Renal system

A fifth of the cardiac output squeezes through two arterioles in series; the pressure between them sets the GFR, and most of the diseases and drugs on this page work by shifting that pressure — until ischaemia lasts long enough to turn a pressure problem into a tissue problem.

What it does

The kidneys take about a fifth to a quarter of everything the heart pumps — roughly 1 litre of blood a minute — but extract only a small fraction of the oxygen in it. That blood is there to be filtered, not to feed the tissue [high flow, low whole-organ oxygen extraction].

Each glomerulus hangs between two arterioles in series: one in (afferent), one out (efferent). Pressure inside the tuft — and therefore the filtration rate (GFR) — is set mainly by the balance of their tone. Squeeze the outflow and pressure rises; open the inflow and pressure rises. Squeeze the outflow hard enough, though, and plasma flow falls so far that GFR falls with it.

Between a mean arterial pressure of roughly 80 and 180 mmHg the kidney holds its own blood flow and GFR nearly constant (autoregulation); the exact lower limit is not a fixed number and sits higher in someone with long-standing hypertension. Two mechanisms do the work: the afferent arteriole tightens when stretched (myogenic response), and the macula densa senses the NaCl concentration of fluid arriving at the end of the thick ascending limb and adjusts afferent tone through adenosine (tubuloglomerular feedback). Locally made prostaglandins buffer the afferent arteriole against constriction — a minor influence in a well-filled person, a decisive one once angiotensin II and sympathetic tone are switched on.

What goes wrong

Prerenal acute kidney injuryAcute tubular necrosis (ischaemic)NSAID kidney injury and the triple whammyGlomerular hyperfiltration and progressive chronic kidney diseaseRenal artery stenosis unmasked by an ACE inhibitor

What we give

Intravenous crystalloid (volume replacement)NSAIDs (non-steroidal anti-inflammatory drugs)ACE inhibitors and angiotensin receptor blockers (ARBs)SGLT2 inhibitors (sodium-glucose cotransporter 2 inhibitors)

A tuft of leaky capillaries wrapped in a three-layered sieve that pushes about 180 litres of plasma water a day into the tubule while holding back nearly all plasma protein and, in health, essentially all cellular elements.

What it does

Blood enters through the afferent arteriole and leaves through a narrower efferent arteriole, so hydrostatic pressure inside the tuft stays high — commonly quoted as 45 to 50 mmHg, with some texts using 60. Bowman capsule pressure and rising plasma oncotic pressure oppose it, leaving a net filtration pressure of only about 10 mmHg. Across the whole kidney that yields a GFR near 125 mL/min, and roughly a fifth of the plasma arriving is filtered (filtration fraction ~0.2).

The sieve has three layers in series: fenestrated endothelium (holes about 70 to 100 nm, covered by a glycocalyx), a type IV collagen and laminin mat (glomerular basement membrane), and the interlocking foot processes of podocytes bridged by slit diaphragms built from nephrin, podocin and NEPH1. Water, electrolytes, glucose, urea and small peptides pass freely. Restriction rises steeply with size from about 7 kDa upwards, and by the size of albumin (about 69 kDa, effective radius ~3.6 nm) the barrier is already holding back the great majority of what arrives.

The barrier also carries fixed negative charge — the endothelial glycocalyx, heparan sulfate proteoglycans in the basement membrane, and sialoproteins such as podocalyxin on the podocyte. Albumin is negatively charged at blood pH, and classical teaching holds that this charge repels it in addition to size restriction.

What goes wrong

Minimal change diseaseNephrotic syndrome — the consequences of the leakFocal segmental glomerulosclerosisDiabetic glomerulopathy

What we give

ACE inhibitors and angiotensin receptor blockersSGLT2 inhibitorsCorticosteroidsLoop diuretics

The workhorse of the nephron: it takes back about two thirds of everything the glomerulus filtered — salt, water, essentially all of the filtered glucose, most of the bicarbonate — before the fluid ever reaches the loop.

What it does

It reabsorbs in bulk, not in fine detail: roughly 65% of the filtered sodium and water. The whole operation is powered by one pump on the blood side of the cell that pushes sodium out (Na+/K+-ATPase), creating a low intracellular sodium that everything else rides on.

