Renal Tubular Acidosis & Inherited Tubulopathies
Potassium, urine pH, and urine chloride name the broken tubule
Approach to a normal-gap acidosis
Gut or kidney? Renal tubular acidoses (RTAs) cause a normal-anion-gap (hyperchloremic) metabolic acidosis, as does diarrhea. The urine anion gap (urine Na + K − Cl) separates them: NH4+ leaves the body with chloride, so the urine gap tracks NH4+ excretion inversely.
- Negative urine AG ("neGUTive"): the kidneys are excreting NH4Cl appropriately, so the bicarbonate loss is GI (diarrhea). Example: urine Na 30, K 25, Cl 90 gives −35. Proximal (type 2) RTA at steady state can also give a negative urine AG, because distal NH4+ excretion is intact.
- Positive urine AG: impaired renal NH4+ excretion, meaning distal (type 1) or type 4 RTA.
The urine AG misleads when unmeasured anions such as ketones or hippurate (toluene) are excreted, or when urine Na is <20 mEq/L from volume depletion.
Then read potassium and urine pH. Serum K and urine pH name the broken tubule:
| Feature | Type 1 (distal) | Type 2 (proximal) | Type 4 (hypoaldosteronism) |
|---|---|---|---|
| Defect | α-intercalated cells cannot secrete H⁺ | PCT cannot reclaim filtered HCO₃⁻ | Aldosterone deficiency or resistance |
| Serum K | Low | Low, worse with alkali | High |
| Urine pH | Always >5.5 | <5.5 at steady state | <5.5 |
| Serum HCO₃⁻ | Can fall below 10 | Self-limited, about 12–20 | Mild, usually ≥17 |
| Stones | Calcium phosphate, nephrocalcinosis | None | None |
| Classic causes | Sjögren, amphotericin B, lithium | Myeloma, tenofovir, carbonic anhydrase inhibitors | Diabetic nephropathy, ACE inhibitors/ARBs, trimethoprim |
| Treatment | Potassium citrate ~1–2 mEq/kg/day | Alkali 10–15 mEq/kg/day plus K, ± thiazide | Stop the drug, lower K, ± fludrocortisone |
Distal (type 1) RTA
Mechanism. α-Intercalated cells cannot secrete H⁺ (or secreted acid leaks back, as with amphotericin B), so urine pH stays above 5.5 despite acidemia. NH4+ excretion falls (positive urine AG), bicarbonate can drop below 10, and renal potassium wasting causes hypokalemia, sometimes with flaccid paralysis.
Causes. Autoimmune disease (Sjögren syndrome most often, so check anti-Ro/SSA and anti-La/SSB in a patient with sicca symptoms; also SLE and RA), amphotericin B, lithium, obstructive uropathy, and sickle cell disease. Inherited forms present in childhood with growth failure and rickets, some with sensorineural deafness.
Stones. Distal RTA produces calcium phosphate stones and medullary nephrocalcinosis for three reasons: alkaline urine favors calcium phosphate precipitation, bone buffering of acid raises urine calcium, and avid proximal citrate reabsorption removes the main stone inhibitor. Potassium citrate (~1–2 mEq/kg/day) corrects the acidosis, the hypokalemia, and the hypocitraturia.
With severe hypokalemia, replace potassium before giving alkali: correcting acidosis drives K into cells and can precipitate paralysis or arrhythmia.
Proximal (type 2) RTA and Fanconi syndrome
A leak with a floor. The proximal tubule cannot reclaim filtered bicarbonate, so it spills until serum HCO₃⁻ falls to a lower threshold (~12–20 mEq/L). Below that level no more bicarbonate escapes, intact distal acidification lowers urine pH below 5.5, and the acidosis is self-limited. Giving alkali raises distal Na and HCO₃⁻ delivery and worsens hypokalemia.
Fanconi syndrome. Generalized proximal failure wastes glucose (glycosuria with normal serum glucose), phosphate (hypophosphatemia leading to osteomalacia or rickets), amino acids, urate (low serum uric acid), low-molecular-weight proteins, and bicarbonate.
