Nephrology E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Serie: Lecture Notes
- Sprache: Englisch
Lecture Notes: Nephrology is a concise introduction to the fundamental principles of nephrology. An ideal study guide for medical trainees, this accessible resource combines the depth of a textbook with the accessibility of a handbook. Succinct chapters describe the clinical implications of renal physiology, examine major renal disorders and diseases, and explain a wide range of management and treatment options.
A new addition to the popular Lecture Notes series, this handbook provides trainees in nephrology with core subject knowledge and enables medical students to gain a more comprehensive understanding of this complex specialty.
- Offers clear, easy-to-understand coverage of all relevant nephrology topics
- Includes MCQs and discussion around the answers, ideal for those preparing for written Internal Medicine examinations, including the certification examination of the American Board of Internal Medicine, the UK-based MRCP and the Australia and New Zealand-based FRACP examinations
- Features chapter summaries and numerous infographics, tables and figures
- Emphasises core management skills needed by medical students and junior doctors
- Is presented in the consistent and well-recognised Lecture Notes format
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Table of Contents
Cover
List of Contributors
Foreword
Acknowledgements
1 Clinical Implications of Renal Physiology
Cortex
Medulla
Renal Vasculature
Glomerulus and Filtration across it
Tubules
Why do the Tubules Reabsorb Na
+
and Water?
Proximal Convoluted Tubule
Loop of Henle
Countercurrent Mechanism
Distal Convoluted Tubule and Collecting Duct
Glomeruli and Tubule Balance each other
Juxtaglomerular Apparatus
Hydrogen Ion and the Kidney
Potassium and Acid Base Balance
References
Questions and Answers
2 Investigation of Renal Diseases
Radiological Investigation of Kidney Disease
Laboratory Evaluation of Renal Function
Urinalysis
Renal Biopsy
References
Further Reading
Questions and Answers
3 Disorders of the Renal Tubules Leading to Disturbances of Acid–Base and Potassium
Disturbance of Na
+
Reabsorption: Metabolic Alkalosis and Hypokalaemia
Renal Tubular Acidosis
References
Questions and Answers
4 Renal Stones
Epidemiology
Aetiology and Pathogenesis
Different Types of Renal Stones and Risk Factors
Clinical Manifestations
Investigation
Management
References
Questions and Answers
5 Kidney Cancer
Causative Factors
Renal Tumour Classification Based on Histology
Presentation
Investigations
References
Questions and Answers
6 Acute Kidney Injury
Definition of Acute Kidney Injury
Staging of Acute Kidney Injury
Classification of Acute Kidney Injury as per the Anatomical Site of Pathology
Pathophysiology
Risk Factors
History Taking
Examination
Investigation and Work‐Up
Management
Oliguric versus Non‐oliguric Acute Kidney Injury
Specific Categories of Acute Kidney Injury
New Horizons in Acute Kidney Injury
References
Questions and Answers
7 Chronic Kidney Disease
Definition
Aetiology and Risk Factors
Consequences of Loss of Kidney Function
Complications
Bone and Mineral Metabolism
Classification of Bone Disease in Chronic Kidney Disease
Neurological Manifestations
Endocrine Manifestations
Dermatological Manifestations
Management of Chronic Kidney Disease
Slowing the Progression of Chronic Kidney Disease
Management of Complications
References
Questions and Answers
8 Nephrotic Syndrome
Pathogenesis of the Components of Nephrotic Syndrome
Minimal Change Disease
Focal Segmental Glomerulosclerosis
Membranous Nephropathy
Membranoproliferative Glomerulonephritis (MPGN) or Mesangiocapillary Glomerulonephritis (MCGN)
Treatment
References
Questions and Answers
9 Glomerulonephritis
Immunoglobulin A Nephropathy
Infection‐Related Glomerulonephritis
Staphylococcal‐Associated Glomerulonephritis
Rapidly Progressive Glomerulonephritis
Anti‐Glomerular Basement Membrane Antibody Disease and Goodpasture's Disease
References
Questions and Answers
10 Renal Vasculitis and Lupus Nephritis
Vasculitis
Large Vessel Arteritis
Medium Vessel Arteritis
Small Vessel Arteritis
Systemic Lupus Erythematosus and the Kidneys
References
Questions and Answers
11 Renovascular Hypertension, Pregnancy‐Related Hypertension, and Thrombotic Microangiopathies
Renovascular Hypertension
Pregnancy‐Related Hypertension
Thrombotic Microangiopathies Including Thrombotic Thrombocytopenic Purpura and Haemolytic Uraemic Syndrome
References
Questions and Answers
12 Hereditary and Familial Renal Diseases
Autosomal‐Dominant Polycystic Kidney Disease
Autosomal Recessive Polycystic Kidney Disease
Alport's Syndrome
Thin Basement Membrane Nephropathy
Tuberous Sclerosis
Fabry Disease
References
Questions and Answers
13 Hepatorenal Syndrome
Pathogenesis
Clinical Presentation
Diagnosis
Treatment
References
Questions and Answers
14 Infections of the Kidney
Cystitis
Complications of Pyelonephritis
Asymptomatic Bacteriuria
Urogenital Tuberculosis
HIV‐Associated Renal Disease
Leptospirosis
References
Questions and Answers
15 Diabetic Nephropathy
Epidemiology
Pathology of Diabetic Nephropathy
Pathogenesis
Clinical Features and Natural History
Diabetic Nephropathy and Cardiovascular Disease
Screening for Diabetic Nephropathy
Diagnosis
Monitoring Renal Function in Patients with Diabetes
Incidence and Progression
Effect of Glycaemic Control on Nephropathy
Effect of Control of Blood Pressure
Effect of Renin‐Angiotensin Blockade, Calcium Channel Blockade, and Sodium‐Glucose Co‐transporter 2 Inhibitors
Other Treatments
Treatment of Diabetes in the Presence of Renal Failure
Alterations in Insulin Action in Renal Failure
Dialysis in Patients with Diabetes
Kidney Transplantation in Patients with Diabetes
Pregnancy in Diabetic Nephropathy
References
Questions and Answers
16 Kidney Disease in Myeloma and Other Monoclonal Gammopathies
Renal Involvement in Monoclonal Plasma Cell Disorders
Myeloma Cast Nephropathy (Myeloma Kidney)
Amyloid Light Chain Amyloidosis
Monoclonal Immunoglobulin Deposition Disease
Monoclonal Gammopathy of Renal Significance
Detection of Monoclonal Protein
Acknowledgement
References
Questions and Answers
17 Tubulointerstitial Diseases
Acute Interstitial Nephritis
Chronic Interstitial Diseases
References
Questions and Answers
18 Maintenance Haemodialysis
Physiology of Dialysis
Haemofiltration and Haemodiafiltration
Patient Selection for Maintenance Haemodialysis
Access for Haemodialysis
Anatomy of a Typical Haemodialysis Session
Haemodialysis‐Associated Complications
Elements of the Basic Haemodialysis Prescription
References
Questions and Answers
19 Peritoneal Dialysis: Principles, Indications, and Common Complications
Principles of Peritoneal Dialysis
Delivery of Peritoneal Dialysis
Mode of Delivery of Peritoneal Dialysis
Peritoneal Dialysis Adequacy
Complications of Peritoneal Dialysis
Advantages of Peritoneal Dialysis over Haemodialysis
Contraindications and Barriers to Peritoneal Dialysis
Patient Survival
Technique Survival
References
Questions and Answers
20 Renal Transplantation
Immunobiology of Kidney Transplantation
Major Histocompatibility Complex
Immune Cells (T Cells, B Cells, and Antigen‐Presenting Cells)
T Cell Stimulation
Activation Pathways and Immunosuppression
Mechanisms of Allorecognition
Recipient Selection
Live and Deceased Donors and Donor Selection
Surgery
Immunological Issues
Outcomes: Graft and Patient Survival
Complications
Other Issues
The Future
References
Questions and Answers
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Urine to plasma ratios of some physiologically important body subst...
