Renal Tubular Disorders
Medicine · Nephrology · lean revision notes
Renal Tubular Disorders
Renal tubular disorders are inherited or acquired defects in tubular transport that produce characteristic electrolyte and acid-base disturbances without significant loss of glomerular filtration. They are a perennial NEET PG favourite because each syndrome has a clean, pattern-based "signature" — a specific acidosis or alkalosis, a potassium derangement, and a diagnostic test (urine anion gap, urine pH, plasma renin/aldosterone). Master the patterns and these become free marks.
Orientation: the two big families
Tubular disorders split conceptually into acid-base defects (the renal tubular acidoses, RTA — types I, II, IV) and salt-wasting / salt-retaining channelopathies (Bartter, Gitelman, Liddle). The RTAs cause a normal anion gap (hyperchloraemic) metabolic acidosis; the channelopathies mostly cause a metabolic alkalosis (except Liddle, which is the salt-retaining odd one out).
High-yield: RTA = normal anion gap (hyperchloraemic) metabolic acidosis. Bartter/Gitelman = hypokalaemic metabolic alkalosis that mimics chronic loop/thiazide diuretic use. Liddle = hypertension + hypokalaemic alkalosis with low renin and low aldosterone.
Renal Tubular Acidosis (RTA) — classification
RTA is a group of disorders where the kidney fails to either reabsorb filtered bicarbonate (proximal/type II) or excrete the daily acid load (distal/type I and type IV), producing a non-anion-gap metabolic acidosis with a normal or near-normal GFR.
| Feature | Type I (Distal) | Type II (Proximal) | Type IV (Hyperkalaemic) |
|---|---|---|---|
| Primary defect | Failure of H⁺ secretion in distal tubule (α-intercalated cell) | Failure of HCO₃⁻ reabsorption in proximal tubule | Aldosterone deficiency / resistance |
| Serum K⁺ | Low (hypokalaemia) | Low / low-normal | High (hyperkalaemia) |
| Urine pH | > 5.5 (cannot acidify) | Variable: > 5.5 when above threshold, < 5.5 once HCO₃⁻ depleted | Usually < 5.5 |
| Plasma HCO₃⁻ (untreated) | Can be very low (< 10) | Moderate (12–18) | Mild (> 17) |
| Urine anion gap | Positive | Positive (variable) | Positive |
| Stones / nephrocalcinosis | Yes (calcium phosphate) | No (rather, rickets/osteomalacia) | No |
| Fanconi syndrome | No | Yes (when generalised) | No |
| Alkali dose needed | Low (1–2 mEq/kg/day) | High (10–15 mEq/kg/day) | Low + manage K⁺ |
High-yield: The single most discriminating bedside value — urine pH > 5.5 in the face of systemic acidosis = distal (type I) RTA. A patient who can drop urine pH below 5.5 has an intact distal acidification mechanism.
Why there is no "Type III"
Type III RTA is a largely obsolete term describing a mixed proximal + distal picture, classically seen in carbonic anhydrase II deficiency (osteopetrosis with RTA and cerebral calcification). It is rarely tested except as a "which type does not exist as a standalone clinical entity" trick.
Type I — Distal RTA
Pathophysiology
The α-intercalated cells of the cortical collecting duct fail to secrete H⁺ (defective H⁺-ATPase, H⁺/K⁺-ATPase, or the basolateral Cl⁻/HCO₃⁻ exchanger AE1/band 3). The kidney therefore cannot lower urine pH below ~5.5 even when the body is profoundly acidotic. Failure to excrete acid → progressive metabolic acidosis; the resulting hypercalciuria and high urine pH precipitate calcium phosphate stones and nephrocalcinosis.
Causes (think: anything that injures the distal nephron)
- Hereditary: AE1, H⁺-ATPase mutations (some with sensorineural deafness).
- Autoimmune: Sjögren syndrome (classic), SLE, rheumatoid arthritis.
- Drugs/toxins: amphotericin B (the prototype — punches holes in the luminal membrane), lithium, ifosfamide.
- Hypercalciuria / medullary sponge kidney, chronic obstruction.
Clinical features
- Children: failure to thrive, rickets, polyuria, recurrent stones.
- Adults: muscle weakness from hypokalaemia (may be severe enough to cause paralysis or arrhythmia), bone pain, recurrent calcium phosphate calculi, nephrocalcinosis.
Diagnosis
- Normal anion gap metabolic acidosis + hypokalaemia + urine pH > 5.5 + positive urine anion gap.
- Confirmatory: ammonium chloride (acid) loading test — fails to acidify urine below pH 5.5. (Furosemide/fludrocortisone test is a modern alternative.)
