Renal Physiology
1. What this chapter covers, and how NEET PG actually tests it
Renal physiology rewards one specific habit: locating the segment.
The nephron is a series of compartments, each with its own transporters, its own permeability to water, its own diuretic and, often, its own genetic disease.
Once you know which segment a question concerns, the electrolyte pattern follows automatically, because each transporter's failure produces a predictable set of losses.
The most efficient illustration is that a loop diuretic and a thiazide have opposite effects on calcium. That is not a fact to memorise separately — it falls out of how calcium is reabsorbed in the two segments they act on.
This chapter covers glomerular filtration and its regulation, tubular transport segment by segment, the countercurrent concentrating mechanism, and acid-base and potassium handling.
| In scope here | Deliberately out of scope |
|---|---|
| GFR, clearance, filtration fraction, autoregulation | Glomerulonephritis histology (see Pathology) |
| Segmental transporters, diuretic sites, tubular syndromes | Dialysis and transplantation (see Medicine) |
| Countercurrent multiplication and exchange, urine concentration | Detailed diuretic pharmacokinetics (see Pharmacology) |
| Bicarbonate handling, ammoniagenesis, renal tubular acidoses | Acid-base disorders of respiratory origin (see Biochemistry) |
2. Glomerular filtration
2.1 The measurements and what each requires
Renal blood flow is roughly 1100 mL per minute, about a fifth of cardiac output, and renal plasma flow is roughly 625 mL per minute.
Glomerular filtration rate is about 125 mL per minute, so the filtration fraction — filtration rate divided by plasma flow — is around 0.2.
Clearance is defined as the volume of plasma cleared of a substance per unit time:
Which substance you choose determines what the clearance measures, and the choice depends on how the kidney handles it.
Inulin is freely filtered and neither reabsorbed nor secreted, so its clearance equals the glomerular filtration rate exactly.
Creatinine is freely filtered but slightly secreted, so creatinine clearance modestly overestimates the filtration rate — a systematic error worth knowing rather than an inaccuracy.
Para-aminohippuric acid is both filtered and extensively secreted, so nearly all of it is removed in one pass. Its clearance therefore approximates renal plasma flow.
2.2 Why afferent and efferent constriction do opposite things
The glomerulus sits between two resistance vessels, and their effects on filtration are opposite because they are on opposite sides.
Constricting the afferent arteriole reduces inflow, so both plasma flow and filtration rate fall.
Constricting the efferent arteriole obstructs outflow, so pressure inside the glomerulus rises. Plasma flow falls but filtration rate rises, and the filtration fraction therefore increases.
This is the physiological basis of two well-known drug effects.
Prostaglandins dilate the afferent arteriole, so NSAIDs constrict it and reduce filtration, particularly when renal perfusion is already marginal.
Angiotensin II constricts the efferent arteriole, so ACE inhibitors dilate it and reduce filtration pressure — protective in diabetic nephropathy by lowering intraglomerular pressure, but dangerous when that pressure was the only thing sustaining filtration.
2.3 Autoregulation and tubuloglomerular feedback
Filtration is held remarkably constant across a wide range of arterial pressures, by two mechanisms.
The myogenic response is intrinsic to vascular smooth muscle: a rise in pressure stretches the afferent arteriole, which contracts.
Tubuloglomerular feedback is the more examinable one.
The macula densa, at the junction of the thick ascending limb and its own glomerulus, senses the sodium chloride concentration of the tubular fluid.
A high concentration signals that filtration is excessive, and the macula densa releases adenosine, which constricts the afferent arteriole and reduces filtration.
A low concentration does the opposite and additionally stimulates renin release.
The elegance is that the sensor and the vessel it controls belong to the same nephron, so each nephron regulates its own filtration independently.
3. Tubular transport, segment by segment
3.1 The proximal convoluted tubule
The proximal tubule reabsorbs the bulk of everything: roughly 65% of filtered sodium and water, essentially all glucose and amino acids, and 80 to 90% of bicarbonate.
Reabsorption here is isotonic, because water follows solute freely.
A generalised failure of this segment is Fanconi syndrome, which produces glycosuria with normal blood glucose, aminoaciduria, phosphaturia and proximal renal tubular acidosis together — the combination reveals the segment rather than any single transporter.
Acetazolamide acts here by inhibiting carbonic anhydrase, blocking bicarbonate reabsorption.