- Acquired: light chains of multiple myeloma (an adult with anemia and bone pain needs SPEP with free light chains), tenofovir disoproxil (switch the regimen), ifosfamide, expired tetracycline, and heavy metals (lead, cadmium).
- Inherited: cystinosis (the most common cause in children), Wilson disease, galactosemia, hereditary fructose intolerance.
- Isolated bicarbonate leak: carbonic anhydrase inhibitors (acetazolamide, topiramate) cause proximal RTA without the glucose, phosphate, and amino acid losses of full Fanconi syndrome.
Treatment. Because added bicarbonate spills into the urine, proximal RTA needs 10–15 mEq/kg/day of alkali, partly as potassium citrate to cover K losses, ± a thiazide (mild volume contraction boosts proximal reabsorption). Fanconi bone disease needs phosphate and calcitriol, and the cause must be removed.
Type 4 RTA
The hyperkalemic RTA. The most common RTA in adults, classically hyporeninemic hypoaldosteronism of diabetic nephropathy. Acid excretion fails indirectly, through potassium:
- ↓ Aldosterone effectDiabetes, ACE inhibitor/ARB, spironolactone, trimethoprim.
- ↓ Distal K⁺ secretionHyperkalemia.
- ↓ Proximal ammoniagenesisHigh K suppresses NH₃ production.
- ↓ NH₄⁺ excretionMild normal-gap acidosis with urine pH <5.5 and a positive urine AG.
Culprits. ACE inhibitors and ARBs, spironolactone and eplerenone, amiloride and triamterene, trimethoprim and pentamidine (ENaC block), heparin (less aldosterone synthesis), NSAIDs (less renin), calcineurin inhibitors, and β-blockers; also primary adrenal insufficiency and obstructive uropathy.
Trimethoprim blocks ENaC just as amiloride does: watch potassium with high-dose TMP-SMX, especially with ACE inhibitors or in the elderly.
Treatment. Stop offending drugs and restrict dietary K. Add a loop or thiazide diuretic (best when hypertensive or edematous) or a potassium binder; fludrocortisone suits hypoaldosteronism without hypertension or volume overload. Lowering K restores ammoniagenesis and often corrects the acidosis; add sodium bicarbonate if needed.
Normotensive hypokalemic alkalosis
Check urine chloride. Renin and aldosterone are high in all causes. Low urine Cl (<20 mEq/L) means vomiting or bulimia, or remote diuretic use; high urine Cl means current diuretics or Bartter or Gitelman syndrome, separated by a urine diuretic screen. Urine Na is unreliable after vomiting because bicarbonaturia drags sodium out. Bulimia clues are dental enamel erosion, parotid swelling, and knuckle calluses (Russell sign).
| Feature | Bartter | Gitelman |
|---|---|---|
| Defect | Thick ascending limb (NKCC2): loop-diuretic-like | Distal convoluted tubule (NCC): thiazide-like |
| Urine calcium | High; nephrocalcinosis | Low |
| Magnesium | Usually normal | Low |
| Onset | Infancy or childhood: polyhydramnios, growth failure | Adolescence or adulthood: cramps, tetany, fatigue; milder |
| Treatment | NSAIDs (blunt prostaglandin excess), K, K-sparing diuretics | K and Mg supplements, ± amiloride or spironolactone |
Hypertensive hypokalemic alkalosis
Renin and aldosterone decide. With hypertension, measure both. When both are suppressed, sodium channels are switched on without aldosterone.
| Feature | Primary hyperaldosteronism | Liddle syndrome | Licorice / apparent mineralocorticoid excess |
|---|---|---|---|
| Renin / aldosterone | Low / high | Low / low | Low / low |
| Mechanism | Adrenal adenoma or bilateral hyperplasia | Autosomal dominant ENaC gain of function; channel stays in the membrane | Glycyrrhetinic acid blocks 11β-HSD2, so cortisol activates the mineralocorticoid receptor |
| Treatment | Spironolactone or eplerenone; adrenalectomy for adenoma | Amiloride or triamterene; spironolactone ineffective | Stop licorice; spironolactone or eplerenone works |