Renal Tubular Acidosis

Etiology

Type 1 Distal

Autoimmune diseases are the commonest cause in adults: Systemic lupus erythematosus (SLE), Sjogren syndrome, rheumatoid arthritis, systemic sclerosis, thyroiditis, hepatitis, primary biliary cirrhosis [2].

Inherited, AD or AR: Genetic primary causes of distal RTA include mutations of genes that encode the chloride-bicarbonate exchanger (AE1) or subunits of the H-ATPase pump respectively

Genetic associations: Marfan syndrome, Ehler Danlos syndrome, sickle cell disease, congenital obstruction of the urinary tract

Nephrocalcinosis: Chronic hypercalcemia, medullary sponge kidney

Tubulointerstitial diseases: chronic pyelonephritis, chronic interstitial nephritis, obstructive uropathy, renal transplant rejection

Hypergammaglobulinemic states: Monoclonal gammopathy, multiple myeloma, amyloidosis, cryoglobulinemia, chronic liver disease

Drugs: Lithium, amphotericin B, NSAIDs, lead, antivirals

Miscellaneous: Idiopathic, familial hypercalciuria, glue sniffing (toluene inhalation in recreational drug abuse) [3]

Type 2 Proximal

Hypergammaglobulinemic states: Most common cause in adults-monoclonal gammopathy(light chain), multiple myeloma, amyloidosis

Inherited: AD or AR putative mutations in Na-H antiporter in apical membrane and Na-HCO3 cotransporter in the basolateral membrane of proximal tubular cells respectively

Drugs: Lead or other heavy metals, carbonic anhydrase inhibitors (e.g., acetazolamide, topiramate) [4], out of date tetracyclines, aminoglycosides, valproate, mercury, tenofovir, and ifosfamide (nephrotoxic)

Autoimmune: Sjogren syndrome, systemic lupus erythematosus (SLE)

Miscellaneous: Interstitial nephritis, Fanconi syndrome, vitamin D deficiency, secondary hyperparathyroidism, chronic hepatitis, idiopathic

Type 3 Mixed

Inherited: Mutations in carbonic anhydrase II.

Type 4 Hyperkalemic RTA

Hyporeninemic hypoaldosteronism: most common cause in adults is diabetic nephropathy-destruction of JG apparatus due to vascular hyalinosis [5]

Drugs: Potassium-sparing diuretics, beta blockers, NSAIDs, calcineurin inhibitors (cyclosporine, tacrolimus), ACEi, ARBs, renin inhibitors, heparin, TMP/SMX

Autoimmune: SLE

Genetic: Sickle cell disease, pseudohypoaldosteronism

Miscellaneous: Interstitial nephritis, chronic obstruction of the urinary tract, adrenal insensitivity to angiotensin II, renal insufficiency

Epidemiology

RTA with its all major subtypes is an uncommon entity. The disease is undiagnosed in most of the cases and also in cases with incomplete RTA. Inherited forms of RTA are much rarer than acquired forms. The most common Type in the United States and worldwide is type 4 hyperkalemic RTA, the main causes of which are diabetic nephropathy leading to hyporeninemic hypoaldosteronism and urinary tract obstruction. There is over 20% incidence of developing RTA after renal transplant in the setting of rejection or immunosuppressive drugs. 

Type 2 Proximal RTA is rarer than type 1 distal RTA and Fanconi syndrome is very rare as a primary disease. The diseases which are associated with Fanconi syndrome, for example, Wilson disease, cystinosis, galactosemia, hereditary fructose intolerance and von Gierke disease, are also rare. RTA associated with certain drugs such as antivirals for the treatment of HIV and viral hepatitis is increasing in incidence [6].

Type 3 Mixed RTA is vanishingly rare hereditary form of disease mostly affecting children from Arabic, North African, and Middle Eastern descent.

Pathophysiology

Type 1 Distal RTA

Distal tubule is responsible for generating new bicarbonate under influence of aldosterone. Damage to alpha-intercalated cells of distal tubule causes no new generation of bicarbonate and thus no hydrogen ions. This raises the pH of urine due to an inability to excrete acid and generate acidic urine in the distal tubule, even in states of metabolic acidosis. It is associated with hypokalemia due to the failure of H/K ATPase.

Other mechanisms include decreased functioning of H-ATPase, increased leak of protons from the tubule back into the lumen as seen in amphotericin B toxicity and reduced sodium reabsorption due to damage to alpha-intercalated cells of distal tubule which decreases the secretion of both protons and potassium. That is why, in cases of impaired sodium reabsorption, which most often occurs with obstructive uropathy or sickle cell disease, hyperkalemia may be observed.

Incomplete distal RTA: Patients with the incomplete form of distal RTA have a persistently high urine pH and hypocitraturia, as in the complete form, but can maintain net acid excretion and the plasma bicarbonate concentration in the normal range. The pathogenesis of this disorder is not well understood. These patients can develop hypercalciuria, hypocitraturia, and nephrolithiasis, and treatment with alkali therapy may ameliorate stone formation. Thus, incomplete distal RTA should be considered in any calcium stone formers with a urine pH persistently 5.5 or higher in the absence of infection.