All of the filtered glucose is normally reabsorbed here, about 90% of it by a sodium-glucose cotransporter in the first segment (SGLT2, low affinity but high capacity) and the rest by a higher-affinity, lower-capacity one further along in S3 (SGLT1). The system has a ceiling — it saturates once blood glucose passes roughly 10 to 11 mmol/L.

This is where filtered bicarbonate is reclaimed — around 80% of it. The cell secretes H+ into the lumen (sodium-hydrogen exchanger, NHE3); that H+ joins filtered bicarbonate to make CO2 and water under brush border carbonic anhydrase; the CO2 diffuses into the cell, where carbonic anhydrase runs the reaction backwards and the regenerated bicarbonate leaves across the basolateral membrane into the blood.

What goes wrong

Glycosuria and osmotic diuresisFanconi syndrome (generalised proximal tubule failure)Type 2 (proximal) renal tubular acidosisAcute tubular necrosisHyperuricaemia and gout

What we give

SGLT2 inhibitors (gliflozins)Carbonic anhydrase inhibitorsProximal tubular toxinsUricosurics

The hairpin that dives from the cortex into the medulla and comes back: it strips salt out of the urine on the way up and packs that salt into the medulla around it, which is what makes a concentrated urine possible — the loop lays down the salt half of the gradient, and urea recycling supplies much of the rest.

What it does

The thick ascending limb drags salt out of the tubule with one pump sitting on the urine side of the cell (the sodium-potassium-two-chloride cotransporter, NKCC2), and it reclaims about a quarter of all the sodium you filter. The proximal tubule handles more (about two thirds), but nothing downstream of the loop has anything like the capacity to make up what the loop lets through. Because the pump faces the lumen, a drug that blocks it has to reach the tubular fluid first — and since loop diuretics are almost entirely albumin-bound, very little is filtered and they get there mainly by proximal secretion.

The descending limb leaks water but not salt; the ascending limb is the reverse — waterproof, but pumping salt out. Salt leaves without water following, so the fluid climbing up gets dilute while the medulla around it gets salty. The two limbs run side by side in opposite directions, so that small difference is multiplied along the length of the loop (countercurrent multiplication), reaching roughly 1200 mOsm/kg at the papillary tip in humans. Urea recycling from the inner medullary collecting duct contributes a large share of that peak osmolality — conventionally put at about half — so the loop builds the gradient but does not build it alone.

Potassium carried in on the pump leaks straight back into the lumen through a potassium channel (ROMK), leaving the tubular fluid positively charged. That positive charge pushes calcium and magnesium out between the cells rather than through them (paracellular reabsorption, via the claudin-16/19 pore).

What goes wrong

Loss of the medullary gradient (washout)Ischaemic injury of the outer medulla (acute tubular necrosis)Hypokalaemic metabolic alkalosis with calcium and magnesium wastingFluid overload the loop can no longer clear (diuretic resistance)

What we give

Loop diureticsPotassium-sparing diureticsDesmopressinThiazide or thiazide-like diuretic added to a loop diuretic (sequential nephron blockade)

The nephron's fine-tuning segment: it makes the final adjustment to sodium before the collecting duct and sets how much calcium the body keeps — which is why it is where thiazides work.

What it does

It reclaims only about 5 to 7 percent of the filtered sodium, using a carrier that brings sodium and chloride in together from the urine (the sodium-chloride cotransporter, NCC), with the basolateral sodium-potassium ATPase keeping intracellular sodium low so the carrier keeps working.

The wall of the DCT proper is effectively waterproof: it has no ADH-regulated water channels, so salt is pulled out but water cannot follow and the fluid leaving is more dilute than the fluid arriving. (Only at the very end, where it merges into the connecting tubule, does the epithelium begin to respond to ADH.) The DCT, with the thick ascending limb above it, is where dilute urine gets made.

Calcium is let into the cell from the urine through a channel on the surface (TRPV5), ferried across by calbindin, and moved out the back of the cell by a swap that trades three sodiums in for one calcium out (the sodium-calcium exchanger, NCX1) alongside a calcium pump (PMCA). Parathyroid hormone turns the whole process up.

