Renal Transplant-Associated Hyperuricemia and Gout

Gout is a common problem among renal transplant patients with a prevalence of 2 to 13%. Hyperuricemia is even more common (1‐7). This association is important in two respects. First, gout is a disabling disease, and may cloud the outcome of a patient for whom rehabilitation has been particularly hard fought. Second, the treatment of gout in renal allograft recipients poses more potential pitfalls than in the general population. This article will explore the metabolic basis of gout in allograft recipients. The currently available methods for treating gout will be examined with particular emphasis on drug interactions and specific needs of the transplant patient. Pathophysiology of Hyperuricemia and Gout Gout is a painful disorder caused by an inflammatory reaction to monosodium urate crystals in joint fluid and periarticular tissue. The propensity for developing gout is directly related to tissue uric acid content. Most uric acid in the extracellular fluid is in the form of monosodium urate. A uric acid concentration .7 mg/dl favors the spontaneous crystallization of monosodium urate. The actual probability of gout arising in a joint depends not only on the tissue content of urate, but the pH and temperature of the joint fluid, as well as its macromolecular constituency. However, any condition promoting increased production or reduced excretion of uric acid can predispose to gout. In primates, the kidneys are the main route for disposal of purine metabolites. Uric acid is freely filtered by the glomerulus. Tubular processing of uric acid is complex. Secretion occurs in the early proximal tubule via an organic acid transporter. At more distal sites in the proximal tubule, reabsorption and further secretion occur. Other organic anions compete with urate for proximal secretion; thus, uric acid levels may rise in patients with lactic acidosis or ketoacidosis. To the extent that the body’s uric acid content rises with reduced excretion, one might surmise that gout is common among patients with chronic renal failure (CRF). In fact, its prevalence is lower than expected, an observation that may have several explanations. Extrarenal disposal of uric acid is probably enhanced in CRF (8). In addition, the fractional excretion of uric acid rises in remnant nephrons (9 ‐11). The importance of this phenomenon is upheld by the observation that tubulointerstitial renal diseases demonstrate an especially strong tendency toward hyperuricemia (12). Finally, there is evidence that the inflammatory response to monosodium urate crystals may be suppressed by the uremic state (13,14). Hypertensive nephropathy is associated with high serum uric acid levels. It has been hypothesized that sodium-dependent hypertension and hyperuricemia may be pathogenetically linked, possibly reflecting damage to the peritubular microcirculation causing reduced delivery of uric acid to its tubular secretion sites, or increased ambient generation of lactate to compete for secretion at those sites (12). Many drugs and toxins influence nephronal handling of uric acid. Several of these deserve mention. Lead intoxication may evoke a syndrome of hypertension, progressive renal insufficiency, and hyperuricemia. Both loop and thiazide diuretics reduce uric acid excretion, presumably by causing mild volume depletion with consequent enhancement of proximal tubular reabsorption. Loop agents may also compete with uric acid for secretion by the proximal organic acid transporter.