Mednotes

L1 Renal Introduction to the Renal Module

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tagsrenal, lecture
aliasesL1 Renal Introduction to the Renal Module

20 min read

Overview

An orientation lecture for the third year Renal module. It sets out what the module expects you to master (renal anatomy, physiology and pathophysiology, and the link between physiological change and clinical presentation), then walks through the normal physiology that the rest of the module builds on: filtration and sodium handling, autoregulation of glomerular perfusion, tubular sodium entry, the urine concentrating mechanism and aquaporins. It then turns to what happens when the kidney is damaged, using urinalysis and the nephrotic/nephritic continuum as the framework, introduces the two integrated clinical cases (acute glomerulonephritis, and diabetic chronic kidney disease), and finishes with the epidemiology and extra-renal impact of CKD in Aotearoa New Zealand, the module’s links to other modules, and assessment logistics.

Module objectives and framing

  • Understand renal anatomy, physiology and pathophysiology, and link changes in kidney physiology to clinical presentations. This is particularly important in acute kidney injury.
  • Drugs work by correcting pathophysiology. The named examples are ACE inhibitors, ARBs, diuretics and SGLT2 inhibitors.
  • The kidneys are the key regulator of blood pressure and hypertension.
  • Understand the importance of urinalysis, specifically haematuria and proteinuria, in detecting kidney disease, and the importance of proteinuria for the prognosis of both kidney and cardiovascular disease.
  • Glomerulonephritis: understand the basic immunopathology that explains the different clinical presentations.
  • Chronic kidney disease, with diabetic kidney disease as the main example. Know the factors that contribute to progression of kidney disease.
  • CKD is the biggest risk for cardiovascular disease, and has extra-renal manifestations.
  • The module integrates with cardiovascular, metabolic/diabetes and pharmacology teaching. Lecture overviews link to two integrated clinical cases: acute glomerulonephritis, and diabetic kidney disease as progressive CKD.
  • Quoted framing: “To be a good doctor one has to be a good physiologist” (W Hall).

Normal renal physiology: the numbers

  • The kidneys receive a quarter of cardiac output.
  • Filtration is 180 L/day carrying 25,200 mmol Na+/day (1.46 kg of salt).
  • Urine output is 2 L/day containing 100 to 300 mmol Na+/day (17 g of salt).
  • Reabsorption is distributed as 80% proximal tubule, 15% cortical collecting tubule, 5% medullary collecting tubule.
  • Framing quotation (Maurice B Strauss): the evolutionary ascent from sea to salt-poor fresh water “made immense demands upon the glands. Salt must be saved, water is free.”

Structure of the filtering unit

  • Gross structure: kidney with cortex, medulla, calyces, renal pelvis, renal artery, renal vein and ureter; the nephron comprises glomerular capsule, proximal convoluted tubule, nephron loop, distal convoluted tubule and collecting duct. Water and waste are extracted from blood, and urine is concentrated by water absorption through collecting duct cells.
  • The renal corpuscle, viewed into Bowman’s capsule at the glomerular capillary tuft, contains: afferent and efferent arterioles, podocytes, macula densa, juxtaglomerular cells, renal nerve, and the proximal convoluted tubule leaving it. At capillary level the labelled structures are the glomerular basement membrane (GBM), podocyte foot processes and the slit diaphragm.
  • The glomerular filtration barrier is a three-layer barrier that normally prevents protein filtration: fenestrated endothelial cell, GBM, and epithelial (podocyte) foot processes. Protein is excluded at this barrier.

Glomerular filtration and autoregulation

Filtration pressures across the glomerular capillary:

