Clinical Companion in Nephrology [2nd Edition] 9783030383206

Table of contents :
Preface......Page 5
Contents......Page 7
Abbreviations......Page 11
Part I: Physiology and Assessment......Page 14
1: Structure and Function of the Kidney......Page 15
2: Assessment of GFR......Page 23
Further Reading......Page 27
3: Proteinuria......Page 28
Further Reading......Page 32
4: Haematuria......Page 33
Further Reading......Page 36
Part II: Disorders of Renal Metabolic Function......Page 37
5: Hyponatraemia......Page 38
Further Reading......Page 42
6: Hypokalaemia......Page 43
7: Hypocalcaemia and Hypercalcaemia......Page 46
8: Hypophosphataemia and Hypomagnesaemia......Page 50
9: Disorders of Acid Base Balance......Page 53
Part III: Acute Kidney Injury......Page 57
10: Causes of Acute Kidney Injury......Page 58
Further Reading......Page 66
11: Rhabdomyolysis......Page 67
Further Reading......Page 71
12: Cardiorenal Failure......Page 72
Further Reading......Page 77
13: Hepatorenal Syndrome......Page 78
Further Reading......Page 81
14: Thrombotic Microangiopathies (TMA) in Adults......Page 82
Further Reading......Page 87
15: Myeloma and the Kidney......Page 88
Further Reading......Page 92
16: Investigation, Management and Outcome of Acute Kidney Injury......Page 93
Further Reading......Page 98
17: Fluid Management......Page 99
Further Reading......Page 104
18: Hyperkalaemia......Page 105
Further Reading......Page 111
19: Rapidly Progressive Glomerulonephritis......Page 112
Further Reading......Page 116
Part IV: Chronic Kidney Disease......Page 117
20: Overview of Chronic Kidney Disease......Page 118
Further Reading......Page 123
21: Glomerular Disease......Page 124
Further Reading......Page 130
22: Renal Disease and Diabetes......Page 131
Further Reading......Page 137
23: Renovascular Disease......Page 138
Further Reading......Page 143
24: Hypertension......Page 144
Further Reading......Page 149
25: Antihypertensive Drugs......Page 150
Further Reading......Page 153
26: Polycystic Kidney Disease......Page 154
Further Reading......Page 157
27: Renal Anaemia......Page 158
Further Reading......Page 163
28: Mineral Metabolism......Page 164
Further Reading......Page 170
29: Nutrition in Renal Disease......Page 171
Part V: Miscellaneous Renal......Page 175
30: Gout and the Kidney......Page 176
Further Reading......Page 181
31: Urinary Tract Infection......Page 182
Further Reading......Page 189
32: Renal Stone Disease......Page 190
Further Reading......Page 193
33: Managing Pain in Chronic Kidney Disease......Page 194
Further Reading......Page 199
34: The Effect of Kidney Disease on Drugs......Page 200
35: The Effect of Drugs on Kidney Disease......Page 204
35.2 Chronic Kidney Disease......Page 205
35.3 Renal Transplantation......Page 207
36: Pregnancy and Renal Disease......Page 208
Further Reading......Page 211
37: Blood Borne Viruses......Page 212
Further Reading......Page 215
38: Rarer Renal Diseases......Page 216
Further Reading......Page 221
Part VI: Renal Replacement Therapy......Page 222
39: Haemodialysis......Page 223
Further Reading......Page 230
40: Peritoneal Dialysis......Page 231
Further Reading......Page 237
41: Renal Transplantation......Page 238
42: Dialysis and Poisoning......Page 247
Further Reading......Page 251
43: Hypertension and Fluid Balance in Dialysis Patients......Page 252
44: Tunnelled Dialysis Catheters......Page 257
Further Reading......Page 260
45: Catheter Related Blood Stream Infection......Page 261
Further Reading......Page 264
46: The Challenges of Renal Replacement Therapy in the Frail Older Adult......Page 265
Further Reading......Page 270
Part VII: Practical Nephrology......Page 271
47: Urinalysis and Microscopy......Page 272
48: Dialysis Line Insertion......Page 278
49: Renal Biopsy......Page 283
50: Spotting the Glomerulus: Basics in Biopsy Interpretation......Page 288
Further Reading......Page 296
Appendix B: Treatment of Hypokalaemia......Page 297
Appendix C: Treatment of Hypocalcaemia......Page 298
Further Reading......Page 299
Appendix E: Treatment of Hypophosphataemia and Hypomagnesaemia......Page 300
Hypocalcaemia......Page 301
Hypotension......Page 302
Azathioprine (AZA): Remission Maintenance Dose......Page 303
Further Reading......Page 304
Further Reading......Page 305
Appendix I: Dietary Potassium Advice......Page 306
Appendix J: Dietary Phosphate Advice......Page 307
Appendix K: Antibiotics for Urinary Tract Infection......Page 308
Notes......Page 309
IV Iron Adverse Reactions......Page 310
Further Reading......Page 311
Lanthanum......Page 312
After Discharge......Page 314
Symptoms of Hypocalcaemia......Page 315
Appendix O: Prescribing for Chronic Pain in CKD......Page 316
Further Reading......Page 317
Review of Treatment Modality......Page 318
Appendix Q: Immediate Management of PD Peritonitis......Page 319
Contraindications to Urokinase......Page 320
Appendix S: Reference Values......Page 321
Index......Page 322

Citation preview

Clinical Companion in Nephrology Jack Fairweather Mark Findlay Christopher Isles Second Edition

123

Clinical Companion in Nephrology

Jack Fairweather • Mark Findlay  Christopher Isles

Clinical Companion in Nephrology Second Edition

Jack Fairweather Renal and Transplant Unit Queen Elizabeth University Hospital Glasgow UK

Mark Findlay Renal and Transplant Unit Queen Elizabeth University Hospital Glasgow UK

Christopher Isles Dumfries and Galloway Royal Infirmary Dumfries UK

ISBN 978-3-030-38319-0    ISBN 978-3-030-38320-6 (eBook) https://doi.org/10.1007/978-3-030-38320-6 © Springer Nature Switzerland AG 2015, 2020 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

Preface

It is a pleasure to produce our second edition of this Clinical Companion in Nephrology. In 2015, we published edition one, a handbook for medical students and junior doctors aiming to demystify the nuances of renal medicine and provide an accessible knowledge base in clinical nephrology. Our feedback from edition one was clear—short, simple and easy-to-grasp explanations of common renal conditions were essential. The use of diagrams could not be underestimated, and the traditional ward-round teaching style of clinically relevant questions and answers was a positive. Using our readers’ feedback we have strived to improve this latest edition. Firstly, we have maintained our original format of questions and answers, progressing from clinically applied anatomy and physiology through presentations of renal disease including haematuria, proteinuria and electrolyte disorders to more complex renal conditions. Much of the book remains devoted to AKI and CKD as the topics commonly managed by general physicians. We include a part on miscellaneous renal disease, covering topics from renal stone disease to pregnancy, and we have introduced additional chapters on ‘the effect of renal disease on drugs’ and ‘the effect of drugs on renal disease’, in response to feedback. We devote a part to renal replacement therapy in a way that we hope will make clearer to non-nephrologists exactly what goes on inside dialysis and transplant units, and now discuss the role of dialysis in poisoning. As a concluding chapter, we introduce another new part, Practical Nephrology, where we explore the practical skills of nephrology, ranging from urinalysis to renal biopsy. And in response to the bewildered stares of medical students and junior doctors at biopsy meetings, we unveil our beginners guide to interpreting renal histopathology, ‘Spotting the Glomerulus: Basics in Biopsy Interpretation’. For this particular chapter, we are grateful for David Kipgen’s input. Each chapter is now preceded with a ‘best of five’ question, a format adopted by undergraduate and Royal College examinations where a clinical vignette is followed by five plausible answers, of which only one is the best option. This provides the reader with a bank of 50 questions over this book. Finally, to appeal to our visual learners, we have increased the number and altered the style of diagrams to mimic classroom notes.

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Preface

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Finally, we dedicate this work to our wives, Luisa, Maytal and Karen, for their tolerance and patience during the many evenings we spent drafting and redrafting this book. Again. Glasgow, UK Glasgow, UK  Dumfries, UK 

Jack Fairweather Mark Findlay Christopher Isles

Contents

Part I Physiology and Assessment 1 Structure and Function of the Kidney ������������������������������������������   3 2 Assessment of GFR��������������������������������������������������������������������������  11 Further Reading ��������������������������������������������������������������������������������  15 3 Proteinuria����������������������������������������������������������������������������������������  17 Further Reading ��������������������������������������������������������������������������������  21 4 Haematuria��������������������������������������������������������������������������������������  23 Further Reading ��������������������������������������������������������������������������������  26 Part II Disorders of Renal Metabolic Function 5 Hyponatraemia��������������������������������������������������������������������������������  29 Further Reading ��������������������������������������������������������������������������������  33 6 Hypokalaemia����������������������������������������������������������������������������������  35 7 Hypocalcaemia and Hypercalcaemia ��������������������������������������������  39 8 Hypophosphataemia and Hypomagnesaemia ������������������������������  43 9 Disorders of Acid Base Balance������������������������������������������������������  47 Part III Acute Kidney Injury 10 Causes of Acute Kidney Injury������������������������������������������������������  53 Further Reading ��������������������������������������������������������������������������������  61 11 Rhabdomyolysis ������������������������������������������������������������������������������  63 Further Reading ��������������������������������������������������������������������������������  67 12 Cardiorenal Failure ������������������������������������������������������������������������  69 Further Reading ��������������������������������������������������������������������������������  74 13 Hepatorenal Syndrome��������������������������������������������������������������������  75 Further Reading ��������������������������������������������������������������������������������  78 14 Thrombotic Microangiopathies (TMA) in Adults������������������������  79 Further Reading ��������������������������������������������������������������������������������  84 vii

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15 Myeloma and the Kidney����������������������������������������������������������������  85 Further Reading ��������������������������������������������������������������������������������  89 16 Investigation, Management and Outcome of Acute Kidney Injury ����������������������������������������������������������������������������������  91 Further Reading ��������������������������������������������������������������������������������  96 17 Fluid Management ��������������������������������������������������������������������������  97 Further Reading �������������������������������������������������������������������������������� 102 18 Hyperkalaemia �������������������������������������������������������������������������������� 103 Further Reading �������������������������������������������������������������������������������� 109 19 Rapidly Progressive Glomerulonephritis�������������������������������������� 111 Further Reading �������������������������������������������������������������������������������� 115 Part IV Chronic Kidney Disease 20 Overview of Chronic Kidney Disease�������������������������������������������� 119 Further Reading �������������������������������������������������������������������������������� 124 21 Glomerular Disease�������������������������������������������������������������������������� 125 Further Reading �������������������������������������������������������������������������������� 131 22 Renal Disease and Diabetes������������������������������������������������������������ 133 Further Reading �������������������������������������������������������������������������������� 139 23 Renovascular Disease���������������������������������������������������������������������� 141 Further Reading �������������������������������������������������������������������������������� 146 24 Hypertension������������������������������������������������������������������������������������ 147 Further Reading �������������������������������������������������������������������������������� 152 25 Antihypertensive Drugs������������������������������������������������������������������ 153 Further Reading �������������������������������������������������������������������������������� 156 26 Polycystic Kidney Disease �������������������������������������������������������������� 157 Further Reading �������������������������������������������������������������������������������� 160 27 Renal Anaemia �������������������������������������������������������������������������������� 161 Further Reading �������������������������������������������������������������������������������� 166 28 Mineral Metabolism������������������������������������������������������������������������ 167 Further Reading �������������������������������������������������������������������������������� 173 29 Nutrition in Renal Disease�������������������������������������������������������������� 175 Part V Miscellaneous Renal 30 Gout and the Kidney������������������������������������������������������������������������ 181 Further Reading �������������������������������������������������������������������������������� 186 31 Urinary Tract Infection ������������������������������������������������������������������ 187 Further Reading �������������������������������������������������������������������������������� 194

Contents

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32 Renal Stone Disease ������������������������������������������������������������������������ 195 Further Reading �������������������������������������������������������������������������������� 198 33 Managing Pain in Chronic Kidney Disease ���������������������������������� 199 Further Reading �������������������������������������������������������������������������������� 204 34 The Effect of Kidney Disease on Drugs������������������������������������������ 205 35 The Effect of Drugs on Kidney Disease������������������������������������������ 209 35.1 Acute Kidney Injury �������������������������������������������������������������� 210 35.2 Chronic Kidney Disease �������������������������������������������������������� 210 35.3 Renal Transplantation ������������������������������������������������������������ 212 36 Pregnancy and Renal Disease �������������������������������������������������������� 213 Further Reading �������������������������������������������������������������������������������� 216 37 Blood Borne Viruses������������������������������������������������������������������������ 217 Further Reading �������������������������������������������������������������������������������� 220 38 Rarer Renal Diseases ���������������������������������������������������������������������� 221 Further Reading �������������������������������������������������������������������������������� 226 Part VI Renal Replacement Therapy 39 Haemodialysis���������������������������������������������������������������������������������� 229 Further Reading �������������������������������������������������������������������������������� 236 40 Peritoneal Dialysis���������������������������������������������������������������������������� 237 Further Reading �������������������������������������������������������������������������������� 243 41 Renal Transplantation �������������������������������������������������������������������� 245 42 Dialysis and Poisoning �������������������������������������������������������������������� 255 Further Reading �������������������������������������������������������������������������������� 259 43 Hypertension and Fluid Balance in Dialysis Patients������������������ 261 44 Tunnelled Dialysis Catheters���������������������������������������������������������� 267 Further Reading �������������������������������������������������������������������������������� 270 45 Catheter Related Blood Stream Infection�������������������������������������� 271 Further Reading �������������������������������������������������������������������������������� 274 46 The Challenges of Renal Replacement Therapy in the Frail Older Adult�������������������������������������������������������������������������������������������������� 275 Further Reading �������������������������������������������������������������������������������� 280 Part VII Practical Nephrology 47 Urinalysis and Microscopy�������������������������������������������������������������� 283 48 Dialysis Line Insertion�������������������������������������������������������������������� 289 49 Renal Biopsy ������������������������������������������������������������������������������������ 295

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50 Spotting the Glomerulus: Basics in Biopsy Interpretation���������� 301 Appendix A: Treatment of Hyponatraemia������������������������������������������������ 309 Appendix B: Treatment of Hypokalaemia ������������������������������������������������ 311 Appendix C: Treatment of Hypocalcaemia������������������������������������������������ 313 Appendix D: Treatment of Hypercalcaemia���������������������������������������������� 315  Appendix E: Treatment of Hypophosphataemia and Hypomagnesaemia������������������������������������������������������������������������������������ 317 Appendix F: Plasma exchange������������������������������������������������������������������ 319 Appendix G: Vasculitis Protocol���������������������������������������������������������������� 321 Appendix H: Glucose Lowering Drugs and CKD ������������������������������������ 323 Appendix I: Dietary Potassium Advice������������������������������������������������������ 325 Appendix J: Dietary Phosphate Advice ���������������������������������������������������� 327 Appendix K: Antibiotics for Urinary Tract Infection�������������������������������� 329 Appendix L: Iron and Erythropoeisis Stimulating Agents������������������������ 331 Appendix M: Phosphate Binders �������������������������������������������������������������� 333 Appendix N: Control of Calcium After Parathyroidectomy���������������������� 335 Appendix O: Prescribing for Chronic Pain in CKD���������������������������������� 337 Appendix P: Optimal Medical Care on Haemodialysis���������������������������� 339 Appendix Q: Immediate Management of PD Peritonitis�������������������������� 341 Appendix R: Urokinase Protocol for Blocked Tunnelled Lines���������������� 343 Appendix S: Reference Values������������������������������������������������������������������ 345 Index���������������������������������������������������������������������������������������������������������� 347

Contents

Abbreviations

(S)FLC (Serum) free light chains ABPM Ambulatory blood pressure monitor ACE Angiotensin-converting enzyme ACEi Angiotensin-converting enzyme inhibitor ACR Albumin: creatinine ratio ADH Anti-diuretic hormone ADPKD Autosomal dominant polycystic kidney disease aHUS Atypical haemolytic uraemic syndrome AKI Acute kidney injury ANA Anti-nuclear antibody ANCA Anti-neutrophil cytoplasmic antibody ANP Atrial natriuretic peptide Anti-GBM Anti-glomerular basement membrane APD Automated peritoneal dialysis ARB Angiotensin II receptor blocker ARVD Atherosclerotic renovascular disease ATN Acute tubular necrosis AV Arteriovenous BBV Blood borne viruses BC Blood culture bd bis die (twice daily) BJP Bence Jones proteinuria BP Blood pressure Ca Calcium CAPD Continuous ambulatory peritoneal dialysis CCB Calcium channel blocker CCD Cortical collecting duct CK Creatine kinase CKD Chronic kidney disease CM Conservative management CMV Cytomegalovirus CNI Calcineurin inhibitor CNS Central nervous system COPD Chronic obstructive pulmonary disease CRBSI Catheter-related bloodstream infection CRP C-reactive protein CT Computed tomography xi

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CXR Chest X-ray DBD Donation following brain death DCD Donation following cardiac death DCT Distal convoluted tubule ECF Extracellular fluid ECV Extracellular volume eGFR Estimated glomerular filtration rate EPO Erythropoietin ERF Established renal failure (equivalent to end-stage renal failure/ disease (ESRD)) ESA Erythropoiesis-stimulating agent ESBL Extended-spectrum beta-lactamase ESP Encapsulating sclerosing peritonitis FMD Fibromuscular dysplasia GFR Glomerular filtration rate GN Glomerulonephritis GPA Granulomatous polyangiitis GTN Glyceryl trinitrate Hb Haemoglobin HBc Hepatitis B core HBPM Home blood pressure monitor HBsAg Hepatitis B surface antigen HBV Hepatitis B virus HCV Hepatitis C virus HD Haemodialysis HELLP Haemolysis, elevated liver enzymes, low platelets HF Heart failure HIV Human immunodeficiency HLA Human leukocyte antigens HPT Hyperparathyroidism HR Heart rate HRS Hepatorenal syndrome HUS Haemolytic uraemic syndrome ICV Intracellular volume INR International normalised ratio IV Intravenous IVP Intravenous pyelogram K Potassium L of H Loop of Henle L Litre LMWH Low molecular weight heparin LV Left ventricle LVH Left ventricular hypertrophy MAHA Microangiopathic haemolytic anaemia MCV Mean cell volume MDRD Modification of diet in renal disease mg milligram MGRS Monoclonal gammopathy of renal significance

Abbreviations

Abbreviations

xiii

MGUS Monoclonal gammopathy of unknown significance MHT Malignant hypertension mL millilitres MMF Mycophenolate mofetil MPA Microscopic polyangiitis MRI Magnetic resonance imaging Na Sodium NICE National Institute for Health and Care Excellence NSAID Non-steroidal anti-inflammatory drug OA Osteoarthritis Osm Osmolality PCP Pneumocystis carinii pneumonia PCR Protein: creatinine ratio PCT Proximal convoluted tubule PD Peritoneal dialysis PO4 Phosphate PTH Parathyroid hormone PTLD Post-transplant lymphoproliferative disorder qds quarter die sumendum (four times a day) RAAS Renin-angiotensin-aldosterone system RPGN Rapidly progressive glomerulonephritis RR Relative risk RRT Renal replacement therapy RVD Reno-vascular disease SC Sub-cutaneous SCr Serum creatinine SIADH Syndrome of inappropriate ADH STEC-HUS Shiga toxin-producing E. coli haemolytic uraemic syndrome TAL Thick ascending limb (of Henle) TCVC Tunnelled central venous catheter tds ter die sumendum (three times a day) TIPSS Transjugular portosystemic shunt TLD Thiazide-like diuretic TMA Thrombotic microangiopathy TSAT Transferrin saturation TTP Thrombotic thrombocytopenic purpura U&E Urea & electrolytes UF Ultrafiltration ULN Upper limit of normal URR Urea reduction ratio USS Ultrasound scan UTI Urinary tract infection vWF von Willebrand factor VZV Varicella zoster virus WCC White cell count WHO World Health Organization

Part I Physiology and Assessment

1

Structure and Function of the Kidney

Question 1 A 23  year old female presents to the medical receiving department with a 48 h history of profuse diarrhoea and vomiting. Clinically she appears dehydrated. Her serum creatinine is 62 μmol/L and her blood urea 14.3  mmol/L.  Her potassium is 3.4 mmol/L and her bicarbonate 22 mmol/L. Which ONE of the following is true regarding tubular function?

2. Creatinine is freely filtered then reabsorbed at the proximal tubule. 3. Nearly all urinary potassium is secreted by the proximal tubule under the influence if aldosterone. 4. Hydrogen ions are secreted in the proximal tubule. 5. Bicarbonate is reabsorbed in the distal convoluted tubule.

1. Urea is freely filtered then reabsorbed in the proximal tubule.

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_1

3

1  Structure and Function of the Kidney

4

AORTA

Left KIDNEY ABDOMINAL

Right KIDNEY

INFERIOR VENA CAVA

Q1: Describe basic kidney anatomy A basic understanding of normal renal anatomy is essential to those who wish to understand renal disease. Most people are born with two kidneys, lying either side of the spine from roughly T12 to L3 vertebral level. In adults, kidneys are smooth round structures, often approximated as ‘the size of your fist’. Two vessels and a ureter join the midpoint (or hilum) of each kidney, Fig. 1.1. Each contains approximately one million nephrons—the functional units of the kidney. The outer surface—the cortex—is where the glomeruli are found and the deeper portion the medulla— where the tubules and collecting ducts con-

Fig. 1.1  Normal renal anatomy Fig. 1.2  Anatomy of a nephron

verge to produce urine. Normal renal function can be maintained with a single kidney as evident from transplant recipients and in the not uncommon scenario where an otherwise healthy person is incidentally found to have been born with only one kidney; so called ‘renal agenesis’. Q2: Draw and label a nephron The nephron consists of a glomerulus, a proximal tubule, the loop of Henle with its thick ascending limb, the distal tubule and the cortical collecting duct. In reality, the glomerulus lies a little closer to the distal tubule than shown in Fig. 1.2, enabling the juxtaglomerular apparatus, which produces renin, to sense sodium levels in the distal tubule (see later). Healthy glomeruli filter around 100mls of blood to produce around 1  ml of urine per minute. Q3: List the functions of the kidney There are four functions relating to waste, water, electrolytes and acids: 1. Excretion of metabolic waste products e.g. urea and creatinine. 2. Regulation of body water volume. 3. Regulation of electrolyte balance, particularly sodium and potassium. 4. Regulation of acid base balance. PROXIMAL CONVOLUTED TUBULE (PCT) DISTAL CONVOLUTED TUBULE (PCT)

GLOMERULAR FILTRATE 100mL/min

CORTICAL COLLECTING DUCT (CCD)

LOOP OF HENLE (L of H)

THICK ASCENDING LIMB (TAL) URINE VOLUME 1mL/min

1  Structure and Function of the Kidney

5

And four hormonal functions: 1. Mineral metabolism 2. Production of renin. 3. Production of erythropoietin 4. Role in glucose metabolism—see Chap. 22 We will devote the rest of this chapter to describing these functions in more detail. We do so from a clinician’s rather than a physiologist’s view in the belief that clinically relevant physiology is more easily remembered. Q4: Explain how the kidney excretes urea and creatinine? The waste products which are of most interest in monitoring excretory renal function are urea and creatinine. Both are freely filtered at the glomerulus. The tubules then re-absorb some urea (but not creatinine) and secrete some creatinine (but not urea— see Fig.  1.3). The body’s ability to excrete waste products is determined by the glomerular filtration rate (GFR). Normal GFR is approximately 100 mL/ min. The human body can tolerate a substantial loss in renal function before suffering significant illeffects and it is not until the GFR falls below 30 mL/ min that things begin to go seriously wrong. Fig. 1.3  Movement of urea and creatinine within the nephron

Q5: How do the kidneys regulate body water volume? If our glomerular filtration rate is approximately 100 mL/min and average urinary output is only 1  mL/min (1500  mL per day), this means that 99 mL of glomerular filtrate is reabsorbed every minute. The concentration of urine in this way is driven by a series of complex mechanisms, which we can simplify as follows: • The proximal convoluted tubule (PCT) and Loop of Henle reabsorb huge amounts of sodium, which creates a hyperosmolar medulla. • Water follows passively through the Loop of Henle in an attempt to reduce the hyperosmolarity. • Fine tuning of body water volume takes place in the distal convoluted tubule (DCT) and cortical collecting duct (CCD) under the influence of aldosterone and in the CCD under the influence of antidiuretic hormone (ADH). • The production of aldosterone and ADH is regulated by anti-natriuretic peptide (ANP) released by the atria of the heart in response to changes in central body water volume. UREA reabsorbed

UREA & CREATININE

CREATININE secreted

1  Structure and Function of the Kidney

6

For example if a patient is volume overloaded (or ‘wet’) the atria release ANP.  ANP switches off the production of aldosterone by the adrenal cortex and of ADH by the posterior pituitary, Fig.  1.4. A lack of aldosterone and ADH mean that the kidney excretes more salt and water thereby restoring normal central body volume. Q6: How do the kidneys regulate sodium? The tubules may be thought of as having an insatiable desire to reabsorb sodium. This is an active process. Sodium is transported out of tubule and back into the body by a series of pumps in the proximal convoluted tubule (65%), thick ascending limb of the Loop of Henle (25%), distal convoluted tubule (5%) and cortical collecting duct (5%). The pumps in the distal nephron are under the influence of aldosterone (Fig. 1.5). Fig. 1.4  Regulation of body water

WET (+)

Q7: How do the kidneys regulate potassium? Regulation of potassium is another critically important function of the kidney. Dietary intake is usually of the order 50–100  mmol/day. The bulk of our body’s potassium is stored intracellularly, specifically in muscle. Potassium is actively pumped into muscle cells by a number of mechanisms (shown in Fig. 1.6), three of which we take advantage of when treating patients with hyperkalaemia (see Chap. 18). The kidney is mainly responsible for excreting potassium from the body with the gut playing a lesser role unless the patient has diarrhoea. Nearly all filtered potassium is reabsorbed passively with sodium in the PCT (Fig. 1.7), and actively with sodium in the thick ascending limb of the Loop of Henle. Nearly all urine (-)

ALDOSTERONE Adrenal Cortex

Cardiac Atrial Cells

DRY (-) VASOPRESSIN (ADH) (-) Posterior Pituitary

Fig. 1.5  Regulation of sodium

Na 60-65%

Na

100% Na Filtered

5% Na 4% Na Nearly all the filtered Na is reabsorbed in the PCT, TAL and DCT

25-30%

Day to day control of Na excretion takes place in the distal nephron under the influence of aldosterone

1  Structure and Function of the Kidney

7

Fig. 1.6  Regulation of potassium

Dietary intake 50100mmol/day

Excreted by kidney under influence of aldosterone

(+) Insulin

K+

(+) β-agonism

Na+

(-) Acidosis GUT

Minimal losses unless diarrhoea

Fig. 1.7 Renal excretion of potassium

Na

(K+)

100% K+ Filtered

PRINCIPAL CELL S K+ K+ K+ Nearly all the filtered K+ is reabsorbed in proximal nephron

potassium is secreted by the principal cells of the cortical collecting duct of the distal nephron under the influence of aldosterone. The intercalated cell of the CCD is responsible for reabsorbing potassium when hypokalaemia is present. Q8: How do the kidneys regulate acid base balance? The kidneys play an important role in maintaining the body’s hydrogen ion concentration (pH) within fairly narrow and well defined limits.

