Renal acid-base handling

What it normally 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.

  Poison that enzyme or damage the proximal cell and filtered bicarbonate pours into the urine: proximal (type 2) RTA, and exactly what acetazolamide does on purpose.

• 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.

  If that pump fails, or the acid it exports leaks back through a damaged membrane, urine pH does not fall below about 5.5 and no new bicarbonate appears: distal (type 1) RTA.

• 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.

  Lose nephrons and you lose ammonium capacity - the acidosis of chronic kidney disease. And estimating whether ammonium is coming out (the urine anion gap) is how you tell a sick kidney from a sick gut.

• Aldosterone runs acid and potassium out of the same tap. In the principal cell it increases the number and activity of sodium channels (ENaC); sodium leaving the lumen makes the lumen electrically negative, and that negative charge favours secretion of both K+ and H+ after it. Aldosterone also stimulates the H+-ATPase in the neighbouring acid-secreting cell directly.

  Take aldosterone away, or block ENaC, and potassium and acid are retained together: type 4 RTA - the renal tubular acidosis that runs with a high potassium rather than a low one.

What goes wrong

• Proximal (type 2) renal tubular acidosis← from “The glomerulus filters about 4300 mmol of bica…”

  The proximal cell's reclamation machinery fails - enzyme blocked by a drug, or transporters wrecked by a toxin or light chains. The threshold for holding onto bicarbonate falls from about 24 mmol/L to roughly 15-18. Bicarbonate spills into the urine until plasma bicarbonate drops to that new set point; then reclamation resumes and the acidosis stops getting worse. The distal pump is untouched, so at steady state the urine can still be acidified below pH 5.5 (though it is alkaline while bicarbonate is still spilling, and after a bicarbonate load). Bicarbonate reaching the distal nephron is a poorly reabsorbed anion that increases distal K+ secretion, so potassium falls. Whatever damaged the cell rarely stops at bicarbonate - glucose, phosphate, urate and amino acids leak too (Fanconi syndrome).

  Type 2 is a leaky proximal tubule with a low bicarbonate set point. Glycosuria with a normal blood glucose is the giveaway. The acidosis is usually mild and self-limiting; alkali has to be given in much larger amounts than in type 1 because most of it is filtered straight back out, and because that spilled bicarbonate worsens the hypokalaemia, potassium replacement goes with it.

  You would find: Hyperchloraemic (normal anion gap) acidosis that plateaus around bicarbonate 15-18 and goes no lower, with hypokalaemia, glycosuria despite a normal blood glucose, low phosphate and low urate. Adults: myeloma light chains, tenofovir, ifosfamide, valproate, acetazolamide, topiramate. Children: cystinosis, presenting as failure to thrive and rickets.

• Distal (type 1) renal tubular acidosis← from “New bicarbonate is made further down, in the a…”

  The alpha intercalated cell cannot pump H+ out, or the acid leaks straight back through a damaged luminal membrane. No H+ exported means no new bicarbonate generated, so the daily acid load accumulates with nothing to stop it - bicarbonate can fall below 10 mmol/L. Urine stays above pH 5.5 while the blood is frankly acidotic. The lumen-negative voltage that H+ secretion would have dissipated instead drives K+ secretion, and sodium wasting with secondary aldosteronism adds to it, so potassium falls. Alkaline urine, calcium released from bone buffering the acid, and low urinary citrate together make calcium phosphate stones and nephrocalcinosis. Bone is the buffer, so children stop growing and adults get osteomalacia.

  Type 1 cannot acidify the urine even when frankly acidotic. Alkaline urine plus hypokalaemia plus stones plus severe acidosis. Type 2 spills bicarbonate but can still acidify once plasma bicarbonate has fallen below its set point - that is the split.

  You would find: Normal anion gap acidosis, potassium low, urine pH stuck above 5.5, and nephrocalcinosis or recurrent calcium stones on ultrasound. Look for Sjogren syndrome or SLE in a middle-aged woman, or the drugs: amphotericin B forms pores in the luminal membrane so acid leaks back; also lithium, and topiramate, which inhibits carbonic anhydrase and impairs both proximal reclamation and distal acidification (often an incomplete distal RTA).