ComponentValue
Mean glomerular capillary pressure45 mmHg
Intracapsular pressure10 mmHg
Mean hydrostatic pressure gradient35 mmHg
Mean colloid osmotic pressure25 mmHg
Mean pressure driving ultrafiltration10 mmHg
  • Because the net driving pressure is only 10 mmHg, minor changes in perfusion pressure can reduce GFR. Perfusion pressure is therefore closely regulated despite changes in systemic pressure: autoregulation.
  • Mechanisms preserving kidney function:
    • Vascular changes in the glomeruli (vasoconstriction and vasodilation) giving fine control of filtration pressure, via myogenic responses and juxtaglomerular cells.
    • Tubuloglomerular feedback: changes in Na+ delivery are sensed by the macula densa.
    • Hormonal and neural: renin to angiotensin II and the sympathetic nervous system in the short term; aldosterone in the long term.
    • These mechanisms are to be linked to clinically observed changes in kidney function: oliguria, blood pressure and urinary sodium excretion.
  • Autoregulation curve (intraglomerular pressure against mean arterial pressure, gridlines at 80, 120 and 160 mmHg):
    • Normal: a flat plateau across most of the pressure range, so intraglomerular pressure is held constant.
    • Chronic hypertension with normal renal function: the plateau is shifted right, to higher pressures.
    • Chronic hypertension with chronic renal disease: the flat autoregulatory plateau is lost and the curve rises with arterial pressure, so intraglomerular pressure tracks systemic pressure.

Tubular sodium handling

  • The gradient for reabsorption is established by the active Na+ ATPase on the basolateral surface of tubular epithelial cells. This is an obligatory requirement for oxygen and energy.
  • Apical (luminal) Na+ entry mechanisms by segment:
    • Proximal tubule: two Na+ entry routes, one coupled to H+ exit.
    • Loop of Henle: Na+/K+/2Cl- symporter, with K+ exit.
    • Distal tubule: Na+/Cl- symporter.
    • Collecting tubule: selective Na+ channel, plus a K+ channel.
  • With the exception of the selective Na+ channels in the collecting tubules, Na+ reabsorption in the more proximal segments is linked to the reabsorption or secretion of other solutes.
  • Thick ascending limb in detail: apical Na+/2Cl-/K+ symporter (NKCC2) brings Na+, Cl- and K+ into the cell, with K+ leaking back into the lumen; basolateral Na+/K+-ATPase pumps 3 Na+ out and 2 K+ in, alongside a K+/Cl- cotransporter. The lumen-positive potential created drives a paracellular pathway carrying Na+, K+, Ca2+ and Mg2+. NKCC2 expression in tubular cells is demonstrable by immunohistochemistry.
  • Frusemide acts here: it blocks the apical Na+/2Cl-/K+ symporter and thereby also the paracellular cation reabsorption that the symporter drives.

Urine concentrating mechanism

  • The countercurrent mechanism runs across cortex, outer medulla and inner medulla, with countercurrent exchange in the vasa recta.
  • Descending limb: NaCl and water movement, water via AQP1.
  • Descending vasa recta: AQP1 and UT-B.
  • Cortex: NCC (TSC) transporter moving Na and Cl, urea handling, and water exit via AQP2 and AQP3.
  • Outer medulla: K+/ROMK1 channel and the Na/K/2Cl symporter (NKCC2/BSC1), with urea handling.
  • Inner medulla: NaCl/ClC-K1 channel, UT-A1 and UT-A3 urea transporters, Na and urea handling, water exit via AQP2 to AQP4, and urea recycling.
  • The thick ascending limb reabsorbs NaCl without being water permeable, which concentrates the interstitium.

Aquaporins

  • Aquaporins are membrane-inserted water channel proteins and the main route of transmembrane water movement.
  • Nine different aquaporins have been described; AQP1 to AQP4 are present in the kidney.
  • AQP1: apical and basolateral membranes of the proximal tubule, and the descending vasa recta.
  • AQP2: normally expressed in the principal cells of the cortical and medullary collecting duct, localising apically and subapically.
  • Regulation of AQP2-mediated water transport by arginine vasopressin (AVP), which is antidiuretic hormone, in the collecting duct principal cell:
    1. AVP binds the V2 receptor on the basolateral membrane.
    2. Gαs activates adenylate cyclase.
    3. cAMP is generated.
    4. cAMP activates protein kinase A.
    5. PKA phosphorylates phosphoproteins.
    6. AQP2-containing vesicles traffic to and insert into the apical membrane.
    7. Water moves from lumen into the cell through apical AQP2 and out across the basolateral membrane through AQP3 and AQP4 into the interstitium.

Detecting kidney damage: urinalysis

  • What the module asks: the pathophysiology of acute and chronic kidney injury, the clinical presentations of both, and the impact of CKD, especially its integration with the cardiovascular module.
  • Nephrology is an ancient specialty: historical uroscopy (physicians examining urine flasks, the urine wheel for diagnosing disease by urine colour) and a first century quotation from Pliny the Younger noting that “bloody urine is a bad sign”.
  • Urine dipstick analysis, microscopy and proteinuria are part of a routine clinical examination. Dipstick colour reaction zones are read against a reference chart; blood-tinged urine is visible macroscopically in more marked cases.
  • Glomerular haematuria: red blood cells are seen within the glomerular capillaries and Bowman’s space on histology.