What goes wrong

Primary hypertension (the salt-sensitive component)Idiopathic hypercalciuria and recurrent calcium stonesThiazide-induced hyponatraemiaGitelman syndrome

What we give

Thiazide and thiazide-like diureticsThiazides used for their calcium effectPotassium-sparing diureticsCalcineurin inhibitors

The last stretch of the nephron and the body's final say on urine: ADH decides how much water you keep, aldosterone decides how much salt you keep and how much potassium you throw away.

What it does

Antidiuretic hormone (ADH, also called vasopressin) is the water tap. Released from the posterior pituitary when the blood gets concentrated (and, more powerfully but less precisely, when blood volume falls), it binds V2 receptors on the blood-side membrane of the principal cell and drives water channels (aquaporin-2) into the wall facing the urine. Water then leaves the tubule and returns to the blood. With ADH switched off, almost no aquaporin-2 sits in that wall and the duct is close to waterproof.

Aldosterone is the salt lever. It binds a receptor inside the principal cell and tells it to build more sodium channels (ENaC) in the urine-facing wall and more Na/K pumps on the blood side. Sodium is pulled out of the urine and water follows, so blood volume rises. The negative charge left behind in the tubule then gives potassium the electrical push to leave the cell through ROMK into the urine.

Alongside the principal cells sit intercalated cells. Type A cells pump hydrogen ions into the urine with an H+-ATPase and generate NEW bicarbonate for the blood — note that filtered bicarbonate is reclaimed far upstream in the proximal tubule, not here; type B cells do the reverse and secrete bicarbonate (through pendrin) when the blood is alkaline. This is the last nephron segment where urine acidification is fine-tuned. Aldosterone helps twice over: the lumen-negative voltage from ENaC sodium entry makes H+ secretion easier, and aldosterone stimulates the H+-ATPase directly. But how much acid actually leaves the body is set less by the pump than by how much ammonia is in the urine to buffer the protons — an unbuffered urine bottoms out near pH 4.5 having carried away almost nothing.

What goes wrong

Central diabetes insipidus (arginine vasopressin deficiency, AVP-D)Nephrogenic diabetes insipidus (arginine vasopressin resistance, AVP-R)Syndrome of inappropriate ADH (SIADH)Primary aldosteronism (Conn syndrome)Type 4 renal tubular acidosis (hyporeninaemic hypoaldosteronism)

What we give

Desmopressin (synthetic ADH analogue, V2-selective agonist)Vaptans — V2 receptor antagonists (tolvaptan)Mineralocorticoid receptor antagonists (spironolactone, eplerenone)ENaC blockers — potassium-sparing diuretics (amiloride)

A tiny sensing station where the end of a nephron's own tubule sits against that same nephron's glomerular arterioles — it reads renal perfusion pressure and tubular salt, and releases renin, the switch for the blood pressure and salt-retaining hormone system.

What it does

Granular cells (juxtaglomerular cells) in the wall of the incoming arteriole (afferent arteriole) store renin and release it in response to three main stimuli: pressure inside that arteriole falls, sympathetic nerves fire on their beta-1 receptors, or the tubule beside them delivers less salt.

Renin cuts angiotensinogen from the liver into angiotensin I; angiotensin converting enzyme (ACE), mostly on lung capillary lining, cuts that into angiotensin II. Angiotensin II constricts arterioles and tells the adrenal cortex (zona glomerulosa) to make aldosterone, which drives sodium reabsorption and potassium excretion in the late distal tubule and collecting duct.

Angiotensin II constricts the outgoing arteriole (efferent) harder than the incoming one, which holds pressure up inside the glomerulus. Locally made prostaglandins (PGE2, PGI2) keep the incoming arteriole open.

What goes wrong

Renovascular hypertension (renal artery narrowing)Neurohormonal activation in heart failurePrimary aldosteronismHaemodynamic acute kidney injury (the triple whammy)Diabetic kidney disease and glomerular hyperfiltration

What we give

ACE inhibitors (and sartans where cough prevents use of an ACE inhibitor)Mineralocorticoid receptor antagonistsSGLT2 inhibitorsLoop diuretics

Almost all potassium hides inside cells and the kidney fine-tunes the rest in one short segment under aldosterone — so aldosterone, acid-base and the ECG are three views of the same number.

