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      Effect of Febuxostat on the Progression of Renal Disease in 5/6 Nephrectomy Rats with and without Hyperuricemia

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          Abstract

          Background/Aims: The effect of febuxostat (Fx), a non-purine and selective xanthine oxidase inhibitor, on glomerular microcirculatory changes in 5/6 nephrectomy (5/6 Nx) Wistar rats with and without oxonic acid (OA)-induced hyperuricemia was evaluated. Methods: Four groups were studied: 5/6 Nx+vehicle (V)+placebo (P) (n = 7); 5/6 Nx+V+Fx (n = 8); 5/6 Nx+OA+P (n = 6) and 5/6 Nx+OA+Fx (n = 10). OA (750 mg/kg/day, oral gavage) and Fx (3–4 mg/kg/day, drinking water) were administered for 4 weeks. Systolic blood pressure, proteinuria and plasma uric acid were measured at baseline and at the end of 4 weeks. Measurement of glomerular hemodynamics and evaluation of histology were performed at the end of 4 weeks. Results: 5/6 Nx+OA+P rats developed hyperuricemia, renal vasoconstriction and glomerular hypertension in association with further aggravation of afferent arteriolopathy compared to 5/6 Nx+V+P. Fx prevented hyperuricemia in 5/6 Nx+OA+Fx rats and ameliorated proteinuria, preserved renal function and prevented glomerular hypertension in both 5/6 Nx+V+Fx and 5/6 Nx+OA+Fx groups. Functional improvement was accompanied by preservation of afferent arteriolar morphology and reduced tubulointerstitial fibrosis. Conclusion: Fx prevented renal injury in 5/6 Nx rats with and without coexisting hyperuricemia. Because Fx helped to preserve preglomerular vessel morphology, normal glomerular pressure was maintained even in the presence of systemic hypertension.

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          Most cited references 22

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          A role for uric acid in the progression of renal disease.

          Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 +/- 2.5 versus 17.5 +/- 3.4%; P < 0.05) and interstitial fibrosis (1.89 +/- 0.45 versus 1.52 +/- 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhibitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.
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            Febuxostat compared with allopurinol in patients with hyperuricemia and gout.

            Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 micromol per liter) to receive either febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 micromol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of febuxostat vs. allopurinol; P=0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of febuxostat vs. allopurinol; P=0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group). Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups. Copyright 2005 Massachusetts Medical Society.
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              Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.

              Hyperuricemia is associated strongly with the development of hypertension, renal disease, and progression. Allopurinol decreases serum uric acid levels by inhibiting the enzyme xanthine oxidase. We hypothesized that administrating allopurinol to decrease serum uric acid levels to the normal range in hyperuricemic patients with chronic kidney disease may be of benefit in decreasing blood pressure and slowing the rate of renal disease progression in these patients. We conducted a prospective, randomized, controlled trial of 54 hyperuricemic patients with chronic kidney disease. Patients were randomly assigned to treatment with allopurinol, 100 to 300 mg/d, or to continue the usual therapy for 12 months. Clinical, hematologic, and biochemical parameters were measured at baseline and 3, 6, and 12 months of treatment. We define our study end points as: (1) stable kidney function with less than 40% increase in serum creatinine level, (2) impaired renal function with creatinine level increase greater than 40% of baseline value, (3) initiation of dialysis therapy, and (4) death. One patient in the treatment group dropped out because of skin allergy to allopurinol. Serum uric acid levels were significantly decreased in subjects treated with allopurinol, from 9.75 +/- 1.18 mg/dL (0.58 +/- 0.07 mmol/L) to 5.88 +/- 1.01 mg/dL (0.35 +/- 0.06 mmol/L; P < 0.001). There were no significant differences in systolic or diastolic blood pressure at the end of the study comparing the 2 groups. There was a trend toward a lower serum creatinine level in the treatment group compared with controls after 12 months of therapy, although it did not reach statistical significance (P = 0.08). Overall, 4 of 25 patients (16%) in the allopurinol group reached the combined end points of significant deterioration in renal function and dialysis dependence compared with 12 of 26 patients (46.1%) in the control group (P = 0.015). Allopurinol therapy significantly decreases serum uric acid levels in hyperuricemic patients with mild to moderate chronic kidney disease. Its use is safe and helps preserve kidney function during 12 months of therapy compared with controls. Results of this study need to be confirmed with an additional prospective trial involving a larger cohort of patients to determine the long-term efficacy of allopurinol therapy and in specific chronic kidney disease subpopulations.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2008
                May 2008
                24 April 2008
                : 108
                : 4
                : p69-p78
                Affiliations
                Departments of aNephrology and bPathology, INC Ignacio Chavez, Mexico City, Mexico; cTAP Pharmaceutical Products Inc., Lake Forest, Ill., and dNephrology, Hypertension and Transplantation, University of Florida, Fla., USA
                Article
                127837 Nephron Physiol 2008;108:p69
                10.1159/000127837
                18434753
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 1, References: 34, Pages: 1
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