Management
- Oral alkali — potassium citrate is preferred (corrects both acidosis and hypokalaemia and reduces stone formation); 1–2 mEq/kg/day. Sodium bicarbonate is an alternative but can worsen hypokalaemia.
High-yield: Distal RTA → hypokalaemia + nephrocalcinosis + calcium phosphate stones. Amphotericin B and Sjögren syndrome are the two most-asked causes.
Type II — Proximal RTA
Pathophysiology
The proximal tubule cannot reabsorb the filtered HCO₃⁻ load (defective Na⁺/H⁺ exchanger NHE3, basolateral Na⁺/HCO₃⁻ cotransporter NBCe1, or carbonic anhydrase). Bicarbonate spills into the urine until plasma HCO₃⁻ falls to a new lower threshold (~15 mEq/L), at which point the reduced filtered load can finally be reabsorbed and a new steady state is reached. This is why proximal RTA is self-limiting in severity and rarely causes HCO₃⁻ below ~12.
A key teaching point: once the plasma bicarbonate falls below threshold, the distal nephron is intact, so the patient can acidify urine to pH < 5.5. But when treated with alkali (pushing plasma HCO₃⁻ above threshold), bicarbonaturia resumes and urine pH rises — hence the "variable urine pH."
Fanconi syndrome
When the proximal defect is generalised, it causes the Fanconi syndrome: a global proximal reabsorptive failure with:
- Glycosuria (with normal blood glucose)
- Phosphaturia → hypophosphataemia → osteomalacia / rickets
- Aminoaciduria
- Uricosuria, proximal RTA (bicarbonaturia)
High-yield: Proximal RTA + glycosuria + phosphaturia + aminoaciduria = Fanconi syndrome. Bone disease (rickets/osteomalacia) dominates, not stones.
Causes
- Children: cystinosis (commonest inherited cause of Fanconi syndrome), Wilson disease, galactosaemia, hereditary fructose intolerance, Lowe syndrome, tyrosinaemia.
- Acquired: multiple myeloma (light chains), tenofovir, ifosfamide, acetazolamide (carbonic anhydrase inhibitor — pure proximal RTA), heavy metals (lead, cadmium, mercury), aminoglycosides, valproate, expired tetracyclines, amyloidosis.
Management
- Requires large doses of alkali (10–15 mEq/kg/day) because much is lost in urine; potassium citrate preferred.
- Thiazides can be used (induce mild volume contraction → enhances proximal HCO₃⁻ reabsorption); add phosphate and vitamin D for bone disease.
High-yield: Tenofovir, multiple myeloma, cystinosis (kids) and acetazolamide are the exam's go-to causes of proximal RTA / Fanconi.
Type IV — Hyperkalaemic RTA
Pathophysiology
The unifying mechanism is aldosterone deficiency or aldosterone resistance, reducing distal Na⁺ reabsorption and K⁺/H⁺ secretion. The resulting hyperkalaemia further impairs renal ammoniagenesis, reducing acid excretion → mild non-anion-gap acidosis. Unlike type I, the distal H⁺-ATPase still works, so urine pH is usually < 5.5, but acid excretion is inadequate because of the hyperkalaemia and low ammonium.
Causes
- Diabetic nephropathy with hyporeninaemic hypoaldosteronism (the single commonest cause).
- Drugs: ACE inhibitors/ARBs, spironolactone/eplerenone, amiloride, triamterene, trimethoprim, NSAIDs, heparin, calcineurin inhibitors (ciclosporin, tacrolimus).
- Addison's disease (primary adrenal insufficiency), congenital adrenal hyperplasia.
- Obstructive uropathy, sickle cell nephropathy (aldosterone resistance).
Management
- Fludrocortisone (mineralocorticoid replacement) if hypoaldosteronism; loop diuretics and low-potassium diet to manage hyperkalaemia; stop offending drugs.
High-yield: Type IV is the only RTA with hyperkalaemia. Diabetic with mild hyperchloraemic acidosis + high K⁺ + urine pH < 5.5 = type IV RTA.
The urine anion gap (UAG) — the key investigation
The UAG is a surrogate for urinary ammonium (NH₄⁺) excretion, helping distinguish renal from GI (extra-renal) causes of a normal-anion-gap acidosis.
UAG = (Urine Na⁺ + Urine K⁺) − Urine Cl⁻
- Negative UAG (< 0): high urinary NH₄⁺ → kidney is appropriately excreting acid → cause is extra-renal, classically diarrhoea (think "negative = GI loss, e.g. diarrhea"). Mnemonic: "neGUTive" — negative UAG points to the GUT.