Table 1.2 Absorption of various ions and water across different segments of t...
Table 1.3 Differences between types 1 and 2 renal tubular acidosis (RTA)
Chapter 2
Table 2.1 Calcium, phosphate,
and parathyroid hormone
levels in different type...
Chapter 3
Table 3.1 Differentiating features between types 1 and 2
renal tubular acidosi
...
Chapter 4
Table 4.1 Risk factors for renal calcium stones
Table 4.2 Risk factors for non‐calcium renal stones
Chapter 5
Table 5.1 Tumours associated with
Von Hippel Lindau
(
VHL
) disease
Table 5.2 TNM staging of renal cancer
Chapter 6
Table 6.1 Staging of AKI is based on two criteria: rise in
serum creatinine
(
S
...
Table 6.2 Causes of
acute tubular necrosis
Chapter 7
Table 7.1 List of markers of
chronic kidney disease
(
CKD
): CKD is defined by t...
Table 7.2
Glomerular filtration rate
(
GFR
) categories in
chronic kidney disease
...
Table 7.3 Albuminuria categories in
chronic kidney disease
(
CKD
)
Table 7.4 Risk factors for
cardiovascular disease
in
chronic kidney disease
Table 7.5 Indications for bone biopsy in
chronic kidney disease‐mineral and bo
...
Table 7.6 Dermatological manifestations of
chronic kidney disease
Table 7.7 Parenteral iron preparations in
chronic kidney disease
Table 7.8
Erythropoiesis‐stimulating agents
in
chronic kidney disease
Table 7.9 Diagnostic criteria for epoetin‐associated pure red cell aplasia
Table 7.10 Management of uraemic bleeding
Table 7.11 Indications of parathyroidectomy in
chronic kidney disease
Chapter 8
Table 8.1 Aetiology of
focal segmental glomerulosclerosis
(
FSGS
)
Table 8.2 Secondry causes of
membranous nephropathy
(MN)
Table 8.3 Causes of immune complex
membranoproliferative glomerulonephritis
(M...
Table 8.4 Causes of complement‐mediated
membranoproliferative glomerulonephrit
...
Chapter 9
Table 9.1 MEST criteria for Oxford classification of
immunoglobulin (Ig) A nep
...
Table 9.2 Chief differences between
poststreptococcal glomerulonephritis
(PSGN...
Table 9.3 Causes of lung haemorrhage with
rapidly progressive glomerulonephrit
...
Chapter 10
Table 10.1 Clinical presentation of
polyarteritis nodosa
(PAN)
Table 10.2
Antineutrophil cytoplasmic antibody
(ANCA)‐associated small vessel vas...
Table 10.3 Chief differences between
granulomatosis with polyangiitis
(
GPA
),
m
...
Table 10.4 Specificity and sensitivity of antibodies to
extractable nuclear an
...
Table 10.5 American College of Rheumatology Criteria for the diagnosis of lup...
Table 10.6 Features of spontaneous versus drug‐induced lupus
Table 10.7 Histological classification of lupus nephritis by the Internationa...
Chapter 11
Table 11.1 Aetiology of secondary hypertension (the first two causes are the ...
Table 11.2 Clinical clues to the diagnosis of renovascular hypertension
Table 11.3 Clinical risk factors that are associated with the likelihood of d...
Table 11.4 Indications for delivery of women with preeclampsia
Table 11.5 Indications of severe preeclampsia. In preeclampsia, the presence ...
Table 11.6 Differential diagnosis of
microangiopathic haemolytic anaemia
(
MAHA
Chapter 12
Table 12.1 Renal manifestations of autosomal‐dominant polycystic kidney disea...
Table 12.2 Extra‐renal manifestations of autosomal‐dominant polycystic kidney...
Table 12.3 Ultrasound criteria for diagnosis of autosomal‐dominant polycystic...
Table 12.4 Diagnostic criteria for tuberous sclerosis (TSC)
Chapter 13
Table 13.1 Diagnostic criteria for hepatorenal syndrome
Table 13.2 Medical treatment of hepatorenal syndrome albumin is an essential ...
Chapter 14
Table 14.1 Risk factors for
urinary tract infections
(UTIs) in women
Table 14.2 Risk factors for developing
urinary tract infections
(UTIs) with mu...
Table 14.3 First‐line antimicrobial choices and doses for uncomplicated cysti...
Chapter 15
Table 15.1 Key elements in the pathogenesis of diabetic nephropathy
Table 15.2 Approach to diagnosis of deteriorating renal function in a patient...
Table 15.3 Potential benefits of
peritoneal dialysis
(
PD
) versus
haemodialysis
Table 15.4 Pre‐pregnancy planning for women with diabetic nephropathy
Chapter 16
Table 16.1 Revised International Myeloma Working Group diagnostic criteria fo...
Table 16.2 Histological lesions present with distinct clinical entities in mo...
Table 16.3 Comparison of serum protein electrophoresis and immunofixation for...
Chapter 17
Table 17.1 Common causes of
acute interstitial nephritis
Table 17.2 Causes of chronic interstitial nephritis
Table 17.3 Common features of chronic tubulointerstitial diseases
Chapter 18
Table 18.1 Assess for the underlying cause and treat appropriately
Table 18.2 Commonly prescribed levels of dialysate electrolytes and variation...
Chapter 19
Table 19.1 Calculation of Kt and V
Chapter 20
Table 20.1 Type and distribution of
major histocompatibility complex
(
MHC
) I a...
Table 20.2 Major contraindications to kidney transplantation
Table 20.3 Immunosuppressive drugs commonly used in kidney transplantation
Table 20.4 Early complications following kidney transplantation
Table 20.5 Infections after kidney transplantation
Table 20.6 Risk factors for
BK virus nephropathy
Table 20.7 Differences between
acute cellular rejection
(
ACR
) and acute antibo...
List of Illustrations
Chapter 1
Figure 1.1 The renal cortex, medulla (with the pyramids), and minor and majo...
Figure 1.2 Parts of glomerulus and the
juxtaglomerular apparatus
(
JGA
).
PCT
,...
Figure 1.3 Diagram showing the movement of sodium (Na
+
), chloride (Cl
−
Figure 1.4 Action of
carbonic anhydrase
(
CA
) in reclaiming bicarbonate (HCO
3
Figure 1.5 Transport mechanisms in the
thick ascending limb
of the loop of H...
Figure 1.6 Absorption of calcium (Ca
+
) and magnesium (Mg
+
) through the parac...
Figure 1.7 Countercurrent mechanism: reabsorption of sodium (Na
+
) with relat...
Figure 1.8 Anti‐diuretic hormone (vasopressin), acting through cyclic adenos...
Figure 1.9 Ion transport in collecting tubule principal cells. Aldosterone, ...
Figure 1.10 Relation between blood pressure and renin–angiotensin–aldosteron...
