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Renal tubular acidosis (RTA) was observed in a preterm boy shortly after birth. His mother had glaucoma and had been treated during pregnancy with oral acetazolamide, a carbonic anhydrase inhibitor. When RTA developed, acetazolamide was detected in his serum demonstrating transplacental acetazolamide passage.
The primary or hereditary form of distal renal tubular acidosis (dRTA), although rare, has received increased attention recently because of dramatic advances in the understanding of its genetic basis. The final regulation of renal acid excretion is effected by various acid/base transporters localized in specialized cells in the cortical collecting and outer medullary collecting tubules. Inherited defects in two of the key acid/base transporters involved in distal acidification, as well as mutations in the cytosolic carbonic anhydrase gene, can cause dRTA. The syndrome is inherited in both autosomal dominant and recessive patterns; patients with recessive dRTA present with either acute illness or growth failure at a young age, sometimes accompanied by deafness, whereas dominant dRTA is usually a milder disease and involves no hearing loss. The AE1 gene encodes two Cl-/HCO3- exchangers that are expressed in the erythrocyte and in the acid-secreting intercalated cells of the kidney. AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane. Several mutations in the AE1 gene cosegregate with dominant dRTA. The modest degree of hypofunction exhibited in vitro by these mutations, however, does not explain the abnormal distal acidification phenotype. Other AE1 mutations have been linked to a recessive syndrome of dRTA and hemolytic anemia in which hypofunction can be discerned by in vitro studies. Several mutations in the carbonic anyhdrase II gene are associated with the autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification. Some of these individuals present with deafness of the conductive type. By contrast, more recent studies have shown that mutations in ATP6B1, encoding the B-subtype unit of the apical H(+) ATPase, are responsible for a group of patients with autosomal recessive dRTA associated with sensorineural deafness. Thus, the presence of deafness and the type provide an important clue to the genetic lesion underlying hereditary dRTA.
Nephrocalcinosis and distal tubular acidosis are two infrequent processes caused by several etiologies which can present in association. This paper describes a clinical case of tubular acidosis and explains the differential diagnosis of both entities.
The case is reported of a 47 year old female patient admitted with asthenia, anorexia, nausea and constipation. The poor clinical features contrasted with the severe biological disturbances: 1 mmol.l-1 serum potassium, pH 7.26, 19 mmHg PaCO2, 8 mmol.l-1 bicarbonate, myoglobinaemia and myoglobinuria. The electrocardiogram showed a flattened T wave, an U wave, and a depressed ST segment. Potassium was given intravenously at a rate of 0.38 mmol.kg-1.h-1 during the first 24 h. Renal biopsy confirmed the diagnosis of distal renal tubular acidosis, but no aetiology could be found. This patient's excellent clinical tolerance of a severe hypokalemia suggested that the potassium pool could be replaced at slower rates than those suggested in the literature for patients with severe symptoms and signs.
Familial distal renal tubular acidosis (dRTA) and Southeast Asian ovalocytosis (SAO) may coexist in the same patient. Both can originate in mutations of the anion-exchanger 1 gene (AE1), which codes for band 3, the bicarbonate/chloride exchanger in both the red cell membrane and the basolateral membrane of the collecting tubule alpha-intercalated cell. Dominant dRTA is usually due to a mutation of the AE1 gene, which does not alter red cell morphology. SAO is caused by an AE1 mutation that leads to a nine amino acid deletion of red cell band 3, but by itself does not cause dRTA. Recent gene studies have shown that AE1 mutations are responsible for autosomal recessive dRTA in several countries in Southeast Asia; these patients may be homozygous for the mutation or be compound heterozygotes of two different AE1 mutations, one of which is usually the SAO mutation.
A case of anorexia nervosa in a 28-year-old woman with laxative abuse, hypopotassemia and severe metabolic acidosis, is described. The diagnosis of classical renal tubular acidosis, Type I, was confirmed by our inability to decrease urinary pH beyond 5.5 and to increase ammonia excretion during an ammonium chloride loading test. A bicarbonate loading test and normal plasma aldosterone with high renin activity excluded proximal renal tubular acidosis, hyporeninemic-hypoaldosteronemic renal tubular acidosis and Bartter's syndrome. The inability to increase ammonium excretion during severe metabolic acidosis following ammonium chloride loading did not favor the possibility of a transient physiological adaptation of ammoniagenesis at the tubular cell level, related to potassium depletion. Although mental disorder, laxative abuse, abstinence from food intake and severe potassium depletion intermingled in a vicious cycle, we assume that one of the following possibilities may explain the clinical presentation in our patient: either two separated and unrelated disorders, or laxative abuse as the cause of renal tubular acidification impairment.
Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities. Kidney Na+/HCO3- cotransporter (kNBC1) cDNA from peripheral lymphocytes from a patient with permanent isolated pRTA and bilateral glaucoma was screened, and a novel homozygous mutation, namely a cytosine-to-thymine transition at nucleotide 234, which resulted in the formation of a stop codon at codon 29, was identified. This homozygous mutation, Q29X, was identified in the unique 5'-end of the kNBC1 gene (SLC4A4) of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals indicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a truncated kNBC1 protein that lacks the 1007 amino acids of the carboxyl-terminus, and the effect on kNBC1 cotransport activity is likely to be a loss of function. In contrast, the pancreatic Na+/HCO3- cotransporter of the patient is not likely to be affected by this nonsense mutation. These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation.
Neither severe distal renal tubular acidosis nor hypercalciuria have been recognized to cause severe hypocalcaemia. We describe a 53 years old woman with distal renal tubular acidosis and hypercalciuria who demonstrated severe hypocalcemia, normalized after calcium and vitamin D supplementation and treatment with thiazide.
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The Canadian physiologist PA Stewart advanced the theory that the proton concentration, and hence pH, in any compartment is dependent on the charges of fully ionized and partly ionized species, and on the prevailing CO2 tension, all of which he dubbed independent variables. Because the kidneys regulate the concentrations of the most important fully ionized species ([K+], [Na+], and [Cl-]) but neither CO2 nor weak acids, the implication is that it should be possible to ascertain the renal contribution to acid-base homeostasis based on the excretion of these ions. One further corollary of Stewart's theory is that, because pH is solely dependent on the named independent variables, transport of protons to and from a compartment by itself will not influence pH. This is apparently in great contrast to models of proton pumps and bicarbonate transporters currently being examined in great molecular detail. Failure of these pumps and cotransporters is at the root of disorders called renal tubular acidoses. The unquestionable relation between malfunction of proton transporters and renal tubular acidosis represents a problem for Stewart theory. This review shows that the dilemma for Stewart theory is only apparent because transport of acid-base equivalents is accompanied by electrolytes. We suggest that Stewart theory may lead to new questions that must be investigated experimentally. Also, recent evidence from physiology that pH may not regulate acid-base transport is in accordance with the concepts presented by Stewart.
Amiloride is a "potassium-sparing" diuretic agent of moderate natriuretic potency with site of action in postmacula densa segments of the distal nephron. In isolated segments of mammalian cortical distal nephron, amiloride diminishes sodium reabsorption and transtubular electrical PD and inhibits potassium secretion. We investigated the effects of long-term administration of a demonstrably maximal dose of amiloride (1.0 mg/kg b.i.d.) on plasma and urine acid-base and electrolyte composition in fixed steroid-replaced ADX dogs. Amiloride administration resulted in potassium retention and hyperkalemia and reduced net acid excretion and caused chronic hyperchloremic metabolic acidosis. The cumulative reduction in net acid excretion and severity of systemic acidosis were not significantly different in additional groups in which potassium retention was prevented by restriction of dietary potassium during amiloride administration or in which amiloride was administered to animals with pre-existing dietary potassium depletion. The response of urine pH and ammonium excretion, however, differed among groups. In the steady state of chronic acidosis, urine pH and ammonium concentration were lowest in the hyperkalemic group and highest in the hypokalemic group, and among the three groups pH and ammonium were positively correlated (r = 0.67, p less than 0.001). Ammonium concentration varied inversely with plasma potassium concentration. Net acid excretion rates returned to control levels during the steady state of chronic amiloride-induced acidosis in the three groups. During continued amiloride administration, sustained correction of acidosis by long-term oral administration of sodium bicarbonate did not result in negative values of net acid excretion; that is, amiloride did not cause net wasting of base at normal plasma bicarbonate concentration. The results of these studies suggest that chronic amiloride administration results in a sustained impairment of renal hydrogen ion secretion restricted to the distal nephron and not dependent on alterations in potassium balance. Differences in potassium balance (positive or negative) appeared to influence only the availability of ammonia for diffusion into urine and steady-state urine pH, but not the steady-state net rate of renal hydrogen ion secretion during amiloride. These studies identify an experimental model of chronic distal renal tubular acidosis in which external hydrogen ion balance is re-established during chronic acidosis even when the availability of ammonia for excretion is decreased.
Of nine women with hyperglobulinaemic renal tubular acidosis four presented with acidosis and five had the "incomplete" form of the disorder. Seven patients had nephrogenic diabetes insipidus, but none had the Fanconi syndrome. Investigation showed abnormal immunoglobulins and autoantibodies in all nine patients. Diseases coexisting with renal tubular acidosis were Sjögren's syndrome, hyperglobulinaemic purpura, autoimmune liver and thyroid disease, diffuse pulmonary fibrosis, and a peripheral neuropathy. It is suggested that this type of renal tubular acidosis might be due to an autoimmune process.
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