Renal syndromes: a continuum

Nephrotic and nephritic syndromes lie on a continuum rather than being discrete entities.

  • Nephrotic syndrome: hypoalbuminaemia, oedema, proteinuria > 3 g/24 hr, hyperlipidaemia. Renal function is often normal.
  • Nephritic syndrome: haematuria, oliguria, acute kidney injury, hypertension.

Clinical case 1: acute glomerulonephritis

  • Presentation: an 18 year old with macroscopic haematuria, decreased urine output (oliguria), periorbital oedema and hypertension, on a background of skin infections.
  • The background skin infection is impetigo: pustular lesions with crusting, shown on the hand and face.
  • This is acute nephritic syndrome (haematuria, oliguria, oedema, hypertension with acute kidney injury). The case asks you to explain the mechanisms of the oliguria, the hypertension, the oedema and the acute kidney injury.
  • Histology: acute proliferative glomerulonephritis with intraluminal leukocytes, and immunofluorescence showing granular IgG and C3 deposition, compared against a normal glomerulus.
  • Pathophysiology sequence for acute nephritic syndrome:
    1. Glomerular injury.
    2. Directly produces haematuria, proteinuria and a fall in GFR.
    3. Glomerular injury also activates RAAS, the sympathetic nervous system and AVP.
    4. That activation causes sodium retention.
    5. Sodium retention causes hypertension, and causes water retention.
    6. Water retention causes oedema, oliguria, and a raised JVP with cardiomegaly.
  • Learning points: presentation of glomerulonephritis; impact of socio-economic determinants of health on presentation; mechanisms of immune mediated injury (linked to the GN lecture); mechanisms and pathophysiology of acute kidney injury as it applies to this presentation; comparison with second year case 1 (hypotension and oliguria after a motor vehicle accident); and the link to acute kidney injury pathophysiology.

Nephrotic syndrome mechanism

  • The lesion is injury to the podocytes in the glomeruli. The glomerular filtration barrier is altered, causing proteinuria. There is no proliferative response, so kidney function is often normal at presentation.
  • Oedema formation, understood through Starling’s law, has two converging arms from glomerular disease:
    • Oncotic arm: increased filtration of proteins, then proteinuria, then hypoalbuminaemia, then decreased plasma oncotic pressure.
    • Hydrostatic arm: sodium retention (driven by tubular Na handling, SNS and RAAS, and reinforced by perceived low arterial perfusion pressure), then plasma volume expansion, then increased capillary hydrostatic pressure, with blood pressure low to normal.
    • Both arms converge on water movement from the intravascular to the interstitial space, producing oedema.

Warning

Two slides in this lecture (the “Kidneys working! - How?” slide and the “Testing for peripheral oedema” slide) carry only illustrative photographs with no figure content, so no diagram detail could be transcribed from them. The text points above are taken from the slide text itself.

Clinical case 2: chronic kidney disease due to diabetes

  • Chronic kidney disease due to diabetes, integrating with other modules as Cardiovascular-Kidney-Metabolic Syndrome.
  • Key distinction, macrovascular versus microvascular disease:
    • Macrovascular: ischaemic heart disease, peripheral vascular disease, cerebrovascular disease.
    • Microvascular: retinopathy, neuropathy (peripheral and autonomic), nephropathy.
  • Impact of diabetes on the community and the individual, including ethnic differences for Māori and Pacific peoples, and the extra-renal manifestations of CKD.
  • Natural history of diabetic nephropathy, in order:
    1. Hyperglycaemia (with retinopathy branching off at this point).
    2. Increased glomerular filtration rate.
    3. Microalbuminuria.
    4. Frank proteinuria. (Steps 2 to 4 span 5 to 10 years.)
    5. Decreased glomerular filtration rate.
    6. Possible development of nephrotic syndrome.
    7. End stage renal disease.
  • Impact and management themes: hypertension, the importance of proteinuria, cardiovascular risk, and bone health (calcium, vitamin D, parathyroid hormone); management of CKD to slow progression, linked to evidence based medicine; the role of ACE inhibitors and ARBs for hypertension and proteinuria; the role of glycaemic control; SGLT2 inhibitors in both diabetic and non-diabetic kidney disease; and goal directed medical therapy.
  • Clinical demonstration: a case on Kura Cloud (course 2026d3_Renal) linking the acute nephritic presentation with subsequent progression of CKD due to diabetes. It must be reviewed before Friday June 5th, ahead of an interactive lecture that afternoon. It will not be recorded because it contains patient information.