Figure 1.11 Mechanism of hydrogen (H
+
) secretion and bicarbonate (HCO
3
−
...
Chapter 2
Figure 2.1 Ultrasound images of normal kidney and in hydronephrosis. (a) Nor...
Figure 2.2 Ultrasound images of renal echogenic lesions. Ultrasound is sensi...
Figure 2.3 Simple renal cyst seen on (a) ultrasound and (b) computed tomogra...
Figure 2.4 Ultrasound images of Bosniak IV category renal cyst. Solid areas ...
Figure 2.5 Digital subtraction angiography distinguishes between atheroscler...
Figure 2.6 Normal renal scintigraphy: (top) renal blood flow in 0–60 seconds...
Figure 2.7 Diuresis renogram showing obstructed right kidney causing tracer ...
Figure 2.8 Captopril renogram showing delayed peak activity and excretion of...
Chapter 3
Figure 3.1 Ion transport mechanisms in the distal convoluted tubule. The Na
+
Figure 3.2 Points of mutation in the four types of Bartter syndrome. Chlorid...
Chapter 4
Figure 4.1 Different types of urinary crystals.
Figure 4.2 Ultrasound image of ureteric calculi.
Chapter 5
Figure 5.1 Incidental renal mass detected on ultrasound.
Figure 5.2 Pathogenesis of renal cell carcinoma in Von Hippel Lindau disease...
Chapter 6
Figure 6.1 The relationship between mean arterial pressure (MAP) and renal b...
Figure 6.2 During the first 48 hours of renal injury, there is no biomarker ...
Figure 6.3 Serum cystatin C and
urinary neutrophil gelatinase‐associated lip
...
Figure 6.4 Most acute kidney injuries (AKIs) are due to prerenal factors and...
Chapter 7
Figure 7.1 Consequences of loss of renal function. CKD, chronic kidney disea...
Figure 7.2 In metabolic acidosis, the excess extracellular hydrogen (H
+
) ent...
Figure 7.3 Role of glutaminase in generating ammonium from glutamine: In the...
Figure 7.4 Mechanisms of genesis of
chronic kidney disease–mineral and bone
...
Chapter 8
Figure 8.1 Glomerular filtration barrier.
Figure 8.2
Electron microscopy
picture showing extensive glomerular foot pr...
Figure 8.3 Light microscopy picture showing focal sclerosis (arrow pointing ...
Figure 8.4
Light microscopy
picture showing subepithelial spikes along the
Figure 8.5 Complement pathways: C3 nephritic factor stabilizes alternative p...
Figure 8.6
Light microscopy
picture showing
membranoproliferative glomerulo
...
Chapter 9
Figure 9.1 Classification of the various types of glomerulonephritis (GN) ba...
Figure 9.2 H and E stain 20× magnification showing increased mesangial matri...
Figure 9.3 Electron micrograph showing increased mesangial matrix in immunog...
Figure 9.4
Immunofluorescence
showing heavy mesangial deposit of immunoglob...
Figure 9.5 H and E stain 20× magnification showing mesangial and endothelial...
Figure 9.6 Electron micrograph of
poststreptococcal glomerulonephritis
(PSGN...
Figure 9.7
Immunofluorescence
showing garland pattern of C3 deposition in
p
...
Figure 9.8 (a) Normal glomeruli with single layer of parietal epithelium; (b...
Chapter 10
Figure 10.1 Takayasu arteritis affecting subclavian artery proximal to origi...
Figure 10.2 Computed tomography angiogram showing multiple aneurysms and irr...
Figure 10.3 Pathogenesis of lupus.
Figure 10.4 Light microscopy image of class IV lupus nephritis showing incre...
Figure 10.5 Direct immunofluorescence showing strong mesangiocapillary stain...
Chapter 11
Figure 11.1 (a) Spiral computed tomography image of a right
renal artery ste
...
Figure 11.2 Blood supply to the uterus showing the highly coiled spiral arte...
Figure 11.3 Pathogenesis of preeclampsia. HELLP,
h
aemolysis,
e
levated
l
iver ...
Chapter 12
Figure 12.1 Pathogenesis of autosomal‐dominant polycystic kidney disease. (a...
Figure 12.2 Abdominal computed tomography scan of patient with autosomal‐dom...
Figure 12.3 Abdominal computed tomography scan of patient with autosomal‐dom...
Chapter 13
Figure 13.1 Pathogenesis of hepatorenal syndrome (HRS). ADH, antidiuretic sy...
Chapter 14
Figure 14.1 Ascension of bacteria via urethra to urinary bladder causes cys...
Chapter 15
Figure 15.1 Light microscopy image with periodic acid–Schiff (PAS) staining ...
Figure 15.2 Light microscopy image of
diabetic nephropathy
with trichrome st...
Figure 15.3 Comparison of (a) a normal nephron, (b) a nephron in
diabetic ne
...
Chapter 16
Figure 16.1 Myeloma cast nephropathy. (a) Low‐power magnification shows peri...
Figure 16.2 Renal Amyloid light chain (AL) amyloidosis. (a) Congophilic mate...
Chapter 17
Figure 17.1 Histopathology of acute tubulointerstitial nephritis. (a) Normal...
Chapter 18
Figure 18.1 Blood and dialysis solution flow pathways through a hollow‐fibre...
Figure 18.2 Various components of the haemodialysis circuit (P1, P2 and P3 a...
Figure 18.3 Modification to the ‘sawtooth’ pattern in patients undergoing th...
Chapter 19
Figure 19.1 Delivery of
peritoneal dialysis
(
PD
) and position of PD catheter...
Figure 19.2 Common
peritoneal dialysis
(PD)
regimens. CAPD,
continuous ambu
...
Chapter 20
Figure 20.1 Calcineurin pathway: activation of
T cell receptor
(
TCR
) leads t...
Figure 20.2 Direct and indirect pathways of antigen presentation to recipien...
Figure 20.3 Graft survival at one year for kidney transplants performed in A...
Figure 20.4 Kaplan–Meier graph of graft survival for first deceased donor (D...
Guide
Cover
Table of Contents
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Lecture Notes: Nephrology
A Comprehensive Guide to Renal Medicine
Edited by
Dr Surjit Tarafdar
General Physician and Nephrologist
Blacktown and Mt Druitt Hospital
Blacktown
New South Wales, Sydney, Australia
Conjoint Senior Lecturer
Department of Medicine
Western Sydney University
Sydney, Australia
This edition first published 2020© 2020 by John Wiley & Sons Ltd
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Library of Congress Cataloging‐in‐Publication Data
Names: Tarafdar, Surjit, editor.Title: Lecture notes: Nephrology : a comprehensive guide to renal medicine /edited by Dr. Surjit Tarafdar.Other titles: NephrologyDescription: Hoboken, NJ : Wiley Blackwell, 2020. | Includes bibliographical references and index.Identifiers: LCCN 2019035286 (print) | LCCN 2019035287 (ebook) | ISBN 9781119058045 (paperback) | ISBN 9781119058083 (adobe pdf) | ISBN 9781119058113 (epub)Subjects: MESH: Kidney DiseasesClassification: LCC RC918.N43 (print) | LCC RC918.N43 (ebook) | NLM WJ 300 | DDC 616.6/1–dc23LC record available at https://lccn.loc.gov/2019035286LC ebook record available at https://lccn.loc.gov/2019035287
Cover Design: WileyCover Image: © PIXOLOGICSTUDIO/Science Photo Library/Getty Images
To my family for their patience and support. Their belief in my ability helped me to go through those days when I was overwhelmed and exhausted.