What it does

About 98% of the body's potassium sits inside cells. That steep gradient across the membrane is what holds nerve and muscle at their negative resting voltage (resting membrane potential).

The kidney filters potassium freely and takes nearly all of it back in the proximal tubule and loop of Henle. The amount that actually leaves the body is decided further downstream, in the late distal tubule, connecting tubule and cortical collecting duct, where aldosterone makes the principal cell pull sodium in through a channel (ENaC), leaving the lumen electrically negative, and that negative lumen drags potassium out through its own channel (ROMK). High tubular flow adds a second, flow-activated potassium channel (BK).

Insulin and adrenaline (through the beta-2 receptor) push potassium into cells by driving the sodium-potassium pump (Na+/K+-ATPase) in muscle. Neither removes any potassium from the body.

What goes wrong

Hyperkalaemia and its ECGToo little aldosterone effect (Addison disease, type 4 renal tubular acidosis)Too much aldosterone effect — hypokalaemia with alkalosisThe diabetic ketoacidosis potassium trap

What we give

Intravenous calcium (calcium gluconate or calcium chloride)Intracellular shift agents — insulin with glucose, and nebulised salbutamolMineralocorticoid receptor antagonists and epithelial sodium channel blockers (potassium-sparing diuretics)Mineralocorticoid replacement — fludrocortisone

The kidney does two separate jobs with acid: the proximal tubule takes back the bicarbonate it filtered, and the collecting duct makes new bicarbonate by pumping H+ out onto urinary buffers, mostly ammonium. Break the first job, the second job, or the ammonium supply, and you get three different renal tubular acidoses.

What it does

The glomerulus filters about 4300 mmol of bicarbonate a day (GFR ~180 L x ~24 mmol/L) and essentially all of it is reclaimed - roughly 80% in the proximal tubule, most of the remainder in the thick ascending limb, and the last few percent distally. Almost none of it crosses the cell as the bicarbonate ion itself. The proximal cell pumps H+ into the lumen on a sodium-hydrogen exchanger (NHE3); that H+ joins a filtered bicarbonate to make carbonic acid; an enzyme on the brush border (carbonic anhydrase IV) splits it to CO2 and water; the CO2 diffuses into the cell, where carbonic anhydrase II rebuilds bicarbonate, which leaves across the basolateral membrane to the blood on the Na+-3HCO3- cotransporter NBCe1. Huge workload, no new base made - the kidney is only breaking even.

New bicarbonate is made further down, in the acid-secreting cells of the collecting duct (alpha intercalated cells). A hydrogen pump (H+-ATPase, with a smaller contribution from H+/K+-ATPase) drives H+ into the urine against a steep gradient - urine can reach pH 4.5 - and every H+ exported leaves a bicarbonate behind, which crosses the basolateral membrane into blood on a chloride-bicarbonate exchanger (band 3, AE1). This is where the roughly 70 mmol of acid a day (about 1 mmol/kg) from diet and metabolism actually leaves the body.

Free H+ cannot carry the acid load on its own - even at pH 5.0 free H+ is only 0.01 mmol/L, a trivial fraction of the daily load. It travels bound to a buffer: about two thirds of net acid excretion leaves as ammonium (NH4+) and about one third as titratable acid, mostly phosphate. The proximal cell burns glutamine to make NH4+, and the leftover carbon skeleton (alpha-ketoglutarate) yields two new bicarbonates for the blood. Acidosis and low potassium switch this on; high potassium switches it off. It needs living proximal tubular cells, so the capacity scales with nephron mass.

What goes wrong

Proximal (type 2) renal tubular acidosisDistal (type 1) renal tubular acidosisType 4 RTA (hyporeninaemic hypoaldosteronism)Metabolic acidosis of chronic kidney diseaseDiarrhoea - the same blood gas, an innocent kidney

What we give

Carbonic anhydrase inhibitorsOral alkali (bicarbonate and citrate salts)Mineralocorticoid replacementENaC blockers (one of them hiding as an antibiotic)

The kidney performs the final activating step of vitamin D and is where parathyroid hormone does much of its work — so the kidney sets the calcium and phosphate the skeleton is built from.