3.2 The loop of Henle
The thin descending limb is permeable to water but not to solute, so fluid within it becomes concentrated as it descends into the hypertonic medulla.
The thick ascending limb is the reverse: it actively transports sodium chloride out via the sodium-potassium-2-chloride cotransporter but is impermeable to water.
So fluid leaving the loop is dilute, which is why this segment is called the diluting segment.
Loop diuretics block that cotransporter, and this creates a second, less obvious effect.
The cotransporter's activity generates a lumen-positive potential that drives paracellular reabsorption of calcium and magnesium.
Abolishing it therefore increases calcium excretion, which is why loop diuretics are used in hypercalcaemia and why they can cause hypocalcaemia.
Bartter syndrome is a genetic defect of the same cotransporter, so it behaves like a lifelong loop diuretic — hypokalaemic metabolic alkalosis with hypercalciuria.
3.3 The distal convoluted tubule
The distal tubule reabsorbs sodium through the sodium-chloride cotransporter, blocked by thiazides, and is also impermeable to water.
Calcium here is reabsorbed transcellularly and under parathyroid hormone control, by a completely different route from the loop.
Blocking sodium entry lowers intracellular sodium, which enhances basolateral sodium-calcium exchange and therefore increases calcium reabsorption.
So thiazides reduce calcium excretion, the exact opposite of loop diuretics, which is why they are used to prevent calcium stones and can cause hypercalcaemia.
Gitelman syndrome is the corresponding genetic defect, behaving like a lifelong thiazide — hypokalaemic alkalosis with hypocalciuria and hypomagnesaemia.
Bartter and Gitelman are best learned as the pair that mirrors the two diuretics, since the calcium direction distinguishes them cleanly.
3.4 The collecting duct
Two cell types share this segment.
Principal cells reabsorb sodium through the epithelial sodium channel and secrete potassium through ROMK, both under aldosterone control.
Amiloride and triamterene block the channel directly; spironolactone blocks the mineralocorticoid receptor upstream.
Liddle syndrome is a gain-of-function mutation of the same channel, so sodium is reabsorbed regardless of aldosterone.
The result is hypertension with hypokalaemia and metabolic alkalosis, but with low renin and low aldosterone — because the channel is active without needing them.
That suppressed aldosterone is what distinguishes Liddle syndrome from primary hyperaldosteronism, which produces an otherwise identical picture.
Intercalated cells handle acid-base. Alpha cells secrete hydrogen ions and generate new bicarbonate; beta cells secrete bicarbonate when needed.
This segment is also where antidiuretic hormone acts, inserting aquaporin-2 channels to permit water reabsorption.
4. Concentrating the urine
4.1 Countercurrent multiplication
Producing urine more concentrated than plasma requires a hypertonic medullary interstitium, and the loop of Henle builds it.
The single effect is the thick ascending limb pumping sodium chloride into the interstitium without water following.
That alone creates only a small osmotic gradient at any level. Multiplication comes from the countercurrent arrangement: fluid descending encounters progressively more concentrated interstitium, so the small step is repeated and compounded along the length of the loop.
The result is a gradient rising from about 300 mOsm at the corticomedullary junction to roughly 1200 mOsm at the papilla.
Longer loops build a steeper gradient, which is why species and individuals with more juxtamedullary nephrons concentrate urine more effectively.
4.2 Urea and the vasa recta
Urea contributes substantially to the medullary gradient rather than merely being waste.
Antidiuretic hormone increases urea permeability in the inner medullary collecting duct, so urea moves into the interstitium and is recycled back into the loop.
This is why a low-protein diet impairs urinary concentrating ability — less urea means a weaker gradient.
The vasa recta must supply the medulla without dissolving the gradient it just built.
Their hairpin arrangement solves this by countercurrent exchange: solute entering the descending limb passes back out of the ascending limb, and water does the reverse.
Exchange preserves the gradient; multiplication creates it. Keeping those two words distinct is worth doing deliberately, since questions use them interchangeably as distractors.
Slow blood flow through the vasa recta also protects the gradient, which is why high medullary flow washes it out and impairs concentration.
5. Acid-base and potassium
5.1 How the kidney handles acid
The kidney does two separate jobs, and confusing them causes most errors here.
First it reclaims filtered bicarbonate, almost entirely in the proximal tubule, using carbonic anhydrase. This prevents loss but adds nothing new.