List of Contributors
Edwin AnandAssistant ProfessorJacobs School of Medicine & Biomedical SciencesThe State University of New York at BuffaloBuffalo, NY, USA
Anthea AnantharajahClinical Immunologist / ImmunopathologistThe Canberra Hospital, Garran, ACT;Clinical Lecturer, Australian National UniveresityActon, Australia
Dipankar BhattacharjeeMD(Calcutta), FRCP (Edin), FRCP (Lon), FCPS (B’Desh)Consultant physician and Nephrologist, NHS, UKHonorary Senior Lecturer (Ex) United Kingdom
Robert CarrollConsultant Nephrologist, Central Northern AdelaideRenal and Transplantation Service, Central AdelaideLHN, SA Health, Adelaide, Australia
Philip ClaytonConsultant Nephrologist, Central Northern AdelaideRenal and Transplantation Service, Central AdelaideLHN, SA HealthAdelaide, Australia
Alexander GilbertAdvances Trainee in Nephrology, Royal Prince AlfredHospital, Sydney, Australia
Pankaj HariProfessor, Department of Paediatrics, All IndiaInstitute of Medical Sciences, New Delhi, India
Yena HyeDepartment of Geriatric MedicineNepean‐Blue Mountains HospitalPenrith, Australia
Rajini JayaballaMBChB, FRACP, Staff Specialist in Diabetes andEndocrinology, Western Sydney Diabetes, Blacktown &Mount Druitt Hospitals, Sydney, Australia
R. JayasuryaConsultant Nephrologist, Apollo Gleneagles HospitalKolkata, India
Lukas KairaitisHead of Renal Services, Blacktown & Mount DruittHospitals, Sydney; Sub‐Dean, Blacktown & MountDruitt Clinical School, School of MedicineWestern Sydney UniversitySydney, Australia
Amanda MatherStaff Specialist Renal Physician, Royal North ShoreHospitalSydney, Australia
Stephen McDonaldConsultant Nephrologist, Central Northern AdelaideRenal and Transplantation service, Central AdelaideLHN, SA Health, Adelaide;South Australia Executive Officer, ANZDATA Registry,SA Health and Medical Research Institute;Clinical Professor, Adelaide Medical School,University of Adelaide, Adelaide, Australia
Mark McLeanStaff Specialist in Diabetes and Endocrinology,Blacktown & Mount Druitt Hospitals, WestmeadHospital, Sydney; Conjoint Professor of Medicine –Western Sydney UniversitySydney, Australia
Karumathil MuraliFRACP, MD Senior Staff specialist in Renal MedicineWollongong Hospital; Clinical Associate ProfessorGraduate School of Medicine, University ofWollongongWollongong, Australia
M.K. PhanishConsultant Nephrologist, Renal Services; Lead consultant,Living Donor Kidney Transplantation, Epsom;St.Helier University Hospitals NHS Trust; Leadconsultant, Diabetes‐Renal Services, CUH, Epsom, UK
Priyamvada P.S.Additional Professor, Department of NephrologyJIPMER, Puducherry, India
Richard J. QuiggArthur M. Morris Professor of Medicine andBiomedical Informatics Chief, Division of Nephrology Jacobs School of Medicine & Biomedical SciencesThe State University of New York, The State Universityof New York, Buffalo, NY, USA
Gowri RamanCurrent Palliative Care Advanced Trainee, Universityof NewcastleAustralia
Wayne RankinChemical Pathologist, SA Pathology and ClinicalSenior Lecturer, Discipline of Medicine, University ofAdelaideAdelaide, Australia
Vinay SakhujaEmeritus Professor, Department of Nephrology, PostGraduate Institute of Medical Education & ResearchChandigarh, India
Sarah SoRenal Advanced TraineeWestmead and Blacktown HospitalsSydney, Australia
Kamal SudDepartment Head of Renal Medicine, ClinicalAssociate ProfessorUniversity of Sydney ‐ Nepean Clinical SchoolNepean HospitalKingswood, Australia
Sanjay SwaminathanProfessor, Clinical Dean, Blacktown & Mount DruittClinical School, Western Sydney University; ClinicalImmunologist, Westmead and Blacktown HospitalSydney, Australia
Surjit TarafdarConsultant Nephrologist and General Physician,Blacktown and Mount Druitt HospitalBlacktown, NSW, Sydney; Conjoint Senior LecturerDepartment of Medicine, Western Sydney UniversitySydney, Australia
Muh Geot Wong MBBS, PhD, FRACPStaff Specialist, Department of Renal Medicine, RoyalNorth Shore Hospital; Senior Clinical LecturerUniversity of SydneySydney, Australia
Foreword
The title ‘Lecture Notes’ undersells the comprehensive nature of this textbook, which fills a largely vacant niche in nephrology bookshelves, between lecture notes for medical students and junior trainees usually covering specific aspects of nephrology, and comprehensive speciality tomes targeted at those requiring specialized knowledge about any or all aspects of nephrology. Lecture Notes: Nephrology is aimed specifically at early‐stage physician trainees who in the Australian system are preparing to undertake the basic physician trainee examination, or more senior trainees who have completed that exam, but are seeking expert knowledge as a trainee in general medicine, or are just starting specialized training in nephrology. However, its reach is much broader than that and it will appeal to anyone wanting to understand nephrology at a level greater than that found in general medical textbooks, including more advanced nephrology trainees, subspecialty nephrologists seeking knowledge beyond their subspecialty, general physicians and nephrologists wishing to brush up on all aspects of nephrology, and teachers of nephrology at any level. Whereas its reach is broad, it does not pretend to cater to those seeking highly specialized knowledge of particular aspects of nephrology. It is full of practical, contemporary information useful for day‐to‐day application on any aspect and at any level of renal diagnosis, investigation and management. Even the nephrologist who has been practising his or her craft for many years will find exciting new gems. In reviewing the book I found myself looking forward to reading each of the chapters at a more leisurely pace, and to applying its new knowledge for teaching and clinical practise.
The authors of Lecture Notes: Nephrology range from international, national and local experts on particular aspects of renal science and its clinical application, to advanced trainees in nephrology who under the supervision of senior colleagues need to have this level of expertise and knowledge for their day‐to‐day supervision of nephrology patients. Each chapter has been reviewed thoroughly by other authors and content experts, and achieves high standards of readability, immediacy and clinical applicability. The chapters cover all aspects of nephrology, including physiology appropriately linked to clinical disease, general nephrology, dialysis and transplantation. Of particular relevance to those preparing for nephrology examinations, and others wishing to test how well they have assimilated the book's new knowledge, is a comprehensive set of multiple choice questions, which have been written by those well placed to do so; that is, trainees preparing for or having recently completed general physician and nephrology examinations.
Surjit Tarafdar and his colleagues have produced a renal textbook of high utility, which will occupy a place of honour on nephrology bookshelves.
David CH HarrisAM, MD (USyd), BS, FRACPProfessor of Medicine,University of SydneyDirector of Nephrology & Dialysis,Western Sydney Renal ServicePast‐President, International Society of Nephrology
Acknowledgements
I am indebted to the following groups and individuals for their contributions:
The Histopathology Department at ICPMR, Westmead Hospital, Sydney, Australia.
