that a concurrent duodenal graft biopsy can be obtained by inserting a gastrointestinal biopsy alligator forceps through the cystoscope.1 Experimental and clinical studies have shown that rejection of the graft duodenum highly correlates with rejection of the pancreas. However, the absence of duodenal rejection does not preclude rejection of the pancreas.115–117 Cytoscopic biopsies are associated with a low complications rate. In case of macrohematuria, continuous bladder irrigation using a three-way Foley catheter usually corrects the bleeding.1 The main drawback of cystoscopic biopsies is their invasiveness, especially in male recipients, usually requiring hospitalization and general or regional anesthesia.116,117 Obviously, this technique can only be used in bladder-drained pancreas recipients. Graft biopsy: Percutaneous Percutaneous biopsies under US guidance in ­bladder-drained pancreas recipients were first described by Allen et al.108 After its safety was confirmed,118,119 this technique was used for other exocrine drainage procedures as well.120 Percutaneous biopsies can also be performed under CT guidance121 or with a combination of US and CT.122 They can be performed under local anesthesia, with or without additional IV sedatives or analgesics. Major complications are reported in 3% including bleeding and need for surgical reexploration.122 Relative contraindications include overlying bowel loops and coagulation derangements; CT nonavailability and cost are also issues. On the positive side, the hospital stay is shorter than with open biopsies.1

Graft biopsy: Laparoscopic The laparoscopic pancreas graft biopsy technique was first described by West and Gruessner123 and subsequently performed by others.124,125 It has become an alternative to CT- or US-guided graft biopsies in case of overlying and adherent small bowel loops. The main concern is technical: recipients have already undergone at least one previous laparotomy, and adhesions are frequent. But, in contrast to a percutaneous biopsy, a laparoscopic biopsy allows direct visualization, and hemorrhage can easily be controlled by endoelectrocautery. Therefore, pancreas recipients undergoing a laparoscopic biopsy can usually be discharged several hours after the procedure.123 Nevertheless, large series of laparoscopic biopsies have not been reported, because radiologists have become increasingly comfortable with percutaneous biopsy techniques.1 Graft biopsy: Endoscopic gastroduodenal and enteric biopsies Nakhleh et al.115–117 demonstrated that duodenal rejection is usually concommittent with pancreatic rejection while the absence of duodenal rejection does not preclude pancreas rejection. In the era of enteric drainage, new or modified surgical techniques were designed to permit direct endoscopic visualization of the duodenal graft for improved immunological monitoring.126 Zibari et  al.127 described a technique of whole pancreaticoduodenal transplantation with enteric drainage to an end-to-side Roux-en-Y loop. A temporary jejunostomy facilitated graft biopsy and allowed direct endoscopic vision of the duodenal segment. The same group performed a series of pancreas transplants in which the allograft jejunum was anastomosed to the anterior portion of the stomach,53,128 reviving Calne’s earlier description of gastric drainage of exocrine secretions.129 This technique also facilitated graft biopsy and allowed direct endoscopic vision of the duodenal segment. In 2008, De Roover et al.52 published a series of pancreas transplants with anastomosis of the graft duodenum to the lower third of the recipient’s duodenum. Other groups adopted this technique130–133 because it facilitates endoscopic access for rejection surveillance. It also allowed performance of endoscopic pancreas biopsies under endoscopic ultrasound examination. Major drawbacks of the duodenoduodenostomy technique are potentially serious complications such as biopsy-related perforations and fistulas, as well as the safe handling of the native duodenum after graft removal.134 For duodenal biopsies in enteric-drained patients, Margreiter et  al. used various endoscopic techniques such as push enteroscopy, single-balloon enteroscopy, or ­double-balloon enteroscopy.126,135 Primary results of protocol biopsies of the graft duodenum appear ­promising133,135–137 and effective for early diagnosis of rejection.

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Clinical presentation of pancreas graft dysfunction and rejection

Biopsy algorithm In 1998, Laftavi et al.138 proposed a biopsy algorithm for pancreas biopsies. Percutaneous biopsies should be attempted first, on an outpatient basis, irrespective of the drainage technique (bladder drainage, enteric drainage, or duct injection). Even for bladder-drained pancreas recipients, the percutaneous technique was considered the first choice because cystoscopic biopsies are usually not performed on an outpatient basis. If the percutaneous approach fails cystoscopic biopsy should be performed next in bladder-drained recipients and both duodenal and pancreas graft biopsies should be obtained. With the introduction of gastroduodenal and duodenoduodenal drainage techniques allowing an easier endoscopic approach to the duodenum, the biopsy algorithm should be adapted accordingly. Therefore, a duodenal graft biopsy should be considered the first choice for gastroduodenal and duodenoduodenal drainage techniques. If all of the above techniques fail and a definitive histopathologic diagnosis is necessary, the final step is an open biopsy irrespective of the drainage technique. A graphic depiction of the modified biopsy algorithm is shown in Fig. 3.

