Renal Tubular Acidosis

The term Renal Tubular Acidosis (RTA) is applied to a group of transport defects in the reabsorption of bicarbonate (HCO₃-), the excretion of hydrogen ion (H+), or both. This condition was first described in 1935,¹Lightwood R. Calcium infarction of the kidneys in infants. Arch Dis Child 1935;10: 205-206.   confirmed as a renal tubular disorder in 1946,²Albright F, Burnett CH, Parson W, Reifenstein EC, Roos A. Osteomalacia and late rickets: Various etiologies met on United States with emphasis on that resulting from specific forms of renal acidosis, therapeutic implications for each etiological subgroup, and relationship between osteomalacia and Milkman’s syndrome. Medicine 1946;25: 399-479.   and designated as “renal tubular acidosis” in 1951.³Pines KL, Mudge GH. Renal tubular acidosis with osteomalacia. Am J Med 1951;11: 302-311.  

RTA is a clinical syndrome characterized by metabolic acidosis secondary to a disorder in renal acidification. The acidification may be manifested by a defect in the renal tubular reabsorption of bicarbonate and/or urinary excretion of hydrogen ion.^4-6Sethi S, Singh N, Gil H, Bagga A. Genetic studies in a family with distal renal tubular acidosis and sensorineural deafness. Indian Pediatrics 2009;46:425-427.

Sharma A, Singh R, Yang C et al. Bicarbonate therapy improves growth in children with incomplete distal renal tubular acidosis. Pediatr Nephrol 2009;24:1509-1516.  

Statistics of RTA

There are no widely accepted statistics on the prevalence rate of RTA. The disease, however, may at any age and afflicts men more than women.

Types of RTA

In terms of clinical and physiopathological aspects this disease can be classified into three groups: distal RTA or type I, proximal RTA or type II, and hyperkalemic RTA or type IV (Table 1).⁵Rodríguez J. Renal Tubular Acidosis: The clinical entity. J Am Soc Nephrol 2002;13:2160-2170.  ^,7Taslipinar A, Kebapcilar L, Kutlu M, Sahin et al. HDR syndrome (hypoparathyroidism, sensorineural deafness and renal disease) accompanied by renal tubular acidosis and endocrine abnormalities. Inter Med 2008;47:1003-1007.  

Type 1 (distal) RTA: Type 1 is impairment in hydrogen ion secretion in the distal tubule, resulting in a persistently high urine pH (> 5.5) and systemic acidosis. Plasma HCO₃ is usually < 15 m Eq/L, and hypokalemia, hypercalciuria, and decreased citrate excretion are often present.

This syndrome is rare. Sporadic cases occur most often in adults and may be primary (nearly always in women) or secondary. Familial cases usually first manifest in childhood and are most often autosomal dominant. Potassium level may be high with chronic obstructive uropathy or sickle cell anemia.

Type 1 RTA is confirmed by a urine pH that remains > 5.5 during systemic acidosis. The acidosis may occur spontaneously or be induced by an acid load test (administration of ammonium chloride, 100 mg/kg po). Normal kidneys reduce urine pH to < 5.2 within 6 hour of acidosis.

Type 2 (proximal) RTA: Type 2 is impairment in HCO₃ resorption in the proximal tubules, producing a urine pH > 7 if plasma HCO₃ concentration is normal, and a urine pH < 5.5 if plasma HCO₃ concentration is already depleted from ongoing losses. This syndrome may occur as part of a generalized dysfunction of proximal tubules and can be associated with increased urinary excretion of glucose, uric acid, phosphate, amino acids, citrate, calcium, potassium, and protein. Osteomalacia or osteopenia (including rickets in children) may develop. Mechanisms may include hypercalciuria, hyperphosphaturia, alterations in vitamin D metabolism, and secondary hyperparathyroidism.

This sometimes has other etiologies, including vitamin D deficiency, chronic hypocalcemia with secondary hyperparathyroidism, kidney transplantation, heavy metal exposure, and other inherited diseases eg, fructose intolerance, Wilson’s disease, oculocerebrorenal syndrome [Lowe syndrome], cystinosis.

Type 2 RTA is diagnosed by measurement of the urine pH and fractional HCO₃ excretion during HCO₃ infusion (NaHCO₃, 0.5 to 1.0 m Eq/kg/h IV). In type 2, urine pH rises above 7.5, and the fractional excretion of HCO₃ is > 15%. Because intravenous HCO₃ can contribute to hypokalemia, potassium supplements should be given in adequate amounts before infusion.