Epidemiology and burden of CKD

  • Global prevalence of CKD is 14.3%, and CKD is projected to be the 5th leading cause of death by 2030.
  • Prevalence of CKD in Otago Southland is 12%. Odds ratio for CKD is 1.56 for Māori and 2.62 for Pacific peoples. Prevalence is 33% among Samoans in Auckland and 24% among Māori.
  • Risk stratification in an Australian or New Zealand healthy adult community: increased risk 1 in 3, CKD 1 in 7, on dialysis or transplant 1 in 1400.
  • In New Zealand, 16% of adults over 25 years have protein or blood in the urine or a moderately severe reduction in kidney function: GFR < 60 mL/min in 7.5%, albumin in urine 6.6%, blood in urine 2.5%.
  • KDIGO risk classification: a heat map with GFR categories G1 (normal or high, ≥ 90 mL/min/1.73m²) through G5 (kidney failure, < 15) as rows, and albuminuria categories A1 (normal to mildly increased, < 30 mg/g), A2 (moderately increased, 30 to 299 mg/g) and A3 (severely increased, ≥ 300 mg/g) as columns. Cells are colour-coded from green (low risk, not CKD if no other markers of kidney disease) through yellow (moderately increased risk), orange (high risk) to red (very high risk), with management intensity rising toward worse GFR plus higher albuminuria: screen, then treat, then treat and refer. The same classification carries a similar risk for cardiovascular disease.
  • CKD predicts all-cause death (age standardised per 100 person years, HMO population, n = 1,120,295 adults, median follow-up 2.8 years, Go et al. NEJM 2004), rising sharply as eGFR falls:
eGFR (mL/min/1.73m²)Rate of death
> 600.76
45-591.08
30-444.76
15-2911.36
< 1514.14
  • Extrarenal manifestations of CKD: increased cardiovascular risk; normochromic normocytic anaemia; renal bone disease with alterations in Ca2+, PO43-, parathyroid hormone and vitamin D metabolism.

Kidney replacement therapy in Aotearoa New Zealand

  • Incidence of KRT 1993 to 2022 rose from 231 new patients (65 per million population) in the early 1990s through 320 (85), 462 (117), 468 (111), 524 (119), 628 (130) to 682 (133) near 2022, peaking around 700 with a slight late dip, while the national population rose from about 3.5 to about 5 million.
  • Unadjusted incident KRT rate by ethnicity, 2002 to 2022: Pasifika highest, rising from roughly 250 to 300 per million to peaks around 350 to 400+; Māori intermediate at roughly 200 to 270; non-Māori non-Pasifika lowest and flattest at roughly 70 to 95 throughout.
  • Primary cause of kidney disease in new KRT patients, 2022, New Zealand versus Australia: diabetic kidney disease approximately 50% vs 40% (the largest single category in New Zealand); glomerular disease 19% vs 18%; hypertension/renal vascular 9% vs 12%; familial/hereditary 6% vs 7%; tubulointerstitial disease 6% vs 8%; other systemic diseases 3% vs 3%; miscellaneous kidney disorders 7% vs 13%; not reported 1% vs 2%.
  • Comorbid conditions at KRT entry in New Zealand, 2010 to 2020: coronary disease highest at roughly 30 to 38% and roughly stable or slightly declining; peripheral vascular disease roughly 13 to 22%; lung disease roughly 14 to 24%; cerebrovascular disease lowest and falling from about 18% to 7 to 10% over the decade.
  • Prevalence of dialysis and transplantation 1992 to 2021: dialysis rose from 674 to 3155 patients (through 935, 1462, 1997, 2395, 2771); transplantation rose from 670 to 2297 (through 821, 1058, 1259, 1490, 1789). Both rose steadily, with dialysis consistently higher.
  • CKD awareness is poor, illustrated by a highway sign reading “emergency 174 km ahead”.

