Renal tubular acidosis type 1, also called distal renal tubular acidosis, is characterized by hyperchloremic metabolic acidosis, hypokalemia, hypercalciuria, hypocitraturia, and low urinary NH4+. Its etiology is variable and includes sporadic, hereditary, and acquired forms. It should be differentiated from other forms of RTA and other causes of metabolic acidosis. Long-term alkali therapy is the mainstay of the treatment. In this article, etiology, pathophysiology, symptoms, diagnosis, differential diagnosis, treatment and prognosis of renal tubular acidosis type 1 are described.
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renal tubular acidosis_type1

RTA Type 1


Definition

Renal tubular acidosis (RTA) is a group of renal tubular disorders characterized by hyperchloremic metabolic acidosis resulting from the failure of net renal acid excretion, usually from an inability to conserve bicarbonate or to excrete H+ ions. Distal RTA, also called RTA type 1, is characterized by impaired distal tubular acidification mechanism in kidneys.

Epidemiology of Distal Renal Tubular Acidosis

Primary or Hereditary forms of distal RTA usually present in infancy or childhood, while secondary forms present during adulthood. The exact prevalence of distal RTA is unknown.

Etiology of Distal Renal Tubular Acidosis

Primary causes

  • Sporadic forms
  • Inherited forms:
    • Autosomal recessive forms: defects in HCO3/Cl exchanger or H+ ATPase
    • Autosomal dominant form: defect in HCO3/Cl exchanger (SLC4A1 gene on chromosome 17)
  • Inherited syndromes: Marfan syndrome, Wilson disease, Ehler-Danlos syndrome, Fabry’s disease, hereditary elliptocytosis
  • Familial hypercalciuria

Secondary causes

  • Urologic causes: obstructive uropathy, vesicoureteral reflux
  • Intrinsic renal causes:
    • Nephrocalcinosis: hyperparathyroidism, hypervitaminosis D, milk-alkali syndrome, hyperoxaluria, idiopathic hypercalciuria, etc.
    • Interstitial nephritis, pyelonephritis, sickle cell nephropathy, medullary sponge kidney, transplant rejection
  • Systemic diseases: systemic lupus erythematosus, primary biliary cirrhosis, Sjogren’s syndrome
  • Hypergammaglobulinemic states: myeloma, amyloidosis, cryoglobulinemia
  • Drugs: amphotericin B, lithium, NSAIDs, cyclophosphamide, ifosfamide, cisplatin, foscarnet
  • Others: hepatic cirrhosis, chronic active hepatitis, idiopathic pulmonary fibrosis, thyroiditis, HIV-associated nephropathy

Conditions associated with voltage defect distal RTA

  • Decreased distal delivery of Na+ – hypovolemic states, Gordon syndrome (pseudohypoaldosteronism 2)
  • Decreased distal reabsorption of Na+:
    • ENaC defect: pseudohypoaldosteronism 1, drugs (amiloride, triamterene, trimethoprim, pentamidine)
    • Na/K ATPase defect – cyclosporine
    • Lupus nephropathy, sickle cell nephropathy, chronic transplant rejection, methicillin

Pathophysiology of Distal Renal Tubular Acidosis

Important renal mechanisms for maintaining acid-base homeostasis include reabsorption of filtered HCO3 and excretion of nonvolatile acids. Normally, 85—90 % of HCO3 is reabsorbed in proximal tubules and distal segments cause acidification of urine by the reclamation of remaining HCO3 and by active secretion of H+ in form of titrable acid, NH4+, and free ions. α-intercalated cells of collecting ducts contain H+ ATPase and basolateral anion exchanger type 1 (AE1), while β-intercalated cells contain H+ ATPase and Cl/HCO3 exchanger (pendrin).

Pathophysiology of type 1 RTA may involve a secretory defect (most common) or a nonsecretory defect (gradient defect, buffer defect, or voltage defect).

In secretory defect, there is a failure of secretion of H+ by intercalated cells, possibly due to defective H+ ATPase, H+/K+ ATPase, or HCO3/Cl exchanger. This type of RTA is also called classic distal RTA or rate-limiting RTA.

Gradient defect distal RTA is characterized by an inability to maintain the gradient due to back-diffusion of the secreted H+, which may result from the abnormal permeability of membrane or defective cell junctions. This defect is also called back-leak defect; a classical example is distal RTA caused by amphotericin B.

Buffer defect distal RTA is characterized by decreased delivery of NH3 to the distal collecting tubule that results in decreased buffering capacity. This type of RTA is also called low buffer type distal RTA; important examples are distal RTA associated with nephrocalcinosis and chronic interstitial nephritis.

