Diabetes and Kidney Disease 3030860191, 9783030860196

Table of contents :
Contents
Contributors
Chapter 1: Historical Background of Diabetic Kidney Disease
Introduction
The Discovery of Diabetic Kidney Disease
The Pathology of Diabetic Renal Disease
Initial Studies of Renal Biopsies
Radioimmunoassay and the Concept of Microalbuminuria
The Renin–Angiotensin–Aldosterone System and Diabetic Kidney Disease
Value of Glycemic Control
Treatment of Hyperglycemia
Intensive Glycemic Control
The Impact of Glucose-Lowering Drugs on Diabetic Kidney Disease Progression
Sodium Glucose Transporter Inhibitors (SGLT2i)
Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists
Bardoxolone
Recent Updates
Conclusion
References
Chapter 2: Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines
Introduction
Glycemic Management
Glycemic Monitoring and Targets
Medical Therapy for Hyperglycemia
Older Agents
Newer Agents
Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)
Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA)
Insulin Use in Type 2 DM
Hypertension Control in DKD
Hypertension Management
Albuminuria Management
Lifestyle Management
Tobacco Cessation
Dietary Modifications
Physical Activity and Exercise
Self-management Programs and Team-Based Care
References
Part I: Natural Course, Pathogenesis, Morphology and Genetics
Chapter 3: Diabetic Kidney Disease: Scope of the Problem
Epidemiology of Diabetic Kidney Disease
Obesity, Metabolic Syndrome, and Diabetic Nephropathy
Geriatrics and Diabetic Nephropathy
References
Chapter 4: Natural Course (Stages/Evidence-Based Discussion)
Introduction
Natural History of DKD in T1DM
Stage 1: Hypertrophy-Hyperfiltration
Stage 2: The Silent Stage
Stage 3: Microalbuminuria or Incipient Diabetic Nephropathy (IDN)
Stage 4: Macroalbuminuria
Stage 5: Uremia
Natural History of Diabetic Kidney Disease in T2DM
Stage 1: Initial Stage in T2DM
Stage 2: Normoalbuminuria
Stage 3: Microalbuminuria or Incipient Diabetic Nephropathy
Stage 4: ODN
Stage 5: ESRD
Non-albuminuric DKD
References
Chapter 5: Pathogenesis: Hemodynamic Alterations
Introduction
Single Nephron GFR Versus Total GFR
Renin-Angiotensin-Aldosterone System
Angiotensinogen
ACE-Ang II-AT-1R Axis
ACE2-Ang (1–7)-Mas Axis
Ang (1–9)
Renin/Prorenin
Aldosterone
Neprilysin
Prolyl Oligopeptidase
How Hyperglycemia Affects Single Nephron GFR
Hemodynamics as an Upstream Pathomechanism in Diabetic Nephropathy
References
Chapter 6: Pathogenesis: Structural Changes in the Kidneys in Type 1 and Type 2 Diabetes
Introduction
A Bit of History
Morphologic Findings in Diabetic Nephropathy and Related Physiopathology
Comparison of Diabetic Nephropathy in Type 1 and 2 Diabetic Patients
Pathologic Classification of Diabetic Nephropathy
Understanding the Pathology in Diabetic Kidney Disease: From the Research Laboratory to the Evaluation of Kidney Samples
Reversibility of Structural and Functional Damage in Advanced Diabetic Kidney Disease
Microalbuminuria: The Gold Standard for Diagnosis of Diabetic Kidney Disease
Other Urinary Biomarkers of Diabetic Kidney Disease
Other Biomarkers of Diabetic Kidney Disease Under Study
Differential Diagnosis of Diabetic Kidney Disease
Superimposed Pathology (Nondiabetic Lesions) That Can Alter Structural Alterations in Diabetic Nephropathy Cases
Conclusions
References
Chapter 7: Diabetes in Children and Adolescents
Introduction
Epidemiology of DM
Etiology of DM
Pathophysiology of DM
Development of the Pancreas
Developmental Programming of DM
Clinical Manifestations of DM
Acute Complications of DM
Diagnosis
Monogenic DM
Genetic Defects of β-Cell Function
Other Causes of Familial DM
Treatment of DM
Treatment of T1DM
Insulin
Insulin Regimens
Monitoring
Treatment of T2DM
Treatment of DKA and HHS
Treatment of Monogenic DM
Chronic Complications and Comorbidities of DM
Diabetic Kidney Disease
Diabetic Kidney Disease
Hyperfiltration
Inflammation
ESRD
Screening and Prevention of DM
Transition of Adolescents with DM to Adult Healthcare Service
References
Part II: Clinical Presentation and Associated Conditions
Chapter 8: Screening, Early Diagnosis, Genetic Markers and Predictors of Progression
Introduction
Screening
Albuminuria
Glomerular Filtration Rate
Diagnosis
Other Clinical Predictors of Diabetic Kidney Disease
Age
Hypertension
Hyperglycemia
Diabetic Retinopathy
Novel Biomarkers
Proteomics
Genetic Markers
Conclusion
References
Chapter 9: Atypical Presentations
Overview of Traditional and Nontraditional Concepts in Diabetic Kidney Disease
Hyperfiltration and Increased GFR Herald the Onset of Diabetic Kidney Disease
The Roles of Glucotoxicity, Oxidative Stress (OS), and Inflammation in Diabetic Kidney Disease
AGEs, Oxidative Stress and the Impact on the Diabetic Kidney
Endogenous AGEs
Exogenous AGEs
Role of Polyclonal Free Light Chains (pcFLCs) in Diabetic Nephropathy
Antioxidants and Inhibition of Inflammation
Treatment with RAAS Inhibitors
Aldosterone Blockade and Protection Against Diabetic Nephropathy
Allopurinol
Conclusion
References
Chapter 10: Albuminuria and Proteinuria
Definitions of Proteinuric States in Diabetic Kidney Disease
Justification of the Term “Albuminuria-Proteinuria”
Measurement of Urinary Albumin
Significance of Albuminuria in Type 1 Diabetic Patients
Significance of Albuminuria in Type 2 Diabetic Patients
Mechanisms of Albuminuria in Diabetes
Extrarenal Manifestations of Albuminuria
Albuminuria and Cardiovascular Disease
Albuminuria and Hypertension
Determinants of Albuminuria
Screening for Albuminuria
Proteinuria of Nondiabetic Origin
Treatment of Albuminuria-Proteinuria
Podocyte-Specific Drugs
Conclusions
References
Chapter 11: Hypertension and Diabetes
Introduction
Pathophysiology of Hypertension in Diabetics
Hypertension and Type 1 Diabetes Mellitus
Hypertension and Type 2 Diabetes
Cardiovascular Outcomes in Hypertensive Diabetics vs. Hypertensive Non-Diabetics
Renal Outcomes in Hypertensive Diabetics
Hypertension Treatment Strategies in Diabetics
Lifestyle Modifications
Effects of Antihypertensive Drugs on Incident Diabetes
Pharmacological Treatment of Hypertension in Diabetes
Overview
ARBs
ACE-Inhibitors
Renin Inhibitor(s)
Calcium Antagonists
Beta-Blockers
Diuretics
Other Drug Classes
Blood Pressure Treatment Targets for All Diabetics?
References
Chapter 12: Obesity and Metabolic Syndrome
The Role of Visceral Adiposity
Renal Alterations in Obesity
Increased Sympathetic Nervous System Activity
The Role of Adipose Tissue and Kidney Disease
Metabolic Syndrome
Quantification of Adipose Tissue in Chronic Kidney Disease
Treatment
Lifestyle Modifications
Drug Therapy
Bariatric Surgery
Management Obesity in Patients with ESKD
Conclusion
References
Chapter 13: Anemia and Diabetes
Definition and Prevalence of Anemia in CKD
Causes of Anemia
Iron Deficiency
Erythropoietin Deficiency and Hypo Responsiveness
Nephrotic Syndrome
ACE Inhibitors and Angiotensin Receptor Antagonists
Consequences of Anemia
Quality of Life
Progression of Kidney Disease
Cardiovascular Disease
Clinical Trials of Erythropoietin-Stimulating Agents
Kidney Outcomes
Cardiovascular Outcomes
Cardiovascular Events
Clinical Practice Guidelines for Evaluation of Anemia
Recommendations for Treatment of Anemia
KDIGO and NKF Clinical Practice Guidelines
Food and Drug Administration
Anemia Management
Monitoring Response to Treatment
Adverse Side Effects of Therapy
Economic Burden of Anemia
Areas of Uncertainty
Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor (HIF-PHI): A New Beginning?