INTERCALATED CELLS

Nearly all the urinary K+ is secreted by the distal nephron

Normal hydrogen ion concentration is between 35 and 45  nmol/L, corresponding to a pH of between 7.36 and 7.44. The kidney does this in three ways as depicted in Fig. 1.8:

1 . By glomerular filtration of acids 2. By reabsorption of bicarbonate at the proximal convoluted tubule 3. By secretion of hydrogen ions at the cortical collecting duct

1  Structure and Function of the Kidney

8 Fig. 1.8  Regulation of acid-base balance

Filtered Acids

PCT

CCD

Reabsorbed Bicarbonate

Secreted Hydrogen ions

Detailed knowledge of the regulation of acid base balance by the kidney is not necessary. Both glomerular and tubular dysfunction can lead to acidosis. Patients with advanced renal failure are acidotic mainly because they no longer filter acids (glomerular dysfunction). Renal tubular acidosis (RTA) occurs when the tubules fail to appropriately acidify the urine. Q9: Describe the kidney’s contribution to mineral metabolism. The kidney plays an important role in PTH, Vitamin D, calcium and phosphate metabolism. Much of this activity is centred on maintaining a normal serum calcium. In health, low serum calcium triggers the parathyroid gland to produce PTH. This has multiple functions with one goal— raising serum calcium. This is achieved in three ways. First, PTH has a direct action on bone increasing osteoclastic activity which releases calcium into the blood stream. Second, PTH stimulates calcium reabsorption and phosphate secretion by the kidneys. Third, PTH increases the activity of the 1 alpha hydroxylase enzyme that converts inactive Vitamin D (25OHD) to its active form (1,25(OH)2D). 1,25(OH)2D stimulates the absorption of calcium from the gut. Once the serum calcium in back in the normal range, the secretion of PTH is ‘switched off’ by negative feedback, Fig. 1.9.

Q10: How do the kidneys regulate blood pressure? Renin is an enzyme secreted by the juxtaglomerular apparatus (JGA) of the kidney in response to a number of stimuli, principally a fall in renal perfusion pressure and sodium depletion. The JGA lies between the glomerulus and the distal convoluted tubule (DCT) which allows the JGA to sense the sodium concentration in the DCT.  Renin converts angiotensinogen to angiotensin I which in turn is converted to angiotensin II by Angiotensin Converting Enzyme (ACE). Angiotensin II has a number of important actions both within the kidney and in the systemic circulation including a direct pressor effect raising blood pressure. It also stimulates the adrenal gland to produce aldosterone which leads to sodium retention and potassium excretion by the kidney, with negative feedback that then switches off the production of renin (see Fig.  1.10). In health, the renin angiotensin system is a ­mechanism for controlling blood pressure by raising blood pressure when it is too low and lowering it when blood pressure is too high. Increased production of renin in patients with renovascular disease is one of the mechanisms for the development of hypertension in that disorder (see Chap. 23).

1  Structure and Function of the Kidney Fig. 1.9  PTH action in response to low serum calcium

9 Negative Feedback (-)

PTH GLANDS

Hypocalcaemia (+)

Active VIT D

PTH

BONE

GUT

KIDNEY

Renal & Enteral Ca2+ reabsorption

2+

Ca release

Rising Calcium

Fig. 1.10 The renin-angiotensin-­ aldosterone system

ANGIOTENSIN I

Low BP Na depletion

LUNGS

RENIN

ANGIOTENSIN II (+) Direct vasoconstrication BP (-) Raised BP Na retention

ADRENAL CORTEX

ALDOSTERONE

Q11: What role do the kidneys have in erythropoiesis? In a steady state, the human body is capable of producing approximately two million red blood cells per second. This is possible through the presence of adequate stores of essential substrates e.g. iron, vitamin B12 and folate, and stimulating factors—of which erythropoi-

etin is the main player. Erythropoietin is predominantly made by the kidneys in adults, and to a far lesser degree by the liver. In the presence of hypoxia, EPO-producing cells (specifically peritubular interstitial cells between the proximal tubules) proliferate, increasing red cell production by the bone marrow and thus oxygen carrying capacity (Fig. 1.11). In health,

1  Structure and Function of the Kidney

10 Fig. 1.11 Renal production of erythropoietin is essential for erythropoiesis

GI TRACT

Hypoxia

IRON B12 FOLATE (+)

BONE MARROW

EPO

(-)

RED CELLS

this is a tightly regulated process. However, patient-induced hypoxia will trigger red-cell production pathologically, as in smokers, or to athletic advantage in those who exercise at altitude. Objectives: Structure and Functions of the Kidney After reading this chapter, you should be able to answer the following:

Q10: How do the kidneys regulate blood pressure? Q11: What role do the kidneys have in erythropoiesis?

Q1: Describe basic kidney anatomy Q2: Draw and label a nephron Q3: List the functions of the kidney Q4: Explain how the kidney excretes urea and creatinine? Q5: How do the kidneys regulate body water volume? Q6: How do the kidneys regulate sodium? Q7: How do the kidneys regulate potassium? Q8: How do the kidneys regulate acid base balance? Q9: Describe the kidney’s contribution to mineral metabolism.

In this scenario the patient has developed renal dysfunction due to volume loss, or a ‘pre-renal’ cause. The history gives this away, but the pattern of renal dysfunction can be a clue. As described in this chapter urea and creatinine are freely filtered at the glomerulus. Along the tubule creatinine is secreted (hence option 2 is incorrect), and urea is reabsorbed. In the presence of dehydration, the uptake of urea is greater. Option 3 is incorrect, intercalated cells increased potassium reabsorption, and options 4 and 5 are incorrect; hydrogen ions are secreted at DCT, and bicarbonate reabsorbed in the PCT.

Answer 1 1. Urea is freely filtered then reabsorbed in the proximal tubule

2

Assessment of GFR

Question 2 You are asked to review a 67 year old man. He is 48 h following a hemicolectomy and complains of abdominal pain. He is drowsy but rousable, his heart rate is 97 beats per min, his blood pressure 97/60  mmHg. You note his empty catheter bag and discover he has been completely anuric for the last 9 h. You suspect he has developed acute kidney injury from a post-operative infection. His bloods are updated: Test Haemoglobin White cell count Platelets

Result 97 g/L 14.3 × 109/L 286 × 109/L

Reference 120–160 g/L 4–11 × 109/L 150–450 × 109/L

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_2

Test Urea Creatinine Potassium eGFR CRP

Result 13.6 mmol/L 186 μmol/L 4.7 mmol/L 34 mL/min 147

Reference 2.5–7.0 mmol/L 70–120 μmol/L 3.5–5.5 mmol/L >60 mL/min 60 mL/min/1.73 m2. If, for some reason, they were to undergo a bilateral nephrectomy, their actual GFR would fall to zero immediately. The creatinine would only rise marginally in the first few minutes, to say 82 μmol/L. Entering this value into the MDRD equation would still produce an eGFR >60 mL/min/1.73 m2. Even after several hours, in the complete absence of both kidneys, they may still have a reported eGFR within the normal range. In this circumstance, the urine output would be the first measure to indicate a problem, and creatinine would start to rise more slowly. Thus, in acute kidney injury, where the actual GFR is unstable, urine output is the most sensitive early indicator, serum creatinine is less sensitive but still useful, but eGFR has no role. It helps, particularly when it comes to prescribing drugs such as gentamicin, to consider that when the urine output is zero the eGFR is effectively zero, irrespective of the serum creatinine. By contrast, when the GFR is stable or only slowly changing, eGFR is very useful (e.g. CKD monitoring). Objectives: Assessment of GFR After reading this chapter you should be able to answer the following: Q1: How accurate is blood urea as a measure of renal function? Q2: How accurate is serum creatinine as a measure of renal function? Q3: What is the relation between serum creatinine and glomerular filtration rate (GFR)? Q4: How was GFR assessed in the past? Q5: How is GFR assessed now? Q6: What is the Cockcroft-Gault Equation?

Further Reading

Q7: Describe the pros and cons of estimating rather than measuring GFR Q8: Estimating GFR allows classification of chronic kidney disease. Discuss. Q9: Describe how severity of CKD may be related to treatment goals. Q11: Explain why eGFR isn’t a useful measure in acute kidney injury Answer 2

15

context. Assuming normal range urea and creatinine prior to surgery, both values are raised. However acute kidney injury is a dynamic process, and blood results give very static results. eGFR is calculated using these measured values, describing an apparent filtration rate of 34  mL/ min. However, the prolonged absence of urine output in this man suggests he has a current filtration rate of 0 mL/min. Finally, whilst very important in renal disease, serum potassium is not a marker of renal function.

4. Urine output Or in this man’s case, absence of urine output Urea and creatinine are important but imperfect markers of renal function and their limitations must always be considered in the clinical

Further Reading NICE CG182. Chronic kidney disease in adults: assessment and management. July 2014.

3

Proteinuria

Question 3 A fit 26 year old male is undergoing a work-­ related medical examination and is found to have proteinuria. He is informed he may have kidney disease and is advised to attend his GP for further investigations. Which of the following is not a cause of proteinuria?

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_3

1. Postural 2. Cardiac failure 3. Exercise 4. Febrile illness 5. High protein diet

17

18

Q1: What is proteinuria and how is it classified? Proteinuria simply means the presence of protein in the urine. We all pass a small amount of protein in our urine—up to 150  mg daily. Proteinuria in excess of this warrants further attention. A useful clinical classification of proteinuria is transient, postural or persistent. Transient proteinuria occurs after vigorous exercise, during febrile illnesses and in heart failure. Postural (aka orthostatic) proteinuria occurs in young adults after standing for prolonged periods. It disappears after lying down and can therefore be excluded in an early morning specimen. Postural proteinuria is completely benign. The rest of this chapter will be devoted to the discussion of persistent proteinuria, which may be further classified by either it’s source: glomerular, tubular, overflow or post-renal or by its severity: moderately increased albuminuria (previously called ‘microalbuminuria’), severely increased albuminuria (previously ‘macroalbuminuria’) and nephrotic range proteinuria (see below). Q2: Give examples of each source of proteinuria. The presence of proteinuria must always raise the suspicion of glomerular disease; however it is important to note that losses can originate from other parts of the urinary tract. • Glomerular proteinuria—predominately albumin, range from 1 to 20 g daily, occurs due to increased glomerular permeability to macromolecules from conditions such as diabetes. • Tubular proteinuria—low molecular weight proteins, usually 350

>3.5 g

3 Proteinuria

20

Q9: Moderately increased albuminuria used to be called microalbuminuria, what’s changed? Microalbuminuria literally means the urinary excretion of very small amounts of albumin. This can be earliest sign of diabetic nephropathy in patients with diabetes and may also occur in non-­diabetic patients with ­vascular disease, possibly reflecting endothelial d­ amage. Renaming proteinuria in this way reflects our increasing understanding of this risk factor, and reinforces the importance of early recognition and therefore earlier follow-up ± initiation of treatment. Q10: Why is proteinuria important when assessing patients with CKD? Large population studies, studies of patients at risk of CKD e.g., people with diabetes and studies of patients with established CKD have all shown that proteinuria is an independent risk factor not only for vascular disease but also for progressive renal failure. The risk of vascular disease is greater than the risk of progressive renal failure and the greater the level of proteinuria the higher is that risk.

Fig. 3.1  ACEi and baseline urine PCR in non-diabetic proteinuria (Reproduced from Jafar et al. Ann Int Med. 2001;135:73–87)

Q11: What can be done to reduce risk in patients with persistent proteinuria? There are two key recommendations. The first is to control blood pressure and the second is to use an ACE inhibitor or angiotensin receptor blocker as these drugs have both antihypertensive and anti-proteinuric properties. The NICE guideline on chronic kidney disease suggests that in people with CKD one should aim to keep the systolic pressure somewhere between 120 and 139  mmHg and a diastolic pressure less than 90 mmHg. A lower target of systolic pressure of between 120 and 129 mmHg with diastolic pressure less than 80  mmHg is recommended for people with CKD and diabetes, also in those with urine PCR >100  mg/ mmol. We recognise that while such tight BP control might be desirable it is not usually achievable. NICE recommend that ACE inhibitors or angiotensin receptor blockers should now be considered as first line drug therapy for people with diabetes whose urine ACR exceeds 3 mg/mmol, for people with hypertension with urine PCR >50 mg/mmol and for anyone with urine PCR >100 mg/mmol irrespective of their blood pressure. Figure  3.1 is a meta-­analysis

Urine PCR, mg/mmol

HR 1.35

0.78

2.35

300

0.25

0.5 ACE Beneficial

1

2 ACEi harmful

4

Further Reading

showing that ACE inhibitors have a beneficial effect on renal outcome in non-diabetics but only when urine PCR >50 mg/mmol. Objectives: Proteinuria After reading this chapter you should be able to answer the following: Q1: What is proteinuria and how is it classified? Q2: Give examples of each source of proteinuria. Q3: How is proteinuria detected? Q4: Discuss the advantages and limitations of the dipstick test for measuring urine protein. Q5: What is Bence Jones proteinuria? Q6: Why is a 24 h urine collection for quantifying urine protein no longer recommended? Q7: How is urine protein quantified currently? Q8: ACR or PCR? Q9: Moderately increased albuminuria used to be called microalbuminuria, what’s changed? Q10: Why is proteinuria important when assessing patients with CKD? Q11: What can be done to reduce risk in patients with persistent proteinuria?

21

Answer 3 5. High protein diet The presence of proteinuria must always raise the suspicion of renal disease. However, as described in this chapter there is a range of other causes one should consider. Benign postural proteinuria is a common finding in young adults, and easily ruled out on an early morning urine sample. Systemic illness such as cardiac failure and sepsis can cause a transient proteinuria—prompting repeat sampling in convalescence and exercise is capable of producing low levels of proteinuria. In otherwise healthy individuals the presence of a high protein diet should not produce proteinuria.

Further Reading Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3(Suppl):1–150. National Institute for Health and Care Excellence. Chronic kidney disease: early identification and management of chronic kidney disease in primary and secondary care. CG182. London: National Institute for Health and Care Excellence; 2014.

4

Haematuria

Question 4 A 73 year old male is attends his GP with an episode of visible haematuria occurring 24 h earlier. Other than a recent cold, he is well. He has no significant past medical history, his BP is 134/70 mmHg, his renal function normal and he is not taking an anticoagulant. Examination of his urine in clinic looks clear to the naked eye, but remains positive for blood. Protein, leukocytes and nitrites are negative.

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_4

Which of the following is the next most important step? 1. Referral to urology for cystoscopy and imaging 2. Referral to nephrology for renal biopsy 3. Urinary protein:creatinine ratio 4. ASO titres 5. Vasculitis screen

23

24

Q1: What is haematuria and how is it classified? Haematuria simply means the presence of red blood cells in the urine. It has historically been described as macroscopic or microscopic until recent recommendations by the Renal Association and the British Association of Urological Surgeons that patients are considered as having visible or nonvisible haematuria. Non visible haematuria may further be classified as spurious, transient or persistent and also as symptomatic (urgency, frequency, dysuria) or asymptomatic. The causes of haematuria are either urological or renal (see below). Q2: What is meant by the term spurious haematuria? The commonest cause of spurious haematuria is contamination of the urine specimen by menstrual blood loss. The term is also used to describe false positive dipstick tests which occur in rhabdomyolysis and haemoglobinuria because myoglobin and haemoglobin cross react with the chemical reagent on the test strip; and the red or pink urine that is sometimes seen with foods such as beetroot or drugs such as rifampicin. Q3: What are the causes of transient haematuria? The two most important ones are urinary tract infection and vigorous exercise. Patients with suspected uncomplicated urinary infection should receive an appropriate empirical course of antibiotic e.g. trimethoprim followed by repeat urine dipstick 2 weeks later. If the dipstick is negative no further tests are required. See below for what to do if the dipstick is positive. Q4: How should haematuria be investigated? All adults with a single episode of visible haematuria should be referred to a urologist for renal imaging, usually ultrasound, and cystoscopy. The likelihood of finding a urological malignancy depends on age, gender and whether the haematuria is visible or invisible, as shown in Box 4.1. A possible exception to the urology first rule is

4 Haematuria

the young adult 40 years – 8 24 Male 40 years – 5 19 Female 50 mg/mmol. The urological and renal causes of non-visible haematuria are shown in Box 4.2.

Box 4.2 Causes of Haematuria Causes of non-visible haematuria Urological Nephrological • Cancers of kidney, • IgA nephropathy bladder or prostate • Stones • Henoch Scholein Purpura • Urinary infections • Alports Syndrome • Benign tumours e.g. • Other glomerular bladder papilloma disease (usually with proteinuria) • Trauma • Polycystic kidney • Medullary sponge • Trauma

Q7: What further investigations are indicated for a patient with persistent non visible haematuria? This will depend on the age of the patient, the presence or absence of lower urinary tract symptoms (urgency, frequency, dysuria) and whether or not a renal cause is more likely than a urological one (hypertension, renal impairment and proteinuria). With these points in mind, Box 4.3 demonstrates the common scenarios:

1. Any age of patient with a pointer towards a renal cause (hypertension, renal impairment or proteinuria)—refer to nephrology. 2. Older patient (>60  years) without suggestion of a renal cause (regardless of lower urinary symptoms) refer to urology for renal ultrasound and cystoscopy. 3. Younger patient (275 mosm/kg 2. Urine osmolality 265 umol/L. Cardiorenal failure is also dangerous. In a study of 1004 patients hospitalized with symptoms and signs of heart failure, 27% developed worsening renal function. There was a sevenfold increased risk of death in hospital in this group, after adjusting for medical history, clinical signs and lab values. The management of cardiorenal failure is challenging, in keeping with its high mortality rate. Q3: What are the causes of cardiorenal failure? The classification of causes adopted by experts in this field recognises five subtypes: acute or chronic cardiorenal, acute or chronic renocardiac and a fifth group, often referred to as ‘secondary cardiorenal syndrome’ in which a systemic disease—not specific to either organ e.g. sepsis— causes both. Bilateral renovascular disease can also be considered a cardio-renal syndrome, and is an important one to remember, given the ­potential improvement with revascularisation in selected cases. A simpler and more practical approach to cardiorenal failure is to consider that either the heart causes the kidneys to fail, the kidneys cause the heart to fail, or some other condition causes both to fail concurrently. Examples of these categories are described in more detail in Box 12.1.

12  Cardiorenal Failure

Box 12.1 Causes of Cardiorenal Failure

• Cardiac disease causing the renal failure. This includes type 1 and 2. In inpatient setting the classic presentation is a result of cardiogenic shock, resulting from, for example, an acute anterior STEMI.  In the outpatient clinic it may be that a patient with progressive pump failure develops associated CKD.  This often goes hand in hand with medical therapies to manage the heart failure, e.g. diuretics and ACE inhibitors. • Renal disease causes the cardiac failure. This includes types 3 and 4. In AKI, cardiac injury—thought to be induced by acidosis, inflammation and fluid overload -predisposes to acute pump failure and dysrhythmias. Chronically, patients with established renal failure often have a myriad of structural and functional cardiovascular abnormalities: myocardial and vascular wall remodelling and stiffening are often associated with heart failure. • Systemic disease causes both. For example, atherosclerotic bilateral renovascular disease. This is the most interesting of the causes because it offers the chance of a cure for both the cardiac and the renal failure. Unfortunately, reversible cardiorenal failure due to bilateral renovascular disease only accounts for a small proportion of patients who present in this way. The others have hypertensive nephrosclerosis.

Q4: When might you suspect bilateral renovascular disease as a cause of cardiorenal failure? All patients with cardiorenal failure should have echo and renal ultrasound as part of their initial investigations. An echo showing LVH without dilatation (Fig. 12.1) and a renal ultrasound showing inequality of renal size (one kidney > 1.5 cm smaller than the other) is highly suggestive, although it should be borne in mind that, patients

12  Cardiorenal Failure

71

Fig. 12.1  Chest X-ray appearance of pulmonary oedema with cardiomegaly (left) and cardiac ECHO showing LVH without LV dilation

with bilateral renal arterial disease do not always have significant asymmetry. Acute renal deterioration following ACE inhibitor use is another useful clue. In cases where revascularisation may be appropriate this discovery should lead to imaging of the renal arteries to confirm a diagnosis of bilateral renovascular disease (see Chap. 23).

Case Report

A 75 year old woman with previous inferior myocardial infarction required temporary haemodialysis when she became moribund with cardiorenal failure while receiving an angiotensin converting enzyme inhibitor. Blood pressure was 102/58 mmHg and she had gross pulmonary and peripheral oedema. Echo showed LVH.  Her serum creatinine concentration was 731 μmol/L. She had had three less severe episodes of cardiorenal failure in the previ­ ous 15 months, each associated with an angiotensin converting enzyme inhibitor. The left kidney measured 7.0 cm on ultraso­ nography and the right kidney 9.5  cm. Arteriography showed occlusion of the left

renal artery and 90% stenosis of the right renal artery, which was stented. An angi­ otensin converting enzyme inhibitor was restarted. During 8 months follow up (Fig. 12.2) she had no further episodes of cardiac or renal failure. Blood pressure at her last visit was 193/81  mmHg and a serum creatinine concentration was 110  μmol/L while taking lisinopril 20  mg daily, furosemide 20 mg daily, amlodipine 10 mg daily, simvastatin 20 mg at night and aspirin 75 mg daily

Q5: Why do patients with bilateral r­ enovascular disease develop pulmonary oedema? The mechanism of the cardiac failure in bilateral renovascular disease is shown in Fig. 12.3. Essentially this is a consequence of fluid retention due to the unopposed action of aldosterone. Sodium loss (via pressure ­natriuresis) does not occur because the kidneys do not sense the high blood pressure as they are protected by their narrowed renal arteries.

