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      Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease

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          Abstract

          Background

          The role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline.

          Methods

          This is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m 2 and who were followed up for > 1 year were included in our analysis. Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in male and ≥ 6.0 mg/dL in female or when hypouricemic medications were prescribed.

          Results

          Hyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR (−6.3% per year vs. −0.9% per year, p = 0.008). However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: −5.3 ± 8. 2 vs. 0.2 ± 6.2 mL/min/1.73 m 2 per year, p = 0.001 by Wilcoxon signed-rank test).

          Conclusions

          Although hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency.

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          Most cited references24

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          Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells.

          Recent experimental and human studies have shown that hyperuricemia is associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remodeling. Elevated levels of C-reactive protein (CRP) have emerged as one of the most powerful independent predictors of cardiovascular disease. In addition to being a marker of inflammation, recent evidence suggests that CRP may participate directly in the development of atherosclerotic vascular disease. For investigating whether uric acid (UA)-induced inflammatory reaction and vascular remodeling is related to CRP, the UA-induced expression of CRP in human vascular smooth muscle cells (HVSMC) and human umbilical vein endothelial cells (HUVEC) was examined, as well as the pathogenetic role of CRP in vascular remodeling. It is interesting that HVSMC and HUVEC expressed CRP mRNA and protein constitutively, revealing that vascular cells are another source of CRP production. UA (6 to 12 mg/dl) upregulated CRP mRNA expression in HVSMC and HUVEC with a concomitant increase in CRP release into cell culture media. Inhibition of p38 or extracellular signal-regulated kinase 44/42 significantly suppressed UA-induced CRP expression, implicating these pathways in the response to UA. UA stimulated HVSMC proliferation whereas UA inhibited serum-induced proliferation of HUVEC assessed by 3H-thymidine uptake and cell counting, which was attenuated by co-incubation with probenecid, the organic anion transport inhibitor, suggesting that entry of UA into cells is responsible for CRP expression. UA also increased HVSMC migration and inhibited HUVEC migration. In HUVEC, UA reduced nitric oxide (NO) release. Treatment of vascular cells with anti-CRP antibody revealed a reversal of the effect of UA on cell proliferation and migration in HVSMC and NO release in HUVEC, which suggests that CRP expression may be responsible for UA-induced vascular remodeling. This is the first study to show that soluble UA, at physiologic concentrations, has profound effects on human vascular cells. The observation that UA alters the proliferation/migration and NO release of human vascular cells, mediated by the expression of CRP, calls for careful reconsideration of the role of UA in hypertension and vascular disease.
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            Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.

            Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease. We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes. Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 +/- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy. Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.
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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

                Contributors
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central
                1471-2369
                2014
                16 April 2014
                : 15
                : 63
                Affiliations
                [1 ]Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
                [2 ]Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea
                [3 ]Transplantation Research Institute, Seoul National University Medical Research Center, Seoul, Korea
                [4 ]Department of Medicine, Program of Immunology, The Graduate School, Seoul National University, Seoul, Korea
                [5 ]Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
                [6 ]Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
                [7 ]Department of Pediatrics and Adolescent Medicine, Seoul National University College of Medicine, Seoul, Korea
                [8 ]Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Korea
                [9 ]Transplantation Center, Seoul National University Hospital, Seoul, Korea
                [10 ]Department of Internal Medicine, Eulji General Hospital, Eulji University, 14 Hangeulbiseong-ro, Nowon-gu, Seoul 139-872, Korea
                [11 ]Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-Ro Jongno-Gu, Seoul 110-744, Korea
                Article
                1471-2369-15-63
                10.1186/1471-2369-15-63
                4021172
                24739095
                09cbf022-9869-4b81-9bcd-8eef6c9c142c
                Copyright © 2014 Han et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 October 2013
                : 1 April 2014
                Categories
                Research Article

                Nephrology
                glomerular filtration rate,hyperuricemia,polycystic kidney,autosomal dominant,uric acid
                Nephrology
                glomerular filtration rate, hyperuricemia, polycystic kidney, autosomal dominant, uric acid

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