The contribution of residual nephrons within the chronically diseased kidney to urate homeostasis in man

Abstract

Forty-nine clearance studies were performed in thirty-six patients with stable chronic renal disease in order to elucidate the role of residual nephrons in the maintenance of urate homeostasis. With increasing severity of disease, plasma urate neither became elevated as soon nor did it increase to so great a degree as plasma urea nitrogen. This appeared to be at least partially explicable on the basis of a marked increase in urate excretion per nephron (UV urate: C inulin), which was particularly striking when inulin clearance had decreased to less than 15 ml. per minute. At this level of renal function a fivefold increase in UV urate: C inulin was observed whereas the plasma urate concentration had less than doubled. Pyrazinamide, a potent inhibitor of tubular secretion of urate, was administered to all patients in order to assess the role of each component of the bidirectional transport system for urate at different stages of disease. Until the inulin clearance had decreased to less than 10 ml. per minute, an appropriate augmentation of tubular secretory rate for urate (TS ur) was observed for any degree of hyperuricemia. Reabsorption of filtered urate remained essentially complete in patients with C inulin over 15 ml. per minute. With advanced disease, urate secretion was markedly reduced in association with a striking increase in fractional excretion of filtered urate. The latter phenomenon was of much greater quantitative significance, thus accounting for the marked increase in excretion per nephron in advanced disease. Repeat studies following the induction of normouricemia by allopurinol administration indicated that urate secretion of patients with disease, as in normal subjects, is profoundly influenced by the plasma urate level, as opposed to fractional excretion of urate, which was not predictably altered. Thus, until advanced uremia supervenes, residual nephrons of the chronically diseased kidney retain integrity of urate reabsorptive and secretory transport. When disease becomes severe, glomerulotubular imbalance evolves, permitting excretion of 45 per cent of the filtered urate. Thus, although substrate-regulated tubular secretion is the principal homeostatic mechanism for urate excretion in normal and the majority of diseased kidneys, glomerular filtration assumes this role in far advanced renal disease.