What it does

Essentially all circulating calcitriol is made in the kidney. The liver makes 25-hydroxyvitamin D (the storage form, and the one actually measured), then 1-alpha-hydroxylase in the proximal tubule adds the 1-hydroxyl to make the active hormone 1,25-dihydroxyvitamin D (calcitriol). Calcitriol drives active transcellular calcium absorption in the duodenum. (Macrophages in granulomatous disease can also 1-hydroxylate, which is why sarcoidosis causes hypercalcaemia — but they contribute essentially nothing normally.)

Parathyroid hormone (PTH) does three things at the kidney: it increases calcium reabsorption in the distal convoluted tubule and connecting tubule (via TRPV5), it inhibits phosphate reabsorption in the proximal tubule (it internalises the NaPi-IIa/IIc cotransporters) so phosphate is lost into the urine, and it switches on 1-alpha-hydroxylase.

Phosphate balance is set by the kidney. Roughly 60-70% of dietary phosphate is absorbed, and the kidney excretes essentially all of that absorbed load; the unabsorbed remainder simply passes in the stool (which is exactly what phosphate binders exploit). As nephrons are lost, osteocytes release more FGF23, which — with its co-receptor Klotho — suppresses proximal tubule phosphate reabsorption so each surviving nephron excretes more; FGF23 also switches 1-alpha-hydroxylase off and switches 24-hydroxylase (which degrades calcitriol) on.

What goes wrong

Secondary hyperparathyroidism of chronic kidney diseaseRenal bone disease (renal osteodystrophy)Vascular calcification and calciphylaxisTertiary hyperparathyroidismHypoparathyroidism after neck surgery

What we give

Active vitamin D analoguesPhosphate bindersCalcimimeticsOral calcium salts with an active vitamin D analogue

The kidney is the body's oxygen meter, and erythropoietin is the message it sends to the marrow — so when the kidney scars, nobody tells the marrow to make red cells.

What it does

Peritubular interstitial fibroblast-like cells in the renal cortex and outer medulla measure oxygen and make most of the body's erythropoietin (the liver makes a small amount, and is the main source in the fetus). When oxygen is low, the transcription factor HIF-2 alpha escapes destruction and switches on the erythropoietin gene. When oxygen is normal, prolyl hydroxylase enzymes (PHD1-3) hydroxylate HIF-2 alpha, the von Hippel-Lindau protein then ubiquitinates it and the proteasome destroys it within minutes (the HIF-PHD-VHL oxygen-sensing axis). These interstitial cells sit exactly where the kidney scars.

Erythropoietin travels to the bone marrow and binds its receptor on committed red cell precursors (late BFU-E, CFU-E and proerythroblasts). Its dominant action is survival — it rescues precursors from apoptosis — and it also drives their proliferation and differentiation. Either way it cannot act faster than erythropoiesis itself: reticulocytes take days and a measurable haemoglobin rise takes weeks.

Erythropoietin achieves little without iron to build haemoglobin with. Iron leaves gut enterocytes and macrophages through ferroportin, the only cellular iron exporter so far identified. The liver hormone hepcidin binds ferroportin, occluding it and triggering its internalisation and degradation. Hepcidin rises with inflammation (IL-6) and with iron loading, and it is a small peptide cleared by the kidney, so it climbs in kidney disease.

What goes wrong

Anaemia of chronic kidney diseaseFunctional iron deficiency and erythropoietin resistanceOver-correction: hypertension and thrombosisSecondary polycythaemia (too much erythropoietin)

What we give

Erythropoiesis-stimulating agents (ESAs)Iron replacement, intravenous preferred in CKDHIF prolyl hydroxylase inhibitors (HIF-PHIs)Red cell transfusion

The kidney's core job is filtering plasma, but filtration cannot be seen or directly measured — so we infer it from a muscle waste product in the blood, and read the urine for everything that number misses.

