Proximal renal tubular acidosis. A defect in bicarbonate reabsorption with normal urinary acidification.

Extract: This report concerns two patients with primary renal tubular acidosis (RTA) in whom the abnormality in hydrogen excretion was shown to result from inappropriate urinary loss of bicarbonate due to a low renal hicarbonate threshold. On the basis of the findings, a new definition and reclassification of RTA is proposed. The clinical course and response to medication is illustrated in figs. 1-4. Repeated measurements of clearances of creatinine, inulin, and PAH gave normal values (table I). Excretion of aminoacids (table II) was normal in both patients. After water restriction, the urinary osmolality was 990 mOsm/kg water for K.J. and 1088 mOsm/kg water for S.G. No reducing substance was found in the urine of K.J.; glucose was present in trace amounts on several occasions in the urine of S.G. Tubulare absorptiono f phosphate was always in the normal range, 80 to 90 percent of the filtered amount. Both children had an adequate response to the oral administration of ammonium chloride, providing no alkali therapy was being administered at the time of the test (table III). In fig. 5, rates of reabsorption and excretion of bicarbonate, expressed as mmoles/100 ml glomerular filtrate (GF) are plotted against serum bicarbonate concentration in mmoles/liter. Data from 2 studies are included in the figure. K.J. started to excrete bicarbonate into the urine at a serum bicarbonate level of 18 to 19 mmoles/liter; the Tm of reabsorption was low, being approximately 2.1 mmoles/100 ml GF. In S.G., although the threshold was similarly depressed (19 to 20 mmoles/liter), the Tm of reabsorption was at the lower limit of the normal range (2.5 to 2.6 mmoles/100 ml GF). The ratio of reabsorbed bicarbonate to Tm has been plotted as a function of the ratio of filtered bicarbonateto Tm (fig. 6). The data from the studies in K.J. demonstrate a splay very similar to that of normal infants. S.G., however, has a markedly increased splay. During bicarbonate infusion and when rates of bicarbonate reabsorption were near the Tm, acetazolamide was administered intravenously in a single dose of 100 mg. In both children, marked inhibition of bicarbonate reabsorption was demonstrated. At similar rates of filtered bicarbonate, the urinary excretion increased two-to-three-fold with a concomitant decrease in the rate of reabsorption (table V). Results for glucose reabsorption in K.J. are close to those of normal adults with a threshold of 300 mg/min/1.73 m2 and a Tm of over 400. In contrast, S.G. had small amounts of glucose in the control urines and the glucose threshold was abnormally low, approximately 100 mg/min/1.73 m2. Although blood glucose was not maintained at high values long enough to be certain that the Tm had been reached, values as high as 327 mg/min/1.73 m2 were obtained, suggesting that his glucose Tm was normal. After administration of histamine, the acidity of the gastric fluid increased markedly and the values of free acid and total titratable acid compare closely with that of normal children (table VI). Histologic examination of a percutaneous renal biopsy specimen from K.J. showed minimal hypercellularity of the glomerular stalks. The lumens of the proximal convoluted tubules were frequently open; no significant histologic abnormalities were seen. No glomerular or tubular abnormalities were observed in a biopsy specimen from S.G. Both patients reported here were able to respond normally during metabolic acidosis with excretion of very acid urine containing adequate amounts of titratable acid and ammonium. However, when alkali was administered and serum bicarbonate levels were brought into the range of normal, the urine, normally neutral or slightly acid at this time, contained inappropriately large amounts of bicarbonate and was consistently alkaline. During bicarbonate titration, bicarbonate was found in urine only when the threshold was exceeded. Below this level, the urine was normally acid and therefore bicarbonate free. At a plasma bicarbonate concentration above the threshold, an abrupt increase in urine bicarbonate concentration occurred, as in the normal subject. This observation helps to differentiate this type of abnormality from the bicarbonate loss in gradient type RTA, in which a small constant rate of excretion of bicarbonate in urine persists despite lowering of plasma bicarbonate concentration well below threshold values. A satisfactory classification of RTA must take into account patients with acidification defects as well as those with abnormalities in bicarbonate reabsorption. A distinction should also be made between primary and secondary disease. RTA is a condition in which there is a defect in renal excretion of hydrogen or reabsorption of bicarbonate, or both, out of proportion to impairment of glomerular filtration. It is suggested that RTA be divided into two forms: 1. a proximal form caused by a defect in bicarbonate reabsorption; and 2. a distal form due to inability to establish an adequate pH gradient between blood and distal tubular fluid. Although pH gradients are established throughout the length of the nephron and bicarbonate reabsorption is not confined to the proximal segment, most filtered bicarbonate is reabsorbed in the proximal tubule whereas production of ammonium and titratable acid with low urinary pH is primarily a distal function. The patients described belong to the first category and as such represent a new form of RTA. Patients with proximal RTA require inordinately high doses of citrate or bicarbonate to maintain serum bicarbonate levels within the normal range, due to the great loss of bicarbonate in urine. Failure of a patient with RTA to respond to usual doses of bicarbonate may be a clue that the defect is of the proximal type. Speculation: The studies presented appear to justify distinguishing between two types of renal tubular acidosis; one resulting from a proximal tubular lesion, the other a distal malfunction. Since the ultimate prognosis seems to vary with the site of the acidification deficit, this distinction has more than academic importance.