Voltage defect distal RTA is characterized by dysfunction of principal cells that results in loss of luminal electronegativity and impaired secretion of H+ by intercalated cell. The principal cell dysfunction may be caused by defective ENaC channel or by drugs affecting function of ENaC. Reduced H+ secretion is associated with increased reabsorption of K+. Hence this type of distal RTA is associated with hyperkalemia (hyperkalemic type 1 RTA). Important examples of this type of distal RTA are obstructive nephropathy, sickle cell nephropathy, salt-losing congenital adrenal hyperplasia, and certain drugs.

Inherited forms of distal RTA are usually due to defect in HCO3/Cl anion exchanger or in H+ ATPase.

In distal RTA, due to lack of H+ in tubular lumen, bicarbonate is lost in urine, which results in increased chloride absorption causing hyperchloremia. Increased K+ secretion occurs distally as a compensatory response to decreased H+ secretion, which causes hypokalemia. Hypercalciuria is often present due to inhibition of calcium reabsorption by luminal alkalinization, which can lead to nephrocalcinosis or nephrolithiasis. The risk of nephrocalcinosis/nephrolithiasis is further increased by high urine pH and hypocitraturia, which is caused by proximal citrate reabsorption induced by acidosis. Urine NH4+ excretion is low.

Bone disease (osteopenia or osteomalacia) seen in distal RTA results from chronic acidosis, which causes bone matrix calcium resorption. Impaired growth hormone release may be a contributing factor for growth retardation in children with distal RTA.

Incomplete distal RTA is considered to be a milder form or a variant of distal RTA, which is characterized by normal serum HCO3, but inability to acidify urine due to defective tubular secretion of acid. Hypercalciuria and hypocitraturia are present and there is increased ammoniagenesis to maintain net acid excretion.

Symptoms of Distal Renal Tubular Acidosis

Important symptoms of distal RTA include polyuria, polydipsia, and growth retardation. Poor feeding, vomiting, and failure to thrive may be presenting symptoms in initial years of life. Proximal muscle weakness, fatigue, constipation or paralysis may be present due to hypokalemia.

Nephrolithiasis and/or nephrocalcinosis may be present. Nephrocalcinosis usually irreversible and may lead to polyuric chronic renal failure, while nephrolithiasis occurs later and can be prevented by alkali therapy.

Distal RTA seen in childhood is usually primary or inherited. Some forms of autosomal recessive distal RTA caused by H+ ATPase defects are associated with sensorineural hearing loss.

Incomplete distal RTA clinically presents with renal stones or unexplained osteoporosis. Diagnosis of incomplete distal RTA should be suspected in patients with idiopathic nephrolithiasis with alkaline urine, patients with Sjogren syndrome and patients with amphotericin toxicity.

Diagnosis of Distal Renal Tubular Acidosis

Hallmark of RTA is non-anion gap metabolic acidosis (NAGMA) or hyperchloremic metabolic acidosis. Important laboratory findings in distal RTA are low serum HCO3, hyperchloremia, hypokalemia (except in hyperkalemic type distal RTA), hypercalciuria, hypocitraturia, and low urinary NH4+. Serum calcium, serum phosphate, and urinary phosphate are normal. (High-yield information)

Measurement of urinary Na+ is important as low urinary sodium is associated with voltage-dependent acidification defect. Measurement of urinary NH4+ by formaldehyde titration method is cumbersome; hence urinary anion gap is calculated as an indirect method for approximate estimation of urinary NH4+ excretion.

Urine anion gap (UAG) is helpful to differentiate between renal and non-renal causes of NAGMA.

UAG = [NA+]Ur + [K+]Ur – [Cl]Ur

UAG is positive in normal conditions and in RTA. When urinary excretion of NH4+ is high (as in extrarenal bicarbonate loss), UAG becomes negative.

However, interpretation of UAG is invalid in conditions associated with the significant presence of unmeasured ions (lithium, ketones, acetylsalicylate, etc) in urine or when urine pH is more than 6.5 (due to significant excretion of bicarbonate in urine).

Urine osmolal gap (UOG) helps to differentiate between renal and non-renal causes of NAGMA when there is a significant presence of other anions.

UOG = [Osm]Ur – (2[Na+]Ur + 2[K+]Ur + [Urea]Ur + [Glu]Ur)

When there is an increased secretion of NH4+, UOG equals or is greater than 100 mmol/L. the value of UOG/2 is roughly equal to [NH4+]Ur. However, UOG is invalid in conditions associated with the significant presence of unmeasured osmolals like lithium.