Type 4 (generalized) RTA: Type 4 results from aldosterone deficiency or unresponsiveness of the distal tubule to aldosterone, because aldosterone triggers Na resorption in exchange for K and hydrogen, there is reduced K excretion, causing hyperkalemia, and reduced acid excretion. Hyperkalemia may decrease ammonia excretion, contributing to metabolic acidosis. Urine pH is usually appropriate for serum pH (usually < 5.5 when there is serum acidosis). Plasma HCO₃ is usually > 17 m Eq/L. This disorder is the most common type of RTA. It typically occurs sporadically secondary to impairment in the renin-aldosterone-renal tubule axis (hyporeninemic hypoaldosteronism).

Type 4 RTA is confirmed by a transtubular K concentration gradient of < 5 (normal value > 10), which indicates inappropriately low urinary K excretion, suggesting hypoaldosteronism or tubular unresponsiveness to aldosterone.

Clinical presentations of RTA

Patients are typically asymptomatic; very rarely they may present with Kussmaul’s breathing due to severe acidosis and respiratory compensation. Laboratory findings together with a past medical history of conditions associated with RTA should prompt further investigation for RTA if necessary.

RTA is usually asymptomatic. However, bony involvement (eg, bone pain and osteomalacia in adults and rickets in children) may occur in type 2 and sometimes in type 1 RTA. Nephrolithiasis and nephrocalcinosis are possible, particularly with type 1 RTA.

Management of RTA

The goals of pharmacotherapy are

• To correct the acidosis
• To reduce morbidity
• To prevent complications

Alkalinizing agents, electrolytes, diuretics, mineralocorticoids, and vitamin D supplements can be used against acidosis.

Alkalizing agents

These are used as gastric, systemic, and urinary alkalinizers and have been used in the treatment of acidosis resulting from metabolic and respiratory causes, including diarrhea, kidney disturbances, shock, and diabetic coma. Alkanizing agents like potassium citrate, sodium citrate, citric acid, sodium bicarbonate are being used widely. Alkaline citrates have been used as an efficient therapy in hypocitraturic calcium nephrolithiasis, uric acid lithiasis, cystinuria, and renal tubular acidosis.

Growth was evaluated in a group of 10 infants and children with familial or idiopathic classic renal tubular acidosis in whom alkali therapy was initiated at ages ranging from 8 days to 9.5 years. The results of the this study indicate that in infants and children with classic RTA, impaired growth can be prevented or corrected when alkali therapy is continuously provided in amounts that sustain correction of acidosis.⁸Elisabeth Mcsherry, R. Curtis Morris. Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. The Journal of Clinical Intivestigation 1978;61:509-527.  

A study was conducted by Nash MA et al on children suffering from renal tubular acidosis. The effect of alkali therapy on growth of these children was evaluated. Treated with high-dose alkali therapy, most of these patients showed improvement in growth rate. These patients were followed up to 8 years from the initiation of the alkali therapy, seven out of these nine patients were completely normal even after the therapy was stopped.⁹Nash MA et al. Renal tubular acidosis in infants and children. The Journal of Peadiatrics 1972;80(5):738-748.  

Shiohara M et al reported a case of a 12-year-old girl who presented with permanent isolated proximal renal tubular acidosis (pRTA), glaucoma, band keratopathy, mild cataract and short stature.¹⁰Shiohara M, Igarashi T, Mori T, Komiyama A. Genetic and long-term data on a patient with permanent isolated proximal renal tubular acidosis. Eur J Pediatr 2000;159(12):892-4.   Severe metabolic acidosis was caused by the impairment of bicarbonate reabsorption in the proximal tubules and alkali therapy improved her acidemia. Her height and height velocity (HV) were very low (-4.0 SD and -4.4 SD, respectively) before alkali treatment, but both improved after initiating alkali therapy at the age of 2 years and 3 months. The patient’s body height and HV were 131.5 cm (-2.7 SD) and 4.0 cm (-2.0 SD), respectively at the age of 12 years.

Role of potassium citrate in renal tubular acidosis

Electrolytes are used to correct disturbances in fluid and electrolyte homeostasis or acid-base balance and to reestablish the osmotic equilibrium of specific ions.

Potassium chloride is essential for the transmission of nerve impulses, the contraction of cardiac muscle, the maintenance of intracellular tonicity, skeletal and smooth muscle function, and the maintenance of normal renal function.