Dr Pei Dai, Advanced Trainee in Immunology at Westmead Hospital, Sydney, for the Immunofluorescence slides.
Dr Simon Gruenewald, Consultant Nuclear Physician at Westmead Public Hospital, Sydney, and Dr Basim Alqutawneh, Consultant Radiologist at Blacktown Hospital, Sydney, for the radiographs and imaging material.
Professor Jeremy Chapman, Associate Professor Gopala Rangan and Dr Brian Nankivell from the Department of Renal Medicine of Westmead Hospital, Sydney, and Professor Ravindra Prabhu A, Department of Nephrology at Kasturba Medical College, Manipal, India, for reviewing portions of the book.
Dr Alexander Gilbert, renal Advanced Trainee at Prince Alfred Hospital, Sydney, for proofreading almost the entire book in addition to co‐writing
Chapter 14
.
Lashnika Bandaranayake and Thilan Pasanjith Subasinghe, the wonderful team of fifth‐year medical students from Western Sydney University, who helped with most of the diagrams and illustrations.
To the lovely librarians at Blacktown Hospital, Sydney, for letting me stay back in the Peter Zelas Library many a day past closing time.
To the following junior doctors and registrars who reviewed the book and provided valuable feedback on the language and content:
Dr Shrikar Tummala
Dr Tu Hao Tran
Dr Hannah Jsu
Dr Shaun Khanna
Dr Sumreen Nawaz
Dr Ye Min Kuang
Dr Marlies Pinzon
Dr Serge Geara
To Yogalakshmi Mohanakrishnan, the project editor from the publisher's office, for her patience, guidance and prompt responses.
Finally, I am extremely thankful to Professor David Harris from Westmead Hospital, Sydney. Despite being the President of the International Society of Nephrology at a time when the World Congress of Nephrology was being held in Australia, Professor Harris found time to review the book and provide pearls of wisdom which added immensely to the quality of the finished work.
1Clinical Implications of Renal Physiology
Surjit Tarafdar
Summary
Besides maintaining a stable acid base, electrolyte, and fluid status of the body, kidneys also have an important endocrine role in producing and secreting 1,25‐dihydroxycholecalciferol (calcitriol), renin, and
erythropoietin
More than 98% of water in the filtered urine is reabsorbed in the tubules; 90–95% of water is reabsorbed as it follows sodium (Na
+
), which is avidly reabsorbed by the Na
+
‐deficient epithelial cells, except in the
collecting duct
(
CD
), where 5–10% of water is reabsorbed (independent of Na+) under the direct influence of vasopressin or
anti‐diuretic hormone
(
ADH
)
The tubular epithelial cells constantly lose three Na
+
and gain two potassium (K
+
) ions from the basolateral membrane (due to the Na+‐K+‐ATPase), which keeps these cells deficient in Na
+
The countercurrent mechanism, which is dependent on the impermeability of the
thick ascending limb
(
TAL
) to water, leads to the creation of an increasing osmotic gradient from the cortex to the deeper medulla, which in turn enables ADH to reabsorb water in the CD
Aldosterone helps in Na
+
reabsorption in the CD and also leads (directly) to K
+
and (indirectly) to hydrogen (H
+
) secretion into urine
All diuretics act by inhibiting tubular reabsorption of Na
+
Formation of urine begins in the glomerular capillaries where the filtrate has to cross the three filtration layers: endothelium,
glomerular basement membrane
(
GBM
) and the foot processes of the podocytes; all these three layers are negatively charged and hence repel anionic proteins like albumin
Nephrotic syndrome, which is marked by abnormally increased filtration of plasma proteins in the urine, may be due to widening of the pores in the three filtration layers, but is almost always associated with loss of negative charges in these layers
Nephritis, which is due to glomerular inflammation, is characterized by haematuria with red blood cell (RBC) casts and dysmorphic RBCs, some degree of oliguria, hypertension, and reduction in
glomerular filtration rate
Goodpasture’s disease, which is characterized by antibodies against subtype of type IV collagen, can lead to nephritis and haemoptysis, as this particular collagen is found predominantly in the GBM and alveolar membranes of the lungs
Familial hypocalciuric hypercalcaemia
, which manifests with hypercalcaemia, characteristically low urinary calcium and normal to high serum parathyroid hormone (PTH) level, is due to mutation in the calcium‐sensing receptor (found in the kidney and parathyroid gland) leading to abnormally increased renal reabsorption of calcium and inappropriate secretion of PTH
Distal renal tubular acidosis (type 1 RTA) is due to an inability of the distal tubules to excrete H
+
, whilst proximal renal tubular acidosis (type 2 RTA) is due to an inability of the proximal tubules to reabsorb bicarbonate (HCO
3
−
)
Metabolic acidosis leads to hyperkalaemia and vice versa
The kidneys are paired retroperitoneal structures that are normally located between the transverse processes of the T12–L3 vertebrae, with the left kidney typically somewhat more superior in position than the right. Each kidney has an outer cortex and an inner medulla which protrudes into the pelvis. The pelvis is practically the funnel‐shaped dilated upper end of the ureter.
The kidney maintains a stable acid base, electrolyte, and fluid status inside the body by selective elimination or retention of water, electrolytes, and other solutes (Table 1.1). It does so by three mechanisms:
Filtration of blood in the glomerulus to form an ultrafiltrate (water with low molecular weight solutes) which then enters the tubule.
Selective reabsorption of water, electrolytes, and solutes from the tubules into the interstitium and peritubular capillaries.
Selective secretion from the peritubular capillaries across the tubular epithelium into the tubular fluid.
Besides these mechanisms, the kidneys also play an active endocrine role by the production and secretion of:
1,25‐dihydroxycholecalciferol
: cholecalciferol is derived from 7‐dehydrocholesterol in the skin on exposure to the ultraviolet rays in sunlight. Cholecalciferol then undergoes two subsequent hydroxylations by 25‐hydroxylase in the liver and 1‐hydroxylase in the proximal tubules of the kidney to yield 1,25‐dihydroxycholecalciferol (calcitriol). Calcitriol is the active form of vitamin D, without which calcium cannot be absorbed from the intestine.
Table 1.1 Urine to plasma ratios of some physiologically important body substances
Substance
Urine to plasma ratio
Glucose
0
Sodium
0.6
Urea
60
Creatinine
150
Renin
: discussed later under
juxtaglomerular apparatus
.
Erythropoietin
(EPO)
: specialized interstitial cells in the inner cortex and outer medulla of the kidney produce and secrete EPO, which stimulates red blood cell (RBC) production in the bone marrow.
The kidney consists of nephrons with the supporting interstitium, collecting ducts (CDs), and the renal microvasculature. The nephron consists of a glomerulus and a twisted tubule which drains into the CD. The tubule consists of a proximal and a distal tubule connected by Henle's loop [1]. Each kidney has approximately one million nephrons and we cannot develop new nephrons after birth.
Cortex
This is the outer layer of the kidney and all the glomeruli are located here (Figure 1.1). The tubules of the superficial and midcortical nephrons are situated entirely within the cortex. The juxtamedullary nephrons (in the deeper regions of the cortex and nearer the medulla) have longer tubules and their loop of Henle goes down into the medulla and helps in the countercurrent mechanism, as discussed later.
