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Renal Tubular Acidosis, Pediatric

Basics

Description

- 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

  • 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 IIMutation in sodium bicarbonate cotransporter
  • Genetic causes of distal RTA:Mutation in anion exchanger 1 (AE1) in alpha-intercalated cellMutation in H+-ATPaseMutation in carbonic anhydrase II
  • Genetic causes of Fanconi syndrome/proximal RTA:Lowe syndromeDent diseaseCystinosisTyrosinemiaGalactosemiaHereditary fructose intoleranceWilson diseaseFanconi-Bickel syndromeMitochondrial disorders
  • Acquired causes of proximal RTA:Drugs:IfosfamideCisplatin/oxaliplatinValproic acidCarbonic anhydrase inhibitor (e.g., acetazolamide)TopiramateAminoglycosidesAntiretroviral therapy (tenofovir)
  • Acquired causes of distal RTA type I:Autoimmune disordersDrugs:Lithium toxicityAmphotericinIfosfamide
  • Acquired causes of distal RTA type IV:Aldosterone resistance/deficiencyDiabetic renal diseaseObstructive uropathyAdrenal insufficiencyDrugs:Nonsteroidal anti-inflammatory medicationsHeparinPotassium-sparing diureticsAngiotensin-converting enzyme inhibitor or angiotensin receptor blockerCalcineurin inhibitors (e.g., tacrolimus or cyclosporine)TrimethoprimPentamidine

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 weaknessConstipation
  • 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 electrolytesTo identify metabolic acidosis with normal anion gap, and hypokalemia or hyperkalemiaMagnesium level (can be low in Fanconi syndrome)Phosphorus level (can be low in Fanconi syndrome)
  • Serum creatinine: to evaluate GFR
  • Urine electrolytesUrine 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.
  • UrinalysisUrine 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).