In case of diarrheal dehydration there is huge amount of electrolyte imbalance in the body. A double blind, randomized study was conducted on 94 children aged less than 5 years with severe diarrheal dehydration and acidosis were randomly treated with world health organization’s oral rehydrating solution (WHO-ORS) containing sodium chloride, potassium chloride, sodium bicarbonate and glucose or an oral solution with tripotassium citrate monohydrate replacing the sodium bicarbonate and potassium chloride in the WHO solution (Potassium citrate ORS).¹¹Islam R. Can potassium citrate replace sodium bicarbonate and potassium chloride of oral rehydration solution? Arch Dis Child 1985. 60(9):852-5.   A significant improvement in the serum potassium concentration was observed both at 24 hours (P< 0.02) and at 48 hours (P< 0.01) after the start of treatment in the group receiving potassium citrate rehydration solution (Table 2). This study shows that potassium citrate salt can be used in place of sodium bicarbonate and potassium chloride in oral rehydration solution.

Gradual potassium depletion occurs via renal excretion, through gastrointestinal loss, or because of low intake. Depletion usually results from diuretic therapy, primary or secondary hyperaldosteronism, diabetic ketoacidosis, severe diarrhea (if associated with vomiting), or inadequate replacement during prolonged parenteral nutrition.

Diuretics

Diuretics are used to overcome fluid overload. They increase the distal delivery of sodium by rendering the collecting tubule impermeable to chloride and increase the exchange of sodium for hydrogen and potassium.

These diuretics increase the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. The dose must be individualized to patient. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced.

Some of the diuretics act from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the sodium, potassium, and chloride carrier system. It increases urinary excretion of sodium, chloride, and water, but does not significantly alter the glomerular filtration rate, renal plasma flow, or acid-base balance.

Mineralocorticoids

Mineralocorticoids may be useful for aldosterone deficiency. Combine mineralocorticoid therapy with sodium loading and diuretics to prevent heart failure. These mineralocorticoids promote increased sodium reabsorption and potassium loss in renal distal tubules.

Vitamin D supplements

Vitamin D is a fat-soluble vitamin that promotes the absorption of calcium and phosphorus in the small intestine. It also promotes renal tubule phosphate resorption. It is used in pRTA as multi therapy with large quantities of alkali and potassium supplementation.

Conclusion

RTA has been reported in patients with various metabolic disorders, such as diabetic ketoacidosis, thyrotoxicosis with acute pancreatitis, alcoholic liver disease, and sickle cell disease, as well as in children with chronic hydronephrosis. It has also been described in a variety of conditions related to drugs, such as amphotericin B therapy for fungal infections, lithium for manic disorders, hydrochlorthiazide and triamterene for hypertension during pregnancy, as well as after toluene abuse. With delayed diagnosis and treatment, the disease evolves towards renal failure as a consequence of nephrocalcinosis; however excellent prognosis is associated with early diagnosis and treatment.

Due to varying clinical presentations of RTA the treatment approach may differ. But the management of acidosis with alkali supplements remains the first line treatment.

References

1. Lightwood R. Calcium infarction of the kidneys in infants. Arch Dis Child 1935;10: 205-206.
2. Albright F, Burnett CH, Parson W, Reifenstein EC, Roos A. Osteomalacia and late rickets: Various etiologies met on United States with emphasis on that resulting from specific forms of renal acidosis, therapeutic implications for each etiological subgroup, and relationship between osteomalacia and Milkman’s syndrome. Medicine 1946;25: 399-479.
3. Pines KL, Mudge GH. Renal tubular acidosis with osteomalacia. Am J Med 1951;11: 302-311.
4. Sethi S, Singh N, Gil H, Bagga A. Genetic studies in a family with distal renal tubular acidosis and sensorineural deafness. Indian Pediatrics 2009;46:425-427.
5. Rodríguez J. Renal Tubular Acidosis: The clinical entity. J Am Soc Nephrol 2002;13:2160-2170.
6. Sharma A, Singh R, Yang C et al. Bicarbonate therapy improves growth in children with incomplete distal renal tubular acidosis. Pediatr Nephrol 2009;24:1509-1516.
7. Taslipinar A, Kebapcilar L, Kutlu M, Sahin et al. HDR syndrome (hypoparathyroidism, sensorineural deafness and renal disease) accompanied by renal tubular acidosis and endocrine abnormalities. Inter Med 2008;47:1003-1007.
8. Elisabeth Mcsherry, R. Curtis Morris. Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. The Journal of Clinical Intivestigation 1978;61:509-527.
9. Nash MA et al. Renal tubular acidosis in infants and children. The Journal of Peadiatrics 1972;80(5):738-748
10. Shiohara M, Igarashi T, Mori T, Komiyama A. Genetic and long-term data on a patient with permanent isolated proximal renal tubular acidosis. Eur J Pediatr 2000;159(12):892-4.
11. Islam R. Can potassium citrate replace sodium bicarbonate and potassium chloride of oral rehydration solution? Arch Dis Child 1985. 60(9):852-5.