Summary
References
Chapter 14: Cardiovascular Disease and Diabetic Kidney Disease
Cardiovascular Disease in Patients with Diabetes
Heart Failure and Type 2 Diabetes
Cardiovascular Disease in Chronic Kidney Disease
Cardiovascular Disease and Diabetic Kidney Disease
Sodium-Glucose Cotransporter-2 Inhibitors
Conclusion
References
Chapter 15: Dyslipidemia and Diabetes
Introduction
DKD: Definition and Diagnosis
Lipid Disturbances in Diabetes, CKD, and DKD
Management of CKD
Guidelines
Conclusions
References
Chapter 16: Bone Disease and Diabetes
Introduction
Epidemiology: Fracture Risk
Bone Density in Diabetes
Underlying Mechanisms of Bone Fragility
Insulin
AGEs
Vitamin D and Calcium
Bone Microarchitecture
Sarcopenia
HbA1c
Adiposity-Related Factors
Therapy
Diabetic Kidney Disease
Assessment
Treatment
References
Chapter 17: Diabetic Retinopathy
Hyperglycemia
Hypertension
Hyperlipidemia
Pregnancy
Kidney Disease
Other Risk Factors
Classification of Diabetic Retinopathy
Non-proliferative Diabetic Retinopathy
Diabetic Macular Edema
Proliferative Diabetic Retinopathy
Screening for Diabetic Retinopathy
Treatment of Diabetic Retinopathy
Other Ocular Manifestations
References
Chapter 18: Pregnancy and Diabetes
Introduction
Maternal Pregnancy Outcomes
Fetal Pregnancy Outcomes
Gestational Diabetes Mellitus
Treatment of Diabetes and CKD from Diabetic Kidney Disease During Pregnancy
Preeclampsia Prevention
Antihyperglycemic Treatment
Hypertension Treatment
Anemia of Chronic Kidney Disease
Mineral Bone Disease of CKD
Postpartum Treatment
Preconception Counseling
Special Considerations: Kidney Biopsy During Pregnancy
Conclusion
References
Chapter 19: Kidney Transplantation and Kidney Pancreas Transplantation
Introduction
Transplant Options for Patients with Diabetic Kidney Disease
Patient Selection and Kidney Transplant
Pancreas Transplantation
Indications for Pancreas Transplants
Pancreatic Islet Cell Transplantation
Posttransplant Diabetes Mellitus (PTDM)
Summary and Conclusions
References
Chapter 20: Diabetic Kidney Disease and Covid-19
Introduction
Diabetic Kidney Disease and SARS-CoV-2: An Immunological Approach
Diabetic Kidney Disease and SARS-CoV-2: A Therapeutics Approach
Metformin and DPP-4 Inhibitors
Sodium-Glucose co-Transporter-2 (SGLT2) Inhibitors
Glucagon-like Peptide 1 Receptor Agonists (GLP-1RAs)
Statins and Vitamin D: Common Drugs Used in Diabetic Patients
Conclusions
References
Part III: Treatment and Prognosis
Chapter 21: Glycemic Control
Introduction
Assessment
Estimation of Kidney Function and Staging of Diabetic Kidney Disease
Glycemic Target
UKPDS, DCCT, and Kumamoto
ACCORD, ADVANCE, and VADT
Management
Non-insulin Medications
Oral
Biguanides
Sulfonylureas
Meglitinides
Thiazolidinediones
Dipeptidyl Peptidase-4 Inhibitors
Alpha-Glucosidase Inhibitors
Sodium-Glucose Co-transporter-2 Inhibitors
Parenteral
Glucagon-Like Peptide 1 Receptor Agonists
Amylin Analogues
Others
Dopamine Agonists
Bile Acid Sequestrants
Insulin
Recommendation for Type 2 Diabetes Management in Chronic Kidney Disease
Recommendation for Management of Diabetic Ketoacidosis in End-Stage Kidney Disease
Monitoring
Measuring Glycemic Control
Hypoglycemia
References
Chapter 22: Computerized Clinical Decision Support
Scope of the Problem
Epidemiology
Early Recognition
Proven Interventions
Under-Recognition of CKD
Under-Treatment of CKD
Introduction to CDS
Clinically Relevant CDS
Future Directions with CDS
Existing CDS Systems for Diabetes, Hypertension, and CKD
Preventing Adverse Drug Events in CKD
CDS to Prompt Recognition of CKD
CDS Systems to Improve Blood Pressure Control
CDS Systems to Improve Diabetes Management
CDS to Treat CKD
Optimal CDS for Diabetes and CKD
Identifying High-Risk Patients
Preventing Drug Adverse Events
Identifying Patients Not Meeting Treatment Goals
Recommendations to Help Providers Reach Treatment Goals
Engaging Patients
Ensuring Success
Monitoring Outcomes
References
Chapter 23: Antihypertensive Therapies
Introduction
Interventions for Early Diabetic Kidney Disease
Glycemic Control
Inhibitors of the Renin-Angiotensin System
Angiotensin-Converting Enzyme Inhibitors
Angiotensin II Receptor Blockers
Direct Renin Inhibitor(s)
Aldosterone Antagonists
Other Combinations of RAS Blockers
Blood Pressure Lowering
Dietary Protein Restriction
Dietary Sodium Restriction
Sodium-Glucose Linked Transporter-2 (SGLT-2) Inhibitors
Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists
Summary
References
Chapter 24: Diabetes and Kidney disease: metformin
Metformin: Mechanisms of Action (Fig. 24.1)
Metformin-Positive Effects in the Diabetic Kidney
Experimental Work
Clinical Studies
Metformin and Lactic Acidosis in Patients with Diabetes: The Role of Kidney Function
Guidelines on the Use of Metformin in Patients with Kidney Disease (Fig. 24.2)
Conclusions
References
Chapter 25: Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors
Introduction
Basic Pharmacology of SGLT2i
Cardiorenal Benefits of SGLT2i in Patients with Type 2 Diabetes
Adverse Effects
Urogenital Infections
Diabetic Ketoacidosis (DKA)
Acute Kidney Injury (AKI) and Volume Depletion
Amputations
Use in Kidney Transplant Recipients
Approved Uses and Pharmacological Properties of Individual SGLT2i
Practical Considerations
References
Chapter 26: Glucagon-like Peptide-1 Receptor Agonists (GLP1-RA)
Introduction
Glucagon-like Peptide-1 Physiology and Natural Functions
Natural Roles of GLP-1
Glucose Homeostasis
Immunity
Currently Available GLP-1 Receptor Agonist Therapies
Kidney Disease Outcome Data
Lixisenatide
Liraglutide
Semaglutide
Dulaglutide
Exenatide
Putative Mechanisms of Kidney Protection by GLP-1 Receptor Agonists
Guideline Recommendations on GLP-1 Receptor Agonist Use in DKD
Conclusion
References
Chapter 27: Dipeptidyl Peptidase-4 (DPP4) Inhibitors
Introduction
Mechanism of Action
DPP-4 Enzyme
Antiglycemic Effects of DPP-4 Inhibitors (DPP-4i)
Potential Effects of DPP-4i on the Mechanisms of Diabetic Kidney Disease
Benefits of DPP-4i in Patients with Type 2 Diabetes Mellitus
Adverse Events (AEs)
Pancreatitis
Hospitalization for Heart Failure (hHF)
Arthralgias
Application of DPP-4i in Special Populations
Kidney Transplant Recipients
Dialysis
Practice Considerations
References
Chapter 28: Novel Treatments and the Future of DKD: What Is on the Horizon?
Introduction
The Role of Immune System and Prospects of Immunotherapy in Type 1 Diabetes
The Immune System and Type 2 Diabetes
Epithelial-to-Mesenchymal Transition and Kidney Fibrosis: Potential for Reversibility
The Promise of Metabolomics and Proteomics
Genes, Epigenetics, and MicroRNAs
Nanotechnology in Diabetes Research and Treatment
In Pursuit of Futuristic Therapies
Concluding Remarks
References
Chapter 29: Putting it All Together: Practical Approach to the Patient with Diabetic Kidney Disease
Scope of the Problem
Risk Factors for Development of Type 2 Diabetes
Population Considerations
Additional Risk Factors
Screening for Diabetes
Screening for and Diagnosis of Diabetic Kidney Disease
Management
Lifestyle Management
Cardiovascular and Renal Protection
RAAS (Renin-Angiotensin-Aldosterone System) Inhibition
Angiotensin 2 Inhibition
Mineralocorticoid Inhibition
SGLT2 Inhibitors
Newer Therapies
GLP-1RA
Selective Mineralocorticoid Receptor Antagonists
Glycemic Control
Monitoring
Choice of Agents
Metformin
Hypertension Control
Cholesterol Management
Resources
Summary
References
Index

