Basics
Description
- Renal tubular acidosis (RTA) is characterized by hyperchloremic metabolic acidosis in the setting of normal or near-normal glomerular filtration rate (GFR).
- The acidification defect can be localized to the proximal tubule (type II RTA) resulting in incomplete bicarbonate reabsorption, or the distal tubule (type I or type IV RTA) resulting in impaired net acid secretion.
- Type I and II RTA are associated with hypokalemia; type IV is associated with hyperkalemia.
- Timing of onset and severity of presentation are variable, depending on the underlying cause of the acidification defect.
- Type I RTA is associated with nephrocalcinosis, osteopenia, rickets and sometimes hearing loss.
- Four different types of RTA are recognized:
- Type I (classic, hypokalemic, distal)
- Type II (proximal)
- Type III (characteristics of both proximal and distal RTA, rare inherited disorder associated with mental retardation, osteopetrosis, and cerebral calcification)
- Type IV (hyperkalemic, distal)
- Associated with aldosterone deficiency or resistance to its renal effect
Epidemiology
RTA is a rare disorder. Increased prevalence is observed in areas where consanguinity is common. ‚
Etiology
- Genetic causes of proximal RTA:
- Mutation in carbonic anhydrase II
- Mutation in sodium bicarbonate cotransporter
- Genetic causes of distal RTA:
- Mutation in anion exchanger 1 (AE1) in alpha-intercalated cell
- Mutation in H+-ATPase
- Mutation in carbonic anhydrase II
- Genetic causes of Fanconi syndrome/proximal RTA:
- Lowe syndrome
- Dent disease
- Cystinosis
- Tyrosinemia
- Galactosemia
- Hereditary fructose intolerance
- Wilson disease
- Fanconi-Bickel syndrome
- Mitochondrial disorders
- Acquired causes of proximal RTA:
- Drugs:
- Ifosfamide
- Cisplatin/oxaliplatin
- Valproic acid
- Carbonic anhydrase inhibitor (e.g., acetazolamide)
- Topiramate
- Aminoglycosides
- Antiretroviral therapy (tenofovir)
- Acquired causes of distal RTA type I:
- Autoimmune disorders
- Drugs:
- Lithium toxicity
- Amphotericin
- Ifosfamide
- Acquired causes of distal RTA type IV:
- Aldosterone resistance/deficiency
- Diabetic renal disease
- Obstructive uropathy
- Adrenal insufficiency
- Drugs:
- Nonsteroidal anti-inflammatory medications
- Heparin
- Potassium-sparing diuretics
- Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker
- Calcineurin inhibitors (e.g., tacrolimus or cyclosporine)
- Trimethoprim
- Pentamidine
Pathophysiology
- With ingestion of a typical Western diet, healthy adults generate ¢ ˆ ¼1 mEq/kg net acid per day and infants and children ¢ ˆ ¼2 " “3 mEq/kg/day.
- Under physiologic conditions, the proximal tubule is responsible for reclaiming 85 " “90% of filtered bicarbonate.
- Bicarbonate reclamation in the proximal tubule is achieved by a sodium " “hydrogen ion antiporter, which secretes hydrogen ion into the urine resulting in generation of bicarbonate within the cell. Cellular bicarbonate is then transported into the bloodstream via an Na-HCO3 transporter on the basolateral membrane.
- The distal tubule normally reclaims the remaining 10 " “15% of filtered bicarbonate and secretes a net amount of acid, both via hydrogen ion secretion.
- In the distal tubule, hydrogen ion secretion occurs primarily via H+-ATPase.
- Secreted hydrogen ions are buffered in the urinary lumen primarily by ammonia and excreted as ammonium ions.
- In proximal RTA, mutations in the basolateral sodium bicarbonate cotransporter or in carbonic anhydrase prevent adequate bicarbonate reclamation in the proximal tubule.
- Unreclaimed bicarbonate enters the distal nephron, which has limited capacity for bicarbonate reclamation, resulting in bicarbonaturia and non " “anion gap metabolic acidosis (usually serum bicarbonate does not decrease below 16 mEq/L).
- In distal RTA, mutations in the basolateral anion exchanger or the H+-ATPase prevent bicarbonate transport into the bloodstream and hydrogen ion secretion into the lumen, respectively, resulting in impaired net acid secretion and non " “anion gap metabolic acidosis.
- Proximal RTA can be associated with Fanconi syndrome in which there is general proximal tubular dysfunction leading to bicarbonaturia, glucosuria, phosphaturia, and tubular proteinuria.