- Positive UAG (> 0): low urinary NH₄⁺ → kidney is failing to excrete acid → RTA (types I and IV both give a positive UAG).
High-yield: Diarrhoea → negative urine anion gap. RTA → positive urine anion gap. The mnemonic "neGUTive" (negative = GUT/diarrhoea) is the fastest recall.
Diagnostic flow for a normal-anion-gap metabolic acidosis
Confirm normal anion gap acidosis → Check serum K⁺ → if high think type IV → if low/normal, calculate urine anion gap → if negative → GI loss (diarrhoea); if positive → distal/proximal RTA → check urine pH: pH > 5.5 → type I; pH < 5.5 (or variable with high alkali requirement + glycosuria) → type II.
Bartter syndrome
A group of autosomal recessive defects in the thick ascending limb of the loop of Henle (TALH) — functionally equivalent to taking a loop diuretic (furosemide) continuously.
Mechanism & genetics
Mutations affect the NKCC2 cotransporter (type 1), ROMK potassium channel (type 2), ClC-Kb chloride channel (type 3), Barttin (type 4, with sensorineural deafness), or CaSR (type 5). Salt wasting → volume depletion → secondary hyperaldosteronism → renal K⁺ and H⁺ loss.
Features
- Presents early (neonatal/childhood), often with polyhydramnios, failure to thrive.
- Hypokalaemic metabolic alkalosis, salt wasting, normal-to-low blood pressure, high renin and high aldosterone.
- Hypercalciuria → nephrocalcinosis (because the TALH normally drives passive calcium reabsorption).
- Urinary calcium high; serum magnesium usually normal.
Gitelman syndrome
An autosomal recessive defect in the NCCT thiazide-sensitive Na⁺/Cl⁻ cotransporter of the distal convoluted tubule — functionally equivalent to chronic thiazide use. SLC12A3 mutation.
Features
- Presents later (adolescence/adulthood), milder, often incidental.
- Hypokalaemic metabolic alkalosis, normal/low BP, high renin/aldosterone — like Bartter — but:
- Hypocalciuria (low urine calcium) and hypomagnesaemia — the two hallmark distinguishers.
- Tetany, carpopedal spasm, chondrocalcinosis from magnesium loss.
Bartter vs Gitelman — the must-know comparison
| Feature | Bartter | Gitelman |
|---|---|---|
| Tubular site | Thick ascending limb | Distal convoluted tubule |
| Mimics which diuretic | Loop (furosemide) | Thiazide |
| Age at presentation | Neonatal / early childhood | Adolescent / adult |
| Urine calcium | High (hypercalciuria) | Low (hypocalciuria) |
| Serum magnesium | Usually normal | Low (hypomagnesaemia) |
| Nephrocalcinosis | Common | Absent |
| Blood pressure | Normal / low | Normal / low |
| K⁺ / acid-base | Low K⁺, metabolic alkalosis | Low K⁺, metabolic alkalosis |
High-yield: Both Bartter and Gitelman = hypokalaemic metabolic alkalosis with normal BP. Differentiate by urine calcium and serum magnesium: Bartter = hypercalciuria (loop-like); Gitelman = hypocalciuria + hypomagnesaemia (thiazide-like).
Management of Bartter/Gitelman
- Potassium and magnesium replacement, liberal salt and fluid.
- Potassium-sparing diuretics (spironolactone, amiloride) help retain K⁺.
- Bartter: NSAIDs (indomethacin) reduce prostaglandin-driven salt wasting in the neonatal forms.
Liddle syndrome
The salt-retaining outlier — an autosomal dominant gain-of-function mutation of the epithelial sodium channel (ENaC) in the collecting duct (SCNN1B/SCNN1G). Constitutively active ENaC → excessive Na⁺ reabsorption and K⁺/H⁺ loss → "pseudohyperaldosteronism."
Features
- Hypertension (early-onset) + hypokalaemic metabolic alkalosis.
- Low renin AND low aldosterone — the channel is active independent of aldosterone.
Treatment
- Amiloride or triamterene (directly block ENaC). Spironolactone does NOT work because the defect is downstream of the mineralocorticoid receptor — a classic NEET PG trick.
High-yield: Liddle = hypertension + hypokalaemia + low renin + low aldosterone, treated with amiloride (NOT spironolactone). Contrast with primary hyperaldosteronism (Conn): low renin but high aldosterone, responds to spironolactone.