Integration with other modules

  • Immunology and microbiology: glomerulonephritis, urinary tract infection.
  • The renin-angiotensin-aldosterone axis: hypertension, and links to the cardiovascular module including heart failure.
  • Pharmacology: drug action of diuretics, ACE inhibitors and ARBs, re-applying drugs from the cardiovascular module; sodium glucose transporter inhibitors; GLP1 receptor agonists such as semaglutide; mineralocorticoid receptor antagonists such as spironolactone.
  • Pathology: glomerulonephritis.
  • Genetics: autosomal dominant polycystic kidney disease.
  • Gout: tubular transporters of uric acid.
  • Blood: anaemia and erythropoietin.
  • Endocrinology: RAAS and hypertension, parathyroid, vitamin D, calcium and phosphate metabolism.
  • Health economics and ethics: cost of renal replacement therapy, transplant allocation, access to care.
  • Hauora Māori: impact of diabetes and chronic kidney disease. Māori have a two-fold higher incidence of CKD.
  • Pacific health: Pacific peoples have a three-fold higher incidence of CKD.
  • Inequity of access and the social determinants of health.

Module logistics

  • Clinical skills: a video of an integrated clinical examination, and renal visitors in the last week of the module to explore the lived experience of chronic kidney disease and its impact on the individual and family.
  • Assessment: Friday 19th June, a written essay designed to test the ability to integrate physiology, pathophysiology and pharmacology in a relevant clinical setting. It can cover anything within the whole module, and is both summative and formative, with feedback provided on essay scripts. Contact: rob.walker@otago.ac.nz.
  • Some lectures may not be podcast because they contain patient content or are interactive sessions. Critical, examinable information is presented and discussed in these, PDF summaries of key content will be provided, and attendance is strongly recommended.

Self-test

  1. State the daily filtered volume and filtered sodium load, and the corresponding daily urine volume and urinary sodium output.
  2. List the proportions of sodium reabsorption attributed to the proximal tubule, cortical collecting tubule and medullary collecting tubule.
  3. Calculate and explain the mean pressure driving glomerular ultrafiltration from the pressures given, and say why this value matters clinically.
  4. Describe how the autoregulation curve differs between a normal kidney, chronic hypertension with normal renal function, and chronic hypertension with chronic renal disease.
  5. Explain what tubuloglomerular feedback senses and which structure senses it.
  6. List the apical sodium entry mechanism for each of the proximal tubule, loop of Henle, distal tubule and collecting tubule, and state the general rule that distinguishes the collecting tubule from the others.
  7. Explain why the basolateral Na+/K+-ATPase makes tubular reabsorption dependent on oxygen supply.
  8. Predict the effect on paracellular calcium and magnesium reabsorption in the thick ascending limb if frusemide is given, and explain the mechanism.
  9. Describe the steps by which vasopressin increases water reabsorption in the collecting duct principal cell.
  10. State where AQP1 and AQP2 are each expressed in the kidney.
  11. Distinguish nephrotic from nephritic syndrome by their defining features, including the proteinuria threshold.
  12. Describe the pathway from glomerular injury to oedema and oliguria in acute nephritic syndrome.
  13. An 18 year old presents with macroscopic haematuria, oliguria, periorbital oedema and hypertension on a background of skin infection. Name the likely skin condition, the syndrome, and the biopsy findings you would expect.
  14. Explain, using Starling’s law, the two arms that produce oedema in nephrotic syndrome.
  15. Describe the natural history of diabetic nephropathy in order, with the time frame given for its early stages.
  16. Distinguish macrovascular from microvascular complications of diabetes with examples of each.
  17. Describe the two axes of the KDIGO risk classification and how management changes across the grid.
  18. Describe how all-cause death rate changes across eGFR categories, quoting the values at the extremes.
  19. List the extrarenal manifestations of chronic kidney disease.
  20. State the most common primary cause of kidney disease in new KRT patients in New Zealand and its approximate share, and describe how incident KRT rates differ by ethnicity.
  21. Integrative: a patient with long-standing diabetes develops frank proteinuria and a falling GFR. Explain how the physiology covered early in this lecture accounts for their hypertension and oedema, and name the drug classes the module identifies for slowing progression.

Answers

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