HDCN Article Review/Hyperlink

Vezzoli G, Zerbi S, Baragetti I, et al

Nonacidotic proximal tubulopathy transmitted as autosomal dominant trait

Am J Kidney Dis (Apr) 29:490-495 1997

The authors studied a new Italian patient afflicted with several abnormalities in proximal tubular function, and his relatives. The patient had a single episode of nephrolithiasis at age 47. He was first brought to medical attention with proteinuria; this was both albumin and "tubular proteinuria" though the proportions of each are not stated. He was found to have hypercalciuria (whether fasting or not) with normal plasma calcium, high fractional excretion of urate, beta-2-microglobulinuria, glycosuria and aminoaciduria, with low tubular phosphate reabsorption. Serum electrolytes and acid-base values were normal. Serum aldosterone and renin values were high. Serum creatinine was 1.39 mg/dl. Sonography was normal (no nephrocalcinosis) and histology showed no sclerosis, and intraluminal giant cells as observed in two previous similar cases (Vezzoli et al AJKD 25:222 (95), ("probably due to an increased epithelial cell turnover").

The patient's 15 relatives studied included other members of his generation, his children and their cousins. Ten were hypercalciuric, though none were stone formers (a deceased unstudied uncle had had a stone). They did not have altered urate clearance, did not have proteinuria, aminoaciduria, glycosuria and had normal renin and aldosterone levels. Six had hypophosphatemia with low tubular absorption. Lumbar spine mineral bone density was not altered.

Comment: The patient has an interesting constellation of findings, but it is not at all clear that his relatives are afflicted with the same disease. "None of the proband's relatives had the complete tubulopathy". It seems likely that the proband actually has more than one genetic disorder with little basis for the title's implication that this is a distinct "autosomal dominant" disorder. It very well may be polygenic. The proband's single episode of calcium stone disease, distinguishing him from the other hypercalciurics, might be related to his high FE of urate, which only he had (though absolute levels of uricosuria is not given). Stones do not appear to be a familial trait.

The authors state that 1) "hypophosphatemia can be considered as the phenotypic marker of a proximal tubular disorder, genetically determined in this family"; 2) "the increase of plasma 1,25 dihydroxyvitamin D is the most frequent alteration found in this family"; and 3) "that hypophosphatemia was not necessarily associated in the family members with high calcium excretion does not confirm our previous hypothesis on the pathogenesis of the hypercalciuria". Then what is the common feature? They must then conclude that the hypercalciuria could be due to "some other genes predisposing to idiopathic hypercalciuria", a condition common in the general population. They are left to invoke a mechanism shown in Dent's disease (an X-linked hypercalciuric proximal tubulopathy without acidosis, associated with nephrocalcinosis, renal failure and rickets), namely that "a single gene alteration can cause different defects of proximal tubular reabsorption in members of the same family". Of the 15 relatives studied, 13 had some abnormality, a high number even for an autosomal dominant disorder. No control family is studied; this might provide some index of "normal" urinary homogeneity among relatives.

In summary, this is not a very neat study; unfortunately the family is not easily squeezed under a single diagnosis or syndrome. The proband does not have Dent's disease or Fanconi's syndrome, but the authors have not yet figured out what the key, hereditary feature is. (David S. Goldfarb, M.D., NYU School of Medicine)

The abstract of this paper is available from the AJKD online at this site.