Citation preview

Diabetes and Kidney Disease Edgar V. Lerma Vecihi Batuman Editors Second Edition

123

Diabetes and Kidney Disease

Edgar V. Lerma  •  Vecihi Batuman Editors

Diabetes and Kidney Disease Second Edition

Editors Edgar V. Lerma Section of Nephrology University of Illinois at Chicago/Advocate Christ Medical Center, Oak Lawn, IL, USA

Vecihi Batuman Nephrology Section Tulane University New Orleans, LA, USA

ISBN 978-3-030-86019-6    ISBN 978-3-030-86020-2 (eBook) https://doi.org/10.1007/978-3-030-86020-2 © Springer Nature Switzerland AG 2014, 2022 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To all my mentors and friends, at the University of Santo Tomas Faculty of Medicine and Surgery in Manila, Philippines, and Northwestern University Feinberg School of Medicine in Chicago, IL, who have in one way or another, influenced and guided me to become the physician that I am... To all the medical students, interns, and residents at Advocate Christ Medical Center, whom I have taught or learned from, especially those who eventually decided to pursue Nephrology as a career... To my parents and my brothers, without whose unwavering love and support through the good and bad times, I would not have persevered and reached my goals in life … Most especially, to my two lovely and precious daughters Anastasia Zofia and Isabella Ann, whose smiles and laughter constantly provide me unparalleled joy and happiness; and my very loving and understanding wife Michelle, who has always been supportive of my endeavors both personally and professionally, and who sacrificed a lot of time and exhibited unwavering patience as I devoted a

significant amount of time and effort to this project. Truly, they provide me with motivation and inspiration. —Edgar V. Lerma

To my former mentors, colleagues, residents, fellows, and nurses – too many to name individually. They made a career in nephrology an exciting and fulfilling journey. And to my family for their loving support and encouragement. —Vecihi Batuman

Contents

1 Historical Background of Diabetic Kidney Disease������������������������������    1 Vivian Fonseca, Arezu Bhatnagar, and Govind Datta Chamarthi 2 Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines ������������������������������������������������������������������������������������������������   21 Nidhi Aggarwal, Sehrish Ali, and Sankar D. Navaneethan Part I Natural Course, Pathogenesis, Morphology and Genetics 3 Diabetic Kidney Disease: Scope of the Problem������������������������������������   37 Jing Chen 4 Natural Course (Stages/Evidence-Based Discussion) ��������������������������   49 Dragana Lovre and Tina Kaur Thethi 5 Pathogenesis: Hemodynamic Alterations����������������������������������������������   75 Maria Jose Soler, Conxita Jacobs-Cachá, Manga Motrapu, and Hans-Joachim Anders 6 Pathogenesis: Structural Changes in the Kidneys in Type 1 and Type 2 Diabetes����������������������������������������������������������������  105 Guillermo A. Herrera, Luis del Pozo-Yauner, Jeffrey J. Aufman, and Elba A. Turbat-Herrera 7 Diabetes in Children and Adolescents����������������������������������������������������  155 Mary Alice Rossi and Ihor V. Yosypiv Part II Clinical Presentation and Associated Conditions 8 Screening, Early Diagnosis, Genetic Markers and Predictors of Progression ����������������������������������������������������������������  185 Jennifer Tuazon and Janis Cho