Genetic Causes

Autosomal dominant: Mutations of the SLC4A1 gene (chromosome 17q21-q22), which encodes the chloride-bicarbonate exchanger (AE1 or band 3), have been described in several families with distal RTA, causing mild acidosis.

Autosomal recessive with deafness: Patients with mutations in the gene ATP6V1B (chromosome 2p13), which is expressed in alpha-intercalated cells of distal tubule and cochlear encoding the B1 subunit of H-ATPase, have distal RTA and bilateral sensorineural deafness. Untreated patients develop severe metabolic acidosis with poor growth, rickets, and nephrocalcinosis during infancy and early childhood [7].

Autosomal recessive without deafness:  Patients with mutations in the gene ATP6V0A4 (chromosome 7q33-q34), which encodes the a4 subunit of H-ATPase, develop distal RTA without early hearing loss. The severity of metabolic acidosis and its associated findings of failure to thrive, rickets, and nephrocalcinosis are similar to that seen in patients with mutations that affect the B1 subunit.

Investigations have also shown an association of pathogenic alleles of SLC34A1 to both autosomal dominant and recessive forms of the renal stone disease [8].

Type 2 Proximal

Normally 85% to 90% of bicarbonate is reabsorbed at proximal tubule, and only 10% reabsorbed at distal tubule. Due to a bicarbonate leak, impaired proximal HCO3 reabsorption in proximal tubule results in excess HCO3 in urine leading to metabolic acidosis. It is often associated with Fanconi syndrome and is rarer than type 1. Hypokalemia is common due to osmotic diuresis because of decreased HCO3 reabsorption causing increased flow rate to distal tubule and causing increased K excretion.

Due to a reduced capacity to reclaim filtered bicarbonate, a patient with proximal RTA will be able to completely reclaim filtered bicarbonate if the plasma bicarbonate concentration is below the patient’s reduced threshold for reclaiming bicarbonate, thus maintaining the normal or near normal urine pH. If the plasma bicarbonate is above this level, bicarbonate appears in the urine raising the pH of urine, as the filtered bicarbonate load will exceed the reduced absorptive capacity. This is why, in proximal RTA, the urine pH is variable and dependent upon whether the patient is being treated with alkali therapy.

Proximal RTA in adults may also result from carbonic anhydrase inhibitors, which impair proximal bicarbonate reabsorption without affecting the reabsorption of other proximal tubule solutes. Nephrotoxic drugs such as tenofovir and ifosfamide can produce Fanconi syndrome.

Genetic Causes [9]

Autosomal recessive: Rare mutations in the gene SLC4A4, which encodes the sodium bicarbonate cotransporter, are associated with isolated proximal RTA. This disorder presents with severe hypokalemic, hyperchloremic, metabolic acidosis, growth retardation, and ocular abnormalities including glaucoma, cataracts, and band keratopathy.

Autosomal dominant: The molecular basis for this form of familial proximal RTA is unclear, and is not due to a defect in genes that are known to be involved in proximal bicarbonate reabsorption. Clinical manifestations were limited to short stature and metabolic acidosis as reported in some families.

Type 3 Mixed

Type 3 is a vanishingly rare combination of types 1 and 2. Inherited type 3 RTA is caused by mutations of CA II (chromosome 8q22) resulting in carbonic anhydrase II deficiency.

TYPE 4 Hyperkalemic

The principal buffers in the urine are ammonia and phosphate (titratable acid). Ammonium excretion requires the renal synthesis of ammonia and the secretion of hydrogen ions from the collecting tubular cells into the tubular lumen where they are trapped as ammonium (NH4+).

Hypoaldosteronism causes hyperkalemia and metabolic acidosis. Hyperkalemia impairs ammonia genesis in the proximal tubule and reduces the availability of NH3 to buffer urinary hydrogen ions and decreases hydrogen ion excretion in urine. The ability to acidify urine in this type of RTA is due to the inadequate amount rather than the complete absence of NH3 available for buffering of protons. Even if only a few protons are secreted distally, urine pH will fall, and this is why these patients have a urine pH less than 5.5. Most common cause of type 4 RTA in adults is hyporeninemic hypoaldosteronism which is frequently observed among patients with mild to moderate chronic kidney disease, especially if due to diabetic nephropathy.

Resistance to the action of aldosterone is observed in patients with a chronic tubulointerstitial disease, those treated with potassium-sparing diuretics, and rare congenital disorder called pseudohypoaldosteronism. [10]

History and Physical

Type 1 Distal

This type presents with Rickets, growth failure, osteomalacia due to metabolic acidosis. Hypercalciuria, hypocitraturia (citrate is reabsorbed as a buffer for hydrogen ions), and alkaline urine all leading to nephrocalcinosis (calcium phosphate stones) and recurrent UTIs; ESRF may result due to nephrocalcinosis. Hypokalemia can lead to muscle weakness and arrhythmia [11].

Type 2 Proximal

Chronic metabolic acidosis leeches calcium out of bones and causes osteomalacia. Hypokalemia as potassium binds to HCO3 in urine and loss of phosphate in urine leads to hypophosphatemic rickets. There is also the loss of glucose, urate, and amino acids in the urine.