What it does

The two kidneys filter roughly 180 litres of plasma a day and hand almost all of it back. The rate of that filtering (glomerular filtration rate, GFR) is the best overall summary of how much kidney is working — normally about 90 to 120 mL/min/1.73 m2.

Creatine and phosphocreatine in muscle convert to creatinine at a near-constant rate. Creatinine is filtered freely and only a small share (about 10 to 15%) is secreted by the proximal tubule, so the blood level settles where production and clearance balance (creatinine is roughly production divided by GFR).

The glomerulus is a three-layer sieve — fenestrated endothelium, glomerular basement membrane, podocyte foot processes — and its surfaces carry a net negative charge, so it holds back cells and albumin.

What goes wrong

Acute kidney injuryChronic kidney diseaseAlbuminuria in diabetic and hypertensive kidney diseaseGlomerulonephritisA creatinine that rises without any kidney injury

What we give

Non-steroidal anti-inflammatory drugsACE inhibitors and angiotensin receptor blockersSGLT2 inhibitorsTrimethoprim (and, historically, cimetidine)

A 25-30 cm muscular tube that pushes urine to the bladder in waves, is narrow at three points, and reports essentially only stretch — so most of what goes wrong with it is either something blocking it or urine heading the wrong way.

What it does

The renal pelvis has its own pacemaker cells. They fire spontaneously about every 10-30 seconds (roughly 2-6 waves a minute) and send a squeezing wave down the ureter (peristalsis). The wave spreads muscle cell to muscle cell through gap junctions, each contraction driven by calcium entering through L-type calcium channels, and it is turned up by noradrenaline acting on alpha-1 adrenoceptors (alpha-1A and alpha-1D), which are densest in the lower third. At ordinary urine flows the bladder receives boluses rather than a continuous stream; in a large diuresis the ureter fills and flow becomes more continuous.

The tube is narrow at three points: where the renal pelvis funnels into it (pelviureteric junction), where it crosses the pelvic brim over the iliac vessels, and where it tunnels obliquely through the bladder wall (vesicoureteric junction, a few millimetres across and the tightest of the three). In women it runs within about 2 cm of the cervix, passing under the uterine artery.

The last 1-2 cm runs at a slant between the bladder muscle and its lining. There is no true anatomical sphincter here — the pressure of a filling or contracting bladder squashes that tunnel flat against the muscle. It is a one-way flap valve made mostly of geometry.

What goes wrong

Ureteric stone (renal colic)Obstructed infected kidney (infected obstructed system, pyonephrosis)Vesicoureteric reflux and reflux nephropathyPelviureteric junction obstructionExtrinsic obstruction and obstructive acute kidney injury

What we give

NSAIDs (COX inhibitors)Alpha-1A adrenoceptor antagonists (medical expulsive therapy)AminoglycosidesTrimethoprim (low-dose prophylaxis)

A muscular bag that holds urine at low pressure until it is socially convenient, guarded by two taps and emptied through a single tube.

What it does

The bladder wall muscle (detrusor) stretches to hold roughly 400 to 600 mL while the pressure inside barely rises (compliance), then squeezes when parasympathetic nerves from S2 to S4 (pelvic splanchnic) release acetylcholine onto muscarinic receptors. M2 receptors outnumber M3 on the detrusor by roughly three to one, but it is M3 that does most of the contracting, so M3 is the drug target.

There are two taps. The inner one (internal urethral sphincter) is smooth muscle at the bladder neck held shut by noradrenaline on alpha-1 receptors, and it is not under conscious control. The outer one (external urethral sphincter) is striated muscle you hold shut yourself through the pudendal nerve, backed up by the pelvic floor.

Stretch receptors report filling; the pontine micturition centre then runs one coordinated void — the sphincters relax and the detrusor contracts as a single sequence. The frontal cortex vetoes the reflex until you decide otherwise.

What goes wrong

Overactive bladder (urge incontinence)Bladder outlet obstruction and urinary retentionStress incontinenceUrinary tract infection (cystitis)Neurogenic bladder after spinal cord injury

What we give

AntimuscarinicsAlpha-1 blockers5-alpha-reductase inhibitorsUrinary antibiotics