12  Cardiorenal Failure

72 Renal Artery Stent 800 ACEi

ACEi

ACEi

700

Serum Creatinine µmol/L

600

500

400

300

200

100

0 0

24

12 Times (months)

Fig. 12.2  Serum creatinine plotted against time in the patient whose case history is described above. Note marked rise in serum creatinine with ACEi use which Fig. 12.3 Mechanism of volume overload in patients with renovascular disease

no longer occurs following successful stent insertion, Adapted from Brammah et  al BMJ 2003; 326; 489–91

ANGIOTENSIN II

BP ALDOSTERONE

Na Reabsorption Na

RENIN

Loss

Net effect is volume overload

12  Cardiorenal Failure

Q6: What is the preferred method of revascularisation? Historically, this was by aorto-renal bypass, a major surgical undertaking. The number of patients being put forward for intervention increased with the advent of angioplasty, though elastic recoil of ostial stenoses meant that this was not always technically successful. The preferred method of renal artery revascularisation, when it is agreed that this should be undertaken, is now percutaneous transluminal renal angioplasty with stent, Fig. 12.4.

Box 12.2 Trial Titbits

Endovascular intervention for renovascular disease has been evaluated intensively over the last two decades. Two landmark trials had enormous impacts and have influenced practice significantly: ASTRAL, NEJM 2009 and CORAL, NEJM 2013 compared revascularisation with medical therapy and failed to demonstrate benefit for revascularisation in the majority of unselected patients with atherosclerotic renovascular disease. It is generally accepted, though, that selected patients may benefit, so ­revascularisation is still performed occasionally.

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Q7: How would you manage a patient admitted with cardiorenal failure? This is a difficult clinical scenario. If we were to return to the Airway, Breathing, Circulation (ABC) approach of assessing sick patients then straightforward concept is to remember “B comes before K” (for kidneys). This emphasizes the importance and priority of treating pulmonary oedema, regardless of the cost on creatinine level. Paradoxically, offloading fluid in such patients may be associated with an improvement in renal function. Equally, in those with established cardiac failure, but ­evidence of volume loss (e.g. GI losses from diarrhoea, exacerbated by diuretic use), it may be appropriate to rehydrate cautiously. The key in both scenarios is accurate clinical volume status assessment and reassessment following intervention. Those cases arising in the context of cardiogenic shock, are extreme situations and often have poor outcomes. Attempts to improve cardiac pump function (e.g. emergent reperfusion, chemical or mechanical support) may improve renal perfusion, and may be attempted. Renal replacement therapy in this condition can be extremely hazardous and may not result in an improved outcome. Experienced help is necessary.

Fig. 12.4  Renal angiogram showing atheromatous aorta and bilateral renal arterial stenosis (left) and following bilateral stent insertion (right)

12  Cardiorenal Failure

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Q8: How would you manage cardiorenal failure in the clinic? Patients with more chronic cardiorenal failure are also frequently encountered in clinics where the question of treatment with ACEI/ ARB invariably arises. Renal function may improve, stay the same or deteriorate with these drugs and often the only way to find out is to prescribe and see what happens. A modest rise in creatinine with ACEI/ARB is usually considered an acceptable price to be paid for prognostic improvement and keeping the lungs free of fluid. Substitution of the ACEI/ ARB by hydralazine/nitrate, a combination of arterial and venous vasodilator in heart failure, can be considered if the rise in serum creatinine is excessive. This approach has been shown to confer symptomatic but not prognostic benefit. Objectives: Cardiorenal failure After reading this chapter you should be able to answer the following: Q1: What is meant by the term cardiorenal failure? Q2: Why is cardiorenal failure important? Q3: What are the causes of cardiorenal failure? Q4: When might you suspect bilateral renovascular disease as a cause of cardiorenal failure? Q5: Why do patients with bilateral renovascular disease develop pulmonary oedema?

Q6: What is the preferred method of revascularisation? Q7: How would you manage a patient admitted with cardiorenal failure? Q8: How would you manage cardiorenal failure in the clinic? Answer 12 3. Renal arteriography This man has presented with recurrent pulmonary oedema—in the absence of LV systolic dysfunction—and evidence of renal failure ­ ­following use of an ACE inhibitor. This combination is highly suggestive of renal artery stenosis and renal arteriography should be performed to confirm. A renal tract ultrasound may demonstrate asymmetry, but again would not confirm the diagnosis. Twenty hour catecholamines are used to investigate phaeochromocytoma, an adrenaline secreting tumour which presents as episodic hypertension and tachycardia and not as above. Cardiac MRI is unnecessary in the context of preserved LV function on ECHO and BNP is likely to be raised is all cases of cardiorenal syndrome.

Further Reading Ronco C, et al. Cardio-renal syndromes: report from the consensus conference of the Acute Dialysis Quality Initiative. Eur heart J. 2010;31:703–11.

Hepatorenal Syndrome

Question 13 A 33 year old male is admitted tremulous, with abdominal swelling and jaundice. He has no past medical history, but admits to ‘years’ of alcohol excess and more in the last month. During this time, he has taken no prescribed or over the counter medication. He is normotensive, has marked ascites, with splenomegaly and caput medusa. An ascitic tap demonstrates no white cells or organisms. His urinalysis is negative for blood and protein, and renal ultrasound demonstrates no obstruction. He is oliguric, his serum creatinine is 241  μmol/L and potassium

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_13

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3.8  mmol/L.  Two liters of IV saline has not improved his urine output. Last month, his creatinine was 37  μmol/L.  You suspect him to have hepatorenal syndrome. Which of the following is most likely to improve his renal function? 1 . Intravenous terlipressin and albumin 2. Large volume paracentesis with intravenous albumin 3. Haemodialysis 4. Intravenous antibiotics 5. Further IV saline

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13  Hepatorenal Syndrome

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Q1: What is hepatorenal syndrome? Hepatorenal syndrome (HRS) is defined as the occurrence of renal failure in a patient with advanced liver disease in the absence of an identifiable cause of renal failure. It is a diagnosis of exclusion. More commonly a complication of chronic liver disease, HRS will develop in up to 40% of patients with advanced cirrhosis and ascites by 5 years. HRS can also complicate acute liver failure in those who present with fulminant hepatic failure of any cause (e.g. severe alcoholic or viral hepatitis).

It is usually triggered by an episode of severe alcoholic hepatitis or by a septic insult such as spontaneous bacterial peritonitis (SBP) in a patient with severe liver disease. Untreated the median survival of type 1 HRS is approximately 2 weeks. Type 2 HRS occurs in patients with diuretic resistant ascites. It is characterised by a slower and less progressive rise in serum creatinine to a value exceeding 133  μmol/L.  It carries a better prognosis than type 1 HRS with a median survival of 4–6 months, Fig. 13.1.

Q2: Describe the pathophysiology of HRS. This is complex. There are at least three key features: Splanchnic vasodilatation in response to nitric oxide produced as a result of decreased hepatic perfusion; impairment of cardiac function due to cirrhotic cardiomyopathy and reduced production of renal prostaglandins which normally dilate the afferent arteriole. All three mechanisms will compromise renal perfusion.

Q4: How do you diagnose HRS? There is no single diagnostic test. Rather HRS is deemed likely in a patient with clinical stigmata of liver failure or cirrhosis who ­develops acute kidney injury (type 1) or more slowly progressive renal failure (type 2) in the absence of other obvious causes of renal impairment. Diuretic resistant ascites may or may not be present in type 1 and is always present in type 2. Previously, on-going bacterial infection excluded HRS but it is now recognised that ­bacterial infection and in particular SBP is the most important trigger. The revised International Ascites Club criteria for HRS are shown in the box.

Q3: There are two types of HRS. Discuss. Type 1 HRS is characterised by doubling of serum creatinine to a final value greater than 221 μmol/L over a period of less than 2 weeks. Fig. 13.1  The two types of hepatorenal syndrome

Hepatorenal syndrome

HRS Type 1

HRS Type 2

Rapid progression (≤2 weeks)

Rapid progression (≤2 weeks)

Trigger: alcohol/sepsis

Diuretic resistant ascites

SCr doubles to >221µmol/L

SCr increased to >133µmol/L

Untreated, mortality ≈ 2 wks

Better prognosis; 4-6 months

13  Hepatorenal Syndrome

Box 13.1 Criteria for Diagnosis of Hepatorenal Syndrome in Cirrhosis

• • • •

Cirrhosis with ascites Serum creatinine > 133 μmοl/L Absence of shock Absence of hypovolaemia as defined by no sustained improvement of renal function (creatinine decreasing to ­ 100 g/L—if serum albumin is normal then this implies an excess of globulins and should prompt a request for serum electrophoresis. • Bone pain e.g. back pain. Q6: You choose to request a ‘myeloma screen’. What would you send? Demonstrating evidence of a monoclonal protein in the serum or urine is the first step to supporting the diagnosis of myeloma. Sending a serum sample for protein electrophoresis and a urine sample for Bence Jones protein (urinary free light chains) is sufficient for initial screening and capable of detecting ~90% of cases. It is important to have some measure of free light chain production as 10% of myelomas secrete free light chains rather than intact immunoglobulins (so called light chain or Bence Jones myeloma). In many cases, a serum free light chain assay is requested if suspicion is high or renal dysfunction marked. Skeletal imaging to look for evidence of lytic lesions is now performed via cross-sectional Imaging (e.g. MR or non-contrast CT) and is best reserved for those with symptoms or until after initial screening results. Q7: Why might requesting serum free light chains be more useful than Bence Jones protein when screening for myeloma? Serum FLC are filtered by the glomerulus and reabsorbed by the proximal tubules. The serum kappa/lambda ratio in health lies between 0.26 and 1.65. The kappa/lambda ratio in patients with renal disease has a wider range from 0.37 to 3.1, because renal impairment can reduce light chain excretion. The reabsorptive capacity of the PCT (10–30  g/day) far exceeds the FLC production rate (0.5  g/day) which means that detection of urine FLC (Bence Jones protein) is a poor way of diagnosing myeloma, particularly if urine is dilute. Moreover, patients with oligo-anuric AKI may not pass enough urine to detect urine BJP. It

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is also surprising how often a urine sample for BJP is requested in hospital but not collected and so fails to arrive at the lab. Finally, SFLC can be processed fairly briskly if needed. Q8: How is the diagnosis of myeloma made? With increasing availability of the serum free light chain assay and a greater understanding of the pathophysiology of myeloma the criteria for diagnosis have changed. The International Myeloma Working Group criteria emphasize the importance of end-organ damage in the diagnosis and require the following to be present: • Presence of ≥10% clonal plasma cells in bone marrow—or evidence of biopsy proven plasmacytoma PLUS one of: • Presence of myeloma related end-organ ­damage ‘CRAB’ e.g. hyperCalcaemia, Renal insufficiency, Anaemia or lytic Bone lesions OR • Presence of a marker associated with risk of end-organ damage e.g. ≥60% clonal plasma cells, MRI evidence of multiple bone marrow lesions or raised FLC with high ratio (≥100) In practice, most clinicians make a diagnosis of myeloma by detecting a monoclonal protein in the blood or urine and demonstrating evidence of end-organ damage with referral to a haematologist for final confirmation and treatment. Q9: How does myeloma cause kidney injury? Renal disease is almost always due to free light chains. When the concentration of clonal FLC in the glomerular filtrate exceeds the reabsorptive capacity of the proximal tubular epithelium, FLCs co-precipitate with Tamm-Horsfall protein in distal tubules to produce casts. In addition, clonal FLC have a direct inflammatory and cytotoxic effect on proximal tubular epithelium. The histological lesion is called cast nephropathy or myeloma kidney. The other causes for renal impairment in myeloma are infection, drugs (chemotherapy and NSAIDS), amyloid, volume depletion, hypercalcaemia, hyperuricemia and renal tubular dysfunction.

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Q10: What are the treatment options for patients with myeloma? The management of myeloma continues to evolve. High quality supportive care with optimisation of fluid balance, treatment of hypercalcaemia and avoidance of nephrotoxic drugs is important. Bisphosphonates e.g. zoledronate can reduce progression of bone disease by inhibiting osteoclastic activity. The mainstay of management in patients with renal failure is prompt and appropriate chemotherapy, usually combination therapy with high dose dexamethasone, bortezomib, a proteosome inhibitor and thalidomide, an immunomodulatory agent. For more detailed discussion of chemotherapy options see the latest British Committee for Standards in Haematology guidelines. This may be followed, in eligible patients, by stem cell transplantation. Other treatment options include palliative care for the frail elderly and regular follow up without active treatment in those with no myeloma related organ damage or marrow impairment, so called asymptomatic myeloma.

15  Myeloma and the Kidney

Q13: What do you understand by the term monoclonal gammopathy of uncertain significance (MGUS)? MGUS is the term used to describe patients who have a stable paraprotein in their serum, 6.5 mmol/L in an oliguric patient. • Severe acidosis—especially if serum bicarbonate 100:1 (normal range is 60–80:1). Urine/plasma osmolality greater than 1.1 and urine sodium 145 mmol/L (could reduce osmolarity too quickly) • Serum Cl 6  mmol/L (because contains K, although this is controversial) • Head injury (risk of cerebral oedema because slightly hypo-osmolar) • Hepatic failure (may be unable to convert lactate into bicarbonate) Q10: Normal saline isn’t normal. Discuss. Saline 0.9% is generally referred to as normal saline because it used to be thought that its salt concentration was similar to that of plasma. This is now known not to be the case. The main drawback of saline 0.9% is that large volumes can load the extracellular fluid compartment with more sodium and chloride than

is necessary. Five liters saline 0.9% contains 1540 mOsm of solute which sick patients may take up to 5 days to excrete. The retained chloride may reduce GFR and also cause a hyperchloraemic acidosis. The composition of saline 0.9% and other prescribed fluids is shown in Table 17.1 Q11: How much fluid for maintenance? Maintenance daily fluid requirements for a healthy adult are:

Box 17.2 Maintenance Fluid Requirements for Healthy Adult • Water • Sodium • Potassium • Calories

30 mL/kg l mmol/kg 1 mmol/kg 50–100 g/day of glucose to limit starvation ketosis

NICE recommend that we do not exceed 30ml/kg/day and consider prescribing less maintenance fluid for patients who are obese, older, frail or have renal impairment or cardiac failure Q12: Which fluid for maintenance? The conventional approach is to give dextrose 5% with saline 0.9% and added K in ratio 3 dextrose: 1 saline. For a healthy 70 kg adult 3 × 500 mL dextrose and 1  ×  500  mL saline 0.9% given 6  h

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Table 17.1  Composition of IV fluids Fluid Plasma Saline 0.9% Hartmann’sa Plasmalyteb Gelaspanc Isoplexd Dextrose 5%e

Na (mmol/L) 136–145 154 131 140 151 145 0

K (mmol/L) 3.5–5.2 0 5 5 4 4 0

Chloride (mmol/L) 98–105 154 111 98 103 105 0

Osm (mosm/L) 280–300 308 275 294 284 284 278

Other constituents are Lactate 29 mmol/L b Acetate 27 mmol/L and gluconate 23 mmol/L c Gelatin 40 g/L d Lactate 25 mmol/L, magnesium 0.9 mmol/L e Dextrose 50 g/L a

with 40 mmol added K per day will give 2000 mL fluid, 77 mmol Na, 40 mmol K and 300 calories. You could also consider 0.18% saline in 4% dextrose (dextrose-saline) with added K when prescribing for routine maintenance only. For a healthy 70  kg adult, 2100  mL dextrose-saline (30 mL/kg) prescribed at 87 mL/h using 1 L bags will supply all volume, Na, K and calorie needs for up to 3 days. Bear in mind that maintenance fluid is intended for short periods only and consider enteral feeding if the patient hasn’t started eating and drinking by then. Q13: When should you give IV fluid to a patient with acute kidney injury? When the clinical history, signs and lab results suggest they might be dry (see Box 17.1). In every day clinical practice it is generally safe to assume an AKI patient is dry if there is no oedema, no elevation of the JVP, no dyspnoea, no basal crackles, normal respiratory rate and normal SpO2. Q14: How much IV fluid should you give a patient with acute kidney injury? Your aim should be to give as much fluid as required in order to restore renal perfusion, as quickly as possible. Shocked patients with AKI should receive up to 30  mL/kg crystalloid stat. For patients with AKI who are dry but not shocked we commonly give 1 L in the first hour, then 1 L over 2 h and 1 L in the next 4 h i.e. 3 L in the first 7  h. Junior doctors who prescribe

4  hourly bags as replacement fluid need to be aware that 4 hourly bags usually take 5 h to run on a general ward i.e. 100  mL/hour. IV fluid delivered at this rate is equivalent to taking more than 3 h to drink a can of coke. Q15: What should you do if uncertain whether a patient is dry or not? The correct course of action here is to give a fluid challenge of 250  mL saline 0.9% or Hartmann’s, squeezed in over 2–3  min followed by immediate assessment of clinical response. If the heart rate decreases and the blood pressure increases this suggests that the patient was in fact hypovolaemic and should lead to a further fluid challenge i.e. a fluid challenge is only a ‘test dose’ and is not enough in its own right to restore renal perfusion. More fluid must then be given. The usual target is a urine volume >0.5 mL/kg/h. Q16: What if the patient has a history of heart failure? Patients with a history of heart failure are more likely to develop pulmonary oedema during or after a fluid challenge. A rising respiratory rate is the earliest sign, followed by increasing oxygen requirement then basal crackles. This is not a reason to withhold fluid merely advice to be more cautious by infusing lower volumes of fluid less quickly than for patients without cardiac disease. Some patients with AKI also have evidence of cardiac failure at the time of presentation. This is

17  Fluid Management

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known as cardiorenal failure, which makes everything much more complicated. We discuss a strategy for fluid management in cardiorenal failure in more detail in Chap. 12. Objectives: Fluid Challenge After reading this chapter, you should be able to answer the following: Q1: Describe the different body fluid compartments Q2: What is normal fluid intake and output? Q3: Name three things that can go wrong with fluid balance? Q4: How might you decide whether a patient is dry, wet or euvolaemic? Q5: Is it possible to be intravascularly dry and yet oedematous at the same time? Q6: How might you calculate how much fluid to give? Q7: How much and which fluid for resuscitation? Q8: How much fluid for replacement? Q9: Which fluid for replacement? Q10: Normal saline isn’t normal. Discuss. Q11: How much fluid for maintenance? Q12: Which fluid for maintenance? Q13: When should you give IV fluid to a patient with acute kidney injury? Q14: How much IV fluid should you give a patient with acute kidney injury?

Q15: What should you do if uncertain whether a patient is dry or not? Q16: What if the patient has a history of heart failure? Answer 17 3. Postural change in pulse and blood pressure As described above, assessment of fluid status requires a careful consideration of multiple factors. Of the options given, a postural change in pulse and blood pressure would be the most sensitive marker of volume depletion for this man. He has developed oliguric AKI due to severe sepsis. He has a low serum albumin and thus will be peripherally oedematous. It is very possible he has developed ATN and may need more time for renal recovery. A low urine output is therefore a marker of renal failure in him, and not necessarily one of hypovolaemia. Thirst can be induced iatrogenically by oxygen masks or medication. Skin turgor can be influenced by peripheral oedema or advanced age.

Further Reading Intravenous fluid therapy in adults in hospital. National Institute for health and Care Excellence (NICE) Clinical Guideline 174, December 2013.

18

Hyperkalaemia

Question 18 A 32 year old transplant recipient is found to have hyperkalaemia at a routine clinic appointment. Her blood results are shown below. Her baseline creatinine is usually 80 μmol/L. Her BP is 118/69 mmHg. On the morning of the clinic, she took her last dose of an antibiotic, trimethoprim, for a UTI diagnosed via her GP. Test Haemoglobin White cell count Platelets Sodium Potassium Creatinine Bicarbonate CRP Urine dipstick

Result 133 g/L 4.2 × 109/L 203 × 109/L 142 mmol/L 6.3 mmol/L 95 μmol/L 23 mmol/L 6 Clear

Which of the following is the most likely cause of her hyperkalaemia? 1. Rejection 2. Trimethoprim side effect 3. Development of renal acidosis 4. Steroid insufficiency 5. Artefact

Reference 120–160 g/L 4–11 × 109/L 150–450 × 109/L 135–145 mmol/L 3.5–5.5 mmol/L 70–120 μmol/L 22–28 mmol/L 20  mmol/L while bearing in mind that this may cause or worsen oedema and hypertension. All patients with progressive CKD should be referred to a renal dietician for advice on protein, calorie, potassium and

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phosphate intake. Malnutrition is common and difficult to correct (Box 20.6).

Box 20.6 Complications of CKD

Five complications of CKD 1. Anaemia 2. Bone disease 3. Hyperkalaemia 4. Acidosis 5. Malnutrition

Objectives: Chronic Kidney Disease

After reading this chapter, you should be able to answer the following: Q1: What is meant by the term chronic kidney disease? Q2: How common is chronic kidney disease? Q3: What are the symptoms of chronic kidney disease? Q4: What are the signs of chronic kidney disease? Q5: What are the common causes of chronic kidney disease? Q6: What investigations are most helpful in determining the cause of a patient’s chronic kidney disease? Q7: What is the normal size of a kidney by renal ultrasound? Q8: Discuss how renal ultrasound may help in the diagnosis of patients with chronic kidney disease. Q9: Describe in broad terms the management of a patient with chronic kidney disease.

20  Overview of Chronic Kidney Disease

Q10: How may CKD progression be prevented? Q11: How may vascular disease be prevented? Q12: How may the complications of CKD be prevented and treated? Answer 20 3. Glomerulonephritis This is common scenario, known as chronic kidney disease presenting acutely. Whilst diagnosing the underlying cause of renal failure at this stage is unlikely to change his immediate management this may have implications to his potential transplant. The presence of nephrotic range proteinuria is a marker of glomerular disease and the ultrasound finding of small smooth kidneys supportive of this diagnosis. Obstruction would demonstrate hydronephrosis; polycystic kidneys disease, large cystic kidneys; chronic pyelonephritis, scarred kidneys and renal vascular disease may demonstrate asymmetry, or could present with small kidneys. His youth makes vascular disease less likely.

Further Reading Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–150. Scottish Renal Registry Annual Report 2017. www.srr. scot.nhs.uk. Accessed May 2019.

Glomerular Disease

Question 21 A 24  year old female attends A&E with a 3  day history of a sore throat, and new onset brown coloured urine. On examination she has purulent tonsils, with tender cervical lymphadenopathy and is pyrexial at 38.1 °C. Her urinalysis is positive for blood +++ and protein +. Her bloods demonstrate the following: Test Haemoglobin WCC Platelets Creatinine CRP

Result 127 g/L 14.3 180 × 109/L 132 μmol/L 109

21

Which of the following is the most likely diagnosis? 1. IgAN 2. Post-infectious glomerulonephritis 3. Membranous Nephropathy 4. Minimal Change Nephropathy 5. Focal segmental glomerulosclerosis

Reference 120–160 g/L 4–11 × 109/L 150–450 × 109/L 70–120 μmol/L 3  g/24  h (urine PCR > 300 mg/mmol) 3. Hypoalbuminaemia 8 mmol/L, with many requiring lipid lowering therapy. There is no good evidence that protein restriction will slow the decline in renal function of patients with glomerular disease (Box 21.4). Box 21.4 Principles of Supportive Management in Glomerulonephritis

Five Supportive treatments for Glomerular Disease 1. Tight blood pressure control 2. ACEI/ARB for their antiproteinuric effect 3. Loop diuretics for oedema of nephrotic syndrome 4. Statins for CV risk reduction 5. Adequate protein/calorie intake to prevent under-nutrition

Objectives: Glomerular Disease After reading this chapter, you should be able to answer the following: Q1: What does the term glomerular disease mean? Q2: Describe the pathophysiology of glomerular disease Q3: How might you classify glomerular disease? Q4: How does glomerulonephritis present? Q5: What is meant by asymptomatic urinary abnormalities?