Medulla
The renal medulla contains the loops of Henle of the juxtamedullary nephrons, vasa recta (peritubular capillaries surrounding the long loops of the juxtamedullary nephrons), and the CDs. The medulla consists of 7–10 conical subdivisions called pyramids, whose broad base faces the cortex, and the apical papilla points into the minor calyx. After traversing through the pyramid, the CDs open at the papilla and drain the urine into the minor calyx. Two or three minor calyces converge to form a major calyx, through which urine continues into the renal pelvis, which is the funnel‐shaped dilated proximal end of the ureter. There are usually two or three major calyces in each kidney.
Figure 1.1 The renal cortex, medulla (with the pyramids), and minor and major calyces with their relation to the ureter and renal vasculature.
Renal Vasculature
The kidneys receive 1.2–1.3 l of blood per minute (about 25% of the cardiac output), making them highly vascular organs. After originating from the aorta, the renal artery enters the renal sinus and divides into the interlobar arteries, which extend towards the cortex in the spaces between the medullary pyramids. At the junction between the cortex and medulla, the interlobar arteries divide and pass over into the arcuate arteries. The arcuate arteries give rise to the interlobular arteries, which rise radially through the cortex. It is interesting to note that none of these arteries penetrates the medulla.
Afferent arterioles arise from the interlobular arteries and supply the glomerular tufts. The glomerular tufts are drained by the efferent arterioles, which then form the peritubular plexus and are of two types: cortical and juxtamedullary. The shorter cortical efferent arterioles arise from the superficial and midcortical nephrons and supply the cortex. The longer juxtamedullary efferent arterioles, which arise from the deeper nephrons, represent the sole blood supply to the medulla and are termed vasa recta. Whilst the descending vasa recta supply blood to the medulla, the ascending vasa recta drain it.
Glomerulus and Filtration across it
The glomerulus is the invagination of a tuft of capillaries into the dilated proximal end of the nephron called the Bowman's capsule (Figure 1.2). Supplied by the afferent and drained by the efferent arteriole, the glomerular capillary bunch is attached to the mesangium on the inner side and covered by the glomerular basement membrane (GBM) on the outer side. In a way, the GBM forms the skeleton of the glomeruli, with the podocytes (visceral epithelial cells with long foot processes) on the outer side and the capillaries and mesangium on the inner side. Thus, blood within the glomerular capillary is separated from the urinary space by endothelium, GBM, and podocyte.
Formation of urine begins with the filtration of blood from the glomerular capillaries. For this to happen blood must cross three layers:
Endothelium
: these highly fenestrated cells have 50–100 nm pores with a highly electronegative luminal surface.
GBM
: with podocytes externally and endothelium/mesangium internally, its main constituents are collagen IV, laminin, and heparin, all of which are negatively charged.
Visceral epithelium (podocytes)
: a big cell body floating in the urinary space with long primary processes which affix on the glomerular capillaries by foot processes, with filtration slits sized 30–40 nm in between. These slits are bridged by the slit diaphragms, which are themselves penetrated by small pores sized about 8 nm. The luminal surfaces of both the podocyte foot processes and the slit diaphragms are rich in negatively charged proteins such as podocalyxin in the former and nephrin in the latter.
Figure 1.2 Parts of glomerulus and the juxtaglomerular apparatus (JGA). PCT, proximal convoluted tubule.
Whilst water can freely cross these three layers, the filtration of macromolecules depends on both size and charge. Molecules bigger than 8 nm are normally completely restricted by the GBM. Albumin with a diameter of 7.2 nm would have been effectively filtered were it not for its negative charge.
Clinical Notes
Common Glomerular Pathologies
Nephrotic syndrome is characterized by proteinuria >3.5 g/24 hours, hypoalbuminaemia, generalized oedema, and hyperlipidaemia. Nephrotic syndrome is due to abnormally increased filtration of plasma proteins across the glomerular capillary. This may be due to an increase in the size of the pores mentioned earlier, but there is always an associated loss of negative charges across the filtration barrier. Proteinuria leads to hypoalbuminaemia, with a resultant decrease in plasma oncotic pressure in turn leading to oedema. In an effort to compensate for the low oncotic pressure, the liver starts to make excessive lipids, leading to hyperlipidaemia.
Nephritis is characterized by haematuria with RBC casts and dysmorphic RBCs, some degree of oliguria, hypertension, and reduction in
glomerular filtration rate
(GFR). Nephritis is due to glomerular inflammation leading to leakage of RBCs across the filtration barrier. As the RBCs traverse the inflamed filtration barrier and travel down the tubules, they develop cytoplasmic blebs on their surface and are seen as dysmorphic RBCs under the microscope. Whilst travelling through the thick ascending loop of Henle, the RBCs get struck in the physiologically secreted tubular Tamm–Horsfall protein, leading to the formation of RBC casts. Thus, the presence of dysmorphic RBCs and RBC casts in a patient with haematuria helps to differentiate nephritis as the pathology rather than ureteric or bladder pathologies.
Type IV collagen molecules are composed of three alpha chains that form triple‐helical structures through specific interactions of C‐terminal non‐collagenous domains. GBM and alveolar capillary basement membrane collagen consist of alpha3, ‐4, and ‐5 chains, unlike other basement membranes with alpha1 (two of them) and alpha2 chains. Two disease processes pathogenetically caused by defects primarily in the GBM are:
Goodpasture’s disease, characterized by anti‐GBM antibody against the alpha3 chain of the type IV collagen present in the GBM and alveolar membranes in the lungs [
2
]. Patients present with nephritis and haemoptysis.
Alport syndrome, which results from mutations in genes encoding the alpha3, ‐4, and ‐5 chains of type IV collagen (80% are due to mutations in the alpha5 chain) [
3
]. It is the commonest inherited form of nephritis and is often associated with sensorineural deafness and ocular abnormalities due to the presence of similar alpha3, ‐4, and ‐5 chains in the type IV collagen in the basement membranes of the lens and cochlea.
Tubules
With a GFR of 125 ml/min, about 180 l of urine is formed at the glomerular level each day. Thankfully, under physiological conditions almost 98–99% of this filtered urine is reabsorbed by the tubules. More than 90% of this tubular water reabsorption is a passive process and water just follows the sodium (Na+) being reabsorbed. Only in the CD is water absorbed actively and independently of Na+ under the action of vasopressin or anti‐diuretic hormone (ADH).
It is thus obvious that most of the water reabsorption in the tubules is dependent on the reabsorption of Na+. So, what makes the tubules take up Na+ so avidly?
Why do the Tubules Reabsorb Na+ and Water?
The tubular epithelial cells, irrespective of which segment of the tubule they belong to, have a basolateral Na+‐K+‐ATPase that continuously pumps out three Na+ ions and brings in two potassium (K+) ions, thus making the cells permanently Na+ deficient. Thus, the fact that the tubular epithelial cells are always deficient in Na+ helps in the Na+ reabsorption from the tubules. In the same vein, the fact that the tubular cells are rich in K+ helps them to secrete K+ into the tubular lumen.
Water is absorbed osmotically along with solutes, with Na+ being the predominant solute (Table 1.2; Figure 1.3). The two exceptions are in the thick ascending limb (TAL) of the loop of Henle, which is impermeable to water, and the CD, where water is reabsorbed by the action of vasopressin, as discussed later.
Proximal Convoluted Tubule
The bulk of tubular reabsorption occurs in the proximal convoluted tubule (PCT), with 65–70% of the total Na+ being reabsorbed here and about the same amount of water being reabsorbed passively. The PCT is also responsible for reabsorption of the bulk of phosphate (PO3−4), bicarbonate (HCO3−), potassium (K+), calcium (Ca+) and almost all glucose, amino acids, uric acid, and low molecular weight proteins such as microglobulins and the light chain fraction of immunoglobulins.
