Impairment of Tubular Secretion of Urate in Renal Transplant Patients on Cyclosporine

Abstract

The prevalence of hyperuricemia was investigated in 214 kidney allograft recipients, 81 were on azathioprine and steroids and 133 on cyclosprine (CyA) and low-dose steroids or on triple therapy. All had stable renal function, serum creatinine < 2.5 mg/dl, and a follow-up between 12 and 120 months. At the time of the study, blood and urine samples were obtained to perform tests of renal function. The renal handling of urate was evaluated by a combined pyrazinamide and probenecid test in 35 selected patients (12 normouricemic on azathioprine, 9 normouricemic on CyA and 14 hyperuricemic on CyA). The prevalence of hyperuricemia was higher in the group of patients on CyA (19.7 vs. 66.9%, p < 0.001), as well as the concentration of serum urate (6.1 ± 1.9vs.7.6 ± 1.7, p < 0.001), and serum creatinine (1.2 ± 0.3 vs. 1.4 ± 0.4, p < 0.001). In patients on CyA, multivariate analysis showed that the most important predictive variables of hyperuricemia were: serum creatinine, FE_urate, diuretic use and CyA blood levels (r = 0.73, p < 0.0001). Thirteen patients on CyA (9.9%) had at least one episode of gouty arthritis. Those patients were older than the hyperuricemic patients without gout (45.7 ± 6.7 vs. 37.1 ± 13.5 years, p < 0.01), had worse renal function (serum creatinine 1.9 ± 0.4 vs. 1.5 ± 0.4 mg/dl, p < 0.01), and higher prevalence of hypertension (100 vs. 63.1%, p < 0.05). The combined pyrazinamide-probenecid test showed a lower FE_urate during the maximal probenecid-induced uricosuria (p < 0.05) and a lower urate secretion (p < 0.05) in hyperuricemic patients on CyA than in normouricemic on azathioprine or normouricemic on CyA. There were no differences either in the presecretory reabsorption or in the postsecretory reabsorption. According to the previous results, 20 hyperuricemic patients (11 with gouty arthritis) were treated with benziodarone (50-100 mg/day). At 1 month, there was a decrease in the serum urate (10.1 ± 1.8 vs. 5.1 ± 1.4 mg/dl, p < 0.01), and a parallel increase in FE_urate (7.1 ± 2.4 vs. 25.4 ± 7.4%, p < 0.001), that persisted after 1 year of follow-up. The drug was well tolerated, and we did not observe side effects. The serum creatinine, CyA dose and CyA blood levels remained unchanged. In conclusion, hyperuricemia is a frequent complication in transplant patients on treatment with CyA. Our data suggest that the disorder could be due to an impairment of the tubular secretion of urate. Benziodarone is an alternative to allopurinol for the treatment of this complication, which does not have important side effects.

Glomerular and Tubular Function in Renal Transplant Patients Treated with and without Ciclosporin A

“…Hyperuricaemia is another common feature of CsA treatment [8, 12, 13, 14]. In the present study, hyperuricaemia was seen in RTx both with and without chronic CsA treatment.…”

“…In the present study, hyperuricaemia was seen in RTx both with and without chronic CsA treatment. Based on a reduced fractional urate clearance in CsA-treated subjects, previous studies [12, 13, 14]have suggested that the hyperuricaemia is secondary to a CsA-induced tubular dysfunction. One problem with these studies was the use of creatinine clearance as a measure of GFR.…”

“…The most convincing evidence of CsA-induced functional tubular changes comes from reports of increased urinary excretion rates of magnesium [8, 9]and incomplete distal tubular acidification [10, 11]. The hyperuricaemia in CsA-treated patients has also been attributed to an effect of CsA on renal tubular function [12, 13, 14]. Using the lithium clearance method, some studies have tried to evaluate whether CsA affects proximal and distal tubular reabsorption rates of sodium and water [2, 3, 4, 15, 16, 17, 18, 19, 20, 21], but the results are conflicting.…”

Use of Uric Acid-Lowering Agents Limits Experimental Cyclosporine Nephropathy

“…As many as 50% of patients taking CsA become hyperuricemic [5,6,7] and approximately 10% develop gout [8]. The hyperuricemia from CsA results from a decrease in the glomerular filtration rate [9] as well as an increase in net tubular urate reabsorption [10,11]. The most important complication of CsA is nephrotoxicity, which is characterized by striped interstitial fibrosis, tubular atrophy, and arteriolar hyalinosis [1,12,13].…”

A retrospective study of hyperurecemia in renal transplant recipients

“…Post operatively patients received cyclosporine, mycophenolate mofetil, azathioprin, sirolimus or tacrolimis. Cyclosporine and other calcinurin inhibitors are known causes of hyperuricemia 2,[29][30][31][32][33][34][35] . We found in this study that cyclosporine is associated with 76% of the patients with increase uric acid level.…”