• Type 4 RTA (hyporeninaemic hypoaldosteronism)← from “Aldosterone runs acid and potassium out of the…”

  Aldosterone is low, or the tubule cannot hear it. Sodium entry through ENaC falls, the lumen loses its negative charge, and K+ and H+ both stay in. The hyperkalaemia then does most of the damage: potassium loading switches off glutamine metabolism in the proximal cell, ammonium production collapses, and there is little buffer left to carry acid out of the body. The H+ pump itself still works, so the urine can still go below pH 5.5 - there is simply not enough buffer for it to titrate. That is why the acidosis is mild.

  The RTA that runs with a high potassium instead of a low one. Diabetic nephropathy plus an ACE inhibitor. Mild acidosis, acid urine, high K+ - and note the direction of causation: the hyperkalaemia is a major cause of the acidosis by shutting off ammoniagenesis.

  You would find: The commonest RTA you will actually meet. A type 2 diabetic with CKD stage 3: potassium 5.7, bicarbonate 19, normal anion gap, urine pH 5.0. There is nearly always a drug in the picture - ACE inhibitor or ARB, spironolactone, trimethoprim, NSAID, heparin, or a calcineurin inhibitor.

• Metabolic acidosis of chronic kidney disease← from “Free H+ cannot carry the acid load on its own …”

  Nephrons are lost, and the proximal cells that make ammonium go with them. Surviving nephrons each make more, but below about eGFR 30 total ammonium excretion no longer keeps up with the roughly 1 mmol/kg/day of acid generated from protein metabolism. Early on this is largely a normal anion gap acidosis - ammonium failure. As eGFR falls further (broadly below 15-20), sulfate, phosphate, urate and hippurate are retained as well and the anion gap widens. Some of the retained acid is buffered by bone mineral, and the acidosis itself accelerates muscle protein breakdown.

  Starts as normal anion gap (failed ammoniagenesis), becomes high anion gap (retained anions) as GFR falls. It is associated with bone loss and muscle wasting, which is why persistent acidosis is treated rather than ignored - but be honest about the evidence: small early trials suggested alkali slows CKD progression, while the larger BiCARB trial in older adults found no benefit on physical function or kidney outcomes (BASE was only a small dose-finding pilot), so guidelines have become more conservative (KDIGO 2012 aimed to keep bicarbonate at or above 22; KDIGO 2024 suggests supplementing when it is persistently below about 18).

  You would find: Bicarbonate drifting to 18-20 in stage 4 CKD, with muscle wasting and worsening bone disease. In Australia kidney failure falls hardest on Aboriginal and Torres Strait Islander people, who reach kidney failure at several times the national rate and far more than that in remote central Australia - so in a remote clinic this is a routine finding, not a curiosity.

• Diarrhoea - the same blood gas, an innocent kidney← from “Free H+ cannot carry the acid load on its own …”

  Intestinal and pancreatic secretions are rich in bicarbonate. Losing them fast (gastroenteritis, a high-output stoma, an ileal fistula) strips base out of the body without touching the kidney at all. The kidney then does exactly what it was built to do: it ramps up ammoniagenesis and floods the urine with NH4+. Potassium is lost in the stool, and volume depletion drives aldosterone at the same time, so potassium falls too.

  neGUTive: a negative urine anion gap points to the gut, a positive one points to the tubule. Learn it once, and remember it fails when urine sodium is low or another unmeasured anion is present.

  You would find: Normal anion gap acidosis with hypokalaemia - numbers identical to type 1 or type 2 RTA. The urine anion gap separates them: (urine Na+ + urine K+) minus urine Cl-. Negative means a big unmeasured cation, i.e. ammonium, is being excreted - the kidney is working, so the base was lost from the gut. Positive means little ammonium is coming out - it is an RTA. Urine pH can be misleadingly high in diarrhoea because all that ammonium buffers the urine, which is why the anion gap beats the pH. Caveats that matter: the urine anion gap is unreliable if urine sodium is low (under about 20 mmol/L, i.e. marked volume depletion), if there is a high anion gap acidosis, or when another unmeasured anion is being excreted with the ammonium (ketones, D-lactate, hippurate from toluene sniffing) - in those settings the urine osmolar gap is the better estimate of ammonium.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.