NaHCO3 is filtered in the glomeruli and dissociates in the lumen of the PCT into Na+ and HCO3−. Na+ is reabsorbed by the Na+‐hungry tubular epithelial, as already discussed. The HCO3− remaining (from the original NaHCO3) in the lumen combines with hydrogen (H+) by the action of the tubular carbonic anhydrase (CA) to form carbonic acid (H2CO3), which then splits into carbon dioxide (CO2) and water (H2O). CO2 enters the tubular cell and now the reaction goes in the reverse direction, with CO2 combining with H2O to form H2CO3, which is then split to form H+ and HCO3− by the intracellular form of CA. This H+ is then secreted into the PCT lumen in exchange for Na+ by the Na+–H+ exchange transport, whilst the HCO3− diffuses into blood in the peritubular capillaries (Figure 1.4). Thus, for each H+ secreted into the tubule, the body gains an HCO3−.
Table 1.2 Absorption of various ions and water across different segments of the renal tubules
Ion or substance
PCT
Loop of Henle
DCT
CD
Na
+
65–70%
30–35%
5%
1–2%
H
2
O
65–70%
25%
5%
5–10%
K
+
45–50%
40–45%
Secreted by principal cells
Ca
+
70%
20%
10–15%
Mg
+
15–25%
60–70%
5–10%
PO
3−
4
70–80%
Insignificant
Insignificant
Insignificant
HCO
3
−
85–90%
Secreted by beta‐ intercalated cells
Ca+: calcium; CD: collecting duct; DCT: distal convoluted tubule; HCO3−: bicarbonate; H2O: water; K+: potassium; Mg+: magnesium; Na+: sodium; PCT: proximal convoluted tubule; PO3−4: phosphate.
Figure 1.3 Diagram showing the movement of sodium (Na+), chloride (Cl−), potassium (K+), and water (H2O) across various portions of the renal tubule, with the site of action of different diuretics highlighted. ADH: anti‐diuretic hormone; NaHCO3−: sodium bicarbonate; TAL: thick ascending limb.
Figure 1.4 Action of carbonic anhydrase (CA) in reclaiming bicarbonate (HCO3−) in the proximal convoluted tubule (PCT): sodium bicarbonate (NaHCO3) dissociates in the lumen of the PCT into sodium (Na+) and HCO3−; Na+ is reabsorbed by the tubular cells in exchange for hydrogen (H+), whilst the HCO3− combines with the H+ to form carbonic acid (H2CO3) under the influence of tubular CA. H2CO3 then splits into carbon dioxide (CO2) and water (H2O), followed by the CO2 diffusing into the tubular cells and regenerating H2CO3 after combining with H2O. Aided by the intracellular CA, this H2CO3 then splits to form H+ and HCO3−. This H+ is secreted into the PCT lumen in exchange for Na+, whilst the HCO3− diffuses into the peritubular capillaries. ATP, adenosine triphosphate.
Reabsorption of Na+ in the PCT facilitates the reabsorption of glucose, amino acids, phosphate, and uric acid.
Clinical Notes
Disorders of the Proximal Renal Tubules
Proximal renal tubular acidosis (type 2 RTA) is due to a defect in the reabsorption of HCO
3
−
leading to urinary loss of HCO
3
−
and the resultant metabolic acidosis. As already explained, the reabsorption of HCO
3
−
in this segment is linked to the coupled exchange of H
+
and Na
+
(
Figure 1.4
). As Na
+
reabsorption here is linked to the reabsorption of glucose, amino acids, phosphate, and uric acid, the patient may present with glycosuria, hypophosphataemia, and hypouricaemia (due to urinary losses), a condition that is termed Fanconi syndrome. Urine pH is usually less than 5.5 despite bicarbonaturia, as the intact distal tubules excrete excess H
+
as a compensatory mechanism for the acidosis.
Type 2 RTA is discussed further in the clinical notes following the section on the distal convoluted tubule and collecting duct.
Acezolamide, which is a CA inhibitor often used by ophthalmologists for the treatment of glaucoma, can also lead to a type 2 RTA‐like picture, with full‐blown Fanconi syndrome at times. The anti‐epileptic drug topiramate and anti‐HIV medication tenofovir, by their CA inhibitor activity, can also lead to proximal RTA and Fanconi syndrome [
4
].
PCT is responsible for the reabsorption of the easily filtered light chain fragments of immunoglobulins. In myeloma, the excess of light chains is toxic to the PCT and may lead to proximal RTA with or without Fanconi syndrome [
5
].
In prerenal AKI, serum urea increases disproportionately to creatinine due to its enhanced PCT reabsorption that follows the enhanced transport of Na
+
and water. Elevated serum urea/creatinine may also be seen in upper gastrointestinal haemorrhage, since the upper intestinal proteolytic enzymes break down haemoglobin to amino acids, which are then reabsorbed by the body and lead to the generation of urea.
Clinical Notes
Disorders of the Loop of Henle
Bartter syndrome
: an autosomal recessive syndrome that characteristically presents with hypokalaemia and metabolic alkalosis is described later in the chapter with Gitelman syndrome (following the section on the
distal convoluted tubule
and collecting duct).
Familial hypocalciuric hypercalcaemia
(FHH)
: this benign autosomal dominant condition is caused by inactivating mutations in the gene for the CaSR.
CaSR is predominantly found in the parathyroid gland and the kidneys. In the parathyroid gland, it decreases the secretion of PTH in response to serum Ca+. Under normal conditions, the TAL CaSR, on being activated by Ca+, downregulates the production of Ca+‐carrying transcellular proteins Claudrin 16 and 19 by forming Claudrin 14, which has an inhibitory effect on the two [7]. The mutated CaSR in FHH is unable to inhibit Claudrin 16 and 19, leading to uninhibited Ca+ reabsorption and hence hypocalciuria and hypercalcaemia, and at the same time a non‐suppressible serum PTH level. It is easy to confuse this condition with primary hyperparathyroidism unless one looks at the urinary Ca+, which is characteristically low. A spot urine Ca+/creatinine ratio of <1/100 is helpful in differentiating the hypercalcemia with inappropriately high serum PTH levels seen in FHH from primary hyperparathyroidism (where the urinary Ca+ would be high).
About 40–50% of the filtered urea is reabsorbed in the PCT. As urea is reabsorbed in this section along with Na+, in conditions of volume contraction when the PCT reabsorbs more Na+, the net reabsorption of urea is also significantly increased. Thus, a disproportionate rise in blood urea concentration in comparison to creatinine might be a marker of a prerenal cause of acute kidney injury (AKI).
Loop of Henle
The loop of Henle consists of the thick and thin descending limbs and the thick ascending limb (TAL), with a thin ascending limb seen only in long looped nephrons.