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Contents

9 Atypical Presentations ����������������������������������������������������������������������������  219 Louis J. Imbriano, Nobuyuki Miyawaki, Joseph Mattana, Shayan Shirazian, and John K. Maesaka 10 Albuminuria and Proteinuria ����������������������������������������������������������������  243 Surya V. Seshan and Alluru S. Reddi 11 Hypertension and Diabetes ��������������������������������������������������������������������  263 William J. Elliott 12 Obesity and Metabolic Syndrome����������������������������������������������������������  293 T. Alp Ikizler and Melis Sahinoz 13 Anemia and Diabetes ������������������������������������������������������������������������������  305 Uzma Mehdi 14 Cardiovascular Disease and Diabetic Kidney Disease��������������������������  327 Keith C. Ferdinand, Samar A. Nasser, and Ayan Ali 15 Dyslipidemia and Diabetes����������������������������������������������������������������������  341 Anna Gluba-Brzózka, Jacek Rysz, Beata Franczyk, and Maciej Banach 16 Bone Disease and Diabetes����������������������������������������������������������������������  361 Stefana Catalina Bilha and Adrian Covic 17 Diabetic Retinopathy ������������������������������������������������������������������������������  381 Azin Abazari, Nicola G. Ghazi, and Zeynel A. Karcioglu 18 Pregnancy and Diabetes��������������������������������������������������������������������������  401 Anna Marie Burgner and Natalie McCall 19 Kidney Transplantation and Kidney Pancreas Transplantation ��������  417 Sixto Giusti and Vecihi Batuman 20 Diabetic Kidney Disease and Covid-19��������������������������������������������������  431 Luis D’Marco Part III Treatment and Prognosis 21 Glycemic Control ������������������������������������������������������������������������������������  443 Armand A. Krikorian and Angela Pauline P. Calimag 22 Computerized Clinical Decision Support����������������������������������������������  469 Shayan Shirazian, John K. Maesaka, Louis J. Imbriano, and Joseph Mattana 23 Antihypertensive Therapies��������������������������������������������������������������������  499 William J. Elliott 24 Diabetes and Kidney disease: metformin����������������������������������������������  521 Luigi Gnudi and Carlo Alberto Ricciardi

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25 Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors������������������������  533 Ashish Kataria and Christos Argyropoulos 26 Glucagon-like Peptide-1 Receptor Agonists (GLP1-RA) ��������������������  563 Radica Z. Alicic, Emily J. Cox, Joshua J. Neumiller, and Katherine R. Tuttle 27 Dipeptidyl Peptidase-4 (DPP4) Inhibitors ��������������������������������������������  583 Ngoc-Yen T. Pham, Christos Argyropoulos, and Nhan Dinh 28 Novel Treatments and the Future of DKD: What Is on the Horizon? ������������������������������������������������������������������������  601 Hongju Wu and Vecihi Batuman 29 Putting it All Together: Practical Approach to the Patient with Diabetic Kidney Disease������������������������������������������  637 Eudora Eng and Susan Quaggin Index�������������������������������������������������������������������������������������������������������������������� 661

Contributors

Azin  Abazari  Department of Ophthalmology, Stony Brook University Medical Center, Stony Brook, NY, USA Nidhi  Aggarwal  Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Section of Nephrology, Michael E.  DeBakey Veterans Affairs Medical Center, Houston, TX, USA Ayan Ali  MD Candidate, Class of 2021, Tulane University School of Medicine, New Orleans, LA, USA Sehrish  Ali  Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Section of Nephrology, Michael E.  DeBakey Veterans Affairs Medical Center, Houston, TX, USA Radica Z. Alicic  Providence Medical Research Center, Providence Health Care, Spokane, WA, USA University of Washington School of Medicine, Seattle, WA, USA Hans-Joachim Anders  Department of Medicine IV, Renal Division, Hospital of the Ludwig Maximilians University, Munich, Germany Christos Argyropoulos  Department of Internal Medicine, Division of Nephrology, University of New Mexico School of Medicine, MSC 04-2785, 1 University of New Mexico, Albuquerque, NM, USA Jeffrey J. Aufman  Department of Pathology, Largo Medical Center, Largo, FL, USA Maciej Banach  Department of Hypertension, Medical University of Lodz 90-549, Lodz, Poland

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Contributors

Vecihi Batuman  Dr A Rudolph and Ruth Ryder Huberwald Professor of Medicine, John W Deming Department of Medicine, Tulane University Medical School, New Orleans, LA, USA Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA Arezu Bhatnagar  Tulane University, School of Medicine, New Orleans, LA, USA Stefana  Catalina  Bilha  Endocrinology Department, “Sf. Spiridon” Clinical Emergency Hospital, “Grigore T.  Popa” University of Medicine and Pharmacy, Iasi, Romania Anna  Marie  Burgner  Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA Angela Pauline P. Calimag  Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA Govind  Datta  Chamarthi  Tulane University, School of Medicine, New Orleans, LA, USA Jing Chen  Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA Janis  Cho  Division of Nephrology and Hypertension, Northwestern Medicine Lake Forest Hospital, Lake Forest, IL, USA Adrian  Covic  Nephrology Department, Dialysis and Renal Transplant Center, “Dr. C.I. Parhon” University Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania Emily  J.  Cox  Providence Medical Research Center, Providence Health Care, Spokane, WA, USA Nhan Dinh  Department of Internal Medicine, Division of Nephrology, University of New Mexico School of Medicine MSC 04-2785, 1 University of New Mexico, Albuquerque, NM, USA Luis  D’Marco  Nephrology Department, Hospital Clínico Valencia, Spain Instituto de Investigación Sanitaria de Valencia, Valencia, Spain CEU Cardenal Herrera University, Valencia, Spain

Universitario,

William J. Elliott  Department of Biomedical Sciences, Division of Pharmacology, Pacific Northwest University of Health Sciences, University Parkway, Yakima, WA, USA Eudora Eng  Department of Medicine, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Contributors

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Keith C. Ferdinand  Gerald S. Berenson Endowed Chair in Preventive Cardiology, Tulane University School of Medicine, New Orleans, LA, USA Vivian  Fonseca  Department of Medicine, Section of Endocrinology, Tulane University, New Orleans, LA, USA Beata Franczyk  Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland Nicola  G.  Ghazi  Department of Ophthalmology, The Gilbert and Rose-Marie Chagoury School of Medicine, The Lebanese American University Medical Center-­ Rizk Hospital, Beirut, Lebanon Sixto Giusti  Assistant Profressor of Clinical Medicine, Tulane University Medical School, New Orleans, LA, USA Anna  Gluba-Brzózka  Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland Luigi  Gnudi  School of Cardiovascular Medicine & Sciences, Section Vascular Biology and Inflammation, British Heart Foundation Centre for Research Excellence, Faculty of Life Sciences & Medicine, King’s College of London, London, UK Guillermo  A.  Herrera  Department of Pathology, University of South Alabama, College of Medicine-University Hospital, Mobile, AL, USA T.  Alp  Ikizler  Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA Louis  J.  Imbriano  Department of Medicine, Division of Nephrology, NYU Winthrop Hospital, Mineola, NY, USA Conxita  Jacobs-Cachá  Nephrology Research Group, Vall d’Hebron Institut de Recerca (VHIR), Department of Nephrology, Vall d’Hebron Hospital Universitari, Barcelona, Spain Zeynel  A.  Karcioglu  Department of Ophthalmology, University of Virginia, Charlottesville, VA, USA Ashish  Kataria  Department of Internal Medicine, Division of Nephrology, University of New Mexico School of Medicine, MSC 04-2785, 1 University of New Mexico, Albuquerque, NM, USA Armand  A.  Krikorian  Internal Medicine, Endocrinology and Metabolism, Advocate Christ Medical Center, Oak Lawn, IL, USA Dragana  Lovre  Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center and Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA

xiv

Contributors

John  K.  Maesaka  Department of Medicine, Division of Nephrology, NYU Winthrop Hospital, Mineola, NY, USA Joseph Mattana  Department of Medicine, Frank H. Netter School of Medicine at Quinnipiac University, St. Vincent’s Medical Center, Bridgeport, CT, USA Department of Medicine, St. Vincent’s Medical Center, Bridgeport, CT, USA Natalie McCall  Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA Uzma Mehdi  Department of Nephrology, Methodist Richardson Medical Center, Dallas, TX, USA Nobuyuki  Miyawaki  Department of Medicine, Division of Nephrology, NYU Winthrop Hospital, Mineola, NY, USA Manga  Motrapu  Department of Medicine IV, Renal Division, Hospital of the Ludwig Maximilians University, Munich, Germany Samar  A.  Nasser  Department of Clinical Research & Leadership, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA Sankar  D.  Navaneethan  Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Section of Nephrology, Michael E.  DeBakey Veterans Affairs Medical Center, Houston, TX, USA Joshua  J.  Neumiller  College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA Ngoc-Yen T. Pham  Department of Pharmacy, Department of Internal Medicine, Division of Nephrology, University of New Mexico School of Medicine MSC 04-2785, 1 University of New Mexico, Albuquerque, NM, USA Luis  del Pozo-Yauner  Department of Pathology, University of South Alabama, College of Medicine-University Hospital, Mobile, AL, USA Susan  Quaggin  Department of Medicine, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Alluru S. Reddi  Department of Medicine, Division of Nephrology & Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA Carlo Alberto Ricciardi  School of Cardiovascular Medicine & Sciences, Section Vascular Biology and Inflammation, British Heart Foundation Centre for Research Excellence, Faculty of Life Sciences & Medicine, King’s College of London, London, UK

Contributors

xv

Mary Alice Rossi  Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA Jacek  Rysz  Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland Melis  Sahinoz  Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA Surya V. Seshan  Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA Shayan Shirazian  Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, NY, USA Maria Jose Soler  Nephrology Research Group, Vall d’Hebron Institut de Recerca (VHIR), Department of Nephrology, Vall d’Hebron Hospital Universitari, Barcelona, Spain Tina  Kaur  Thethi  Translational Orlando, FL, USA

Research

Institute,

Advent

Health,

Jennifer  Tuazon  Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Elba A. Turbat-Herrera  Department of Pathology, University of South Alabama, College of Medicine-University Hospital, Mobile, AL, USA Katherine  R.  Tuttle  Providence Medical Research Center, Providence Health Care, Spokane, WA, USA University of Washington School of Medicine, Seattle, WA, USA Institute of Translational Health Sciences, Seattle, WA, USA Hongju Wu  Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA Ihor V. Yosypiv  Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA

Chapter 1

Historical Background of Diabetic Kidney Disease Vivian Fonseca, Arezu Bhatnagar, and Govind Datta Chamarthi

Introduction Symptoms of diabetes are recorded as far back as 400  BC; the Indian physician Sushruta describes diabetes in an ancient Hindi document as “madhumeha” or the honeyed-urine disease [1]. Around 150  AD, the Greek physician Aretaeus of Cappadocia wrote: Diabetes is a remarkable disorder, and not one very common to man. It consists of a moist and cold wasting of the flesh and limbs into urine... the secretion passes in the usual way, by the kidneys and the bladder. It is of improbable, also, that something pernicious, derived from other disease which attack the bladder and kidneys may sometimes prove the cause of this affliction. The patients never cease making water, but the discharge is as incessant as a sluice let off. This disease is chronic in character, and is slowly engendered, though the patient does not survive long when it is completely established for the marasmus produced is rapid and death is speedy [2].

For many centuries thereafter, diabetes mellitus was regarded as a disease of the kidney.

V. Fonseca (*) Department of Medicine, Section of Endocrinology, Tulane University, New Orleans, LA, USA e-mail: [email protected] A. Bhatnagar · G. D. Chamarthi Tulane University, School of Medicine, New Orleans, LA, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2022 E. V. Lerma, V. Batuman (eds.), Diabetes and Kidney Disease, https://doi.org/10.1007/978-3-030-86020-2_1

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The Discovery of Diabetic Kidney Disease Following the now famous paper published by Paul Kimmelstiel and Clifford Wilson in 1936, many incorrectly assume that diabetic renal disease was recently recognized. However, the discovery of diabetic kidney disease has been a gradual process, and the meaning of diabetic renal disease has changed over time [3]. Erasmus Darwin [4] described it as urine that could be coagulated by heat, confirming the observations of Cotunnius [5] and Rollo [6] that the urine of some diabetics contained protein [7]. In the 1830s, research conducted by the “father of nephrology” Richard Bright into the causes of kidney disease led to what became known as Bright’s disease. Pierre-François Olive Rayer [8] and Wilhelm Griesinger [9] were the first to hypothesize that diabetes might cause a form of Bright’s disease. In the 1850s, much data on renal histology in patients with diabetes were published. Lionel Beale examined the histology of enlarged diabetic kidneys and analyzed them chemically, showing an excess of fat present in the tubules. Luciano Armanni (1875, cited by Ebstein) and Wilhelm Ebstein [10] described vacuolization of renal tubular epithelium. The concept of diabetic kidney disease continued to develop, and in 1883, Ehrlich confirmed glycogen infiltration—a common postmortem finding in the preinsulin era. For the next 50 years, these tubular deposits of glycogen were the only lesion believed to be specifically associated with diabetes, later called “nephropathia diabetic” by Aschoff in 1911. Kenzo Waku [11] published a description of diffuse capillary wall thickening studied by silver staining in 8 of 13 diabetic patients, in a Japanese journal written in German. No clinical details of the patients were provided, and the study gained little attention. It was not until 1936, when Kimmelstiel and Wilson published their paper “Intercapillary lesions in glomeruli of kidney” in The American Journal of Pathology, that interest intensified in the study of diabetic vascular complications.