Further Reading

Q6: What do you understand by the term acute nephritis? Q7: What do you understand by the term nephrotic syndrome? Q8: What do you understand by the term rapidly progressive glomerulonephritis (RPGN)? Q9: Some patients with glomerular disease simply present with chronic kidney disease. How would you make a diagnosis? Q10: What are the causes of glomerular disease? Q11: Describe the histological features of glomerular disease. Q12: What do you know about minimal change nephropathy (MCN)? Q13: What do you know about membranous nephropathy? Q14: What do you know about focal segmental glomerulosclerosis (FSGS)? Q15: What do you know about IgA nephropathy? Q16: What do you know about focal proliferative GN, mesangiocapillary GN and diffuse proliferative GN?

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Q17: What is treatment?

meant

by

“supportive”

Answer 21 1. IgAN This is a presentation of ‘synpharyngitic nephritis’, or IgA nephropathy. The proximity of the renal presentation to the infection makes this most likely, whereas post infective glomerulonephritis usually occurs 1–2 weeks after the infection. There is no urinary PCR provided, but the presence of only one + proteinuria makes nephrotic syndrome highly unlikely, which would be a feature of all other diagnoses.

Further Reading Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2:139–274.

Renal Disease and Diabetes

Question 22 A 64 year old female with CKD secondary to diabetes attends clinic. She is well, with no particular complaints and you discuss her progressive CKD.  Her previous blood results have demonstrated a loss of GFR at a rate of approximately 10 mL/min per year. Six months ago, her GFR was 30 mL/min. Her diabetes is well controlled on a combination of insulin and metformin. Her bloods return from clinic and her GFR is 25 mL/min.

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_22

22

Which of the following is a necessary change to her medication? 1. 2. 3. 4. 5.

Stop metformin Stop insulin Start SGLT-2 Start GLP-1 Increase insulin

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22  Renal Disease and Diabetes

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Q1: Describe the two types of diabetes and discuss the ways in which they differ Type 1 diabetes results from insulin deficiency, with onset generally in childhood, teens or young adult life. It is roughly ten times less common than type 2 diabetes. In contrast, type 2 diabetes is considered a disease of middle age and usually a consequence of obesity. Far from being insulin deficient those with type 2 diabetes have high levels of insulin in their blood stream— rendered ineffective by cellular insulin resistance. A variant of type 2 diabetes can also be a consequence of steroid therapy, for example after renal transplantation. Post-transplant diabetes is associated with a high risk of vascular disease. Obesity occurring at much younger ages and

Fig. 22.1  Insulin is required at a cellular level to permit glucose into most cells. Without this process, diabetes occurs. There are only two ways this can happen; (1) Insulin is not produced by the pancreas (left side), and so cannot act on the cellular receptors or (2) Insulin is produced (often at high levels), but the cells are resistant to its effects (right side). The left is type 1 diabetes, and the right type 2

advents in genotype testing have made the type 1/ type 2 distinction somewhat muddier (Fig. 22.1). Q2: Describe the complications of diabetes These are usually considered under two headings—microvascular and macrovascular as shown in the diagram. Diabetes accounts for one in seven of all deaths in the UK. The majority of these are cardiovascular. Diabetes is the commonest cause of CKD in the UK (Fig. 22.2). Q3: What do you understand by the term diabetic nephropathy? Diabetic nephropathy or diabetic kidney disease is the classic cause of CKD in people with diabetes. It occurs in up to 40% of patients after

Type 1

Type 2

Insulin

No insulin

Absence of insulin

Insulin resistance

Fig. 22.2  Complications of diabetes Complications of diabetes

Microvascular

Macrovascular

Retinopathy Nephropathy Neuropathy

Coronary Cerebrovascular Peripheral vascular

22  Renal Disease and Diabetes

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Fig. 22.3 Progression of proteinuria in diabetes Nephrotic range 300 Severely ↑ albuminuria ACR mg/mmol

30 Moderately ↑ albuminuria 3 Normoalbuminuria 0 Time

Fig. 22.4 Presentations of renal disease in diabetes, separated by degree of proteinuria

Diabetes with renal impairment

PCR >100mg/mmol

Diabetic nephropathy

15–20 years and is more common in those with poor glucose control. It is likely to occur in type 2 diabetes after 15–20 years though the risk to the individual is greater in type 1 diabetes because they generally have the disease for longer. The clinical hallmark of diabetic nephropathy is proteinuria and the pathological hallmark is glomerulosclerosis. Figure  22.3 shows how diabetic proteinuria may evolve over a number of years: Q4: Do all patients with diabetes and renal impairment have diabetic nephropathy? The triad of diabetes with proteinuria and retinopathy means that the renal disease is highly likely to be due to diabetic nephropathy. Most patients with type 1 diabetes who develop

PCR 50  mg/ mmol. ACE inhibitors and ARBs may cause worsening of existing renal impairment in patients with bilateral renovascular disease or renal artery stenosis to a solitary kidney. These drugs are frequently associated with a small rise in serum creatinine when first given to patients with CKD, though this is not normally a reason to stop: many nephrologists will tolerate a rise in serum creatinine of up to 30% before doing so. ACE inhibitors and ARBs may also increase serum potassium because they lower serum aldosterone. As a rough guide these drugs should not be introduced if serum K is greater than 5 mmol/L and should be stopped if serum K goes over 6  mmol/L.  So far as the other antihypertensive drugs are concerned, thiazides become less effective as antihypertensive agents when serum creatinine exceeds 150  μmol/L, in which case patients should normally be given a loop diuretic such as furosemide if a diuretic is required to

Step 1

A for patients if diabetic or ≤55years or C if >55 & all Afro-carribeans

Step 2

Add A (if on C), C (if on A) or D

Step 3

A&C&D

Step 4

A & C & D & spironolactone if K+   50  mg/mmol). The commonest side effect of an ACE inhibitor is a dry cough, the occurrence of which should prompt a switch to an angiotensin receptor blocker. We have already alluded to the fact that ACE inhibitors can worsen renal function in patients with bilateral renovascular disease and can also cause hyperkalaemia. This is in addition to an acute worsening of renal function if the patient becomes intravascularly deplete. Patients prescribed an ACE inhibitor must be advised to omit this drug and seek help from their general practitioner if they start vomiting or develop diarrhoea in order to reduce the risk of drug induced AKI; so-called ‘sick day rules’.

ACE inhibitors and are also as likely to cause hyperkalaemia, worsen renal function in patients with bilateral renovascular disease and AKI in the context of dehydration. ARBs should not be combined with ACE inhibitors as this may result in more adverse events without any clinical benefit. Q3: What should you know calcium channel blockers? Calcium channel blockers are vasodilators. There are two types: dihydropyridines such as amlodipine and nifedipine which do not lower heart rate, and rate-limiting calcium channel blockers diltiazem and verapamil which do (Fig.  25.3). Amlodipine is the most commonly prescribed dihydropyridine calcium channel blocker. It is generally well tolerated, is easy to combine with other drugs but can cause troublesome ankle swelling. It is important to avoid co-­ prescribing a rate limiting calcium channel blocker with a beta blocker, out-with exceptional Angiotensin receptor blockers CANDESARTAN

Q2: What should you know about angiotensin receptor blockers? These drugs all end in –sartan. Examples are losartan, irbesartan and valsartan (Fig.  25.2). They lower blood pressure by blocking the receptor to which angiotensin II binds, but do not cause cough. ARBs share an antiproteinuric effect with

Fig. 25.2  Examples of angiotensin II receptor blockers

ACE Inhibitors

Calcium channel blockers

RAMIPRIL

VALSARTAN

– SARTAN

IRBESARTAN LOSARTAN

Rate limiting CCB

Dihydropyridine CCB

Verapamil

Amlodipine

Diltiazem

Nifedipine

LISINOPRIL – PRIL CAPTOPRIL

ENALAPRIL

Fig. 25.1  Examples of ACE inhibitors

Lercanidipine

Fig. 25.3  Examples of calcium channel blockers

25  Antihypertensive Drugs

circumstances, as this can lead to profound bradycardia. Q4: What should you know about thiazide diuretics? Bendroflumethiazide 2.5  mg once daily, was and probably still is the diuretic of choice for hypertension. This is despite the NICE recommendation that if a diuretic is to be started or changed clinicians should offer a thiazide-like diuretic such as chlorthalidone 12.5–25 mg once daily or indapamide 1.5 mg modified release or 2.5  mg standard preparation once daily instead. NICE do concede that for people already taking bendroflumethiazide whose blood pressure is stable and well controlled, it is acceptable to continue treatment with bendroflumethiazide. Gout and hyponatraemia are two important side effects. Thiazides are more likely to cause hyponatraemia than loop diuretics because they impair free water clearance to a greater extent. Q5: What should you know about loop diuretics? Furosemide is the most commonly prescribed loop diuretic. Others in this class are Bumetanide and Torasemide. The starting dose of Furosemide is 40 mg daily. This can normally be increased by increments of 40–80 mg twice daily if necessary and if tolerated. As a general rule larger doses of Fig. 25.4  Site of action of loop and thiazide diuretics. DCT distal convoluted tubule; TALoH Thick ascending loop of Henle; Na+ sodium; K+ potassium

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loop diuretics are required for patients with chronic kidney disease than in those with normal renal function. This is because loop diuretics are pumped into the proximal convoluted tubule by what is known as the common anion secretor pathway, where they have to compete with other anionic substances, the levels of which increase as kidney function becomes more impaired. Gout is an important side effect. Q6: Thiazide and loop diuretics frequently cause hypokalaemic alkalosis in patients with normal renal function. Why? As a result of blocking pumps in the thick ascending limb of the Loop of Henle (loop diuretics) and the distal convoluted tubule (thiazide diuretics) more sodium is delivered distally to the cortical collecting duct. Sodium is exchanged for potassium by the principal cells in the cortical collecting duct while potassium is exchanged for hydrogen ions by the intercalated cell, also in the cortical collecting duct. The result is hypokalaemic alkalosis (see Fig. 25.4) Q7: What should you know about alpha-blockers? Alphablockers are vasodilators that act by blocking the alpha receptor on blood vessel walls. The main alpha-blocker used for control of hypertension is Doxazosin, the best tolerated

Thiazide diuretics block cotransporter in DCT

Na+

Na+ Na+ Loop diuretics block co-transporter in TALoH

Principal cells

K+ K+ H+

Intercalated cells

H+ and K+ excreted

25  Antihypertensive Drugs

156

Objectives: Antihypertensive Drugs After reading this chapter, you should be able to answer the following:

β -Blockers

BISOPROLOL ATENOLOL

– LOL

PROPANOLOL CARVEDILOL

Fig. 25.5  Examples of betablockers

preparation of which is Doxazosin MR 4  mg once daily. Doxazosin can be added on to any of the other antihypertensive drugs and is not any more likely to cause side effects in a kidney patient than in patients who do not have chronic kidney disease. Side effects include tiredness, lethargy and dizziness. Q8: What should you know beta-blockers? These drugs all end in –lol. Examples are bisoprolol, atenolol, propranolol and carvediolol (Fig.  25.5). Beta-blockers block beta receptors which are found in many tissues including blood vessels, heart, kidney and lung. They probably lower blood pressure by suppressing the release of renin by the kidney and by reducing cardiac output. You can judge whether a patient is beta-­ blocked or not by checking their pulse, aiming for a heart rate of around 60/min. If lower than this then most would not normally use or increase a betablocker. Beta-blockers used to be one of the mainstays of treatment of hypertension but recent trials have suggested they are less effective than calcium channel blockers and ACE inhibitors and as a result of this they are no longer recommended as first line therapy. Side effects are common and include cold hands, lethargy and erectile dysfunction. They are contraindicated in patients with asthma, also in COPD if the peak flow rate is less than 300 L/min.

Q1: What should you know about ACE inhibitors? Q2: What should you know about angiotensin receptor blockers? Q3: What should you know calcium channel blockers? Q4: What should you know about thiazide diuretics? Q5: What should you know about loop diuretics? Q6: Thiazide and loop diuretics frequently cause hypokalaemic alkalosis in patients with normal renal function. Why? Q7: What should you know about alpha-blockers? Q8: What should you know beta-blockers? Answer 25 2. Can trigger AKI in those with reno-vascular disease Angiotensin II receptor blockers (ARB) have a similar side effect profile to ACE inhibitors (AKI in presence of renal hypoperfusion and hyperkalaemia) but do not produce cough. Although the combination of ACE inhibitor and ARB was previously used to treat proteinuric renal disease this is no longer common or safe practice due to the risk of hyperkalaemia. Similar to ACE inhibitors ARBs are contraindicated in pregnancy due to teratogenic risk.

Further Reading Ashley C, Dunleavy A. The renal drug handbook. 5th ed. Boca Raton, FL: CRC Press; 2018.

Polycystic Kidney Disease

Question 26 A 42 year old male with a strong family history of autosomal dominant polycystic kidney disease attends clinic for review. He was diagnosed with polycystic kidney disease aged 22, and has defaulted from follow-up since. He wishes to know more about this condition and its complications. Which of the following is true regarding ADPKD?

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_26

26

1 . Progressive liver failure is common 2. Childhood screening will detect most cases 3. The presence of two or more cysts confirms the diagnosis in those over 60 4. Recurrence is common in transplanted kidneys 5. Anaemia is less common than other forms of CKD

157

26  Polycystic Kidney Disease

158

Q1: What is ADPKD? Autosomal dominant polycystic kidney disease is a relatively common (prevalence 1  in 1000) and important cause of CKD. Eighty-five percent of cases are caused by mutations of the PKD1 gene with the remaining 15% of cases due to mutations of the PKD2 gene. These mutations cause defective cell signalling which leads to cyst formation. Small cysts develop in childhood but may not be detectable until early adult life. Q2: How might a patient with polycystic kidney disease present clinically? It is probably true to say that most patients with ADPKD have no symptoms. Some experience loin discomfort and others a fullness in their abdomen. When acute pain occurs this is likely to be due to haemorrhage or infection in a cyst. ADPKD may also come to light during investigation of hypertension, chronic kidney disease or subarachnoid haemorrhage, or as an incidental imaging finding. Although polycystic kidneys are the commonest cause of renal masses that find their way into clinical exams, some are easier to feel than others which means that on occasion only one and sometimes neither kidney is palpable. Q3: Describe the extra-renal manifestations of polycystic kidneys. The most important are erythrocytosis, hepatic cyst formation and intracranial aneurysms. Erythrocytosis occurs because the cysts produce erythropoietin. It is usually inferred because patients with polycystic kidney disease are gener-

Fig. 26.1 Ultrasound criteria for diagnosis of ADPKD type I in those with positive family history

ally less anaemic than you would expect for a given level of renal failure. Hepatic cysts can cause hepatomegaly which may be quite striking, though liver failure is rare. Intracranial aneurysms are said to occur in around 10% of patients with polycystic kidneys and may bleed causing subarachnoid haemorrhage. Q4: How is the diagnosis of ADKPD made? If a patient has a family history of polycystic kidneys, palpable masses in both loins and enlarged kidneys containing multiple cysts on renal ultrasound then the diagnosis is very easy and obvious. Difficulties may arise if there is no family history (possible new mutation), kidneys that are difficult to feel (not uncommon) or an ultrasound report which mentions only a few cysts and does not specify the renal size. Ultrasonic criteria for ADPKD are in fact quite well defined. In a patient with a positive family history then a diagnosis of ADPKD is likely if the kidneys are enlarged (>12 cm) with two or more cysts in one or both kidneys by the age of 30, two or more bilaterally by age 59 and four or more cysts in both kidneys from age 60 onwards (Fig. 26.1). In order to diagnose ADPKD when there is no family history there must be bilateral cysts in bilaterally enlarged kidneys or the presence of multiple bilateral renal and hepatic cysts. Ultrasound can detect cysts from 1 cm in diameter and is the preferred form of imaging. CT will show cysts as small as 0.5  cm but exposes the patient to radiation (Fig.  26.2). MR is an equally sensitive alternative to CT.

∆ ADPKD Aged < 30 years

≥2 Cysts ≥1 Kidney

Aged 30-59 years

≥2 Cysts BOTH Kidneys

Aged ≥60 years

≥4 Cysts BOTH Kidneys

26  Polycystic Kidney Disease

Fig. 26.2  CT image showing multiple large renal cysts present in both kidneys

Q5: Whom and when to screen? The inheritance of polycystic kidney disease presenting in adulthood is autosomal dominant which means that 50% of the offspring of an affected parent will have the abnormal gene and develop cysts in both kidneys. Screening those under the age of 20 is not routinely recommended for two reasons; practically, because the cysts grow slowly and may not be visible on ultrasound in childhood and adolescence and, perhaps more importantly, because the risks of labelling a young person with this diagnosis— with potential psychological damage and implications to education and career—are not currently outweighed by any benefits from current treatments. A negative scan at 20 is falsely negative in 4% of cases which means that further scanning will be necessary in order to exclude the disease with certainty. In the absence of hypertension or renal dysfunction, delaying imaging until the age of 30 is good practice—by which time the false negative rate for ultrasound scanning is very nearly zero. Q6: What is the role of genetic testing in ADPKD? Genetic testing isn’t widely performed but it does have a role. For those with equivocal imaging findings or in whom a definite diagnosis is essential it can be very useful, e.g. assessment of a potential living-related donor for kidney transplant.

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Q7: Does the presence of multiple renal cysts mean that a patient has ADPKD? No. Simple renal cysts are common and can be multiple. However, renal size will be normal and there will be no family history of ADPKD in such patients. Other cystic kidney diseases can occur, such as autosomal recessive polycystic kidney disease (ARPKD), medullary cystic kidney disease and medullary sponge kidney. These disorders are discussed in more detail in the rare renal chapter (Chap. 38). Finally, multiple renal cysts can also develop in patients who have had their kidney disease for many years, especially those who are on renal replacement therapy. This is known as acquired cystic kidney disease or ACKD and is harmless. Q8: Discuss the management and outcome of polycystic kidney disease. Until relatively recently, the only treatment option currently available is control of blood pressure which is commonly raised in polycystic kidney disease. ACE inhibitors are usually recom­mended as first-line therapy and we tend to aim for stricter blood pressure control in this group, although the specific target is uncertain. Tolvaptan, an ADH antagonist, has come into use over the last decade as the first medicine shown to be effective at retarding the progression in renal dysfunction in PKD. The key difficulty with its use is the need to drink enormous amounts of fluid when taking it, along with the small risk of LFT abnormalities which mandates frequent monitoring. Tolvaptan can be used for patients who are at risk of rapid progression demonstrated on bloods or serial measurements of renal size.

Trial Titbits

TEMPO (NEJM 2012) showed slower decline in eGFR in patients with good baseline renal function receiving Tolvaptan vs placebo. REPRISE (NEJM 2017) looked at patients with reduced eGFR (25–65 mL/ min/1.732) and declining function. It found that in those who can tolerate the drug, tolvaptan slows decline in kidney function.

26  Polycystic Kidney Disease

160

Q9: Discuss the outcome of polycystic kidney disease Patients may be told that it takes about 10 years to reach dialysis from the moment the creatinine begins to rise, also that the average age at which dialysis is required is around 50 for patients who carry the PKD1 gene and 70 for those with ADPKD type 2. This effectively means that many patients with the milder form of the disease will not require dialysis during their lifetime.

Q6: What is the role of genetic testing in ADPKD? Q7: Does the presence of multiple renal cysts mean that a patient has ADPKD? Q8: Discuss the management and outcome of polycystic kidney disease. Q9: Discuss the outcome of polycystic kidney disease Q10: When is surgery indicated in ADPKD?

Q10: When is surgery indicated in ADPKD? Not very often. Aspiration of large cysts under ultrasound or CT guidance may be of value if these are causing pain. Laparoscopic or surgical cyst defenestration may be indicated if multiple cysts are causing pain. Nephrectomy is reserved for recurrent lifethreatening infection, bleeding, renal cancer (which when it occurs is more often bilateral in ADPKD), and in cases where the kidneys are so large that they would interfere with placement of a renal transplant. Objectives: Polycystic Kidney Disease After reading this chapter, you should be able to answer the following:

5. Anaemia is less common than other forms of CKD

Q1: What is ADPKD? Q2: How might a patient with polycystic kidney disease present clinically? Q3: Describe the extra-renal manifestations of polycystic kidneys. Q4: How is the diagnosis of ADKPD made? Q5: Whom and when to screen?

Answer 26

The cysts of ADPKD are capable of producing EPO, and thus polycythaemia is associated. As CKD progresses patients tend to have a lesser degree of anaemia than would be expected for level of renal function. Progressive liver failure is uncommon, being a feature of childhood polycystic kidney disease (ARPKD). Screening in early life misses many cases, and should be reserved until the third or fourth decades (aged 20–30) so as to prevent false reassurance. Cysts are a common finding with age; in addition to a family history ADPKD would require four or more cysts in both kidneys to be diagnostic.

Further Reading Torres VE, et al. Autosomal dominant polycystic kidney disease. Lancet. 2007;369:1287–301.

27

Renal Anaemia

Question 27 A 42  year old female with progressive CKD attends clinic. She is listed for a renal transplant, and has potential live donors hoping to assist with a pre-emptive transplant. She has also opted for hospital haemodialysis when required. On review, she complains of feeling increasingly tired and has developed exertional dyspnoea. Her bloods are demonstrated below. Test Haemoglobin Ferritin CRP TSAT Reticulocyte count B12 Folate

Result 87 g/L 324 4 32% 27 × 103/μL 191 ng/mL 9.7 ng/mL

Reference 120–160 g/L 15–300 ng/mL 5x >2x

Cervix/vulva/vagina

Pharynx/larynx

Non-melanoma skin

Melanoma, sarcoma

PTLD

Kaposi sarcoma

Liver. CNS

Multiple myeloma

Kidney

Bladder/urothelial

Thyroid

Lung. prostate

252

41  Renal Transplantation

by biopsy. The cells in this tumour were strongly positive for EBV encoded RNA. Withdrawal of tacrolimus and mycophenolate followed by infusion of Rituximab led to a significant reduction in tumour size. When seen at the clinic six years after her initial presentation with PTLD serum creatinine was 137 μmol/l. She remains on prednisolone 5  mg daily for immunosuppression. Her lymphoma was no longer visible on ultrasound. Fig. 41.5  Large basal cell carcinoma

and deliberate tanning by avoiding sun between 11 am and 3 pm and by using sunblock creams. All patients should be offered annual skin checks (Fig. 41.5). Q23: What type of lymphomas may occur in transplant patients? Lymphoma can occur in 1–2% of transplant patients usually within 1 year of the transplant. Ninety-six percentage are non-Hodgkin’s lymphomas. Lymphomas often present as graft dysfunction and may be difficult to distinguish histologically from severe rejection.

Case Report

A 38 year old woman presented with a glandular fever like illness and positive EBV serology, sixteen months after a second cadaveric transplant. Her underlying diagnosis was focal segmental glomerulosclerosis, an early recurrence of which had led to the loss of her first graft. Her second transplant was perfectly matched but highly sensitised so she had been given basiliximab as induction therapy followed by prednisolone, tacrolimus and mycophenolate. Imaging showed a 6 cm soft tissue mass inferior to the transplanted kidney, encircling the femoral vessels. There were no other sites involved. A diagnosis of high grade non Hodgkin’s lymphoma was made

Post-transplant lymphoproliferative disorder (PTLD) is a unique form of lymphoma driven by exposure to EB virus and fuelled by immunosuppressive drug therapy. Treatment consists of reducing the dose of immunosuppressive drugs. Some patients also require rituximab (a monoclonal antibody directed against B cells) or other anti-cancer therapies. Objectives: Renal Transplantation After reading this chapter, you should be able to answer the following: Q1: Which patients are considered for a renal transplant? Q2: What different types of renal transplant are there? Q3: Which is the ‘best’ type of transplant? Q4: What is meant by donation after brain death (DBD)? Q5: What is meant by donation after cardiac death (DCD)? Q6: How is consent obtained for donation in the UK? Q7: How are cadaveric organs allocated? Q8: What information is a transplant surgeon likely to give a patient before adding their name to the waiting list? Q9: Apart from the risks of graft failure what other risks should a patient be aware of? Q10: Name the immunosuppressive drugs that are commonly used to prevent rejection? Q11: Discuss the side effects of the immunosuppressive drugs.

