Proximal Renal Tubular Acidosis in Methylmalonic Acidemia

Abstract

A patient with methylmalonic acidemia was found to have a persistent hyperchloremic acidosis. Investigation documented the presence of a proximal renal tubular acidosis. Between 14 and 18 months of age the urinary pH was as high as 8.0 when the serum bicarbonate was 17 mEq/liter and the threshold for bicarbonate was at 16-17 mEq/liter. When restudied at 33 months of age, the threshold had risen to 20 mEq/liter, but this was still abnormal and supplemental treatment was required to keep the serum concentration of bicarbonate above 20 mEq/liter. It is postulated that organic acid metabolites which accumulate in this and related disorders may interfere with renal tubular function as has been shown for maleic acid in experimental animals.

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

“…Together, these findings suggest that cell and/or mitochondrial autonomous effects, rather than elevations in methylmalonic acid per se, are responsible for the hepatic mitochondrial changes and the GFR decrease associated with proximal tubular mitochondrial dysfunction. This challenges previous theories about methylmalonate as a toxic agent (21,22) and further supports observations from gene therapy studies showing that the long-term correction of Mut −/− mice is mediated by a small number of stably transduced cells (13,23). The concept that a kidney with normal Mut activity may be protected from MMA nephrotoxicity is reinforced by a recent study that proposed providing renal allografts as a form of "cellular" therapy for MMA, despite the implicit knowledge that the allograft will be exposed to very high metabolite concentrations in the recipient patient (24).…”

Progressive neurologic disability in methylmalonic acidemia despite transplantation of the liver

“…A variety of renal complications have been observed in patients with methylmalonic acidemia [3,15,18], including renal tubular acidosis observed in infancy [23], and these have been thought to be direct consequences of the systemic methylmalonic acid accumulation. It is clear from experience with this patient that following transplantation of the liver, and the subsequent improvement that takes place in systemic methylmalonate concentrations, renal dysfunction does not reverse, but rather it relentlessly progresses to renal failure.…”

Persistent hyperkalaemia in vitamin B12 unresponsive methylmalonic acidaemia

“…These abnormalities could be the product of methylmalonic acidaemia, in view of the fact that renal involvement can occur in methylmalonic acidaemia. Such renal involvement includes progressive renal disease associated with hyperuricaemia (Broyer et al, 1974;Whelan et al, 1979), and discrete proximal renal tubular acidosis (Wolff et al, 1985). The aetiology of the renal function abnormalities in our patient is not clear.…”