Second it generates new bicarbonate in the distal nephron, by excreting acid.
Acid is excreted in two forms: bound to phosphate as titratable acid, and as ammonium, produced from glutamine in the proximal tubule.
Ammonium is the adjustable component, and ammoniagenesis increases markedly in chronic acidosis. Titratable acid is limited by how much phosphate is filtered.
Note that hyperkalaemia impairs ammoniagenesis, which is a mechanism that becomes important in the next section.
5.2 The renal tubular acidoses
All renal tubular acidoses produce a normal anion gap, hyperchloraemic metabolic acidosis, so the anion gap does not distinguish them. Three features do.
| Type | Defect | Potassium | Urine pH in acidosis |
|---|---|---|---|
| Type 1 (distal) | Cannot secrete hydrogen ions | Low | Above 5.5 — cannot acidify |
| Type 2 (proximal) | Cannot reabsorb bicarbonate | Low | Below 5.5 once serum bicarbonate falls below threshold |
| Type 4 | Hypoaldosteronism | High | Usually below 5.5 |
Type 4 is the one identified instantly, because it is the only renal tubular acidosis with hyperkalaemia.
Its acidosis is largely a consequence of that hyperkalaemia impairing ammonium production, rather than a primary failure of hydrogen ion secretion.
Type 2's urine pH behaviour is initially confusing but follows logically. Bicarbonate is wasted until the serum level falls below the reabsorptive threshold; below that point there is no bicarbonate left to spill, and the distal acidifying mechanism is intact, so the urine can acidify normally.
Type 1 has no such escape, since the defect is in acidification itself. The persistently alkaline urine promotes calcium phosphate stones and nephrocalcinosis, which type 2 does not cause.
5.3 Potassium handling
Potassium is freely filtered, largely reabsorbed proximally and in the loop, and then secreted by principal cells in the collecting duct.
Because the final step is secretion rather than reabsorption, potassium excretion is determined almost entirely by the collecting duct.
Four factors increase secretion: aldosterone, high distal sodium delivery, high tubular flow rate, and alkalosis.
High distal flow is why almost every diuretic causes hypokalaemia — more sodium and more flow reaching the collecting duct both drive potassium out, regardless of where the diuretic acted.
The potassium-sparing agents are the exception precisely because they act at that final segment.
Acid-base status shifts potassium in a reciprocal way. Acidosis moves potassium out of cells and alkalosis moves it in, which is why the measured serum level can mislead about total body stores.
5.4 The kidney's endocrine outputs
Beyond excretion, the kidney secretes three substances, and each failure has a recognisable clinical signature.
Erythropoietin is produced by peritubular interstitial fibroblasts in response to hypoxia.
Its loss in chronic kidney disease produces a normocytic normochromic anaemia that is proportionate to the decline in function and does not respond to iron alone.
Calcitriol is produced by proximal tubular 1-alpha-hydroxylase, stimulated by parathyroid hormone.
Its loss impairs gut calcium absorption, so calcium falls while phosphate rises from reduced excretion — the combination that drives secondary hyperparathyroidism in renal failure.
Renin completes the set, released by juxtaglomerular cells as described earlier.
Notice that renal failure therefore produces anaemia and bone disease as physiological consequences, not as complications, since both organs depend on hormones only the kidney makes.
Fibroblast growth factor 23, released from bone as phosphate rises, adds a further layer by suppressing 1-alpha-hydroxylase, which accelerates the same cycle.
Worked clinical vignettes
Q1. A patient is given a loop diuretic and later a thiazide. Which effect on urinary calcium does each have, and why do they differ?
Pick an option to check your answer.
Show explanation
Solution. In the thick ascending limb, calcium is reabsorbed paracellularly, driven by the lumen-positive potential that the sodium-potassium-2-chloride cotransporter generates. Blocking that transporter abolishes the driving force, so calcium is lost.
In the distal tubule, calcium is reabsorbed transcellularly. Blocking sodium entry lowers intracellular sodium and enhances basolateral sodium-calcium exchange, so more calcium is reabsorbed.
The opposite effects come from the two segments using different mechanisms, not from the drugs themselves. Answer: (b).
Q2. A patient has hypertension, hypokalaemia and metabolic alkalosis, with low renin and low aldosterone. What is the diagnosis?