Type 3 Mixed

Characterized by a clinical syndrome known as Guibaud-Vainsel syndrome or marble brain disease, with osteopetrosis, RTA of mixed type, cerebral calcification, and mental retardation. Other clinical features include bone fractures (due to increased bone fragility) and growth failure. Excessive facial bone growth leads to facial dysmorphism and conductive hearing loss and blindness due to nerve compression.

Type 4 Hyperkalemic

It differs from other RTAs as causing hyperkalemia due to aldosterone deficiency. Mild metabolic acidosis is present.

Evaluation

Clinicians should consider the presence of RTA in any patient with an otherwise unexplained normal anion gap (hyperchloremic) metabolic acidosis. The first step in the diagnosis of a patient with a reduced serum bicarbonate and elevated chloride concentration is to confirm that metabolic acidosis is present by measuring the blood pH [12][13].

Plasma HCO3 Levels:

• Type 1: Less than 10 to 20 mEq/L
• Type 2: 12 to 18 mEq/L
• Type 4: Greater than 17 mEq/L

Plasma Potassium: Low in type 1 and type 2, high in type 4, type 1 (due to decreased reabsorption of Na in distal tubule) [14]

BUN/Cr: Normal or near normal (rules out renal failure as the cause of acidosis)

Urinalysis: Urine pH inappropriately alkaline (greater than 5.5) despite metabolic acidosis in type 1, also in type 2 if HCO3 above reabsorptive threshold (12 to 18 mEq/L), and acidic less than 5.5 in type 2 and 4

Urine culture: Rule out urinary tract infection with the urea-splitting organism as it may elevate urine pH

Urine anion gap ([Na + K] - Cl): Positive gap signifies low NH4Cl excretion which causes decrease chloride in urine along with hyperchloremic metabolic acidosis suggesting RTA.

Specific tests:

Acid load test: Infuse acid into blood with 100 mg/kg of ammonium chloride and check urine pH hourly and plasma HCO3 at 3-hour interval. A healthy person will be able to excrete acid and will decrease urine pH. Those with distal RTA cannot excrete acid and urine pH will remain basic despite increasingly acidic serum. Plasma HCO3 should drop below 21 mmol/l unless the patient vomits (in which case test should be repeated with antiemetic). If urine pH remains greater than 5.5 despite plasma HCO3 of 21 mmol/L the diagnosis of type 1 RTA is confirmed.

Bicarbonate infusion test: Fractional bicarbonate excretion is measured after an infusion of bicarbonate. The serum bicarbonate concentration approaches the normal level in the body after the infusion, which is more than the reabsorption threshold of the patient with type 2 Proximal RTA. Urine pH rises because of the appearance of greater than 15% of filtered bicarbonate in urine.

Urine Na: Type 4 RTA presents with persistently high urine Na despite restricted Na diet because of aldosterone deficiency or resistance.

Treatment / Management

Correction of chronic academia with alkali administration is warranted to prevent its catabolic effects on bone and muscles. Correction of metabolic acidosis requires Oral bicarbonate replacement at 1-2 meq/kg per day by sodium bicarbonate or potassium citrate [15]. Potassium citrate replacement may be necessary for patients with hypokalemia, nephrolithiasis, or nephrocalcinosis. Underlying conditions should be sought and treated. Most of the bicarbonate is absorbed in the proximal tubule, so distal RTA is relatively easy to correct. Proximal tubule will absorb the given bicarbonate and correct acidosis.

High doses of bicarbonate greater than 10 mmol/kg per day are required to treat type 2 RTA. Raising the serum bicarbonate concentration will increase the filtered bicarbonate load above the proximal tubule's reduced absorptive capacity, resulting in a marked bicarbonate diuresis, so a larger amount of alkali is required to account for these urine loses. Increased bicarbonate concentration in urine induced by alkali therapy also increases urinary potassium losses because increased sodium and water delivery to the distal tubule stimulates potassium secretion. Administration of potassium salts minimizes the degree of hypokalemia associated with alkali therapy. Thiazide diuretics cause volume depletion which will enhance bicarbonate reabsorption in type 2 RTA.

Hypophosphatemia due to decreased proximal phosphate reabsorption and reduced activation of vitamin D also occurs in some patients and may be a major contributor to the development of bone disease. Thus, both phosphate and vitamin D supplementation may be required to normalize the serum phosphate and reverse the metabolic bone disease.

Fludrocortisone 0.1 mg per day is effective in managing hyperkalemia associated with aldosterone deficiency. However, it is not usually used because hypertension, heart failure, and edema may be exacerbated in patients with renal insufficiency. Most patients can be effectively managed with a limitation of dietary potassium to 40 to 60 mEq per day and, if necessary, diuretics, for example, loop or thiazide [16].

Differential Diagnosis

• Cystinosis

• Ehlers-Danos Syndrome

• Multiple Myeloma 

• Pseudohypoaldosteronism

• Pyruvate Carboxylase deficiency 

• Sjorgren Syndrome

• Systemic Lupus Erythematosus 

• Tyrosinemia

• Wilson disease