41  Renal Transplantation

Q12: A patient whose transplant has been functioning well with a baseline creatinine of 106 μmol/L comes to the clinic where it is found that his creatinine has doubled. What could account for this? Q13: What type of illness does CMV cause and how may this be treated? Q14: Can CMV infection be prevented? Q15: When should pneumocystis jirovecii infection be suspected and how can this be diagnosed and treated? Q16: Can pneumocystis pneumonia be prevented? Q17: Discuss what can happen and what you might do if a susceptible transplant patient became infected with VZV. Q18: What steps can be taken to reduce the risk of VZV infection in a transplant patient? Q19: What should you do with immunosuppressive therapy when a transplant patient develops a severe infection? Q20: Is it safe to vaccinate a patient with a functioning transplant? Q21: How likely is a renal transplant patient to develop cancer?

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Q22: Which skin cancers occur in transplant patients? Q23: What type of lymphomas may occur in transplant patients? Answer 41 4. Malignancy This patient has developed post-transplant lymphoproliferative disorder, as described in this chapter. The combination of constitutional symptoms, raised LDH, lymphadenopathy and an extra-nodal mass (in this case encasing the transplant kidney) should raise suspicion to PTLD.  This diagnosis is not easy to make, and conditions such as infection need ruled out. Transplant recipients are at risk of infection at any time; however the combination of features provided make malignancy most likely. Rejection and recurrence may present as a rise in serum creatinine with urinary abnormalities such as blood or proteinuria. Renal obstruction would not cause the describe symptoms unless infected, and the normal urinalysis does not support infection

Dialysis and Poisoning

Question 42 A 47 year old female with bipolar affective disorder and diabetes is admitted following 1 week’s history of diarrhoea and vomiting. Her regular medication includes lithium and metformin. On arrival her heart rate is 102 bpm, her BP 90/42 mmHg and she feels thirsty. Blood testing demonstrates a serum creatinine of 312 μmol/L, potassium 6.1  mmol/L, lactate 3.2 and lithium level of 2.7 mmol/L. She is alert and orientated.

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_42

42

Which of the following is NOT required as part of the immediate management plan? 1. 2. 3. 4. 5.

Stop metformin Stop Lithium Fluid resuscitation Immediate dialysis Cardiac monitoring

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42  Dialysis and Poisoning

256

Q1: Define ‘poison’ A poison is any substance capable of causing death, injury or impairment of a living organism when absorbed either intentionally or accidentally. Poisoning is a common presentation in medical receiving, usually in the form of paracetamol overdose following the intentional actions of certain patients (often with an excess of alcohol). However, it is important to remember that poisoning can occur from all prescribed medicines when taken at doses in excess of approved recommendation. This can happen due to human error or after an unrecognised disturbance in normal physiology: for example the harmful effect of ACE inhibitors after becoming dehydrated following diarrhoea. Q2: What clinical clues would lead you to suspect poisoning? Many cases of poisoning are obvious at presentation. Patients are admitted having been found with empty packets, a friend or family member who was contacted and informed or may provide a clear personal history of intentional drug ingestion. Recognising iatrogenic ‘poisoning’ requires the clinician to recognise symptoms may be drug induced and thereafter careful consideration of the detrimental effects of prescribed and over-the-counter medication. Most challenging are those are unconscious at presentation. Careful review of case notes may reveal prior self-poisoning attempts and may reveal medications the patient has access to. Physical assessment may demonstrate marks of self-harm, altered pupil size, presence of sweating, dysrhythmias or seizures giving clues to specific drug overdoses. In the unconscious patient serum alcohol levels should be measured, as can levels of some suspected drugs. A urinary drug screen dipstick and can quickly provide supportive evidence of suspected illicit drug misuse. Don’t be fooled, however, and attribute someone’s condition to alcohol when the level is raised—there may well be other issues at play e.g. co-ingested poison or intracerebral haemorrhage. The presence of an unexplained acid-base disorder or raised osmolar gap can point to presence of drug ingestion.

Q3: How would you manage a patient who presents with poisoning? Regardless of the poison all patients should be managed using the ABCDE approach—ensuring a secure airway if their GCS is affected, giving supplementary oxygen if hypoxic and assessing for cardiac compromise with a 12 lead ECG, cardiac monitoring and supportive care and cardiovascular support where relevant. IV fluids are given frequently in most overdoses. Intravenous bicarbonate may be beneficial. Glycaemic and temperature control is also important as hypoglycaemia and hyperthermia commonly complicate prescribed and illicit drug overdoses. In some cases, absorption of the toxin may be inhibited by activated charcoal, gastric lavage or bowel irrigation. Poison specific antidotes exist (see Box 42.1) and may be indicated. Early discussion with the local poisons centre is always advisable, and online resources such as Toxbase are indispensable.

Box 42.1 Drugs and Antidotes Drug Paracetamol

Antidote N-Acetylcyteine (‘NAC’) Benzodiazepine Flumazenila Digoxin Digoxin-specific Fab antibody Ethylene glycol Fomepizole Methanol Fomepizole, ethanol Methaemoglobinaemia Methylene blue Opioids Naloxone Beta-blockers Glucagon Flumazenil is rarely given acutely in clinical practice as mixed overdoses may contain drugs capable of lowering seizure threshold. Acute reversal of the benzodiazepine effect can risk life-threatening seizures

a

Q4: What is the role of dialysis in management of poisoning? Dialysis, or more strictly ‘extra-corporeal treatment’ (ECTR), is an effective way of acutely removing toxic solutes which cannot be cleared due to renal failure, or need cleared rapidly so as to prevent organ dysfunction. There is a relative paucity of evidence in use of ECTR in the treat-

42  Dialysis and Poisoning

ment of poisoning even though multiple drugs have been recognised to be effectively cleared by this means. The benefits of using ECTR must be weighed up against the risk of line insertion and the complications of treatment. Early discussion with an intensivist or nephrologist can guide decisions, though in clinical practice it would be fair to say that extracorporeal treatments do not have a major role to play in the management of poisoning. Q5: What factors influence the choice of ECTR? Reflecting back on Chap. 34, ‘The effect of kidney disease on drugs’, factors which affect the handling of a drug depend on Absorption, Distribution, Metabolism and Elimination. All must be considered when planning ECTR for poisoning. The peak level of a drug can be estimated based on its known absorption and timing of ingestion. Modified release preparations take longer and thus more likely to require repeat treatment. The volume of distribution, and binding to lipid or protein binding is important to consider; water soluble drugs are cleared rapidly by haemodialysis whereas lipid soluble tend to clear more slowly and are prone to rebound, thus require longer or repeat treatments. Drugs or their metabolites which are highly protein or lipid bound are ineffectively cleared by haemodialysis and may require charcoal haemoperfusion. Finally, the timing of discontinuing ECRT varies with remaining endogenous elimination. For example, if renal failure has developed as part of the acute poisoning, ECRT is likely to be required for longer. Box 42.2 RRT in Poisoning Drugs where dialysis may be beneficial Lithium Aspirin Methanol/ethylene glycol theophylline

Drugs where haemoperfusion may be beneficial Theophylline Phenytoin/valproate Dapsone Paraquat Methotrexate Amanita myshrooms

257

Q6: What is the difference between haemodialysis and haemoperfusion? The principles of haemodialysis are discussed in Chap. 39. In short, haemodialysis uses ­diffusive and convective clearance to reduce the drug level down a concentration gradient. In contrast, charcoal haemoperfusion may look similar as a treatment—in as much as it is a blood based treatment and uses the dialysis machine—but uses a charcoal cartridge which absorbs lipid and protein bound molecules from the bloodstream. In this process the cartridge is saturated after a 4 h treatment and needs replaced. Thrombocytopenia, hypoglycaemia and hypocalcaemia are more common than with haemodialysis. Charcoal haemoperfusion is not dialysis, thus ineffective for managing complication of renal failure. Q7: How do patients with lithium poisoning present and how are they managed? Lithium is effectively used in the treatment of mania and is almost exclusively renally excreted. Three presentations of toxicity occur—acute (toxicity following de novo ingestion), acute on chronic (toxicity from acute excess in those on maintenance) and chronic (toxicity due to a decline in renal function). Toxicity produces GI, cardiovascular and neurological features, presenting as nausea, vomiting and diarrhoea; prolonged QTc and bradycardia; and tremor, confusion, agitation, seizures and coma. Long term, often permanent, neurological deficits can occur even after effective treatment for toxicity. In addition to general measures ECTR is indicated in the following circumstances: –– Lithium concentration >5  mmol/L; all patients –– Lithium concentration > 4mmol/L; with renal dysfunction –– Lithium concentration >2.5  mmol/L; where aggressive hydration is not safe/possible –– In the presence of low GCS, seizure or life-­ threatening feature regardless of level ERCT should continue until level are consistently 900  mg/L; with renal dysfunction

42  Dialysis and Poisoning

–– Low GCS or –– Hypoxia requiring oxygen Q10: Are there any other common drugs where extracorporeal treatments may be considered? The risk of line insertion, the process of dialysis and non-concordance of a patient intent on self-harm must be weighed up against the benefit of using extra-corporeal therapies to remove toxin burden. Individual cases should be discussed with a nephrologist. In addition to those described above, drugs where dialysis may be considered include gentamicin/vancomycin toxicity, where renal function is diminished such that ototoxicity or prolonged AKI is at risk. This is a more common scenario in those already on dialysis. Metformin taken in overdose or toxicity which develops in the context of AKI can lead to severe lactic acidosis with a high mortality rate. Haemodialysis is indicated if there is severe acidosis, a lactate >20 mmol/L or CNS depression. Finally, dabigatran, a novel oral anticoagulant is removed by haemodialysis and there are case reports of its use in uncontrolled bleeding. Objectives: Dialysis and Poisoning After reading this chapter, you should be able to answer the following: Q1: Define ‘poison’ Q2: What clinical clues would lead you to suspect poisoning? Q3: How would you manage a patient who presents with poisoning? Q4: What is the role of dialysis in management of poisoning? Q5: What factors influence the choice of ECTR? Q6: What is the difference between haemodialysis and haemoperfusion? Q7: How do patients with lithium poisoning present and how are they managed? Q8: How do patients with methanol and ethylene glycol poisoning present and how are they managed? Q9: How do patients with salicylate poisoning present and how are they managed?

Further Reading

Q10: Are there any other common drugs where extracorporeal treatments may be considered? Answer 42 4. Immediate dialysis This patient is likely to have pre-renal, dehydration, induced AKI. This has led to an accumulation of Lithium, to toxic levels, and a build-up of lactate from her metformin. Initially, both drugs must be stopped and fluid resuscitation

259

commenced. She is likely to be acidotic, has hyperkalaemia and evidence of lithium toxicity. Cardiac monitoring is necessary, including 12 lead ECG to assess for conduction abnormalities. Immediate dialysis is currently not indicated, nor safe, and although can effectively remove Lithium, was in fact never required in this case.

Further Reading The Extracorporeal Treatments in Poisoning Workgroup. https://www.extrip-workgroup.org/. Accessed Sep 2019.

Hypertension and Fluid Balance in Dialysis Patients

Question 43 You are attending the out-patient dialysis centre. You are asked to review a 72 year old lady with end-stage renal disease on haemodialysis who has developed hypertension. Her blood pressure has been progressively higher over the last few dialysis sessions and she complains of a recent development of breathlessness, worse so at night. For the last 3 months she has been unwell, has spent 8 weeks as an in-patient and is yet to regain her appetite.

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_43

43

What is the most likely explanation for her symptoms? 1. 2. 3. 4. 5.

Weight loss Cardiac failure Malignancy Infection Essential hypertension

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43  Hypertension and Fluid Balance in Dialysis Patients

262 Fig. 43.1 Relationship between mortality and BP in general and dialysis population

Mortality

Mortality

BP in general population

Q1: The majority of haemodialysis patients are hypertensive. Why? There are likely to be two reasons. First, they may be hypertensive because the disease that was responsible for their kidney failure was associated with or caused hypertension. This would be true for patients with hypertensive nephrosclerosis, and for most patients with glomerulonephritis, diabetic nephropathy and polycystic kidney disease. Second, they may be hypertensive because they are volume overloaded. A direct relation between volume status and blood pressure is well recognised in dialysis patients. The higher the interdialytic weight gain, the greater the pre-dialysis blood pressure and the greater is the decrease in blood pressure during dialysis.

BP in dialysis population

BP is thought to be 135–155 mmHg for systolic and unchanged at 70–90  mmHg for diastolic. Patients with fistulas may be feeling apprehensive about the insertion of their dialysis needles, and if so this could exaggerate the alarm reaction that occurs every time a patient’s blood pressure is taken. For this reason, the first blood pressure reading that is taken after a patient has started dialysis, which is usually within 5  min of ­initiating treatment before any significant fluid has been removed, may give a better indication of pre-dialysis blood pressure.

Q2: What is the relation between blood pressure and mortality in dialysis patients and how does this differ from that seen in the general population? BP and mortality are inversely related in dialysis patients, a so-called ‘U-’ or ‘J-shaped’ curve. This is the opposite of what is known to be true in the general population (Fig.  43.1). The likely explanation is that cardiac disease in haemodialysis patients lowers blood pressure and raises mortality (not that lowering blood pressure in renal patients is harmful).

Q4: What is the key therapeutic goal for the hypertensive haemodialysis patient? Normovolaemia. Limiting fluid gains between dialysis sessions with close adherence to a fluid restriction is crucial to this, along with salt restriction and appropriate ultrafiltration. Reduction of dry weight is worth attempting in a hypertensive dialysis patient even in the absence of clinical signs of volume overload. If successful then this can reduce and sometimes eliminate the need for antihypertensive drugs. For these reasons it is always more logical to re-evaluate dry weight than to start or increase antihypertensive drugs. Anti-hypertensives may, conversely, make the problem worse in that they may limit the capacity to ultra-filtrate good volumes of fluid (see below).

Q3: What are the targets for pre and post dialysis blood pressures? Although debated, expert opinion, which is based on observational data rather than randomised trials, generally suggests a pre-dialysis SBP 140–160  mmHg and a pre-dialysis DBP between 70 and 90 mmHg. Optimal post dialysis

Q5: What does the term dry weight mean? “Dry weight” is the term used to indicate a dialysis patient’s optimal body weight. This is the weight at which they are euvolaemic, i.e. neither too wet nor too dry. A common issue for patients on long term RRT is fluid overload or being “wet”, especially when any residual renal func-

43  Hypertension and Fluid Balance in Dialysis Patients Fig. 43.2 Clinical pointer to fluid status in a dialysis patient

Underfilled

HR

263 Dry weight

HR

67 KG

tion has declined and they’re anuric. Bearing in mind that 1kg of body weight approximates 1 L of water a patient’s weight can be used to monitor their fluid balance (Fig.  43.2), and in particular their inter-dialytic weight gain (see Q8).

HR BP

BP Thirst

Wet

BP

70 KG

Dyspnoea

73 KG

could become an all-consuming task—is not usually recommended. Instead, patients should be advised to limit their interdialytic weight gain to a maximum of 2 kg, which is equivalent to 2 L of fluid. They should be reminded that fluids include soups, puddings, jellies and ice cream in addition Q6: How might you know if a patient was to cups of tea, coffee or water. For patients who do fluid overloaded? not pass any urine at all, fluid restriction of this Practically, by checking their weight pre-­ order can be quite demanding. As a rough guide dialysis. Clinically, a patient who is over their an anuric patient should be advised to drink not dry weight will often have oedema and/or be more than 800 ml/day. breathless, though a surprising number of overloaded patients have no symptoms whatsoever. Q9: Can a patient whose pre-dialysis weight They might well be hypertensive. The most is not greater than expected still be likely reason for being over dry weight in a dial- overloaded? ysis dependent patient is failure to adhere to fluid Yes. This usually means that the patient’s dry restriction. weight has dropped because they have lost lean body mass. This should prompt questions about Q7: What other causes of peripheral appetite and food intake, and should always lead oedema may occur in a dialysis patient? to referral to the renal dietitian. You should check Other causes of peripheral oedema in a dialy- dialysis adequacy as poor URR may be the cause sis patient include the nephrotic syndrome, heart of poor appetite and food intake (Fig. 43.3). failure, liver disease, deep vein thromboses, cellulitis, drugs and a ruptured Baker’s cyst. Q10: What might happen to the patient if Hypoalbuminaemia from other causes may also you take too much fluid off too quickly? contribute, for example acute or chronic inflamThe patient will usually complain of dizziness matory disorders. The commonest drugs causing and feeling warm or sick, just before they ‘crash’ oedema are the dihydropyridine calcium channel or may just crash without any preceding sympblockers, such as amlodipine or nifedipine. toms. ‘Crash’ is the term used to describe a patient who collapses suddenly on dialysis as a result of Q8: What advice should a dialysis patient excessive fluid removal. This can be a frightening be given in order to reduce his or her risk of experience for the patient, the nurses and the other becoming overloaded? patients in the unit. It is the equivalent of a very For some patients, particularly if they are bad faint. The patient will be hypotensive, may be thirsty, fluid restriction is the hardest part of dialy- bradycardic and may fit. In severe cases it can sis. Meticulous measuring of fluid intake—which look as if they have had a cardiac arrest.

43  Hypertension and Fluid Balance in Dialysis Patients

264 88 87

Measured weight

86

Weight (KG)

85 84 83 82

‘Dry’ weight

81 80

Patient presents with breathlessness

79 78 Dialysis sessions

Fig. 43.3  Weight on dialysis. The “Measured Weight” line shows the rapid changes in weight experienced by dialysis patients due to loss/gain of fluid. Observing the “Dry Weight” line (the patient’s ideal weight) we can see that as time passes they are losing weight (protein/fat). If

this goes unnoticed, we may falsely believe that at 86kg, they are only carrying an extra 2  L, as opposed to true value of 4 L extra. This can results in symptomatic overload—shown here as a presentation with breathlessness

Q11: What precisely should you do when a patient crashes? Follow an ABCDE structured approach. Crashes present like any cause of collapse on dialysis, and so your approach should be structured and differential remain wide. Move quickly to tip the patient backwards, stop ultrafiltration, and administer saline and oxygen if the patient is hypoxic. The volume of saline required will vary from patient to patient. You should run in at least 250 ml stat then review progress. Screen the patient off if possible and reassure the other patients.

Q13: If it is not possible to control a dialysis patient’s blood pressure by removing fluid then which antihypertensive drugs can you use? The short answer is that all classes of antihypertensive drugs may be used to treat hypertension in haemodialysis patients, with one or two provisos. Dihydropyridine calcium channel blockers e.g. amlodipine are probably the easiest to use, though their commonest side effect is ankle swelling which may make it more difficult to assess dry weight. The pros and cons of the other antihypertensive drugs in dialysis patients are shown in Box 43.1.

Q12: What steps can you take to ensure that a patient does not crash during dialysis? You can reduce the risk of crashing by making a careful assessment of the fluid that must be removed at the beginning of dialysis and by using the online blood volume monitor. The ultrafiltration rate should not normally exceed 500  ml/h. The online blood volume monitor measures a patient’s haematocrit which is the proportion of the blood volume that is occupied by their red blood cells. If fluid is removed too rapidly from the blood compartment and is not replaced by fluid from the tissues then the haematocrit will rise. If the haematocrit rises too far or too quickly then the patient is likely to crash.

Box 43.1 Pros and Cons of Antihypertensive Agents

ACE inhibitors: Commonest side effect is cough. Not advised if pre-dialysis potassium >5.0 mmol/l Angiotensin receptor blockers: Generally well tolerated. Not advised if pre-­ dialysis potassium >5.0mmol/l α-blockers: Often makes patients feel non-­ specifically unwell. Not contraindicated in advanced renal failure

43  Hypertension and Fluid Balance in Dialysis Patients

β-blockers: Commonly cause cold hands and lethargy. Not contraindicated in advanced renal failure Calcium channel blockers: Main side effect is oedema but otherwise well tolerated. Not contraindicated in advanced renal failure Thiazides: Unlikely to be effective when serum creatinine >100 μmol/l Spironolactone: Not advised if pre-dialysis potassium >4.5 mmol/l Loop diuretic: May be very useful for managing fluid balance (and therefore blood pressure) if the patient still has residual renal function, although large doses may be needed

Q14: Antihypertensive drugs may increase the risk of symptomatic intradialytic hypotension. Why? By interfering with the compensatory vasoconstriction that maintains BP in the face of the rapid reduction in intravascular volume that occurs during haemodialysis. It is for this reason that we often advise a hypertensive patient who is taking antihypertensive drugs to withhold these until after his or her dialysis session has been completed. Objectives: Hypertension and Fluid Balance in Dialysis Patients Q1: The majority of haemodialysis patients are hypertensive. Why? Q2: What is the relation between blood pressure and mortality in dialysis patients and how does this differ from that seen in the general population? Q3: What are the targets for pre and post dialysis blood pressures? Q4: What is the key therapeutic goal for the hypertensive haemodialysis patient? Q5: What does the term dry weight mean?

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Q6: How might you know if a patient was fluid overloaded? Q7: What other causes of peripheral oedema may occur in a dialysis patient? Q8: What advice should a dialysis patient be given in order to reduce his or her risk of becoming overloaded? Q9: Can a patient whose pre-dialysis weight is not greater than expected still be overloaded? Q10: What might happen to the patient if you take too much fluid off too quickly? Q11: What precisely should you do when a patient crashes? Q12: What steps can you take to ensure that a patient does not crash during dialysis? Q13: If it is not possible to control a dialysis patient’s blood pressure by removing fluid then which antihypertensive drugs can you use? Q14: Antihypertensive drugs may increase the risk of symptomatic intradialytic hypotension. Why? Answer 43 1. Weight loss This lady presents with clinical evidence to support volume overload—demonstrated by hypertension and orthopnoea. Her recent illness with loss of appetite is likely to have led to weight loss. Fluid retention in dialysis patients may mask weight loss and if not recognised patients may present with volume overload because the difference between their pre-dialysis weight and true weight becomes wider (see chapter, Fig. 43.3). Cardiac failure may present as orthopnoea but hypertension would be unusual whereas essential hypertension would present with hypertension but not orthopnoea. Malignancy would only present as hypertension in the rare circumstance of hormonally active tumours. There are no features to support infection.

Tunnelled Dialysis Catheters

Question 44 A 42  year old right handed male is admitted with hypertension and evidence of renal failure. On arrival his serum creatinine is 834  μmol, urea 34 mmol/L and potassium 5.2 mmol/L. Inves­tigation demonstrates bilateral small kidneys and heavy proteinuria. He requires to commence dialysis but has no access. He agrees to a tunnelled central venous catheter.

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_44

44

Which vessel would be the first choice? 1 . Right internal jugular 2. Left internal jugular 3. Either subclavian vein 4. Right femoral vein 5. Left femoral vein

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Q1: Describe the different types of vascular access for haemodialysis There are four, summarised in Box 44.1.

