Might distal renal tubular acidosis be a proximal tubular cell disorder?

Incomplete renal tubular acidosis (RTA) and overt distal RTA may be different stages of the same underlying pathophysiology in certain individuals. The rationale that draws these conditions together is the relatively alkaline pH of the urine, hypocitraturia, and a possible familial association. The rate of excretion of ammonium (NH4+), on the other hand, suggests that these conditions stem from fundamentally different lesions. To explain this difference, we suggest that two possible disorders may result in the evolution from incomplete RTA to overt distal RTA. One subgroup could have gradient-limited distal RTA, while the other subgroup may have a lower pH of the intracellular fluid of the proximal convoluted tubular epithelium. Indices of proximal intracellular pH (rates of excretion of NH4+, NH3, and citrate) were culled from the literature spanning the years 1959 to 1991 on patients with incomplete RTA and overt distal RTA. Three points emerge: (1) the rate of excretion of NH4+ was lower in patients with overt distal RTA than in normals following an acute acid load (23 +/- 1 v 49 +/- 3 mumol/min); (2) the concentration of NH3 in the urine was almost 25-fold higher in incomplete RTA than in normals (69 +/- 14 v 3 +/- 0.4 nmol/min); and (3) in incomplete RTA, the pH of the urine fell to very low values (4.9 +/- 0.1) when high urine flows were induced with furosemide. The low pH of the urine would therefore suggest that many of these patients do not gradient-limited distal RTA, but more likely have proximal renal epithelial cell acidosis. We hypothesize that this high rate of excretion of NH4+ and low rate of excretion of citrate in the absence of acidosis or hypokalemia is consistent with proximal cell acidosis. To explain a transition from incomplete RTA to overt distal RTA, we speculate that toxicity of high concentrations of NH3 in the medullary interstitium as well as nephrolithiasis and nephrocalcinosis due to low urinary citrate and possibly an alkaline medullary interstitium may lead to damage of structures in this region.