The Pathology of Diabetic Renal Disease Paul Kimmelstiel (1900–1970), a native of Hamburg, Germany, came to the USA in 1933. Clifford Wilson (1906–1997), a relatively unknown British clinician, went to Harvard University as a Rockefeller travelling fellow and met Kimmelstiel. Their first paper [12] described glomerular lesions in eight patients who died of renal failure. The lesions were attributed to diabetes mellitus because seven of the eight patients were known to have the disease. Most of the patients had hypertension, heavy albuminuria, and edema and were aged 48–68 years. The diabetic patients had diabetes from a range of 10 months to 10 years. Their glomeruli showed uniform lesions involving large expansion of the intercapillary space. This expansion

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was shown to be continuous with the hyaline lesions of the afferent glomerular arteriole. Kimmelstiel and Wilson did not emphasize the association of these lesions with diabetes but suggested that the appearance was an acceleration of senile glomerulosclerosis. They noted that it was a rare finding and that it could complicate glomerulonephritis. Although Kimmelstiel and Wilson’s observations were received initially with uncertainty, they stimulated interest in diabetic vascular pathology. After their publication, the eponym “Kimmelstiel–Wilson nodules” began to be applied to diabetic renal lesions. However, it was Arthur Allen (1941) who clarified the link with diabetes [13]. He studied autopsies of 105 patients with diabetes (all of which were over age 40), 100 patients with hypertension, 100 patients without hypertension or diabetes, and 34 patients with glomerulonephritis. Thirty-four percent of the diabetics showed the lesion, but otherwise it was seen in only three other patients. Type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes are etiologically and epidemiologically distinct conditions and affect different divisions of the population. However, there has been no major difference identified between the nephropathies seen in both conditions, either pathophysiologically or in terms of their management. They can thus be conveniently considered together. It should be remembered, however, that patients with type 2 diabetes tend to be older and more hypertensive and so more likely to have concomitant hypertensive and renovascular disease [14].

Initial Studies of Renal Biopsies Before 1950, renal histology samples were mostly obtained from autopsied patients. The only way of analyzing kidney tissue from a live person was through an open operation. In 1951, Danish physicians Poul Iversen and Claus Brun described a method involving needle biopsy [15]. It became possible to obtain renal specimens of diabetic patients in all stages of disease. By the end of the 1950s, there were a large amount of data collected such as those published by Robert Kark in Chicago [16]. These data revealed that patients with mild glomerular disease may have heavy proteinuria and patients with less renal involvement may have complex lesions of nodular glomerulosclerosis. In 1957 the electron microscope [16] and in 1959 immunofluorescent protein tracing [17] were used to study glomerular lesions in patients with diabetes mellitus. Using these techniques, the hypothesis of a diffuse thickening of the basement membrane in diabetics was proven. In 1956, Ruth Østerby-Hansen published a study, [18] which showed that there was no thickening of the peripheral glomerular basement membrane in early diabetic patients. This finding brought forth the possibility of treatment through modifying whatever was causing subsequent changes.

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Radioimmunoassay and the Concept of Microalbuminuria In New York, in the 1950s, Rosalyn Yalow1 and Solomon Aaron Berson developed the technique of radioimmunoassay, and they later published their findings [19]. The technique allowed for the precise measurement of minute amounts of proteins and hormones. In 1960, Harry Keen and associates from Guy’s Hospital used the technique to detect small amounts of albumin in the urine of diabetics. Their paper [20] was published in The Lancet in 1963. Keen studied diabetics at all stages of disease, including those who had no proteinuria on conventional testing. Keen realized that elevated albumin excretion below the proteinuric level might be important in the natural history of diabetic kidney disease, and the concept of microalbuminuria was developed. In 1982, GianCarlo Viberti published findings that confirmed that microalbuminuria could predict the subsequent evolution of overt nephropathy with proteinuria in type 1 diabetics, [21] and in 1984, Carl Erik Mogensen showed the same finding in type 2 diabetics [22]. Concurrently, it became apparent that the reduction of blood pressure could postpone renal failure [23].

 he Renin–Angiotensin–Aldosterone System and Diabetic T Kidney Disease In the 1950s, Mann et al. documented the natural history of diabetic renal disease. Death from renal failure that resulted from diabetic kidney disease usually occurred in patients who had long-standing type 1 diabetes. However, after the 1970s with improved treatments, much larger number of patients with type 2 diabetes began to survive and develop end-stage renal disease. Attention began to shift from the treatment to the prevention of diabetic kidney disease. Pharmacologic blockade of the renin–angiotensin–aldosterone system (RAAS) has become the standard of care for patients with type 2 diabetes mellitus and renal involvement [24]. The history of the discovery of the RAAS began in 1898 with the studies by Tigerstedt and Bergman, who reported the pressor effect of renal extracts; they named the renal substance renin based on its origin [25]. Angiotensin-­ converting enzyme inhibitors (ACE-i) were the first class of clinically applicable drugs that specifically block the RAAS. Originally, ACE-i were developed as antihypertensives, in particular aimed at the treatment of high-renin hypertension. The first proposals [26, 27] that the outcome of diabetic kidney disease could be improved using RAAS blockade with ACE-i drugs began in the early 1980s. Brenner and Zatz showed that rats with diabetes that were treated with ACE-i were protected against nephropathy; however, conventional blood pressure lowering agents did not 1  By injecting radioactive iodine, they were able to track insulin and prove that type 2 diabetes is due to an inefficient use of insulin. This discovery awarded them a Nobel Prize.

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[28]. The first controlled trial [29] of ACE-i in humans with diabetes appeared in 1987. In 1993, the landmark study using captopril was published [30]. The trial demonstrated that captopril protected against deterioration of renal function in patients with type 1 diabetes and diabetic kidney disease and was significantly more effective than blood pressure control alone. Captopril reduced the risk of doubling of the serum creatinine by 48% when compared with standard antihypertensive therapy. Both treatment groups had similar blood pressures; thus, the effect of captopril on progression was determined to be independent of its antihypertensive properties, an effect termed “renoprotection.” In 2001, the Irbesartan diabetic kidney disease Trial, [31] designed to ascertain whether the use of the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine provided similar renoprotection in overt nephropathy associated with type 2 diabetes, was published. Irbesartan was shown to reduce the risk of doubling the serum creatinine by 33% when compared with standard antihypertensive therapy and by 37% when compared with treatment with amlodipine. Blood pressures were again similar across groups, indicating that these salutary effects were a result of renoprotection. Similar results were reported using losartan in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial [32]. Results of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) trial were also published in 2001. IRMA 2 studied the effects of the use of irbesartan (300 or 150 mg/day versus placebo) to prevent progression from the earlier stage of microalbuminuria to the later stage of overt nephropathy in patients with hypertension and type 2 diabetes. The study demonstrated that patients receiving irbesartan (300  mg/day) had about one third the risk of developing overt nephropathy compared with the patients not receiving (adjusted risk reduction 68% at 300 mg/day) [33].

