Nonacidotic proximal tubulopathy transmitted as autosomal dominant trait

The family of a patient with a nonacidotic and hypercalciuric proximal tubulopathy was studied. The proband showed glycosuria, aminoaciduria, tubular proteinuria, renal hypophosphatemia, and urate tubular hyporeabsorption without bicarbonate loss. He also presented increased urine calcium excretion, plasma 1,25-dihydroxyvitamin D, and enteral calcium absorption. Clinical consequences of the tubulopathy were osteopenia and calcium kidney stones. Fifteen of the proband's relatives were studied; six of them had renal hypophosphatemia, 10 presented hypercalciuria, and three showed both hypercalciuria and hypophosphatemia. No other reabsorption defects were observed. High plasma levels of 1,25-dihydroxyvitamin D were found in 13 family members; their values correlated positively with calcium excretion and negatively with tubular phosphate reabsorption. None produced stones or had reduced mineral bone density. Hypophosphatemia and hypercalciuria occurred in the two generations studied; their transmission was independent of gender, and male-to-male transmission occurred for both defects. Our findings suggest that a genetic alteration of proximal tubular function could cause multiple reabsorption defects in the proband or renal phosphate leakage in the proband's relatives. The genotypic alteration causing the proximal dysfunctions may be monogenic, with an autosomal dominant pattern of inheritance and variable expressivity. Increased calcium excretion may be due to the proximal tubular alteration; alternatively, it may be the result of a genetic background predisposing to idiopathic hypercalciuria. Phosphate and calcium loss could stimulate 1,25-dihydroxyvitamin D synthesis in proximal tubular cells.