Pick an option to check your answer.
Show explanation
Solution. Hypertension with hypokalaemic alkalosis suggests excess mineralocorticoid effect, but here both renin and aldosterone are suppressed.
That combination means the sodium channel is active without hormonal stimulation, which is the gain-of-function mutation of Liddle syndrome.
(a) would show a high aldosterone; (b) would show a high renin; (d) causes hypotension or normotension, not hypertension. Answer: (c).
Q3. A patient has a normal anion gap metabolic acidosis with hyperkalaemia and a urine pH of 5.2. Which renal tubular acidosis is this?
Pick an option to check your answer.
Show explanation
Solution. Hyperkalaemia immediately identifies type 4, since types 1 and 2 both cause hypokalaemia.
The mechanism is hypoaldosteronism, and the acidosis arises largely because hyperkalaemia impairs proximal ammoniagenesis rather than because hydrogen ion secretion has failed.
That preserved acidification is why the urine pH is appropriately low, unlike in type 1. Answer: (c).
7. Common exam traps
- Treating creatinine clearance as exactly equal to the filtration rate. It overestimates modestly because creatinine is also secreted.
- Assuming both arteriolar constrictions reduce filtration. Afferent constriction reduces it; efferent constriction raises it and raises the filtration fraction.
- Giving the same calcium answer for loops and thiazides. They act on segments using different calcium mechanisms and therefore have opposite effects.
- Confusing Bartter with Gitelman. Bartter mimics a loop diuretic with hypercalciuria; Gitelman mimics a thiazide with hypocalciuria and hypomagnesaemia.
- Missing suppressed aldosterone in Liddle syndrome. It is what separates it from primary hyperaldosteronism, which otherwise looks identical.
- Mixing up multiplication and exchange. The loop multiplies to create the gradient; the vasa recta exchange to preserve it.
- Forgetting that type 2 renal tubular acidosis can acidify urine. Once serum bicarbonate falls below threshold, the intact distal mechanism works normally.
- Overlooking hyperkalaemia as the fastest way to identify type 4. It is the only renal tubular acidosis that raises potassium.
Summary
- Filtration fraction is filtration rate divided by plasma flow, about 0.2, with a filtration rate near 125 mL per minute.
- Inulin clearance equals the filtration rate exactly, creatinine overestimates it slightly because of secretion, and para-aminohippuric acid clearance approximates renal plasma flow.
- Afferent constriction lowers both flow and filtration; efferent constriction lowers flow but raises filtration and the filtration fraction.
- NSAIDs constrict the afferent arteriole and ACE inhibitors dilate the efferent, which is why both can reduce filtration in vulnerable kidneys.
- Tubuloglomerular feedback uses macula densa sodium chloride sensing and adenosine release to constrict the afferent arteriole of the same nephron.
- The proximal tubule reabsorbs about 65% of sodium and water isotonically, all glucose and amino acids and most bicarbonate; its generalised failure is Fanconi syndrome.
- The thick ascending limb transports salt without water and is the diluting segment; loop diuretics block its cotransporter and increase calcium excretion by abolishing the lumen-positive potential.
- The distal tubule reabsorbs calcium transcellularly, so thiazides reduce calcium excretion — the opposite of loop diuretics.
- Bartter syndrome mimics a loop diuretic with hypercalciuria; Gitelman syndrome mimics a thiazide with hypocalciuria and hypomagnesaemia.
- Collecting duct principal cells reabsorb sodium through the epithelial sodium channel under aldosterone; Liddle syndrome is its gain-of-function mutation, with hypertension but suppressed renin and aldosterone.
- Countercurrent multiplication in the loop creates the medullary gradient up to about 1200 mOsm, and urea recycling contributes to it.
- Countercurrent exchange in the vasa recta preserves the gradient, and slow medullary flow protects it.
- The kidney reclaims filtered bicarbonate proximally and generates new bicarbonate distally by excreting titratable acid and ammonium, the latter being the adjustable component.
- All renal tubular acidoses give a normal anion gap acidosis; type 1 cannot acidify urine, type 2 can once bicarbonate falls below threshold, and type 4 is the only one with hyperkalaemia.
- Potassium excretion is determined at the collecting duct and is increased by aldosterone, distal sodium delivery, high flow and alkalosis, which is why most diuretics cause hypokalaemia.
