Renal Tubular Acidosis – Causes, Symptoms, Treatment

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Renal Tubular Acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine.[1] In renal physiology, when blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for the exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by failure to reabsorb sufficient bicarbonate ions (which are alkaline) from the filtrate in the early portion of the nephron (the proximal tubule) or by insufficient secretion of hydrogen ions (which are acidic) into the latter portions of the nephron (the distal tubule). Although a metabolic acidosis also occurs in those with chronic kidney disease, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes. RTA is usually an incidental finding based on routine blood draws that show abnormal results. Clinically, patients may present with vague symptoms such as dehydration, mental status changes, or delayed growth in adolescents. [rx]

Kidneys play a pivotal role in maintaining the acid-base balance of body along with lungs, and they do so by reabsorbing filtered bicarbonate and removing excess hydrogen ions. Renal disorders due to the removal of HCO3 or acid handling in the presence of relatively preserved GFR are collectively referred to as renal tubular acidosis. It is a non-anion gap hyperchloremic metabolic acidosis.

There are four subtypes of RTA. The three main subtypes of RTA correlate with three mechanisms that facilitate renal acid-base handling, i.e., proximal bicarbonate reabsorption mainly as a result of Na-H exchange (85% to 90%), distal hydrogen ion excretion-primarily a function of collecting tubules and generation of NH3, the principal urinary buffer .

The subtypes are as follows:
  • Type 1: Distal RTA
  • Type 2: Proximal RTA
  • Type 3: Mixed RTA
  • Type 4:Hyporeninemic hypoaldosteronism RTA

Pathophysiology

Type 1 Distal RTA

  • The 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 the 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 .
  • 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 is similar to that seen in patients with mutations that affect the B1 subunit.
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Investigations have also shown an association of pathogenic alleles of SLC34A1 to both autosomal dominant and recessive forms of the renal stone disease .

Type 2 Proximal
  • Normally 85% to 90% of bicarbonate is reabsorbed at the proximal tubule, and only 10% reabsorbed at the 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
  • 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 the 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 of 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. 

Causes of Renal Tubular Acidosis

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 .
  • 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) 
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) , 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
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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 
  • 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
  • MiscellaneousInterstitial nephritis, chronic obstruction of the urinary tract, adrenal insensitivity to angiotensin II, renal insufficiency

Symptoms of Renal Tubular Acidosis

RTA is usually asymptomatic. Severe electrolyte disturbances are rare but can be life-threatening.

  • Nephrolithiasis and nephrocalcinosis are possible, particularly with type 1 RTA.
  • Signs of ECF volume depletion may develop from urinary water loss accompanying electrolyte excretion in type 2 RTA.
  • People with type 1 or type 2 RTA may show symptoms and signs of hypokalemia, including muscle weakness, hyporeflexia, and paralysis. Bony involvement (eg, bone pain and osteomalacia in adults and rickets in children) may occur in type 2 and sometimes in type 1 RTA.
  • Type 4 RTA is usually asymptomatic with only mild acidosis, but cardiac arrhythmias or paralysis may develop if hyperkalemia is severe.
  • pain in the back or side that spreads to the lower abdomen
  • pain while urinating
  • pee that is red, brown, or cloudy
  • frequent urge to urinate
  • nausea and vomiting

Over time, RTA can affect bone development and keep a child from growing as much as he or she should. This is often why doctors suspect RTA in the first place.

Other symptoms of RTA you might notice include:

  • confusion, decreased alertness, or fatigue
  • increased breathing and heart rates
  • decreased urination
  • muscle weakness
  • muscle cramps and pain in the back and abdomen
  • rickets (a disorder that can cause bone pain and skeletal and dental deformities)

Diagnosis of Renal Tubular Acidosis

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 .
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 .
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) 

  • 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.
  • Tests that may be ordered include:
    • Arterial blood gas
    • Blood chemistry
    • Urine pH
    • Acid-load test
    • Bicarbonate infusion test
    • Urinalysis
    • The health care provider will perform a physical exam and ask about your symptoms.
    • X-rays
    • Ultrasound
    • CT scan
Specific tests
  • Acid load test – Infuse acid into the blood with 100 mg/kg of ammonium chloride and check urine pH hourly and plasma HCO3 at a 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 the 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 the urine.
  • Urine Na Type 4 RTA presents with persistently high urine Na despite restricted Na diet because of aldosterone deficiency or resistance.
  • Basic metabolic panel with calculation of the anion gap (hyperchloremic non anion gap metabolic acidosis)
  • Blood urea nitrogen (BUN) and creatinine
  • Urine sodium, potassium and chloride concentrations with calculation of urine anion gap (UAG = [Na+] +[ K+] -[Cl])
  • Urinalysis including urine pH
  • More specialized tests with nephrology consultation could include: fractional K excretion, fractional HCO3 excretion, 24-hour urine collection for creatinine, calcium, and citrate
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Proximal (type 2) renal tubular acidosis
  • Serum bicarbonate 14-20 meq/L
  • Urine pH in steady state below 5.5 (not on alkali treatment)
  • Serum K+ usually low
  • Urine anion gap in metabolic acidosis negative indicating appropriate ammoniagenesis.
  • Response to alkali therapy: high doses required (10-20meq/kg/day) due to urinary loss. Treatment worsens hypokalemia and K+ supplement required. Treatment will result in bicarbonaturia and high urine pH.
  • Accompanying resorptive defects (Fanconi syndrome) may occur with phosphaturia, glucosuria, aminoaciduria, uricosuria.
Distal (type 1) renal tubular acidosis
  • Serum bicarbonate can be severely decreased, less than 10meq/L
  • Urine pH above 5.5 (impaired urinary acidification)
  • Serum K+ may be low or high depending on defect
  • Urine anion gap in metabolic acidosis positive (impaired ammonium excretion)
  • Response to alkali therapy: smaller doses of alkali needed (1-2meq/kg/day) compared to proximal (type 2)
  • Associated clinical clues: nephrocalcinosis, nephrolithiasis (particularly calcium phosphate stones), hypercalcemia, hypocitraturia.
Hypoaldosteronism (type 4 RTA)
  • Serum bicarbonate mildly decreased(>17meq/L)
  • Hyperkalemia
  • Urine anion gap in metabolic acidosis positive (impaired ammoniagenesis)
  • Urine pH less than 5.5
  • Response to treatment: depends on the etiology. Withdraw any causative medications. Fludrocortisone can be effective in hyporeninemic hypoaldosteronism.\
  • Associated medical conditions: primary or acquired hypoaldosteronism, chronic interstitial nephropathies, K+-sparing diuretics.

Treatment of Renal Tubular Acidosis

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 . 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 the bone disease. Thus, both phosphate and vitamin D supplementation may be required to normalize the serum phosphate and reverse 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 .

References

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