Clinical presentation of pancreas graft dysfunction and rejection Regular posttransplant follow-up of all pancreas transplant recipients should include the following: - - - - - -

serum creatinine, fasting plasma glucose, serum lipase and amylase, hemoglobin A1C, serum C-peptide, urine amylase (8–12 h urine collections) in bladderdrained pancreas recipients. - blood Tac (or cyclosporine) levels, and - DSA levels (against the donor of the pancreas allograft). On a less regular basis, routine follow-up should also include: - IVGTT glucose challenge or glucagon stimulating test, - islet antibodies, and - US—Doppler imaging. In general, pancreas allograft rejection should be suspected in all recipients who present with either clinical symptoms or laboratory abnormalities. The most

Recipients with

Recipients with

Recipients with

bladder drainage

enteric drainage

gastro duodenal drainage

-------------------

--------------------

--------------------------------

(duct injection) 1st choice

1st choice

percutaneous PB

percutaneous PB

2nd choice cystoscopic duodenal B

2nd choice laparoscopic PB

and/or

1st choice endoscopic duodenal B

2nd choice endoscopic transduodenal pancreas B

cystoscopic transduodenal PB

3rd choice

3rd choice

3rd choice

laparoscopic PB

open PB

percutaneous PB

4th choice

4th choice

open PB

laparoscopic PB 5th choice open PB

FIG. 3  Modified algorithm for pancreas graft (P) biopsy (B) techniques including recipients with gastroduodenal drainage. Adapted according to Laftavi MR, Gruessner AC, Bland BJ, et al. Diagnosis of pancreas rejection. Cystoscopic transduodenal versus percutaneous computed tomography scan-guided biopsy. Transplantation 1998; 65: 528-532.

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c­ommon presentation is an elevation in serum lipase and/or amylase levels. The next diagnostic step is a pancreas allograft biopsy, usually followed by an inpatient admission.

Recipients of a solitary pancreas transplant (PAK or PTA)

serum creatinine level), should be considered for a kidney graft biopsy to rule out kidney and/or pancreas allograft rejection. If the renal allograft biopsy is consistent with AR, the patient should be treated for rejection without proceeding to pancreas biopsy. If the serum pancreatic enzymes are elevated and the serum creatinine level is normal and the kidney biopsy is negative for rejection, a pancreas graft biopsy must be considered (Fig. 5).

After confirmation of an elevated serum lipase and/ or amylase level, a pancreas ultrasound study or CT imaging with oral contrast (or MRI when eGFR is 50% of glomeruli

IIb

Glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV

I

IIa

control obtained with intensive diabetes therapy was shown to slow the decline in glomerular filtration rate (GFR) overtime,13 indicating a pivotal role for adequate glycemic control. As glomerular structure is completely subverted in the later stages of DKD, with loss of podocytes and lobular transformation of the GBM, interventions aimed at preventing the development and progression of DKD should be implemented at the earliest stages of disease. The American Diabetes Association (ADA) recommends regular monitoring of albuminuria and eGFR and optimization of glucose and blood pressure control to reduce the risk or slow the progression of DKD.2

Effect of PTx alone on native kidney function A number of studies have assessed the effect of PTx alone (PTA) on native kidney function and/or histology. These studies differ in terms of design (uncontrolled or controlled), follow-up duration (from 1 to 12 years), sample size, type of surgery (enteric or bladder drainage for exocrine secretion), outcome measures (GFR measured or estimated with different formulas), and immunosuppressive regimens. Most studies showed a decline in GFR after PTA. At 1 year after PTA, renal function (as estimated by GFR) was either reported to remain stable14,15 or deteriorate significantly.16 Even when no statistically significant difference in renal function parameters was observed, a clinically meaningful proportion of patients (25%) developed substantial deterioration in renal function, with one patient requiring dialysis.14 Conversely, a significant reduction of average urinary excretion rate and regression of proteinuria in several patients 1 year after transplantation was reported by Coppelli and colleagues.15 Studies with longer follow-up consistently showed a decline in GFR. A recent, retrospective controlled study that included 79 recipients of a PTA and 84 nontransplanted type 1 diabetic subjects who were candidates for PTA, all with an eGFR ≥60 mL/ min/1.73 m2, reported that mean eGFR was significantly lower in the PTA group during follow-up (Fig. 1), and a significantly higher percentage of patients in the PTA group developed ESRD, suggesting that there is a considerable risk for deterioration in PTA recipients compared with nontransplanted controls.17 Several studies sought to identify factors that affect renal function after PTA. Among these, high levels of calcineurin inhibitors (CNIs) after PTA17,18 and pretransplant renal function (GFR