Box 44.1 Different Types of Vascular Access

1. Arterio-Venous Fistula (usually known as a fistula) 2. Arterio-Venous Graft (usually known as a graft) 3. Tunnelled Central Venous Catheter (usually known as a tunnelled line) 4. Non-Tunnelled Central Venous Catheter (usually known as a temporary line)

Q2: When should vascular access be discussed with patients? Vascular access requires some planning and should be discussed once a patient with progressive renal failure has considered their options and expressed a preference for haemodialysis rather than PD.  This discussion will generally take place when eGFR is around 20  mL/min and should lead to referral for a fistula formation in the first instance. An exception to this rule is those where a pre-emptive transplant is likely. Preserving the upper limb veins by avoiding venepuncture and cannulas whenever possible should be considered early in patients with CKD. Even if not immediately planning a fistula, one may be required down the line. Q3: What is the recommended form of vascular access for haemodialysis and why? The Renal Association recommend that at least two thirds of patients starting haemodialysis should have a fistula and that at least 85% of a renal unit’s haemodialysis population should have a fistula at any one time. A fistula is the preferred vascular access for haemodialysis because of the lower risk of clot formation and infection provided by the use of native vessels. Fistulas take 6–8 weeks to mature and should be ready to use at the time of first dialysis which means the best time to create a fistula is at least 6–8 weeks before it is needed. However, maturation is faster in selected individuals (a matter of 2  weeks), whereas fistulas in people with diabetes, those

44  Tunnelled Dialysis Catheters

with small arteries or difficult veins may need longer to mature. Timing is everything. Q4: Why do some patients dialyse with a tunnelled line? Tunnelled lines are an effective and very quick method of achieving vascular access but are more likely to become infected than fistulas. Other complications of tunnelled lines include central venous stenosis and poor flow due to kinking or formation of a fibrin sheath on the outside of the catheter. Despite these limitations some patients dialyse quite successfully with a tunnelled line rather than a fistula. These patients are likely to be (Box 44.2):

Box 44.2 Common Reasons for Long-Term Central Venous Catheter Use

• Late presenters in whom there has not been time to create a fistula • Patients with poor peripheral vessels in whom a fistula is not technically possible • Patients with chronic heart failure whose cardiac output might be further compromised by a fistula, because so much of it goes through the fistula • Patients with hypotension whose blood pressure might be further lowered by a fistula • Very elderly patients (>80  years) who may have poor peripheral vessels, chronic heart failure, hypotension and poor life expectancy in whom a fistula might not be of any real benefit • Rarely, patients with a true needle phobia will refuse a fistula or a graft

Q5: What is the best vein for a tunnelled line and why? Nephrologists should remain mindful of future vascular access at all time in patients with established renal failure (ERF). Venous catheter use— particularly those who require multiple insertions—increases the risk of central venous stenosis. Practically, the right internal jugular vein is preferred for catheter placement due to its direct

44  Tunnelled Dialysis Catheters

continuity with the superior vena cava and the right atrium. However, if a right sided fistula is planned then an alternative site may be more appropriate. Alternative sites are the left internal jugular vein (more difficult to place and 50% risk of venous stenosis), subclavian vein (should be avoided because of higher incidence of central venous stenosis) and femoral vein (higher risk of infection). Q6: What is the correct position for a tunnelled line? For an internal jugular line the catheter tip should be positioned in the mid right atrium to optimise flow (Fig. 44.1). Be aware that the catheter tip may retract by as much as 1–2 cm when the patient adopts an upright position as the chest wall is pulled downwards particularly in obese patients or women with large breasts. An internal jugular catheter whose tip lies in the lower right atrium may come in contact with the tricuspid valve and so cause dysrhythmias. When the femoral vein is used for haemodialysis, the length of the catheter must be 20 cm or more and the catheter tip should be positioned in the common iliac vein or inferior vena cava. When the tip of a shorter catheter is positioned in the external iliac vein, high rates of recirculation will be encountered. Q7: What can be done to minimise the risk of infection with tunnelled lines? The first priority is to minimise their use. Using aseptic technique when handling lines, along with chlorhexidine 2% to clean the line exit

269

site and an antibiotic or antimicrobial lock solution when locking the line are all recommended to minimise infection risk. Local protocols should be followed to eradicate staph aureus with agents such as mupirocin, for example. Q8: How do you take blood from a tunnelled line? The short answer is that this should only be done by renal unit staff. If you have to use a tunnelled line in an emergency then you must do so aseptically with gloves and dressing pack. Remember to aspirate the first 2 mL containing the antimicrobial lock and discard before drawing blood for analysis or giving drugs via the line. Remember also to replace the line lock when you have finished. Q9: What should you look for when you examine a tunnelled line exit site? The exit site should be examined for signs of inflammation or tunnel track infections e.g. erythema, pain, secretions, crusts or abscess formation. You should also record whether the dacron cuff is visible. If so then the catheter will usually require to be replaced. For more information on line related infection, see Chap. 45. Q10: What is an acceptable blood flow rate for a tunnelled catheter? Catheters generally allow a blood flow up to 350  mL/min which is necessary for adequate dialysis. Longer catheters provide less blood flow compared to shorter catheters of the same diameter which is a problem particularly for femoral vein catheters. Catheter flow rates of less than 200 mL/min at any site suggests blockage or partial blockage. Q11: What might be done for a tunnelled line with blood flow rate less than 200  mL/ min? (Box 44.3) Box 44.3 Stepwise Protocol for Maintaining Central Line Patency

• If the line is placed in the internal jugular and less than 2 weeks old, check the position of the catheter tip by chest X-ray Fig. 44.1  The correct position of a tunnelled line

44  Tunnelled Dialysis Catheters

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• Follow the Urokinase protocol for blocked tunnelled lines (see Appendix M) • If patency cannot be restored then a contrast study should be arranged to show whether poor flow is due to intraluminal thrombus, catheter tip thrombus or fibrin sheath • A fibrin sheath surrounding the catheter tip requires the prolonged infusion of urokinase to dissove the clot. If this is not successful then the sheath may be stripped by means of a snare catheter, inserted through the femoral vein. This may be tried by the interventional radiologists but is not always successful • Persisting catheter dysfunction requires a new catheter. This can be done over a guidewire unless a fibrin sheath is the cause of the problem, as the fibrin sheath will simply encase the new catheter. For this reason the insertion of a new catheter at a new venous site may be the better option

Objectives: Tunnelled Dialysis Catheters After reading this chapter, you should be able to answer the following: Q1: Describe the different types of vascular access for haemodialysis Q2: When should vascular access be discussed with patients? Q3: What is the recommended form of vascular access for haemodialysis and why? Q4: Why do some patients dialyse with a tunnelled line? Q5: What is the best vein for a tunnelled line and why?

Q6: What is the correct position for a tunnelled line? Q7: What can be done to minimise the risk of infection with tunnelled lines? Q8: How do you take blood from a tunnelled line? Q9: What should you look for when you examine a tunnelled line exit site? Q10: What is an acceptable blood flow rate for a tunnelled catheter? Q11: What might be done for a tunnelled line with blood flow rate less than 200 mL/min? Answer 44 1. Right internal jugular The right internal jugular vein has been recommended as the first option for placement of a tunnelled haemodialysis catheter because it runs in a straight line at a superficial site in the neck, resulting in high accessibility and fewer catheter-­ related problems. Second choice would be the LIJ, but is associated with a greater risk of central venous stenosis, followed by either femoral and finally (and rarely) the subclavian. Femoral lines are associated with greater risk of infection, and subclavian line insertion with the greatest risk of stenosis. It is mentioned that this patient is right handed. A fistula should be created as a matter of urgency if possible, and is preferably in the non-­ dominant arm. Thus TCVC insertion on the right would preserve the left venous system for fistula formation.

Further Reading Kumwanda M, Mitra S, Reid C. Renal associated guidelines. Vascular access for haemodialysis; 2015.

Catheter Related Blood Stream Infection

Question 45 You are the middle grade on for medicine in a district general hospital. You are asked to see Mr Jones, a 24 year old male admitted with rhabdomyolysis 16 days ago. After 48 h of medical therapy, it became evident he required dialysis and has been dialysis dependent since via the same non-tunnelled central venous catheter (NTCVC) in his internal jugular. You are asked to review him due to an acute pyrexia, tachycardia, hypotension and rigor. Clinical examination demonstrates a red, tender exit site around his line and no other source of infection.

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_45

45

Which of the following is the most appropriate management step? 1. Take blood cultures, commence IV antibiotics and leave the line in situ 2. Take bloods culture, commence IV antibiotics and remove the line immediately 3. Take blood cultures and await results prior to treatment 4. Take blood cultures, instil an antibiotic lock and wait results 5. Remove the line and commence oral antibiotics

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45  Catheter Related Blood Stream Infection

272

Q1: How common is catheter related blood stream infection (CRBSI)? Catheter related blood stream infection (CRBSI) is the most important complication of central venous dialysis catheters. The risk of tunnelled line bacteraemia is around 1–3 episodes per 1000 catheter days in most renal units. Tunnelled lines have lower rates of infection than temporary lines and jugular placement carries a lower risk than femoral. Bacteraemia is approximately 10 times more common with lines than with fistulas and this is one of the reasons why a fistula is the preferred form of vascular access for haemodialysis. Tunnelled lines are also associated with significantly higher risks of death from infection than fistulas and grafts. Q2: When should you suspect CRBSI? This diagnosis must be considered in all dialysis patients with a central venous catheter (CVC) who present with pyrexia or acutely raised inflammatory markers. Patients with CRBSI will classically present between dialyses with a rigor and a temperature of 39°. However, the presentation can be subtle and have only minor signs such as low grade fever, hypothermia, hypotension, loss of glycaemic control, lethargy and confusion. Less commonly patients will present with disseminated infection (e.g. discitis) from an untreated access infection. Q3: How should you investigate a patient with suspected CRBSI? Promptly, by simultaneous culture of blood from the line and the periphery before commenc-

ing antibiotic therapy. Blood culture from the line should be from the catheter hub after first removing the line lock i.e. you should discard about 3  mL before using a separate syringe for the ­culture. Clinical examination is usually unrevealing, which is often a pointer to the catheter as the source of infection (i.e. absence of other signs of infection). The exit site and/or tunnel are not always inflamed. Alternative sources of infection should be considered with a focussed history, examination, imaging (especially chest X-ray) and laboratory testing (urine culture if possible). You should also remember to check white cell count and CRP, and swab both the exit site and nose. Vigilance for evidence of disseminated infection, e.g. discitis or endocarditis, is also recommended. Investigation should be appropriately tailored. Q4: What are the likely infecting organisms in a patient with CRBSI? The great majority are staphylococci (see Fig. 45.1). Coagulase negative staphylococci are usually regarded as skin contaminants when grown from peripheral blood cultures but may be pathogenic if isolated from a dialysis line (or any patients with indwelling prosthetic material). Q5: What antibiotic or antibiotics would you choose to give while waiting for the result of the blood culture? In general antibiotics that can be given post dialysis (vancomycin, teicoplanin, cefazolin and ceftazidime) are preferred. Vancomycin is the first choice for empirical therapy of gram positive

Fig. 45.1 Common organisms implicated in CRBSI

CRBSI

Gram negative 25%

Gram positive 75%

Staph Aureus

MRSA

Coag Neg staph

E. coli

Pseudomonas

45  Catheter Related Blood Stream Infection

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organisms in settings where MRSA is prevalent while teicoplanin is a suitable alternative if there has been a previous allergic reaction to vancomycin. Many units give a gentamicin in view of its rapid bactericidal effect, anti-staphylococcal properties and crucially gram negative cover. It is difficult to achieve safe trough levels with post dialysis gentamicin, thereby increasing the risk of ototoxicity and loss of residual renal function. Q6: How might your choice of antibiotic change after the results of blood culture become available? If flucloxacillin-sensitive Staph aureus is grown on culture then best advice is to switch from vancomycin (bacteriostatic) to flucloxacillin (bactericidal), although in practice some units find that the advantages of vancomycin, which can be given through the line at the end of dialysis and which only needs to be given on dialysis days, outweigh those of flucloxacillin.

Q7: Should tunnelled lines (TCVCs) always be removed if infected? This is not always necessary. Patients with uncomplicated CRBSI and those in whom catheter removal would result in complete loss of vascular access may be treated by leaving the catheter in situ and giving IV antibiotics for at least 2 weeks. This approach may cure over two thirds of uncomplicated infections. All other patients should have their tunnelled lines removed. The European Best Practice Guidelines recommend an antibiotic lock as part of the treatment of CRBSI though each unit will have its own protocol and local practice may vary. If an antibiotic lock is used then it will likely contain gentamicin which does not precipitate when diluted with heparin and which has both gram negative and anti-staphylococcal activity. Those with Staph Aureus bacteraemia should always have their lines removed and further investigation to exclude endocarditis. See Fig. 45.2.

Suspected CRBSI

Start IV antibiotic

Complicated: • S. Aureus. P. Aeruginosa, multi-resistant orgs or fungi

Ideally remove catheter

Uncomplicated:

BLC negative

• None of the condition in the panel to left

• Tunnel infection with fever • Endocarditis • Osteitis • Sepsis

If immediate removal impossible or C/I exchange over guide-wire after 3 days successful Rx

Continue ABx with lock: • •

6 weeks for endocarditis 8 weeks for osteitis

Leave catheter, Rx antibiotics with lock for ≥2 weeks

Repeat BLC 1 week after stopping ABx

Fig. 45.2  Stepwise approach to suspected CRBSI

stop antibiotics

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Q8: How would your management differ if the patient had a temporary line? Temporary line sepsis should generally be treated with antibiotics and removal of the line, although rarely the latter is all that’s needed if the patient is well and it’s just an isolated fever or CRP rise. Unlike tunnelled lines which are secured with a dacron cuff, temporary lines slip out very easily. The line should be removed as soon as CRBSI is suspected, i.e. usually following a rigor with temperature 39° and without waiting for the blood culture to become positive. This is done with the patient in the head down position and should be followed by pressure over the exit site for 5 min, or until haemostasis is achieved, and an air occlusive dressing i.e. tegaderm. Remember to send the catheter tip for culture. Ideally the patient should remain “plastic free” for as long as possible whilst continuing antibiotic treatment to reduce re-infection, before inserting a new line. Objectives: Catheter Related Blood Stream Infection After reading this chapter, you should be able to answer the following: Q1: How common is catheter related blood stream infection (CRBSI)? Q2: When should you suspect CRBSI? Q3: How should you investigate a patient with suspected CRBSI? Q4: What are the likely infecting organisms in a patient with CRBSI? Q5: What antibiotic or antibiotics would you choose to give while waiting for the result of the blood culture?

45  Catheter Related Blood Stream Infection

Q6: How might your choice of antibiotic change after the results of blood culture become available? Q7: Should tunnelled lines (TCVCs) always be removed if infected? Q8: How would your management differ if the patient had a temporary line? Answer 45 2. Take blood cultures, commence IV antibiotics and remove the line immediately This patient has sepsis, and the line appears to be the only source. The patient had a temporary internal jugular line in situ for more than 14 days, and it now appears red and tender. Immediate line removal is indicated, and early intravenous antibiotics are indicated for his sepsis. Leaving the line in situ may be considered in rare circumstances where no further access would be possible. An antimicrobial lock would not provide treatment and oral antibiotics second choice in this scenario.

Further Reading Vanholder R, et  al. Diagnosis, prevention and treatment of haemodialysis catheter-related bloodstream infections (CRBSI): a position statement of European Renal Best Practice (ERBP). NDT Plus. 2010;3(3):234–46.

The Challenges of Renal Replacement Therapy in the Frail Older Adult

46

Question 46 An 82 year old male with moderate left ventricular systolic dysfunction and severe COPD attends the low clearance clinic. His eGFR is 9 mL/min. He is breathless at rest, with no signs of oedema and his appetite is unaffected. He has been aware he has progressive renal failure and wishes to discuss his future options. Which of the following is true for this patient?

1. His age is a contraindication to renal transplantation 2. Haemodialysis is his only option 3. Dialysis will improve his quality of life 4. There are no ‘renal’ treatments; discharge him to primary care 5. There is no convincing evidence dialysis will significantly prolong his life

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_46

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46  The Challenges of Renal Replacement Therapy in the Frail Older Adult

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Q1: What is meant by the term frailty? Frailty is a state of health in which multiple body systems gradually lose their in-built reserves, and more common with age. Frail older adults are at risk of dramatic changes in their physical and mental wellbeing after apparently minor events that challenge their health such as an infection or new medication. Frailty frequently coexists with comorbidity which may be defined as the presence of two or more medically diagnosed disease processes. It follows that frail older renal patients, who often have multiple comorbidities, may not always be suitable for a treatment as demanding as dialysis.

In practice, no Scottish patients over the age of 80 years are currently being treated by home haemodialysis. There is no theoretical reason why an older renal patient should not have a pre-­ emptive transplant though this also tends not to happen. If a trial of renal replacement therapy is chosen, this effectively means a choice between hospital based haemodialysis and peritoneal dialysis at home. A UK Renal Registry analysis of RRT patients at the end of 2017 showed 63% were under 65, whilst 37% were over 65. Figure 46.2 shows the age profile for the different RRT modalities, and the clear difference in dialysis vs. transplant rates in older patients.

Q2: Describe the treatment options for frail older patients. Similar to all other patients, frail patients with established renal failure have the option of haemodialysis (hospital or home), peritoneal dialysis, transplantation or conservative care. However, there are noteworthy differences in treatment choices (Fig. 46.1).

Q3: When should you consider conservative care as a treatment option? Conservative care describes the provision of medical care to slow renal disease progression and control the symptoms and complications of advancing renal disease without providing renal replacement therapy. A conversation is usually prompted by the patient, their family members or carers when faced with the limitations of physical frailty and advancing age in the context of kidney failure. Whilst more commonly a discussion with older patients, conservative care may also be an appropriate choice for younger patients if they are frail or have multiple comorbid illnesses. It is the clinician’s responsibility to inform such patients they are not obliged to take on this potentially arduous treatment if after careful consideration of the pros and cons they choose not to. For many frail, comorbid and/or older patients, renal

‘Frail’ patient

Transplant

Conservative care

Hospital HD

PD

Fig. 46.1  Treatment modalities for frail patients Fig. 46.2  Age profile of adult patients prevalent to RRT on 31/12/17 by RRT modality (UKRR)

3.5

% RRT patients

3.0

Tx PD HD

2.5 2.0 1.5 1.0 0.5 0.0 15

25

35

45

55 65 Age (years)

75

85

95

105

46  The Challenges of Renal Replacement Therapy in the Frail Older Adult

Q4: How well does serum creatinine predict the need for dialysis in the frail older patient? Less well than in a younger person. For a given level of serum creatinine, GFR will always be lower in the older adult, especially if underweight. In these circumstances the Cockcroft Gault equation may well give a more precise estimate of residual function than the MDRD formula (because the Cockcroft Gault takes body weight into account). For example, an 80 year old woman who has a serum creatinine of 300  μmol/L and weighs 50 kg will have a creatinine clearance of 10 mL/min. By contrast a 50 year old man with the same level of creatinine who weighs 80  kg will have a clearance of 30 mL/min. The older underweight woman has established renal failure while her younger male counterpart clearly does not. Q5: Why do more frail older patients choose hospital haemodialysis than PD? It is likely that in the frail older patient, physical problems, social circumstances and cognitive impairment conspire to make PD less attractive. This is ironic given that in a recent UK study scores estimating the intrusion of therapy and quality of life were found to be better in PD patients than in those who received haemodialysis. Some units may promote PD more than others as judged by the enormous variation in uptake of PD between units. Q6: How might the uptake of PD be increased in the frail older patient? Automated PD allows the patient to be treated at night with a portable machine that pumps fluid in and out of their peritoneal cavity automatically. With assisted APD a fully trained healthcare assistant visits daily—emptying drainage bags, checking drained fluid for cloudiness, setting up the machine for the next treatment, inspecting the catheter exit site and reviewing stocks of treatment fluids and drugs. These ­assistants maintain contact with the parent unit which can assist if problems arise.

Q7: By how much does dialysis increase survival in the frail older patient? A report from the Lister Unit in Stevenage revisited the survival of older CKD patients in a non-randomised study. Eighty two percent were treated by RRT while 18% received conservative management. Survival was calculated from the first recorded eGFR of 75 years who were managed conservatively (CM) or by renal replacement therapy (RRT) adjusted for age, gender, ethnicity, diabetes and comorbidity. Survival advantage in RRT patients was less than 4  months, which was not statistically significant

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46  The Challenges of Renal Replacement Therapy in the Frail Older Adult

impairment. In CKD stage 5, infection is an ever present increased risk, particularly with tunnelled lines, whilst immobility is common as demonstrated by the number of patients who attend dialysis in wheelchairs. Instability leads to falls and these are greatly increased in chronic kidney disease. Urinary incontinence may be a lesser problem than in the general population since many dialysis patients pass little or no urine. The estimated prevalence of intellectual impairment in end-stage renal failure ranges from 27% to 77% and a real-time decline in cognitive function has been associated with the process of dialysis itself. Thus, cognitive impairment adds to the burden of a very demanding form of treatment. Q9: What kind of quality of life can a frail older dialysis patient expect? Physical quality of life is generally lower in older RRT patients than in age matched populations who do not have chronic kidney disease. In contrast, the emotional quality of life in older RRT patients is usually as good as that of their peers in the general population. A US study followed the progress of all patients 80  years or older who started dialysis between 2000 and 2005. At the start of renal replacement therapy, 78% were living independently at home, 15% were living at home with assistance and 6% were already in nursing homes. After 2 years of follow up only 11% of the original cohort (18% of those still alive) were still living independently at home. The remainder required community or private care support or had been transferred to a nursing home. Q10: In what way is renal palliative care similar to that of non-renal palliative care? The four key principles are exactly the same. These are that: 1. Informative, timely and sensitive communication is an essential component of each individual patient’s care 2. Significant decisions about a patient’s care, including diagnosing dying, are made on the basis of multi-disciplinary discussion 3. Each individual patient’s physical, psycho logical, social and spiritual needs are recognised and addressed as far as is possible

4. Consideration is given to the wellbeing of relatives or carers attending the patient Q11: In what way does renal palliative care differ from non-renal palliative care? Renal palliative care for older dialysis patients should begin at the time of diagnosis and continue throughout life. It differs from non-renal palliative care in many respects, not least of which are the management of renal anaemia and pain. Treatment of symptomatic anaemia with erythropoiesis stimulating agents and intravenous iron can improve wellbeing while reducing the need for blood transfusion. Pain is a frequent symptom in patients with advanced CKD and pain control is often challenging. The active metabolites of morphine accumulate in renal failure and may cause severe symptoms (myoclonic jerks, profound narcosis and respiratory depression) before relieving pain. It is preferable, therefore, to use opiates that do not accumulate in renal disease such as fentanyl or alfentanil. Detailed advice including drug doses is given in the Renal Palliative Care guideline referenced at the end of this chapter. Patients whose pain is not controlled should be referred to the palliative care team if this has not been done already. Renal patients also have an option denied to the rest of us of dialysis withdrawal, which effectively allows them to die at the time of their choosing (Fig. 46.4). Q12: How commonly do older renal patients choose to withdraw from dialysis? Dialysis withdrawal is now the commonest cause of death for older patients on renal replacement therapy. Twenty eight percent of all deaths from 2008 to 2017  in Scotland, in those aged ≥75 years are due to dialysis withdrawal. Average survival time after the last treatment session is 7 days (range 0–88 days). Survival is likely to be longer in patients with residual renal function. Discussion of dialysis withdrawal can be a very sensitive issue if it is seen as the withholding of a lifesaving treatment in an older patient. Many older dialysis patients perceive their quality of life to be much better than we might surmise and nephrologists need to accept that, though it may not be what we would wish for ourselves, some patients appear content to continue dialysis three times a week in hospital to enable them to be at

46  The Challenges of Renal Replacement Therapy in the Frail Older Adult Fig. 46.4 Pain management in CKD 5, on dialysis and at end of life

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CKD 5 or on dialysis patient in pain/pain uncontrolled

Opioid naive

Taking oral morphine

On fentanyl patch

Single dose oxycodone while supply of alfentanil or fentanyl obtained

Convert to fentanyl patch

Increase dose of patch

Start with 1/2 of 12 µg/h fentanyl patch if at home

Alfentanil 100250 µg SC if in hospital

Alfentanil SC breakthrough if in hospital

Oxycodone orally breakthrough if at home

Continuous infusion by syringe pump at end of life if appropriate

home not doing very much but surrounded by their families. Q13: What is advance care planning? Advance care planning—sometimes referred to as anticipatory care planning—refers to the process where patients and clinicians discuss and agree future aspects of their care in relation to death and dying. The goal is to provide a ‘good death’, and therefore includes decisions about treatment escalation plans, cardiopulmonary resuscitation and place of death. Early planning can allow patients to express their personal wishes around dying, nominate a legal welfare attorney and, if necessary, organise appropriate provisions to prevent unnecessary admission allowing symptom control in a place of their choice. This important topic can be upsetting for both parties, and as such is often not addressed. In renal disease there are many scenarios where this conversation may begin: from the low clearance clinic in those opting for conservative care to the dialysis unit where patients are deteriorating despite dialysis or following an acute worsening in well-being. It is advisable to regularly review patient plans and imperative to share their wishes to all involved in their care. Q14: How do renal patients die? The trajectory for organ systems failure is shown in Fig. 46.5. The gradual decline in func-

tion punctuated by hospital admissions which become more frequent towards the end of life is common in renal failure. Death may seem ‘sudden’ to many relatives of renal patients even if the gradual and progressive decline in the patient’s health has been obvious to the hospital team. Most patients whose dialysis is withdrawn die after becoming progressively more drowsy and slipping into uraemic coma. If death occurs suddenly, asystole due to hyperkalaemia is the likely cause. Pain, myoclonus, dyspnoea, respiratory tract secretions, and nausea should be anticipated by prescribing alfentanil, midazolam, hyoscine butylbromide and levomepromazine SC as required. Continuous infusion by syringe pumps may be indicated for each of these drugs if symptoms persist. Many renal units now have renal palliative care nurse specialists who are skilled in uraemic symptom control and whose remit also includes support for the family and carers, both before and after death. Objectives: The Challenges of Renal Replacement Therapy in the Frail Older Adult Q1: What is meant by the term frailty? Q2: Describe the treatment options for frail older patients. Q3: When should you consider conservative care as a treatment option?