Value of Glycemic Control Diabetes is the most common cause of ESRD in Western countries, and glycemic control is correlated with the development and progression of diabetic kidney disease. Epidemiologic studies have demonstrated that diabetic kidney disease risk is higher in patients with poor metabolic control [27, 34, 35]. Although genetic factors modulate DN risk and some patients do not develop this complication despite several years of poor glycemic control, there is evidence that hyperglycemia is a necessary precondition for DN lesions. Two major early glomerular lesions, glomerular basement membrane thickening and mesangial expansion, are not present at diagnosis of diabetes but are found 2–5 years after onset of hyperglycemia [34]. Studies in identical twins who are discordant for type 1 diabetes support the concept that hyperglycemia is necessary for the development of diabetic glomerulopathy. Twin studies show that the nondiabetic siblings had structurally normal

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kidneys, while their diabetic twin pair had glomerular lesions [36]. Moreover, normal kidneys from nondiabetic donors that are transplanted into patients with diabetes develop lesions of DN [37, 38]. A number of articles now suggest a long-term survival advantage with simultaneous pancreas kidney (SPK) transplantation, compared with kidney transplantation alone for patients with end-stage renal disease caused by diabetic kidney disease [39]. SPK offers the opportunity to test the ability of pancreas transplantation to prevent the development of diabetic glomerular lesions, because the renal graft has never been exposed to hyperglycemia. Patients who have dual-organ transplants almost always normalize their glycemic values afterward, and this is partly why these patients live longer than those who get a kidney alone. In 1985, Bohman et al. were the first to demonstrate that the development of diabetic glomerulopathy was prevented in the recipients of SPK [40]. In 1993, the same group confirmed prior observations when they reported data on a cohort of 20 SPK patients who were followed for up to 6 years, compared with a group of 34 kidney transplant recipients with diabetes [41]. More recent studies support the same observation [42, 43].

Treatment of Hyperglycemia Almost 4000 years ago, “diabetes” or a disease describing it was well documented in ancient records from Egypt, India, and across China. Interestingly, all recognized that sweet copious amounts of urine and sweet-scented sweat were associated with obesity and may have a hereditary component to it. They also noted that these phenotypic traits may possibly be occurring due to overindulgence of rich foods such as milk which contains a lot of sugar in it. With very limited resources in regard to the pathophysiology of diabetes, an array of ancient medicines were used. These included oil of roses, dates, raw quinces and gruel, jelly of viper’s flesh, broken red coral, sweet almonds, and fresh flowers of blind nettles [44]. For the most part, diabetes was considered incurable at that time. Knowing now that there are microvascular complications such as diabetic kidney disease, there is much doubt as to whether people survived for that long, whether physicians of that time stopped treatment or tailored treatment to best suit the various stages of this dismal disease [45]. In type 1 diabetes, the Diabetes Control and Complications Trial (DCCT) Research Group demonstrated that intensive treatment was associated with decreased incidence of microalbuminuria and reduced progression to macroalbuminuria as compared with conventional treatment [46]. In type 2 diabetes, the UK Prospective Diabetes Study (UKPDS) Group trial demonstrated a reduced incidence of microalbuminuria in the intensively treated group as compared with conventional treatment, but a parallel finding in macroalbuminuria was not significant [47].

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However, the Kumamoto study [48] and the Veterans Affairs Cooperative study [49] both showed that intensive treatment was effective for primary prevention (decreased incidence of microalbuminuria) and secondary prevention (reduced progression to macroalbuminuria). The Epidemiology of Diabetes Interventions and Complications (EDIC)/DCCT follow-up study [50] and the UKPDS study also found that lowering HbA1c reduced decline in GFR in type 1 and type 2 diabetes, respectively.

Intensive Glycemic Control The benefit of intensive glycemic control for nephropathy is currently under debate. Intensive treatment of hyperglycemia may prevent DN, including development of microalbuminuria, but there is little evidence that it slows the progression of chronic kidney disease [51]. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, assignment of the treatment group to an HbA1c goal of less than 6% led to increased mortality and cessation of the trial [52]. Furthermore, in one analysis of data from the ACCORD study, combined intensive glycemic and blood pressure control did not produce an additive benefit on microvascular outcomes in patients with type 2 diabetes. This differs from the findings of the ADVANCE study, [53] which showed that intensive glucose and BP controls were independently beneficial and their combination produced synergistic benefits in nephropathy, new-onset microalbuminuria, and new-onset macroalbuminuria.

 he Impact of Glucose-Lowering Drugs on Diabetic Kidney T Disease Progression While the impact of good glycemic control on nephropathy progression is generally well accepted, none of the medications for hyperglycemia were shown to have a specific beneficial effect on the kidney in the past. However, recently data has emerged demonstrating that some drugs developed for lowering blood glucose can decrease proteinuria and significantly slow the progression of chronic kidney disease (CKD). While some minor benefits have been seen with DPP-4 inhibitors and thiazolidinediones, the effects of SGLT2 inhibitors and, to a lesser extent, GLP-1 receptor agonists are clinically impactful, and the use of the former has now been incorporated into several clinical guidelines, [54] including the specific treatment of diabetic kidney disease. Figure 1.1 [76] shows the evolution of treatment and management for diabetes.

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V. Fonseca et al. 2005-amylin agonist 1956-First sulfonylurea available in US 1956-Lente Insulin 1918-Guanidine (Synthalin) 1915

1935 1922-Insulin first administered to human subject 1923-Insulin available in US

1946-NPH Insulin

1997-meglitinide 1995-AGI

1936-PZI Insulin 1955

2005-GLP 1 -R agonist

1975

2009-Bromocriptine

1995

2015 1996-TZD

1983-Recombinant human insulin 1984-2nd Generation sulfonylureas

2013-SGLT-2i

2006-DPP-4i 2008-Colesvalem

Fig. 1.1  Evolution of treatment and management for diabetes. (NB: PZI protamine zinc insulin, NPH neutral protamine Hagedorn, AGI alpha glucosidase inhibitors, GLP-1R agonist glucagon-­ like peptide-1 receptor agonist, TZD thiazolidinediones, SGLT2i sodium glucose transporter inhibitors, DPP-4i dipeptidyl peptidase-4 inhibitors)

Sodium Glucose Transporter Inhibitors (SGLT2i) Phlorizin, a molecule from the root bark of apple trees, has been studied for over a century. In 1933, it was discovered to increase renal excretion of glucose, decrease its reabsorption, and lower its overall levels in the body. Phlorizin seemed to be an ideal alternative in managing glucose levels in those with diabetes mellitus (mechanism of action; non-selective inhibitor of both Sodium Glucose Transporters (SGLT) 1 & 2). SGLT1 accounts for the dietary glucose uptake in the intestine and, SGLT2 is responsible for glucose reuptake in the tubular system of the kidney. SGLT1 reabsorbs the remainder of the filtered glucose [55]. Phlorizin’s dramatic reduction in glucose reabsorption in the intestines, its negative effects on the body as well as, its inadequate absorbance when taken orally, became quite evident. For decades, researchers had many concerns about phlorizin and others in the same class due to side effects thought to be related to its nonspecific inhibition of transporters in other organs. Finally, the development and approval of a more specific SGLT2i, canagliflozin, in 2013 by the US Food and Drug Administration (FDA) led to reassurance about such effects. Dapagliflozin and empagliflozin followed in 2014 [56]. Several others in this class are now available worldwide. Large-scale clinical trials mandated by the FDA, Empagliflozin- regulatory outcome (EMPA-REG OUTCOME) and Cardiovascular Assessment Study (CANVAS), examined SGLT2i’s effects in type 2 diabetics. These programs showed an approximate 35% reduction in the incidence of heart failure [55]. Furthermore, there were reductions in mortality and major CV events. These trials also highlighted a