Figure 1.5 Transport mechanisms in the thick ascending limb of the loop of Henle: The basolateral (peritubular) membrane due to the action of Na+‐K+‐ATPase pumps three sodium (Na+) out of, and two potassium (K+) into, the cell. This creates a low intracellular Na+ concentration, which allows the cell to absorb Na+ from the urinary lumen by the electroneutral Na+‐K+‐2Cl− (NKCC2). The cell is rich in K+ and so much of the reabsorbed K+ recycles back into the lumen through the renal outer medullary potassium channel (ROMK) on the apical/luminal membrane. This movement of one cationic K+ into the lumen plus the flux of one reabsorbed Na+ (by Na‐K‐ATPase pump) and two chloride (Cl−) out of the cell and into the peritubular capillary (via Cl− channels) causes the lumen to become more positively charged compared with the cell and peritubular capillaries/interstitium. The resultant electrical gradient promotes passive reabsorption of cations calcium (Ca+) and magnesium (Mg+) via the paracellular pathway. The Cl− channels require interaction with a small protein called barttin to function normally. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate.
The loop of Henle is responsible for the reabsorption of 30–35% of the luminal Na+ but only 25% of the water, as the TAL is resistant to the movement of water across it.
The frusemide‐sensitive and electroneutral Na+‐K+‐2Cl− cotransporter reabsorbs one Na+ and K+ each along with two Cl− ions from the TAL lumen to the tubular epithelial cell (Figure 1.5). High intracellular K+ concentration (due to the basolateral Na‐K‐ATPase pumping out three Na+ and bringing in two K+ ions constantly) causes the reabsorbed K+ to be secreted back into the lumen via the renal outer medullary potassium (ROMK) channel. The Cl− is absorbed into blood by the basolateral Cl− channel (ClC‐Kb), which has barttin as a crucial accessory protein. Movement of one positive charge (K+) into the lumen and net of one negative charge into the peritubular capillary (1 Na+ and 2 Cl−) causes the lumen to be more positive compared to the tubular peritubular capillary and interstitium. This electrical gradient promotes the passive reabsorption of cations Ca+ and Mg+ via the paracellular cleft between the cells. Membrane proteins Claudrin 16 and 19 help in this paracellular reabsorption of Ca+ and Mg+ and are themselves tightly regulated by the calcium‐sensing receptor (CaSR) (Figure 1.6) [6].
Countercurrent Mechanism
A major function of the loop of Henle is to create an interstitial osmotic gradient that increases from the renal cortex (290 mOsm/kg) to the tip of the medullary pyramid (1200 mOsm/kg) (Figure 1.7). This countercurrent mechanism is fundamentally dependent on the impermeability of the TAL to water. The reabsorption of Na+ (and its passage to the interstitium by the basolateral Na+‐K+‐ATPase pump) in the absence of water in the ascending limb has two consequences:
Figure 1.6 Absorption of calcium (Ca+) and magnesium (Mg+) through the paracellular pathway in the thick ascending limb of the loop of Henle. Sodium (Na+) is reabsorbed via the apical Na+‐K+‐2Cl− cotransporter and pumped out basolaterally by the Na+‐K+‐ATPase; chloride (Cl−) exits via the Cl− channel (ClC‐Kb); and potassium (K+) is secreted into the tubular lumen by the renal outer medullary potassium channel (ROMK), thereby generating a lumen‐positive transtubular electric potential. Ca+ and Mg+ are reabsorbed passively across the paracellular pathway because of this lumen‐positive electrical potential. Claudrin 16 and 19 are the two chief transport proteins which help to carry the Ca+ and Mg+ across the paracellular cleft. Blood Ca+ levels regulate this process by stimulating the Ca+‐sensing receptor (CaSR), which then upregulates Claudin‐14 (CLDN14), a protein that normally binds to and inhibits Claudin 16 and ‐19. CaSR controls the production of Claudrin 14 by the calcineurin‐NFATc1‐microRNA pathway. NFAT: nuclear factor of activated T cells.
Figure 1.7 Countercurrent mechanism: reabsorption of sodium (Na+) with relative resistance to the reabsorption of water by the thick ascending limb of the loop of Henle leads to generation of the interstitial osmotic gradient; the gradient is higher for the longer loops of the juxtamedullary nephrons, which travel deeper into the medulla. H2O, water; NaCl, sodium chloride.
A higher concentration of Na
+
in the interstitium leads to higher interstitial osmotic pressure, with the highest osmotic pressure developed in tips of medullary pyramids where the longer loops of Henle reach.
The tubular fluid leaving the TAL is hypotonic because of excess water in comparison to Na
+
.
The creation of this gradient helps in the reabsorption of water in the medullary CD under the influence of vasopressin, with water moving from the hypo‐osmolar tubular environment to the hyper‐osmolar medullary interstitium.
Clinical Notes
Can Frusemide Lead to Hyponatraemia?
Frusemide acts by interrupting the Na+ uptake in the TAL by the Na+‐K+ ‐2Cl− transporter. This interferes with the countercurrent mechanism and the generation of the medullary interstitial osmotic gradient. As discussed, without this gradient, ADH cannot reabsorb water in the medullary CD. Thus, frusemide leads to the excretion of a dilute urine which would prevent the development of hyponatraemia.
Distal Convoluted Tubule and Collecting Duct
The distal convoluted tubule (DCT) is responsible for the reabsorption of 5% of Na+ by the thiazide‐sensitive sodium chloride (NaCl) cotransporter. Between 10% and 15% of the Ca+ is also reabsorbed in this segment in an active process, unlike the more passive process in the proximal parts (70% of Ca+ is co‐transported passively with Na+ in the PCT). Ca+ enters tubular cells via the transient receptor potential vanilloid 5 (TRPV5) channel, and 5–10% of the total Mg+ reabsorption also occurs in this segment by the transient receptor potential melastatin 6 (TRPM6) and TRPM7 channels.
The CD is responsible for reabsorption of up to 2% of the Na+ and water, but this can vary depending on the needs of the body. The two chief types of cells found in the CD are:
Principal cells, which are responsible for Na
+
reabsorption and K
+
secretion (under the influence of aldosterone) and water reabsorption (under the influence of ADH).
Intercalated cells, which are responsible for the secretion of H
+
(by alpha‐intercalated cell) or HCO
3
−
(by beta‐intercalated cell).
ADH
ADH is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and travels down the pituitary stalk to be stored in the posterior pituitary. Secreted in response to decreased intravascular volume or increased plasma osmotic pressure as in dehydration, the main physiological effects of ADH are retention of water by the kidneys and vasoconstriction.
Figure 1.8 Anti‐diuretic hormone (vasopressin), acting through cyclic adenosine monophosphate (cAMP), increases the total number of aquaporin‐2 molecules in the principal cells of the collecting duct; aquaporin‐2 aids in water reabsorption in this part of the renal tubule. H2O: water.
There are three types of ADH receptors: V1A, V1B, and V2. V1A receptors cause vasoconstriction by increasing vascular smooth muscle intracellular Ca+ concentration, whilst V1B receptors lead to adrenocorticotropic hormone (ACTH) release by the pituitary gland. V2 receptors are found on the principal cells in the CD and via the cyclic adenosine monophosphate (cAMP) pathway lead to movement and fusion of the aquaporin 2 (AQP2) water channels to the luminal membrane (Figure 1.8). The medullary osmotic gradient established due to the selective reabsorption of Na+ in the TAL helps in the water being reabsorbed in the CD.
Aldosterone
Aldosterone is secreted by the zona glomerulosa of adrenal cortex and helps in Na+ reabsorption and K+ and H+ excretion by the distal portions of the tubules. On binding to the mineralocorticoid receptor, aldosterone upregulates and activates the basolateral Na+‐K+‐ATPase in the principal cells, causing lower intracellular Na+, and at the same time upregulates