46  The Challenges of Renal Replacement Therapy in the Frail Older Adult

280 Fig. 46.5 Stepwise deterioration leading to death observed in frail patients (Reproduced from Murray et al. BMJ. 2005;28)

High

Function

Mostly heart and lung failure

Death Low

Sometimes emergency hospital admissions Time

Q4: How well does serum creatinine predict the need for dialysis in the frail older patient? Q5: Why do more frail older patients choose hospital haemodialysis than PD? Q6: How might the uptake of PD be increased in the frail older patient? Q7: By how much does dialysis increase survival in the frail older patient? Q8: Older dialysis patients are susceptible to most of the so called ‘Geriatric Giants’. Discuss. Q9: What kind of quality of life can a frail older dialysis patient expect? Q10: In what way is renal palliative care similar to that of non-renal palliative care? Q11: In what way does renal palliative care differ from non-renal palliative care? Q12: How commonly do older renal patients choose to withdraw from dialysis? Q13: What is advance care planning? Q14: How do renal patients die? Answer 46 5. There is no convincing evidence dialysis will prolong his life This older man with significant comorbidity has progressive CKD. Commencing dialysis for

2-5 years, but death usually seems ‘sudden’

life threatening indication can prevent immediate death, but there is no evidence to support significant prolongation of life. Conservative care is most likely to preserve his quality of life, whilst managing his CKD complications and symptoms. Age is not a barrier to transplantation, only another consideration. PD would not be contraindicated. At present he lack symptoms directly related to his renal disease, thus dialysis cannot improve his symptoms. Further, it is likely the burden of dialysis would negative impact on his quality of life. As mentioned, conservative care can provide renal-specific treatments, with the exclusion of renal replacement therapy, targeting complications such as acidosis and anaemia. Discharging him to primary care may deny him these treatments.

Further Reading UK Renal Registry. UK Renal Registry 21st Annual Report—data to 31/12/2017. Bristol: UK Renal Registry; 2019. Available from https://www.renalreg. org/publications-reports/. Renal Palliative Care. Available from https://www.palliativecareggc.org.uk/wp-content/uploads/2015/08/ RenalLastDays-nov-2013.pdf. Chandna SM, et al. Survival of elderly patients with stage 5 CKD: Comparison of conservative management and renal replacement therapy. NDT. 2011;26:1608–14.

Part VII Practical Nephrology

Urinalysis and Microscopy

Question 47 A 68 year old male presents with nasal crusting, haemoptysis, weight loss and deteriorating renal function. His ANCA is strongly positive. On urinalysis, which of the following would be most suggestive of a renal vasculitis?

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_47

47

1. Red-brown urine 2. Dipstick haematuria 3. Proteinuria 4. Red cell casts 5. Lipiduria

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repute. Despite its shady past, urinalysis remains a critical tool in a clinician’s armoury. Q2: What are the indications to perform urinalysis nowadays? Examination of the urine provides complementary evidence to support decision making in a wide array of clinical conditions. In the clinic urinalysis should be requested in those with recognised or suspected renal disease and in a number of systemic diseases such as diabetes to determine if end-organ damage is present—see Box 47.1. Acutely, urinalysis is important in patients under 65 presenting with infective urinary symptoms (the high rate of asymptomatic bacteriuria in older patients make the test less useful).

U Co rin W lou e he r el

Q1: Who were the ‘pisse prophets’? For centuries clinicians have recognised the diagnostic value of urine to detect disease. Early physicians routinely performed ‘uroscopy’— utilising sight, smell and taste to diagnose illness with reasonable accuracy. Armed only with a uroscopy flask and a urine wheel (a light-bulb shaped glass beaker and a quick reference guide of urinary colours, Fig. 47.1) to achieve diagnosis, the confidence in uroscopy was such that many physicians felt able to make a diagnosis from a urine sample alone. Negating the need to speak to patients one could diagnose and prognosticate, often to their own financial gain. Needless to say, by the seventeenth century scientific rigor exposed this practice and the ‘pisse prophets’ fell into dis-

Urine Colour Wheel

U Co rine W lour he el

Fig. 47.1  Urine colour wheel depicting uroscopy flasks containing a range of urinary colours

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Box 47.1 Common Indications and Findings of Urinalysis Indication Suspected/known renal disease  Monitoring of CKD  History of loin pain/renal colic  Self-reported haematuria  Family history of renal disease  Discovery of reduced GRF Monitoring of systemic disease  Diabetes  Hypertension  Chronic inflammatory disorders In the acute receiving unit  Suspected UTI  Suspected renal colic  Suspected DKA Physical assessment screening Screening for drugs of misuse Diagnosis of Pregnancy

Important findings Proteinuria ± haematuria

Glycosuria, proteinuria ± haematuria Proteinuria ± haematuria Proteinuria ± haematuria Leukocytes, Nitrites ± blood/protein Blood ± leukocytes, nitrites, protein Glucose, Ketones ± blood, protein All and any incidental findings Unique urinary dipstick for drugs Unique urinary dipstick for β-HCG

Fig. 47.2 Direct inspection of urine can still provide important clues from normal urine, to frank haematuria, drug effect or hereditary disorders

Urinalysis should be one of the early assessments considered in patients with AKI. Finally, urinalysis forms part of routine physical assessments of otherwise healthy individuals. Q3: What are the components of a complete urinalysis? A complete urinalysis involves gross inspection, performing a urinary dipstick and urinary microscopy. Nowadays, very few samples will undergo microscopy but the importance of this should not be overlooked. Gross inspection of a urine sample is informative and often omitted by the clerking clinician unless inserting a catheter. Inspection allows assessment

of colour (Fig.  47.2), turbidity and detection of any odour which may be present. Although widely reported, cloudy urine and malodourous urine themselves are poorly predictive of urine infections. Q4: What colour should urine be? Normal urine should appear a transparent light shade of yellow; a dilute sample will appear rather pale to colourless. Conversely, concentrated urine—for example in dehydration—will appear darker. A myriad other colours may be seen in the urine, some a harmless effect of medication others a more worrisome marker of disease. Other than yellow, the most commonly

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observed urine colours are red-brown due to haemoglobin or myoglobin pigment, orange due to use of Rifampicin for mycobacterium infection or ‘white’ due to pyuria; most commonly observed transiently after decompressing an obstructed urinary system. Other colours are describe in Box 47.2. Box 47.2 Urinary Colours and Their Associated Clinical Conditions (AIP) Urine colour Red-­ Brown Orange White Pink Green Black Purple

Potential cause Blood, myoglobin, phenytoin, food dyes, beets, rhubarb, senna, acute intermittent porphyria Rifampicin Pyuria, phosphate crystals, chyluria, propofol Uric acid, propofol Methylene blue, propofol, amitriptyline Haemoglobin, myoglobin, onchronosis ‘Catheter bag syndrome’—a quaint occurrence from infection related pigment production in long term catheter users

Q5: You are handed a urine sample and asked to perform a urine dipstick test. Describe how this should be done. This is a common scenario for medical school exams, yet often performed incorrectly in clinical practice potentially leading to false results. The following steps outline the process. 1. Gather all equipment required—gloves, urine sample in clean uncontaminated container, tub of urinalysis dipsticks, paper towels and a mechanism for timing. 2. Ensure the sample is fresh—within 2  h and, where possible, an early morning sample. 3. Wash hands, apply glove and confirm the urinalysis dipsticks are in date. 4. Remove one dipstick and fully submerge all testing panels into the urine ensuring all are saturated. 5. Remove the dipstick from the urine, tapping excess urine back into the container and lay it horizontally onto the paper towels. Holding

Leukocytes

120s

Nitrite

60s

Protein

60s

Blood

60s

Ketone

40s

Glucose

30s

Fig. 47.3  Note specific time-periods, described on the box of dipstick, must pass before interpreting the reagent square so as to ensure accurate results

the dipstick vertically may cause reagent to cross between panels and confuse your results. 6. After the allocated time (see Fig. 47.3) compare the patient’s results to the key on the side of the urinalysis dipstick tub. Be aware—each reagent requires a different time to pass before interpreting the result. A rapid dip and cursory glance may give false reassurance. 7. Dispose of the dipstick, paper towel and (unless sending the sample for further analysis) urine sample. 8. Wash hands and document findings in the medical notes. Q6: Following a ‘long-lie’ a patient is admitted with acute kidney injury, a serum CK >10,000, his urine brown-red in colour and his dipstick is positive for blood. You suspect rhabdomyolysis. Explain his urinalysis findings. The breakdown of skeletal muscle has led to rhabdomyolysis, a cause of acute kidney injury discussed in more detail in Chap. 11. After skeletal

47  Urinalysis and Microscopy

muscle injury, high levels of myoglobin are released from myocytes and accumulate in the tubules leading to renal failure. Much of this is also excreted in the urine, producing the classic brownred colour. Myoglobin is capable of reproducing the same perioxidase reaction on the test panel as haemoglobin, producing a false-positive dipstick haematuria. Box 47.3 outlines other false results you should bear in mind when using the dipstick.

Box 47.3 Potential False Findings Following Dipstick, and Their Clinical Considerations Dipstick finding Assumption Cause of false result Haematuria Positive RBCs in – Haemoglobinuria urine e.g. intravascular haemolysis – Myoglobinuria e.g. rhabdomyolysis Negative Normal – False negative from finding Vitamin C ingestion Proteinuria Positive Glomerular – Non-glomerular proteinuria proteinuria e.g. infection – Non-pathological proteinuria e.g. orthostatic proteinuria Negative Normal – Non-albumin finding proteins e.g. Bence Jones Protein Glucose Positive Diabetes – Proximal tubular loss – SGLT-2 inhibitors Negative Normal finding

Q7: A young woman presents with fever, dysuria and frequency. She has suprapubic tenderness and her urinalysis is ‘positive for leukocytes and nitrites’. Explain the significance of these results. Urinalysis sticks detect leukocyte esterase, which is released from lysed neutrophils and macrophages. Urinary nitrate is converted to nitrite in the presence of nitrate reductase—an enzyme present in many enterobacteriaceae specifies. Thus, the presence of either leukocytes or nitrites

287

may be indicative of infection, however their absence does not always rule it out (Box 47.4).

Box 47.4 Leukocytes and Nitrite on Dipstick: Assumptions and Considerations Dipstick finding Assumption Further considerations Leukocytes Positive Bacterial – Tuberculosis, UTI interstitial nephritis, stones Negative Normal – Concentrated urine – Proteinuria/glycosuria Nitrite Positive Bacterial – Delay in examining UTI sample Negative Normal – Short bladder dwell, non-nitrate reductase (e.g. enterococcus)

Q8: How is urine microscopy performed? Urine microscopy is no longer routine practice, almost never performed by clinicians but still makes it into exams and textbooks. There are a number of conditions where microscopic analysis is useful, such as investigation of urinary tract infection or stone disease. Centrifugation of a fresh sample of urine is required hence this test is often sent to the laboratory for assessment. Microscopy is capable of identifying organisms, cells, casts, crystals and lipids (Fig. 47.4).

Fig. 47.4  Red cell cast. Urinary casts are cylindrical structures formed in the distal convoluted tubule and collecting ducts. Composed of protein and other adherent components, which form part of the nomenclature, they may indicate disease. Red cell casts are always pathological, and in cases of non-visible haematuria indicates glomerular damage

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Q9: A 64  year old male is admitted on a Friday with several weeks of weight loss, joint pains and a rash. He is found to have acute kidney injury with blood and protein on urinalysis. A rapidly progressive glomerulonephritis is suspected. How could urine microscopy aid diagnosis? This clinical presentation should prompt suspicion of renal vasculitis for which a renal biopsy is the definitive test of choice. Specifically, the presence of blood and protein on urinalysis should raise suspicion of a glomerulonephritis, and microscopy of a fresh urine sample may demonstrate ‘red-cell casts’: a finding pathognomonic for proliferative GN. Urinary ‘casts’ are present in a range of clinical conditions. They are formed in the distal convoluted tubule or collecting ducts and consist of a proteinaceous core embedded with various particles as denoted by their prefix. A number of casts are described in Table 47.1. Table 47.1  Urinary cast and associated conditions Case Red cell cast White cell cast Epithelial cell cast

Hyaline cast

Condition Proliferative GN Interstitial inflammation Non-specific tubular desquamation— observed in acute tubular necrosis, interstitial nephritis and glomerulonephritis Non-specific—diuretic use or concentrated urine

Objectives: Urinalysis and Microscopy After reading this chapter, you should be able to answer the following: Q1: Who were the ‘pisse prophets’? Q2: What are the indications to perform urinalysis nowadays?

Q3: What are the components of a complete urinalysis? Q4: What colour should urine be? Q5: You are handed a urine sample and asked to perform a urine dipstick test. Describe how this should be done. Q6: Following a ‘long-lie’ a patient is admitted with acute kidney injury, a serum CK >10,000, his urine brown-red in colour and his dipstick is positive for blood. You suspect rhabdomyolysis. Explain his urinalysis findings. Q7: A young woman presents with fever, dysuria and frequency. She has suprapubic tenderness and her urinalysis is ‘positive for leukocytes and nitrites’. Explain the significance of these results. Q8: How is urine microscopy performed? Q9: A 64 year old male is admitted on a Friday with several weeks of weight loss, joint pains and a rash. He is found to have acute kidney injury with blood and protein on urinalysis. A rapidly progressive glomerulonephritis is suspected. How could urine microscopy aid diagnosis? Answer 47 4. Red cell casts. Red cell casts are pathognomonic of vasculitis and thus most suggestive of vasculitis. All the listed findings described may be found in vasculitis, however they are less specific. Red-brown urine is suggestive of rhabdomyolysis. Dipstick haematuria and Proteinuria are non-specific markers of potential glomerular disease and lipiduria to the nephrotic syndrome.

Dialysis Line Insertion

Question 48 A 56 year old female requires an emergency central venous catheter to commence dialysis for AKI.  This is your second attempt at line. You insert it into the left internal jugular vein  under direct ultrasound guidance using the  technique you have been taught. After advancing the guidewire the patient begins to complain of chest pain and difficulty breathing.  Your supervisor comments the patient has ‘reduced air entry with hyper-resonance on the left’. What is the most likely complication?

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_48

1. 2. 3. 4. 5.

48

Haemothorax Pneumothorax Air embolus Dysrhythmia Arterial puncture

In this chapter, we will outline the method and immediate complications of inserting a ‘temporary’ or ‘emergency’ dialysis line—often referred to as non-tunnelled central venous catheter (to distinguish from tunnelled CVCs). Details on other types of lines and line related blood stream infections are given in Chaps. 44 and 45.

289

48  Dialysis Line Insertion

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Q1: What are the indications for inserting a non-tunnelled central venous catheter (NTCVC) for dialysis? NTCVCs are frequently used in the acute inpatient setting. They form the main mode of dialysis access for patients with AKI requiring emergency haemodialysis. They can also be used for patients with progressive CKD commencing haemodialysis when alternative access isn’t available or possible—for example in those where renal function declines faster than expected and access is either not formed, or not yet usable. Finally, a temporary line may be required in regular dialysis patients whose access has become temporarily unusable, e.g. clotted AV fistula or a dislodged TCVC. Q2: What are the alternatives to inserting NTCVCs? Because of the association with infections, bleeding, the short ‘life’ of a temporary line and the increased risk of central stenosis with repeat procedures we tend to avoid using NTCVCs where possible. If the lack of access is temporary—for example a bruised and transiently unusable fistula—avoiding or delaying dialysis for an additional day or two may be possible, providing the patient and their blood chemistry remain safe. Alternatively, it is preferable to site tunnelled TCVCs (reduced infection rate, greater longevity) or, in units with an enthusiastic surgical team, form an early cannulation AV fistula or graft (even lower infection rates and greater longevity). Finally, and particularly if future preservation of vascular access is important, insertion of a PD catheter—even if transiently—may be considered in the acute setting. Q3: What equipment is required for inserting a NTCVC? Occasionally, a NTCVC needs to be inserted in an emergency—such as acute pulmonary oedema or life-threatening hyperkalaemia. For this reason, many renal units will have a pre-­stocked “line trolley” or pre-packed “line kits” due to the volume of equipment required. A typical equipment list is provided in Table 48.1. Prior to line insertion it is the responsibility of the inserting clinician to ensure patient safety. We recommend checking

Table 48.1  Typical stock for a ‘line trolley’ Dialysis line (with set including needle, guidewire, dilator, line) Sterile ultrasound gel Needles Dressing Scalpel

Skin preparation, e.g. Chlorprep wands

Drapes to cover whole patient, ideally fenestrated and transparent

Ultrasound probe cover Saline flushes Suture Line caps/ connectors

Syringes Local anaesthetic Scissors Gloves, cap, mask, visor, gown

Ultrasound

platelet count, coagulation parameters and review any current anticoagulant use. Absolute coagulation cut-off values vary depending on the clinical circumstance. Patients should provide consent, lie as flat as tolerated in a bed (head down if able for a neck line) and be placed on cardiac monitoring. An assistant is imperative. Q4: What must you consider when selecting the type of line to insert? Depending on the manufacturer of your chosen NTCVCs there will be subtle differences between lines. The three major variables to consider are: shape (straight vs. curved), number of lumens (two vs. three) and length (15  cm vs. 20 cm). Curved lines are generally more comfortable for neck lines, whereas straight are typically used for femoral lines. The number of lumens is a choice between two or three. Those with only two are designed for dialysis only, and a likely to have a lower risk of infection. Triple lumen dialysis lines have a separate central lumen which can be used for central venous access out-with dialysis sessions, allowing blood sampling or drug administration (Fig.  48.1). The length can vary quite significantly, although are generally 15 or 20 cm. Fifteen centimeters lines may be suitable for right internal jugular vein line insertion. Left internal jugular and femoral lines should generally be 20 cm, depending on the patient’s size. Q5: How is a NTCVC inserted? 1. Gather all equipment, an assistant and gain consent from the patient

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2. Position. The patient should be positioned in a bed, within easy reach of the clinician. For neck lines, lying flat or head down will allow the vein to become engorged. Avoid placing the patient in this position until it’s absolutely necessary, however 3. Prepare for an aseptic procedure. Don hat, mask, and visor, then perform surgical scrub before donning gloves and gown 4. Organise yourself. On your table, arrange your equipment carefully. Draw up local

‘Curved’. double lumen line ‘Straight’ triple lumen line

Fig. 48.1 NTCVC lines, demonstrating curved and straight, double and triple lumen

anaesthetic, and flush your line and dilator with saline 5. Clean the skin using a chlorhexidine or iodine based solution and place drapes 6. Envelope the ultrasound probe in a sterile cover and use a small volume of sterile gel (sterile saline is an alternative) to identify vessel with ultrasound 7. Inject local anaesthetic to overlying tissue and allow time to take effect—at least 1 min. Check for anaesthesia before proceeding. This becomes much more difficult if the patient cannot stay still 8. Under real-time ultrasound visualisation, direct the needle (attached to a syringe) into the vein—identified as usually the larger of the two vessels, thin walled and compressible with gentle ultrasound pressure (Fig. 48.2). Pull back on the syringe plunger as you advance until a flashback is achieved 9. Remove the syringe, covering the opening to the needle with a well-timed thumb 10. Carefully advance the guidewire down the needle. Ensure that you never let go. Keep an eye on the cardiac monitor for dysrhythmia, which suggests you’ve advanced too far. The wire should pass very smoothly and shouldn’t need significant pushing

Fig. 48.2 Typical ultrasound view of right internal jugular

Sternocleidomastoid

Internal Jugular

Carotid Artery

292

11. With the needle in place, use the scalpel to make a small incision in the skin to allow the dilator and line to pass 12. With the wire still in place, remove the needle. Then pass the dilator, using gentle pressure and a slight twisting motion to advance it, creating a tract for the line. Once in the vessel, you should feel a “give”. You need not advance this it’s entire length—for most patients the dilator is much longer than will ever be required 13. Remove the dilator and pass the line over the wire 14. Once in place, check that the line is aspirating and flushing easily from all lumens 15. Suture the line in place and apply a dressing. Be wary of the external jugular vessel which will bleed if you pass a suture through it 16. Use an antimicrobial impregnated anticoagulant to “lock” the line 17. Organise a chest X-ray for neck lines to confirm positioning 18. Confirm with nursing staff whether and when the line can be used 19. Document your procedure Q6: Which vessel for NTCVC insertion? The most commonly used veins are the internal jugular veins and femoral veins. Intensivists may favour the subclavian veins, whereas nephrologists will avoid this due to the increased risk of central venous stenosis. The right internal jugular vein is generally the favoured option (Fig.  48.3). This vessel is technically most straightforward to access and is continuous with the SVC and right atrium. Femoral vessels are often used in emergencies and do not required a confirmatory chest X-ray. Femoral access may be preferable, for example, with patients with pulmonary oedema who can’t lie flat or have life-threatening hyperkalaemia and the risk of wire-induced dysrhythmia or delay from organising a chest X-ray is unacceptable. Often femoral access will be chosen in those with bleeding diatheses that can’t be corrected rapidly, to reduce risk of airway compromise from a neck haematoma. The risk of bleeding remains significant, however, and vigilance must remain.

48  Dialysis Line Insertion

Cannulating internal jugular vein

Fig. 48.3  Operator’s view of RIJ line insertion. Asking the patient to look to the left can make the vein more accessible

Q7: What is the role of ultrasound in NTCVC insertion? Real-time, clinician-performed ultrasound should be a routine component of NTCVC insertion. Historically, an anatomical landmark approach—assuming the jugular to be lateral to the carotid—was used. However, significant anatomical variation in jugular positioning is now recognised and the wide availability of bedside ultrasound has made such approach rare. Further, performing a quick bedside scan prior to considering line insertion is advisable for two reasons. Primarily, you can confirm that a patent vessel capable of cannulation exists at your chosen site. Further—you can easily determine intravascular volume state, and decide if further fluid replacement is necessary or appropriate. During line insertion itself, along with guiding the needle into the vessel, the ultrasound can be used to confirm wire placement within the vein prior to dilating (Fig. 48.4). Q8: How should chest X-ray be used to confirm position of the line? For neck lines, chest X-ray should be used to check the line tip is at an appropriate level, and that a pneumothorax has not been caused. The line tip should be visible in the SVC with the tip visible at the junction of the superior vena cava and right atrium. If in the right atrium, the line may function but carries a risk of irritating the atrial wall and causing dysrhythmias, or perforation leading to cardiac tamponade.

48  Dialysis Line Insertion

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Wire Wire

Transverse view

Sagittal view

Fig. 48.4  Ultrasound view of wire, confirming position within vein

Q9: What are the risks associated with NTCVC insertion? The complications are predictable. As is the case for all practical procedures they include ‘pain, infection and bleeding’. Pain should be managed early with careful use of local anaesthetic, which inevitably causes short term pain. Beyond this point, line insertion should not be painful. Bleeding risks should be minimised by correcting platelet count and coagulation parameters if necessary and use of ultrasound guidance to avoid arterial puncture. Bleeding can also occur at the time of removal, or following accidental dislodgement. Upper airway obstruction from haematoma formation has been reported. Infection is a delayed and significant risk. KDOQI guidelines recommend that internal jugular lines should not be used for more than a week, and femoral lines should not be left for more than 5  days. Other important risks include pneumothorax (inadvertent pleural injury on insertion), air embolism (uncapped lines, or uncovered needles at time of insertion), and neurovascular injury (either transient, including effects of anaesthesia, or permanent from local trauma). Objectives: Dialysis Line Insertion After reading this chapter, you should be able to answer the following: Q1: What are the indications for inserting a non-tunnelled central venous catheter (NTCVC) for dialysis?