Urine pH more than 5.5 suggests renal acidification defect when pH is measured in a fresh early morning urine sample. Remember that type II RTA and type IV RTA can present with urine pH < 5.5. (High Yield)

Ammonium chloride loading test is the most commonly used acid-loading test, in which 0.1 g/kg NH4Cl is given orally to induce systemic acidosis and ABG and urine pH are monitored hourly. Normally, urine pH should fall below 5.5 in presence of systemic acidosis. Urine pH more than 5.5 in presence of systemic acidosis suggests distal acidification defect.

Ammonium chloride loading test may cause nausea, vomiting, gastric upset, etc. As it is contraindicated in chronic liver disease, calcium chloride is being used to induce acidosis.

Sodium bicarbonate loading test is performed by oral or intravenous administration of sodium bicarbonate to alkalinize urine (urine pH more than 7.5). Normally, in presence of steady-state serum bicarbonate (23—25 mEq/L) and alkaline urine, urine CO2 is more than 70 mm Hg, urine-to-blood PCO2 gradient (U-B PCO2) is more than 20 mm Hg, and fractional excretion of bicarbonate (FEHCO3) is less than 5 %.

FEHCO3 (%) = (Urine bicarbonate x Plasma creatinine)/(Plasma bicarbonate x Urine creatinine) x 100

In classical distal RTA, urine PCO2 is less than 50 mm Hg, U-B PCO2 is less than 10 mm Hg, and FEHCO3 is less than 5 % on sodium bicarbonate test. In voltage defect distal RTA, urine PCO2 is more than 70 mm Hg, U-B PCO2 is more than 20 mm Hg, and FEHCO3 varies from 5—10 %.

Differential Diagnoses of Distal Renal Tubular Acidosis

  • Other types of RTA
  • Other causes of NAGMA
    • Chronic renal failure
    • Extrarenal bicarbonate loss – diarrhea, intestinal fistula, etc
    • Ketoacidosis
    • Lactic acidosis
    • Exogenous administration of Cl-rich solutions
    • Parenteral nutrition
    • Drug toxicity

Therapy of Distal Renal Tubular Acidosis

Chronic alkali supplementation is the mainstay of treatment. Correction of acidosis is important for improvement of growth in children, to decrease the incidence of hypokalemia and nephrocalcinosis/nephrolithiasis, and to slow progression of the chronic renal disease. The therapeutic goal is to maintain normal serum bicarbonate level (22—24 mEq/L).

Children with severe metabolic acidosis (serum bicarbonate less than 12 mEq/L) are given intravenous bicarbonate, after calculation of required dose of bicarbonate. Half of the required dose is administered over 8 hours and the remaining half dose is administered over next 24 hours. The required dose is calculated using following formula:

Required dose = desired change in serum bicarbonate x body weight (kg) x 0.6

In patients with serum bicarbonate between 12—17 mEq/L, oral bicarbonate therapy is sufficient. Sodium and/or potassium bicarbonate or citrate are used for treatment. Shohl’s solution (1 mEq/mL base, contains citric acid and sodium citrate) is preferred over sodium bicarbonate.

The requirement of alkali decreases with age, which ranges from 5-8 mEq/kg/day in infants, 3—4 mEq/kg/day in children, and 1—2 mEq/kg/day in adults. As secretion of growth hormone peaks during sleep, the larger dose of alkali is administered at bedtime in children.

Low sodium diet and thiazide diuretics are useful to reduce bicarbonate wasting.

Normal serum HCO3 and optimum growth indicate appropriate treatment. As there is an inverse relationship between plasma HCO3 and urinary calcium, the absence of hypercalciuria indicates good control of metabolic acidosis. Annual abdominal sonography should be performed for monitoring of nephrocalcinosis and nephrolithiasis.

Progression and Prognosis of Distal Renal Tubular Acidosis

In distal RTA, calciuria tends to decrease with age. However, if untreated, there may be a rapid progression to end-stage renal disease. There is also an increased risk of acute kidney injury following surgery.

Review Questions

The answers can be found below the references.

1. Which of the following hematologic condition is associated with distal RTA?

  1. Hereditary spherocytosis
  2. Hereditary elliptocytosis
  3. Sideroblastic anemia
  4. G-6-PD deficiency
  5. Acute myeloid leukemia

2. Which of the following drugs can produce a condition similar to voltage defect distal RTA due to inhibition of Na/K-ATPase?

  1. Amphotericin B
  2. Cyclophosphamide
  3. Cyclosporine
  4. NSAIDs
  5. Lithium

3. Which of the following laboratory findings suggests the diagnosis of hypokalemic distal RTA?

  1. Increased NH4+ excretion following acid loading test
  2. Increased urine phosphate excretion following
  3. FEHCO3 > 5 % following bicarbonate loading test
  4. U-B PCO2 < 20 mm Hg following bicarbonate loading test
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