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reduction in the progression of nephropathy, a decrease in proteinuria and, a slower decline in eGFR. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated canagliflozin’s action on inhibiting SGLT2  in advanced CKD due to diabetic kidney disease. The study enrolled patients with significant proteinuria and eGFR as low as 30. Compared to placebo it decreased creatinine levels, preventing progression of CKD, and reduced the rates of mortality secondary to end-stage kidney disease (ESKD) and other cardiovascular effects [57]. Importantly, the drug was continued in people whose eGFR dropped below 30, and no harmful effects were seen, demonstrating possible benefits at a stage where significant reduction in glucosuria was unlikely. The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial that commenced in 2017 has recently halted due to its overwhelming positive effects [58]. DAPA-CKD mirrors CREDENCE but on a broader scale. Its population were those suffering from chronic renal disease without diabetes. Dapagliflozin’s outcome also proved to delay further kidney damage and decrease cardiovascular effects in those suffering with diabetes mellitus. Interestingly, the beneficial effects on eGFR occurs despite an initial drop in eGFR, possibly related to dehydration, which may be associated with incidences of acute kidney injury in a few patients. In addition, and more likely, the effects are due to a corrective action of SGLT2i on the impaired tubulo-glomerular feedback. However, a meta-analysis by Menne et al. concluded that there was no increased risk of AKI in patients taking SGLT2 inhibitors. In addition, they advise physicians that the possibility of AKI should not deter them from prescribing them [59]. Thus, novel approach to treating hyperglycemia by working on the kidneys and reducing the risks of associated macrovascular complications such as cardiovascular disease was established. The results of these trials have spawned many others as well as mechanistic studies to understand the findings. Mechanisms proposed include a reduction in BP, improved energetics in the renal cells, improved blood flow through normalization of juxtaglomerular feedback, and a suppression of activation of intrarenal angiotensin production [60].

Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists Over 100 years ago, Moore et al. [61] discovered that gut extracts contain hormones that regulate the function of the pancreas and administration of these hormones lowers glucose levels in urine. In 1932 Le Barre purified these extracts and called it incretins. The invention of radioimmunoassay (RIA) by Berson and Yalow in 1960 which led to the ability to reliably measure insulin with RIA soon reopened the incretin question. In 1964, [62] McIntyre showed that there was a higher plasma insulin response to glucose given orally than to glucose given intravenously, hence proving the incretin mechanism exists. This report proved a stimulus to studies aimed at identifying and isolating these incretins.

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In 1973 John Brown [63] isolated GIP as an inhibitor of gastric acid secretions but in subsequent studies showed that it is a commanding releaser of insulin during hyperglycemia but could not explain the effect of GIP on insulin secretion after oral glucose. Therefore, the search for other incretins continued. In 1983, Graeme Bell [64] identified two glucagon-like peptides during the cloning and sequencing of mammalian pre-proglucagon and named them GLP-1 and GLP-2, both of which were expressed in the gut. But GLP-1 as such didn’t show a significant insulinotropic effect. In 1987, Habener [65] and Holst [66] independently discovered that GLP-1 was also synthesized in truncated form, which showed an even greater insulinotropic effect, and this led to the birth of GLP-1 drugs based on the incretin concept. The results of the 1993 clinical study by M A Nauck showed that exogenous GLP-1 [7-36 amide] caused normalization of fasting hypoglycemia, without the stimulation of insulin secretion. The first GLP-1RA drug was exenatide and was approved in 2005 [67, 68]. In recent years the efficacy of GLP-1 drugs in lowering blood glucose has been very well established, and also many trials have shown that it has a consistent association in lowering systolic blood pressure and weight [69]. In 2016, the LEADER trial [70] compared cardiovascular event outcomes in 9340 patients with type 2 diabetes with cardiovascular disease or cardiovascular risk factors randomly assigned to subcutaneous liraglutide or placebo. After a median follow-up of 3.84 years, the study showed a significant difference between the groups, in death from cardiovascular events (HR, 0.87), glycemic control (−0.4%), weight loss (2.3 kg), and systolic blood pressure (−1.2 mmHg). In addition to these, the study also showed a significant reduction in nephropathy events (HR, 0.78). This result was driven by the significant reduction in new-onset microalbuminuria (HR, 0.74) in the liraglutide group. A short time after the LEADER trial, the SUSTAIN-6 trial [71] showed very similar results with subcutaneous semaglutide. There was a significant reduction in new or worsening nephropathy in the semaglutide group compared to the placebo group (HR, 0.64). As seen in the LEADER trial, this was driven by a reduction in new-onset microalbuminuria. These studies have shown, when added to usual care, GLP-1RA results in lower rates of development and progression of diabetic kidney disease. On the flip side, some of the studies have shown patients to develop acute kidney injury as a side effect of GLP-1RA treatment. However, this is thought to be due to nausea and vomiting leading to dehydration, rather than a specific toxic effect on the kidney. Some GLP-1RAs such as exenatide have this in their package insert suggesting that they must be used with caution in patients with CKD. In 2019, oral semaglutide became the first FDA-approved oral GLP-1RA drug, and already there are studies looking for its impact in the clinical settings.

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Bardoxolone Bardoxolone was initially developed as an anticancer drug. However, as clinical studies progressed, data consistently showed that bardoxolone had a positive impact on the estimated glomerular filtration rate (eGFR) of these patients [72]. Multiple global trials have assessed its capabilities in alleviating or limiting the progression of chronic kidney disease (CKD) in patients suffering with diabetic kidney disease. The Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus (BEACON) trial was a multicenter, international, phase 3 randomized, double-blind clinical trial that administered bardoxolone once daily to one group and placebo to another group. Their aim was to see if bardoxolone would increase the eGFR in those suffering with stage 4 chronic kidney disease. In total, 2185 patients were randomized into the study. Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. It in fact increased early-onset fluid overloading, especially in those suffering from heart failure or had prior history/hospitalization of heart failure. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted immediate termination of the trial, [73] which was disappointing in light of benefits seen in phase 2 trials. The Phase 2 Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) study took place in Japan after BEACON was terminated. This trial aimed to determine if patients without risk factors can mitigate the risk for fluid overload and whether changes in eGFR with bardoxolone methyl reflect true increases in GFR [74]. The outcome of this trial was extremely interesting to note, factoring in that the incidence of cardiovascular events was deemed lower in CKD patients in Japan versus in clinical trials in the USA. Additionally, the trial found no significant safety concerns, such as fluid overloading and heart failure as were seen in BEACON [75]. Despite an early halt to the study, the BEACON trial did attest to the fact that bardoxolone could preserve kidney function by delaying the progression of CKD and thus end-stage renal disease. Patients who were randomly assigned to placebo had a significant mean decline in eGFR from their baseline value (−0.9 ml per minute per 1.73 m2; 95% CI, −1.2 to −0.5) as compared to those randomly assigned to bardoxolone methyl, who were noted to have had a significant mean increase from their baseline value (5.5 ml per minute per 1.73 m2; 95% CI, 5.2 to 5.9). The difference between the two groups was 6.4 ml per minute per 1.73 m2 (95% CI, 5.9 to 6.9; P