- Distal RTA type I is associated with urine pH >5.5
- Distal RTA type IV is associated with either low aldosterone levels or aldosterone resistance and presents with hyperkalemic non " “anion gap metabolic acidosis.
Diagnosis
History
- Failure to thrive in infants and children
- Polyuria
- Constipation
- Anorexia
- Symptoms of hypokalemia:
- Muscle weakness
- Constipation
- Kidney stones
- Intellectual disability
- Propensity for fractures
Physical Exam
- Constitutional: failure to thrive
- Head: frontal bossing
- Ears: deafness (associated with some forms of RTA)
- Neurologic: developmental and cognitive delay
- Skin: decreased turgor, prolonged capillary refill
Diagnostic Tests & Interpretation
- Serum electrolytes
- To identify metabolic acidosis with normal anion gap, and hypokalemia or hyperkalemia
- Magnesium level (can be low in Fanconi syndrome)
- Phosphorus level (can be low in Fanconi syndrome)
- Serum creatinine: to evaluate GFR
- Urine electrolytes
- Urine anion gap, calculated as (urine sodium + urine potassium ¢ ˆ ’ urine chloride): typically >10 in distal RTA (type I or IV)
- Urine phosphorus: Fractional excretion is high in Fanconi syndrome, resulting in hypophosphatemia.
- Urinalysis
- Urine pH is high in distal RTA, often >6.8 and can be elevated or normal in proximal RTA.
- Look for glucosuria in setting of normal serum glucose.
- Urine spot for calcium/creatinine ratio: Look for hypercalciuria (normal values are age-dependent).
- 24-hour urine collection for citrate (typically low)
Imaging
- Renal ultrasound: Evaluate for nephrocalcinosis and kidney stones.
- Long bone films to look for signs of rickets or osteopenia
Differential Diagnosis
- Renal insufficiency (earlier stages)
- Diarrhea
- Urinary diversion via bowel conduits
- Acetazolamide use
Treatment
Medication
- Alkali supplementation given as sodium or potassium bicarbonate or citrate (typically requires 5 " “8 mEq/kg/24 h in distal RTA and 5 " “15 mEq/kg/24 h in proximal RTA)
- Thiazide diuretics (in proximal RTA) to induce volume depletion which can be sensed by the proximal tubule, resulting in increased proximal tubular reabsorption of bicarbonate
- Mineralocorticoid supplementation (for those with select causes of type IV RTA)
Additional Therapies
General Measures
- Vitamin D supplementation as needed
- Phosphorus supplementation as needed (if concurrent Fanconi syndrome)
Ongoing Care
Follow-up Recommendations
- Frequent monitoring of serum electrolytes
- Close follow-up of linear growth
- Renal ultrasound to monitor for evidence or progression of nephrocalcinosis
Prognosis
- Can rarely progress to chronic kidney disease over time depending on etiology of RTA (as in cystinosis) or if associated with nephrocalcinosis
- May be associated with development of nephrolithiasis
Additional Reading
- Batlle ‚ D, Haque ‚ SK. Genetic causes and mechanisms of distal renal tubular acidosis. Nephrol Dial Transplant. 2012;27(10):3691 " “3704. ‚ [View Abstract]
- Haque ‚ SK, Ariceta ‚ G, Batlle ‚ D. Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies. Nephrol Dial Transplant. 2012;27(12):4273 " “4287. ‚ [View Abstract]
- Karet ‚ FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol. 2009;20(2):251 " “254. ‚ [View Abstract]
Codes
ICD09
- 588.89 Other specified disorders resulting from impaired renal function
ICD10
- N25.89 Other disorders resulting from impaired renal tubular function
SNOMED
- 1776003 Renal tubular acidosis (disorder)
- 24790002 Proximal renal tubular acidosis (disorder)
- 236461000 Distal renal tubular acidosis (disorder)
- 236463002 Hyperkalemic renal tubular acidosis
FAQ
- Q: Can RTA be diagnosed in the setting of renal failure?
- A: No. Typically, RTA is diagnosed in the setting of relatively preserved renal function. Renal function associated with non " “anion or anion gap acidosis typically occurs when GFR is <30 mL/min/1.73 m2.
- Q: Does a urine pH <5.5 exclude RTA?
- A: A low urinary pH excludes distal RTA but could still be consistent with a proximal RTA. However, urine pH as tested on urine dipsticks or formal urinalysis can be unreliable depending on duration between time of sample delivery and analysis.
- Q: What are the available forms of alkali supplementation?
- A: Alkali supplementation is best provided as a combination of sodium and potassium citrate or bicarbonate (except in distal RTA type IV, in which potassium alkali is avoided).