Definition

Impaired acid-base metabolism by the kidney in the setting of normal glomerular filtration, specifically of either renal bicarbonate reabsorption or hydrogen ion excretion.

• Kidney disease must be excluded as etiology of inappropriate acid-base metabolism.
• Characterized by a normal-anion gap metabolic acidosis with hyperchloremia.

** Note: normal urine pH range is 4.5-5.0 as virtually no HCO3 is excreted.

Categories

• Type I RTA (distal):
• Urinary acidification takes place in the distal nephron in the intercalated cells by regeneration of HCO3 (10-20%) and secretion of H+ in the form of H2PO4- and NH4+. In type I RTA, there is impaired secretion of H+ leading to metabolic acidosis.
  • Primary.
  • Amphotericin.
  • Sjogren’s/SLE/RA.
  • Myeloma.
  • Marked volume depletion.
  • Urinary tract obstruction (stones).
  • Potassium sparing diuretics (amiloride).
• Features/Diagnosis:
  • Serum HCO3 may be <10mEq/L as there is no way to excrete the acid load.
  • Urine pH >5.5 reflecting defect in urinary acidification and sufficient NH3 production to buffer few H+ secreted.
• Type II RTA (proximal):
• Reclamation of 80-90% of HCO3 occurs in the proximal tubule. In type II RTA, HCO3 wasting occurs due to failed reabsorption that can be only partially salvaged by the distal nephron.
• Primary.
• Myeloma nephropathy (most common cause in adults).
• Acetazolamide.
• Heavy metals (Pb, Cd, Hg, Cu, others).

• Inherited and acquired Fanconi syndrome.
• Fanconi syndrome refers to generalized proximal tubular dysfunction and can be primary or secondary to many of the above causes of type II RTA. 

• Features/Diagnosis:
• As the serum HCO3 level drops, eventually the lower filtered load of HCO3 into the proximal tubule will be able to be maximally re-absorbed. Serum HCO3 levels will be maintained between 12-20mEq/L, a kind of steady-state.
• Urine pH is variable.
• Giving HCO3 load for acidosis (test dose) raises serum HCO3 levels and overwhelms the proximal tubule absorptive capacity leading to HCO3 excess which raises urine pH >5.5.
• If serum HCO3 is low enough such that all of the filtered HCO3 can be re-absorbed, then the normally functioning distal nephron can acidify, leading to a urine pH <5.3.
• Type IV RTA (distal) - most common type of RTA:
• Aldosterone deficiency or resistance in the intercalated and principle cells of the distal nephron lead to hyperkalemia and impaired NH3/NH4+ production and thus metabolic acidosis.
• Hypoaldosteronism-medicated causes:
• Diabetic nephropathy (most common cause).
• Chronic interstitial nephropathy.
• Drugs (NSAIDS, heparin, ACEI/ARB, trimethoprim, calcineurin inhibitors).
• Addison's disease.
• Aldosterone-resistance mediated causes:
• Sickle cell anemia (most common cause of aldosterone resistance).
• BPH.
• Features/Diagnosis:
• Serum HCO3 usually >15mEq/L.
• Urine pH <5.3: in contrast to type I RTA, there is insufficient NH3 production in type IV RTA, leaving few H+ produced to be left unbuffered and thus cause a low urinary pH.

Evaluation

• Laboratory:
• Urine: UA/urine culture (UTI from urea-producing organisms can raise urine pH by metabolism of HCO3 and NH4+), urine lytes (Na, K, Cl).
  • Calculate urine anion gap: 
    • UAG = UNa + UK - UCl.
    • If UAG <0, not likely RTA. Consider GI causes.
    • Note: UAG cannot be used in setting of presence of other anion (e.g. lactate, DKA) OR with urine sodium <20mEq/L (insufficient Na+ delivery to distal tubule does not allow for H+ exchange and, thus, urinary acidification).
    • If urine sodium <20mEq/L, consider calculating urine osmolar gap (needs urine Na, Cl, K, BUN, glucose, osmolality).
    • UOG = 2(UNa + UK) + U[BUN]/2.8 + Uglucose/18.
    • UOG <50 is suggestive of RTA.

• Serum: ABG, serum chemistry.
  • Hypokalemia: type II RTA (proximal) or type I RTA (distal).
• If type II: in adults, suspect multiple myeloma or nucleotide analogues; in pediatric patients, Fanconi’s syndrome.
• If type I: in adults, suspect urinary obstruction or Sjogren’s/SLE.

• Hyperkalemia: type IV RTA (hypoaldosteronism) or type I RTA (distal).

• If type IV: suspect diabetic nephropathy or sickle cell anemia.
• If type I: suspect impaired Na reabsorption:
• Urinary obstruction.
• Cyclosporine toxicity.
• Autoimmune disorders.
• TMP/SMX can impair Na channels leading to a functional type I RTA.

Treatment

• Type I and II: aggressive K supplementation. Follow with HCO3 supplementation (initial HCO3 supplementation can aggravate K wasting especially in proximal RTA).
• NaHCO3 or Na-citrate: goal normal serum HCO3 in type I. HCO3 >20mEq/L in Type II
• Note: may need close monitoring/repletion of K+, Ca2+, phosphate.
• Type IV: treatment for hyperkalemia.
• Restrict dietary potassium, avoid potassium-sparing diuretics.
• Loop diuretics, thiazides for potassium excretion.
• Fludricortisone in severe cases.

Key Points

• RTA is best diagnosed in the presence of normal GFR (with significant CKD or AKI, most kidney has decreased ammoniagenesis).

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Smulders YM, Frissen PH, Slaats EH, Silberbusch J. Renal tubular acidosis. Pathophysiology and diagnosis. Arch Intern Med 1996;156:1629-1636.

Soriano JR. Renal Tubular Acidosis: The Clinical Entity. J Am Soc Nephrol 13: 2160–2170, 2002.

Sterns RH.  Fluid, electrolyte, and acid-base disturbances.  J Am Soc Nephrol 2003;2:1-7.