Hayim Boichis

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.

The Renal Response of Children to Acute Ammonium Chloride Acidosis

Extract: The present observations were undertaken to establish the response of children to the acute administration of ammonium chloride, in order to provide a basis for identifying and interpreting abnormalities in the mechanisms involved in renal acid base regulation. Fifty-eight normal children aged 4 to 13 years were studied before and for 5 hours following administration of ammonium chloride. Group A, consisting of 23 children, received 75 mEq/m2 body surface area or 2.75 mEq/kg body weight. Group B, consisting of 35 children, received 150 mEq/m2, or 5.45 mEq/kg.Values for serum electrolytes, urea, creatinine, osmolality and acid-base parameters in children in Groups A and B are shown in tables I and III. Urinary pH and rates of excretion of titratable acid and ammonium are shown in tables II and IV. The relations between blood tCO2 and urinary concentration of H+, rate of excretion of titratable acid, and rate of excretion of ammonium for all subjects are shown in figures 1-3. Progressively lower values of pH were observed over the entire range of tCO2 studied. During control periods, an inverse correlation was present between tCO2 and rates of excretion of both titratable acid and ammonium. At levels of tCO2 below 22.5 mmoles/l, the rate of excretion of TA and ammonium became constant, with mean rates of excretion of 52 μEq/min/1.73 m2 (range, ± 2 SD, 33 to 71), and 73 μEq/min/1.73 m2 (46 to 100), respectively.These data are interpreted as demonstrating the importance of the blood tCO2 or, more precisely, the concentratibn of bicarbonate in glomerular filtrate in urinary acidification mechanisms as well as in control of excretion of bicarbonate. Assessment of renal acidifying mechanisms requires administration of sufficient ammonium chloride or other acidifying substance to depress blood tCO2 to levels well below the renal threshold.The physiologic validity of the hydrogen ion clearance index must be questioned, since correcting rates of excretion of hydrogen ion for concentration of total CO2 in blood presumes that there is a fixed relation between these two measurements. In figure 4, urinary excretion of total hydrogen ion is plotted as a function of blood tCO2. Hydrogen ion excretion, negligible at tCO2 levels of 26 or more, increases steadily as tCO2 falls to values below the threshold. The rate of excretion then reaches maximal levels, despite further reduction in blood tCO2. Thus, the hydrogen ion clearance index is valid only over the range of blood tCO2 in which there is a linear relationship with rate of excretion of hydrogen ion. Renal acidification mechanisms should be evaluated with blood tCO2 several millimoles below the threshold, assuring a maximal response and permitting direct comparison with normals. In subjects with a normal bicarbonate threshold, blood tCO2 should be depressed at least to 17–18 mmoles/l in infants and 20–21 mmoles/l in older children. If an abnormal bicarbonate threshold is present the dose must be adjusted accordingly.Speculation: These studies suggest that both the concentration of bicarbonate in glomerular filtrate and the level of the bicarbonate threshold play major roles in the regulation of renal excretion of hydrogen ion.

Bicarbonate reabsorption and hydrogen ionexcretion in children with renal tubular acidosis

Nine children with renal tubular acidosis have been evaluated on the basis ofbicarbonate reabsorption during intravenous infusion, and of excretion of hydrogen ion following administration of ammonium chloride. In 3, who were shown to have distal renal tubular acidosis, bicarbonate threshold and rate of reabsorption were normal; they had small amounts of bicarbonate in urine, however, even at low levels of serum bicarbonate, owing to their inability to depress urinary pH below 6.5. Six children had proximal renal tubular acidosis, primary in 4 and due to the Fanconi syndrome in 2. Although all had a low bicarbonate threshold and 4 had a low Tm, urinary pH and excretion of hydrogen ion during metabolic acidosis were within normal limits in each subject when the serum bicarbonate was below the threshold. Classification of patients with renal tubular acidosis as either proximal or distal is of importance because of major differences in clinical features, complications, and therapy.

Fanconi syndrome with renal sodium wasting and metabolic alkalosis

Abstract A boy with idiopathic Fanconis syndrome is described who exhibited, in addition to the usual features, an unusually large degree of urinary sodium chloride wastage accompanied by a metabolic alkalosis. No evidence of distal tubular abnormality was found and all urinary findings were explicable on the basis of proximal tubular malfunction. Investigations revealed that a combination of sodium, chloride and potassium depletion produced an alkalosis despite the presence of a low bicarbonate threshold commonly found in this syndrome. Detailed studies suggested that although potassium depletion may play a smaller role than sodium chloride wastage, its effects are real and in some degree mediated by an effect upon proximal tubular bicarbonate reabsorption.

Renal excretion of hydrogen ion in children with idiopathic growth retardation

Mild, compensated metabolic acidosis was demonstrated in a group of children with growth retardation of undetermined etiology. In response to administration of a single large dose of ammonium chloride, urinary acidification was normal, but there was a limitation in the rate of excretion of hydrogen ion as titratable acid and as ammonium. Since these children had no other evidence of renal impairment, it is postulated that growth retardation per se modifies renal regulation of acid-base balance through effects on both phosphorus and ammonia metabolism.