Renal pathogenesis of familial hyperuricemia: studies in two kindreds.

The pathogenesis of familial hyperuricemia has been investigated in two kindreds in whom hyperuricemia was present in members of successive generations. Enzymatic and metabolic studies, including the incorporation of isotopically labeled glycine into urinary uric acid and assessment of the total excretion of oxypurines in one family, excluded a metabolic etiology. No secondary cause of hyperuricemia was identified in either family. Fractional excretion of uric acid was less than 6.2% in all hyperuricemic individuals studied, while creatinine clearances were normal. Tubular secretion of uric acid and tubular reabsorption of uric acid were studied in an affected teenager from each family while receiving a purine-free diet. Inhibition of secretion of uric acid with pyrazinamide decreased fractional excretion of uric acid to 0.6% in patient S and to 0.7% in patient B. Tubular secretion of uric acid at maximal response to pyrazinamide in these patients was 0.393 and 0.410 mg/dl glomerular filtration rate(nl response 0.300 to 1.30 mg/min/100ml inulin clearance). Probenecid, an inhibitor of uric acid reabsorption, increased uric acid excretion by 3.9 mg/min and by 3.2 mg/min (nl response 1.7 +/- 0.3 mg/min) in patients S and B. Tubular reabsorption of uric acid distal to secretory sites was determined by assessing the uricosuric response to probenecid plus pyrazinamide. Uric acid excretion increased by only 0.08 mg/min in patient A and by 0.17 mg/min in patient B (nl response 0.9 mg/min). Ascorbic acid increased fractional excretion of uric acid by 7.2% in patient S but was not uricosuric in patient B or any hyperuricemic member of his family. These data suggest that hyperuricemia in these families is due to diminished renal clearance of uric acid and that the reduced clearance is due to increased tubular reabsorption of uric acid distal to secretory sites.