Distinguishing the hypertensive low-renin states
| Disorder | Renin | Aldosterone | Treatment |
|---|---|---|---|
| Liddle syndrome | Low | Low | Amiloride / triamterene |
| Primary hyperaldosteronism (Conn) | Low | High | Spironolactone / surgery |
| Apparent mineralocorticoid excess (11β-HSD2 deficiency, liquorice) | Low | Low | Spironolactone / stop liquorice |
| Glucocorticoid-remediable aldosteronism | Low | High | Low-dose dexamethasone |
Complications across the spectrum
- Distal RTA: nephrocalcinosis, recurrent calcium phosphate stones, CKD, hypokalaemic paralysis/arrhythmia, growth retardation, osteomalacia.
- Proximal RTA / Fanconi: rickets/osteomalacia, growth failure, hypophosphataemia.
- Type IV: dangerous hyperkalaemia, especially when ACEi/ARB or potassium-sparing diuretics are added.
- Bartter/Gitelman: chronic hypokalaemia (arrhythmia), volume depletion, tetany (Gitelman), nephrocalcinosis (Bartter), chondrocalcinosis (Gitelman).
- Liddle: end-organ damage from sustained hypertension; severe hypokalaemia.
Key differentials
- Diarrhoea / GI bicarbonate loss — normal-anion-gap acidosis but negative UAG (vs positive in RTA).
- Surreptitious diuretic/laxative abuse or vomiting — mimics Gitelman/Bartter biochemically; urine chloride and a diuretic screen help (vomiting → low urine Cl⁻; diuretic abuse → high urine Cl⁻ intermittently).
- Primary hyperaldosteronism — hypertensive hypokalaemic alkalosis but high aldosterone (vs low in Liddle).
- DKA/lactic acidosis — high anion gap, distinguishing them from RTA at the very first step.
Recently asked / exam angle
- "Patient with Sjögren syndrome, hypokalaemia, urine pH 6.5, positive urine anion gap" → distal (type I) RTA.
- "Glycosuria with normal blood sugar + phosphaturia + aminoaciduria" → proximal RTA / Fanconi; in a child suspect cystinosis, in an adult on HIV therapy suspect tenofovir, in an elderly patient with bone pain suspect multiple myeloma.
- "Diabetic with mild hyperchloraemic acidosis and hyperkalaemia, urine pH < 5.5" → type IV RTA (hyporeninaemic hypoaldosteronism).
- "Negative urine anion gap in a child with diarrhoea" → appropriate renal NH₄⁺ excretion, not RTA.
- "Hypokalaemic alkalosis, normal BP, low urine calcium, low magnesium, adolescent" → Gitelman; if high urine calcium + nephrocalcinosis in a neonate → Bartter.
- "Young hypertensive, hypokalaemic alkalosis, low renin AND low aldosterone, not responding to spironolactone, responds to amiloride" → Liddle syndrome.
- Drug pairings tested: amphotericin B → distal RTA; acetazolamide / tenofovir → proximal RTA; trimethoprim / spironolactone / NSAIDs → type IV.
- Treatment pairings: distal/proximal RTA → potassium citrate; proximal RTA additionally responds to thiazides; Liddle → amiloride; neonatal Bartter → indomethacin.
Rapid revision
- RTA = normal anion gap (hyperchloraemic) metabolic acidosis with preserved GFR.
- Type I (distal): hypokalaemia, urine pH > 5.5, nephrocalcinosis + calcium phosphate stones; causes — Sjögren, amphotericin B.
- Type II (proximal): bicarbonaturia, Fanconi syndrome, needs high-dose alkali; causes — cystinosis, tenofovir, myeloma, acetazolamide.
- Type IV: the only hyperkalaemic RTA, urine pH < 5.5, due to hypoaldosteronism; commonest cause diabetic nephropathy.
- No clinically meaningful "type III" RTA.
- Urine anion gap: negative → diarrhoea/GI loss ("neGUTive"); positive → RTA.
- Confirmatory for distal RTA = ammonium chloride loading test (urine fails to acidify < 5.5).
- Bartter = loop-diuretic mimic, hypercalciuria, nephrocalcinosis, neonatal onset.
- Gitelman = thiazide mimic, hypocalciuria + hypomagnesaemia, adolescent/adult, milder.
- Bartter and Gitelman both have normal/low BP with high renin and aldosterone.
- Liddle = ENaC gain-of-function: hypertension + hypokalaemic alkalosis + low renin & low aldosterone; treat with amiloride (spironolactone fails).
- Drug of choice for alkali therapy in RTA = potassium citrate (corrects acidosis, hypokalaemia, and reduces stones).