Q2: What are the alternatives to inserting NTCVCs? Q3: What equipment is required for inserting a NTCVC? Q4: What must you consider when selecting the type of line to insert? Q5: How is a NTCVC inserted? Q6: Which vessel for NTCVC insertion? Q7: What is the role of ultrasound in NTCVC insertion? Q8: How should chest X-ray be used to confirm position of the line? Q9: What are the risks associated with NTCVC insertion? Answer 48 2. Pneumothorax The acute onset of pain, breathlessness, reduced air entry and hyper-resonance is typical of pneumothorax, a recognised complication following inadvertent pleural injury at the time of line insertion. Haemothorax would lead to dullness to percussion (in addition to significant cardiovascular compromise), air embolism may present as pain and breathlessness, but with a normal respiratory examination. The same is true for dysrhythmia. Arterial puncture is likely to present with haematoma, although may be the cause of a haemothorax.

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Renal Biopsy

Question 49 A 66  year old male is referred to the renal clinic with persistent non-visible haematuria. He is a smoker. His renal function is normal, he has no detectable proteinuria, normal coagulation and platelets, normal sized kidneys on ultrasound and his blood pressure 137/86 mmHg.

© Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_49

What is the investigation?

most

appropriate

next

1. Renal biopsy 2. 24 h urinary collection for proteinuria 3. Cystoscopy 4. PLA2R antibody 5. Liver ultrasound

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Q1: What is the purpose of a renal biopsy? A careful clinical history, thorough examination and appropriately selected non-invasive tests point towards the majority of underlying renal diagnoses. However, the renal biopsy remains the gold standard to diagnose intrinsic renal disease. When the pathological findings are supported by the clinical presentation a renal biopsy is capable of providing a specific diagnosis, determine renal prognosis and allow treatment planning. Q2: What are the indications for performing a renal biopsy? The decision to perform a renal biopsy should only be made by an experienced nephrologist to limit unnecessary risk. Broadly speaking there are five reasons to undertake a biopsy, summarised in Box 49.1. These include the presence of an unexplained sustained rise in serum creatinine, unexplained acute kidney injury (most commonly in the setting of suspected vasculitis), unexplained or new onset proteinuria defined usually as uPCR >100 mg/mmol and renal transplant dysfunction. Finally—and least commonly—renal biopsy may be performed to confirm an inheritable nephropathy and influence genetic counselling.

Box 49.1 Biopsy Indications

Indications for performing a renal biopsy CKD AKI Proteinuria ± haematuria Transplant dysfunction Prognostication of inherited disease

Q3: What are the risks associated with native renal biopsy? In experienced hands a percutaneous renal biopsy is considered a safe procedure with a low complication rate. As with all procedures, all patients should be give consent, understanding the general risks of ‘pain, infection and bleeding’, although bleeding is by far the most significant complication. Fortunately, this complicates

Table 49.1  Risks associated with percutaneous renal biopsy Major bleeding type Overall major bleeding Transfusion Embolization Death Other morbidity Haemoglobin decrease >2 g/L

All biopsies Elective Emergency (n = 2563) (n = 1499) (n = 1064) 56 (2.2%) 17 (1.1%) 36 (3.4%) 46 (1.8%) 9 (0.4%) 1 (0.04%) 59 (2.3%) 74 (2.9%)

14 (0.9%) 2 (0.1%) 1 (0.04%) 48 (3.2%) 39 (2.6%)

32 (3.0%) 7 (0.7%) 0 (0.0%) 11 (1.0%) 35 (3.3%)

Reproduced from Lees et al. CKJ, 2017

40 should be screened for urological malignancy. In the list of options, Cystoscopy is the most appropriate next step. If urological examinations are normal, the likeliest diagnosis Answer 49 is IgA nephropathy. Renal biopsy is not indicated as this will not change management. Twenty-four hour urinary collection is cumbersome and 3. Cystoscopy unnecessary. PLA2R antibody is a marker of This patient has asymptomatic persistent non-­ membranous nephropathy, a condition that previsible haematuria. Whilst this may be glomeru- sented with nephrotic syndrome and a liver ultralar in origin all patients with persistent haematuria sound is irrelevant here.

Spotting the Glomerulus: Basics in Biopsy Interpretation

Question 50 A 40  year old male presents with swollen ankles, nephrotic range proteinuria and hypo-­ albuminaemia. He is otherwise well, and on no regular medication. He has been taking ibuprofen 400 mg tds for a recent sports injury. A biopsy is performed and the light microscopy is demonstrated below (Fig. 50.1). Immunofluorescence is negative, and electronic microscopy demonstrates widespread foot process fusion. What is the most likely diagnosis? (Fig. 50.1) 1. Membranous Nephropathy 2. Minimal Change disease 3. IgA Nephropathy

50

4. Lupus Nephritis 5. Focal Segmental Glomerular Sclerosis Some medical students can struggle to tell the difference between a renal arteriole and a glomerulus, and it is for this reason that we are including an introduction to renal histology in this edition of the Clinical Companion. We would encourage all students and junior doctors to review biopsies with their renal pathologist even if the first few times will seem a little daunting. Interpretation of renal histology is an advanced skill though some grasp of the language used and the pathology on display will help to make sense of your clinical work.

Fig. 50.1  Light microscopy, medium power, H + E stain (left) and high power, PAS stain (right) © Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6_50

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Q1: What are the different methods of microscopy used to examine a renal biopsy? Percutaneous renal biopsy, discussed in Chap. 49, is performed to achieve a small core of tissue from the renal cortex ideally sampling in excess of 5–10 glomeruli alongside tubules, vessels and interstitium. There are three main methods of microscopy which can be performed on each

sample: light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM). Where there is sufficient tissue, often all three are performed. Whilst light microscopy must be performed on all samples and IF in suspected glomerular disease, the necessity of EM depends on the likely clinical diagnosis. The general indication for each is described in Box 50.1.

Box 50.1 Renal Biopsy Microscopy Options Microscopy method Light (LM)

Reason General overview of renal structure. Permits examination of glomeruli, interstitium, vessels and tubules and assessment of chronicity or inflammation

Diagnostic indication All indications for renal biopsy

Immuno­ fluorescence (IF)

Assessment of immune deposition, immunoglobulins, complement and light chains

Essential in diagnosis of glomerular disease

Electron Microscopy (EM)

Assessment of ultrastructure of glomerulus (particularly basement membrane) and presence of immune complex deposits

Familial renal disease Glomerular disease

Example

50  Spotting the Glomerulus: Basics in Biopsy Interpretation

Q2: On low power light microscopy, what does normal kidney tissue look like? This is an important distinction to make early on and knowing what normal kidney tissue looks like is essential, both to enable comparison with abnormal kidney tissue and to confirm that the biopsied tissue is kidney. This said, several renal diagnoses have been correctly made following biopsy of the wrong organ (e.g. amyloid detected in a spleen). On low power view a healthy renal cortex should consist mostly of proximal tubules, with a few visible glomeruli and arterioles and possibly an artery, and minimal connective tissue or fibrosis. Using a stain which highlights collagen (e.g. Masson’s trichrome) an experienced eye can detect tubular atrophy and interstitial fibrosis, indicative of chronic disease on initial glance of the core (Fig. 50.2). Q3: What common stains are used in light microscopy? Light microscopy—the backbone of renal histology—provides a general overview of the kidney’s structure, the degree of chronic damage and—once you’ve discovered a glomerulus or two—may allow specific diagnoses to be made. In order to examine the specimen in detail a number of stains are applied to different slides to highlight and differentiate the structures. The common stains are described in Table  50.1 and are shown in the light microscopy images.

Fig. 50.2 Core of healthy renal cortex stained with Masson’s trichrome demonstrating glomeruli (black arrow) and ‘back to back’ tubules (left image, multiple circles abut-

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Q4: What are the key steps in examining a renal biopsy? In clinical medicine it would be completely inappropriate to attempt to make a diagnosis without beginning with the history. Interpretation of a renal biopsy should follow similar rules. Thus, a detailed history is necessary prior to attempting any

Table 50.1  Light microscopy stains Stain Hematoxylin & eosin (H&E) (Fig. 50.1) Periodic Acid Schiff (PAS) (Fig. 50.1)

Appearance Stains cytoplasm pink and nuclei blue Stains BM, brush border, Bowman’s capsule red/purple

Silver methenamine (‘Jones silver stain’, Fig. 50.3c)

Stains collagen black; e.g. Kimmelstiel-­ Wilson nodules, basement membrane (not amyloid) Stains: collagen blue, nuclei brown and muscle and immune complexes pink Stains amyloid deposits salmon pink Stains amyloid red

Masson’s trichrome (Fig. 50.2)

Congo red

Sirius red

Clinical use General cellular characteristics Evaluation of basement membrane and mesangium Outlines basement membrane and helps determine nature of nodules

Highlights fibrosis

Amyloid

Alternative amyloid stain

ting each other). In comparison, the core on the right demonstrates sparse tubules with a large volume of blue material (collagen, white triangle), indicative of chronic damage

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a

b

c

Fig. 50.3  Progressive assessment of renal histology can build the diagnosis: (a) H + E stain, no apparent tubulointerstitial or glomerular abnormality at low power, (b) PAS stain, glomerulus shows normal cellularity, the only abnormality a mild increase in mesangial matrix, (c)

d

Methenamine silver stain shows epimembranous spikes in glomerular capillary walls and finally (d) Immunofluorescence: IgG, granular capillary wall deposits giving a diagnosis of Membranous glomerulonephritis

Fig. 50.4  H + E, Normal glomerulus (left), key structures highlighted on right: green line, bowman’s capsule; blue circles, capillary loops; red lines, red blood cells; yellow areas, mesangium

interpretation—a practice the renal pathologist will appreciate on your request forms. After considering possible diagnoses, the light microscopy should comment on the appearance of the whole sample, the glomeruli, the tubulo-­interstitium and finally the vessels. Immunofluorescence should be performed in those with suspected glomerular disease and the positive immune molecules and distribution pattern commented on. An example of how low and high power light microscopy with different stands and then immunofluorescence microscopy are used together to make a diagnosis is shown in Fig. 50.3. Q5: What does a normal glomerulus look like? All visible glomeruli in the section should be examined for abnormalities, initially at low then high power. A normal glomerulus should appear round in shape (‘glomus’, latin: ‘ball of yarn’) outlined by a thin line; Bowman’s capsule. The

capillaries which make up the glomerulus are described as ‘delicate’, with thin walls and are supported by specialised muscle cells, known as ‘mesangium’. Intact red cells may be visible within the capillary loops (Fig. 50.4). Q6: Describe a few common findings in glomerular disease At low power, the glomeruli should be inspected for changes and their distribution specified. Renal pathologists use specific terms to describe whether more or less than 50% of all the glomeruli seen are involved referring to this as ‘diffuse’ or ‘focal’, respectively. Within the individual glomeruli, take note of whether the whole glomerulus is affected, or just a portion; referred to as ‘global’ or ‘segmental’. A few common findings listed in Table  50.2 and Fig.  50.5. Compare the appearances with that of the normal glomerulus (Fig. 50.4).

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Table 50.2  Abnormalities found in glomerular disease Region Glomerular tuft Mesangial matrix Mesangial cellularity

Abnormality Sclerosis

Capillary loops Capillary lumen

Thickened

Bowman’s space

Nodules Increased

Appearance loss of glomerular architecture and replacement with fibrosis Solitary or multiple rounded structures in mesangium More than three cell nuclei surrounded by matrix in a segment of mesangium ‘Rigid’ capillary loops

Thrombi

Smooth intra-capillary clumps of fibrin with or without clumps of RBCs ↑ inflammatory More than four inflammatory cells in capillaries per glomerular cells capillary tuft Dilated Larger visible space containing epithelial cells Crescent More cells visible in Bowman’s space (“increased cellularity”) including inflammatory cells ± fibrin

Possible disease Global—End stage of all (Fig. 50.5a) Segmental—FSGS (Fig. 50.5b) Diabetes (Fig. 50.5c) Amyloid Glomerulonephritis with mesangial hypercellularity (“proliferation”)—e.g. IgA nephropathy (Fig. 50.5d) Membranous, Lupus, MPGN TMA

Glomerulunephritis—e.g. Lupus, post infectious, C3GN, MPGN (Fig. 50.5e) Collapsing glomerulopathy RPGN (Fig. 50.5f)

RBCs red blood cells, FSGS focal segmental glomerular sclerosis, MPGN mesangioproliferative glomerulonephritis, TMA thrombotic microangiopathy, C3GN C3 glomerulonephritis, RPGN rapidly progressive glomerulonephritis

a

d

b

e

Fig. 50.5 (a–f) Examples of common glomerular findings on light microscopy. (a) Global sclerosis. (b) Segmental sclerosis. (c) Nodular sclerosis (DM). (d)

c

f

Mesangial hypercellulartiy. (e) Capillary hypercellularity (f). Crescent within Bowman’s space

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Table 50.3  Abnormalities found in tubular disease Pathology Casts Crystals Acute tubular injury Atrophy Fibrosis Cellular infiltrate Fig. 50.6  H + E normal renal cortex

a

Appearance Any solid material inside tubular lumen e.g. protein, red cells Crystalline material visible inside tubular lumen e.g. oxalate crystals Flattening (or ‘vacuolation’) of epithelial cell cytoplasm, desquamation of cells into lumen Shrunken tubules with thickened or wrinkled tubular basement membranes Blue on trichrome, pink on H + E Lymphocytes, macrophages (groups of which may form granulomas), eosinophils, plasma cells, neutrophils

H + E haematoxylin and eosin

b

c

Fig. 50.7 (a–c) Histology of renal vessels. TMA thrombotic microangiopathy (see Chap. 14). (a) Artery with cholesterol emboli. (b) Arteriole with thrombus (TMA). (c) Artery with intimal fibroelastic thickening

Q7: What does normal tubulo-interstitium look like? In health the tubulo-interstitium is packed with tubules, with very little visible interstitium. Tubules should appear empty (Fig. 50.6). Q8: Describe a few common findings in interstitial disease Tubulointerstitial disease may present as a rising serum creatinine, electrolyte abnormalities or low-grade proteinuria. As stated, the tubulointerstitium should be packed ‘back-to-back’ with tubules. If space is visible between them, further examination is required to determine if this is due to atrophy and fibrosis or cellular infiltrate. Table 50.3 summarises a few common findings in tubulointerstitial pathology: Q9: What diagnoses can be made from examining the vessels? In addition to examining the capillary loops within the glomerulus, it is important to identify

and describe abnormalities of larger vessels visible in the biopsy (Fig. 50.7). Examination of the vessel wall may demonstrate intimal thickening—a sign of prolonged hypertension and marker of chronic disease, whereas ‘onion skinning’ and intraluminal thrombi are acute findings of TMA.  Vessel wall inflammation can be seen in vasculitis and transplant rejection. Finally, a slit like empty space, once occupied by a cholesterol embolus—dissolved during slide preparation—may be visible within the vascular lumen. Q10: How is IF interpreted? Immunofluorescence (IF) is an essential component to describing immune-complex glomerular disease (Fig.  50.8). The principle entails applying a known immunological ‘tag’ to the slide of interest. If those specific antibodies or complement are present they will be highlighted. With knowledge of the chosen tag the observer must determine the significance and pattern of

50  Spotting the Glomerulus: Basics in Biopsy Interpretation

a

307

b

Granular immunofluorescence

Linear immunofluorescence

Fig. 50.8  Immunofluorsnce; (a) Granular capillary wall IgG immunofluorescence (membranous glomerulonephritis), and (b) Linear capillary wall IgG immunofluorescence (anti-GBM glomerulonephritis)

flattened cytoplasm on the inside of the basement membrane which is barely visible at this magnification and a few nuclei present on the mesangial aspect of the capillary wall) and occasional red blood cells (which are dark grey/black on EM) within capillary lumens. A small amount of mesangial matrix is visible (yellow triangle), along with two mesangial cell nuclei (green triangle) towards the bottom of the image. Objectives: Spotting the Glomerulus: Basics in Biopsy Interpretation After reading this chapter, you should be able to answer the following: Fig. 50.9  Normal glomerulus, EM

distribution. The distribution is described as ­‘linear’ or ‘granular’ providing additional information to achieve a diagnosis. Q11: How do you interpret findings in EM? Electron microscopy is not essential to make all diagnoses. This advanced technique is capable of examining the ultrastructure of the glomeruli, visualising the basement membrane and other organelles in great detail (Fig. 50.9). Orientation is the first step to interpretation. When present, the RBC—which presents as a dense black blob (red triangle)—can rapidly highlight the intravascular space. Note the normal podocyte cell bodies (white triangle), the normal podocyte foot processes (blue triangle) on the outer aspects of capillary walls, the normal glomerular basement membrane within the capillary wall, the normal endothelial cells (with

Q1: What are the different methods of microscopy used to examine a renal biopsy? Q2: On low power light microscopy, what does normal kidney tissue look like? Q3: What common stains are used in light microscopy? Q4: What are the key steps in examining a renal biopsy? Q5: What does a normal glomerulus look like? Q6: Describe a few common findings in glomerular disease Q7: What does normal tubulo-interstitium look like? Q8: Describe a few common findings in interstitial disease Q9: What diagnoses can be made from examining the vessels? Q10: How is IF interpreted?

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Q11: How do you interpret findings in EM? Answer 50 2. Minimal Change Disease The glomerulus demonstrated is completely normal on light microscopy. The absence of abnormality, isolated nephrotic syndrome and use

a

of NSAIDs makes minimal change the likeliest diagnosis. This is confirmed by the presence of widespread podocyte foot process fusion and the absence of immune complex deposits on EM (image below). Membranous would demonstrate a thickened GBM, with changes on silver stain, IgA mesangial hypercellularity, with IgA +ve IF, lupus is less likely in a male and characteristically comes with “full house” positivity on IF. There is no sclerosis visible at all, hence this is not FSGS.

b

(a) Normal finger like projections of healthy podocytes. (b) Widespread podocyte effacement

Appendix A: Treatment of Hyponatraemia

Severity of ↓ Na

Action

Hyponatraemia with severe symptoms (vomiting, cardiorespiratory distress, abnormal and deep somnolence, seizures, coma) Hyponatraemia with moderately severe symptoms (nausea, confusion, headache)

1. First hour management, regardless of whether hyponatraemia is acute or chronic, give intravenous infusion of 150 mL 3% hypertonic saline or equivalent over 20 min. 2. Check serum sodium after 20 min while repeating an infusion of 150 mL 3% hypertonic saline or equivalent over the next 20 min. 3. Repeat (1) and (2) twice or until a target of 5 mmol/L increase in serum sodium concentration is achieved. 4. Manage patients with severely symptomatic hyponatraemia in medical HDU

1. Treat the cause wherever possible, stopping medications and other factors that can contribute to or provoke the hyponatraemia. 2. Immediate treatment with a single intravenous infusion of 150 mL 3% hypertonic saline or equivalent over 20 min aiming for a 5 mmol/L/24 h increase in serum sodium. 3. Aim to limit increase in serum sodium to 10 mmol/L in the first 24 h and 8 mmol/L during every 24 h thereafter, until a serum sodium of 130 mmol/L is reached. 4. Check serum sodium after 1, 6 and 12 h. 5. Consider other causes for the symptoms if they do not improve with an increase in serum sodium. 6. Manage patient as in severely symptomatic hyponatraemia if the serum sodium further decreases despite treating the underlying diagnosis. Acute hyponatraemia 1. If possible, stop fluids, medications and other factors that can contribute to or provoke the hyponatraemia. without severe or 2. If the acute decrease in serum sodium >10 mmol/L, give a single intravenous infusion of 150 mL moderately severe 3% hypertonic saline or equivalent over 20 min. symptoms 3. Check the serum sodium after 4 h 1. Stop non-essential fluids, medications and other factors that can contribute to or provoke the Chronic hyponatraemia. hyponatraemia 2. In mild hyponatraemia (Na 130–135 mmol/L), there is no need to treat with the sole aim of without severe or increasing the serum sodium. moderately severe 3. In moderate (Na 125–129 mmol/L) or profound (10 mmol/L during the first 24 h and >8 mmol/L during every 24 h thereafter. 4. Patients with reduced circulating volume—infuse saline 0.9% 6–8 hourly. Note that in case of haemodynamic instability, the need for rapid fluid resuscitation overrides the risk of an overly rapid increase in serum sodium concentration. 5. Patients with expanded extracellular fluid—fluid restrict to prevent further fluid overload. May require salt and fluid restriction with loop diuretic if fluid restriction alone fails. 6. Patients with SIADH—restrict fluid intake as first-line treatment in moderate or profound hyponatraemia. Give combination of low dose loop diuretics and oral sodium chloride if fluid restriction alone fails. Lithium, demeclocycline and vasopressin receptor antagonists no longer recommended.

Further Reading Spasovski G, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170:G1–G47. © Springer Nature Switzerland AG 2020 J. Fairweather et al., Clinical Companion in Nephrology, https://doi.org/10.1007/978-3-030-38320-6

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Appendix B: Treatment of Hypokalaemia

Severity of ↓ K+ Mild 3.0–3.5 mmol/L

Action 1. Approximate deficit 200–300 mmol K 2. Give around 60–80 mmol K per day orally as Sando K 2 tabs 3 times daily (72 mmol K) (Slow K modified release is more likely to cause GI ulcers, although may be better tolerated) 3. Or try potassium preservation with e.g. amiloride 5 mg daily or ACEI/ARB—useful if hypokalaemia is diuretic induced, hypertensive or heart failure 4. Check U&E twice weekly in hospital Moderate 1. Approximate deficit 400–500 mmol K 2.5–2.9 mmol/L 2. Perform an ECG and consider continuous monitoring 3. Replace magnesium if low—see hypomagnesaemia protocol 4. Replace K by mouth if able to take orally and if GI tract functions normally 5. If not, then give IV—see below 6. Give around 100–120 mmol K per day orally as Sando K 3 tabs 3 times daily (108 mmol K) 7. Monitor K daily until serum K >2.9 mmol/L then manage as above mouth or symptomatic, give Addiphos 10–20 mL IV as below Severe 1.9 mmol/L and 2. If post parathyroidectomy and serum calcium remains 1.9–2.1 mmol/L after 24 h increase asymptomatic Sandocal 1000 to 3 tabs bd 3. If remains 1.9–2.1 mmol/L after 72 h despite Sandocal add alfacalcidol 0.25 μg od and repeat serum calcium at 1 week 1. This is a medical emergency Severe 2. Give calcium gluconate 10% 10 mL IV in 50–100 mL dextrose 5% over 10 min with hypocalcaemia cardiac monitoring (contains 2.32 mmol calcium) 25 mmol or 1000 mg/day) 1. May be well tolerated if has risen slowly if symptomatic then prompt treatment usually indicated 2. Rehydrate then give IV bisphosphonate 1. Requires urgent treatment because risk of shock, coma, renal failure 2. Rehydrate then give IV bisphosphonate 3. May need to consider dialysis if severe renal failure 1. Rehydrate with IV saline 0.9% 3–4 L in first 24 h and 2–3 L daily thereafter aiming for urine output urine output >2 L/day 2. IV fluid lowers serum Ca, but will not restore normocalcaemia 3. Loop diuretics do not promote calciuresis but may be needed if develops fluid overload 4. Be more cautious in elderly with renal impairment and with LV dysfunction. 1. IV bisphosphonates are most beneficial for hypercalcaemia of malignancy but can still be used in other causes of hypercalcaemia 2. Do not use until patients are rehydrated 3. If GFR >30 mL/min and still hypercalcaemic after hydration, give IV zoledronate 4 mg over 15 min in 100 mL saline 0.9% 4. If GFR 0.6 mmol/L 4. If nil by mouth or symptomatic, give Addiphos 10–20 mL IV as below Severe 0.5 mmol/L 5. Glycophos can be used as an alternative to Addiphos Severity of ↓ Mg Serum magnesium 0.4–0.6 mmol/L and asymptomatic

Serum magnesium