Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk

Servicio de Nefrología, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Clinical Journal of the American Society of Nephrology (Impact Factor: 4.61). 08/2010; 5(8):1388-93. DOI: 10.2215/CJN.01580210
Source: PubMed


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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    • "Hyperuricemia has been associated with the risk for CKD in observational studies in the general population [18e22], as well as with faster progression to kidney failure in patients with CKD [23] [24] and potential mechanisms whereby uric acid may engender/or amplify renal damage have been lucidly reviewed by Johnson et al. [9]. On the other hand, evidence that lowering uric acid levels may retard CKD progression has been investigated just in a small number of clinical studies [25] [26] and in a recently published, very large observational study in patients with hyperuricemia [27], but we still lack well powered randomized trials with uric acid lowering agents proving that reducing asymptomatic hyperuricemia may impact upon kidney outcomes in CKD patients. In the lack of such a trial we further explored the issue by adopting the T allele of the rs734553 polymorphism, the genetic variant most consistently associated (p < 10 À206 ) with hyperuricemia [2], as an unbiased and unconfounded marker of long term exposure to high uric acid levels. "
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    ABSTRACT: We have recently reported that a polymorphism (rs734553) in a major urate transporter gene (GLUT9) is a strong predictor of incident renal events in stage 2-5 CKD patients implying that life-time exposure to high uric acid levels may be causally implicated in CKD progression. Since disturbed NO bioavailability is a major pathway whereby high uric may cause renal damage, we tested the interaction between the major endogenous inhibitor of NO synthase, asymmetric-dimethylargine (ADMA), and the rs734553 polymorphism for CKD progression in the same cohort. Over a 29 ± 11 months follow-up the risk for incident renal events was higher in patients harboring the risk allele of the polymorphism (T) as compared to those without the risk allele (HR: 2.35, 95% CI: 1.25-4.42, P = 0.008) (p = 0.01). Similarly, patients with ADMA > median value had an increased risk for the same outcome (HR: 1.37, 95% CI: 1.06-1.76, P = 0.016). Interaction analysis showed a strong amplification by ADMA of the risk for renal events associated to the T allele because in adjusted (P = 0.016) and bootstrapping validated (P = 0.020) analyses the risk excess associated to this allele was progressively higher across increasing ADMA levels. The rs734553 polymorphism, the strongest genetic marker of uric acid levels discovered so far, interacts with ADMA in determining the risk for CKD progression in CKD patients. This synergic interaction conforms to biological knowledge indicating that disturbed NO bio-availability is a critical pathway whereby life time exposure to high uric acid may engender renal damage. Copyright © 2014 Elsevier B.V. All rights reserved.
    Nutrition, metabolism, and cardiovascular diseases: NMCD 11/2014; 25(2). DOI:10.1016/j.numecd.2014.10.016 · 3.32 Impact Factor
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    • "Moreover, it has been reported recently that allopurinol also reduced left ventricular mass index and improved flow-mediated dilatation among CKD stage 3 patients [33]. In another prospective, randomized trial, Goicoechea et al. [34] found that CKD patients with eGFR <60 mL/min/1.73 m2 randomized to allopurinol treatment for up to 24 months, displayed a 71 % lower relative risk of CV events, a 62 % lower relative risk of hospitalization, lower uric acid and CRP levels, and a much lower rate of renal disease progression compared with standard therapy. "
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    ABSTRACT: Purpose Allopurinol, for treating hyperuricemia, is associated with lower mortality among hyperuricemic patients without chronic kidney disease (CKD). Greater allopurinol utilization in hemodialysis (HD) in Japan versus other countries provides an opportunity for understanding allopurinol-related HD outcomes. Methods Data from 6,252 Japanese HD patients from phases 1–3 of the Dialysis Outcomes and Practice Patterns Study (1999–2008) at ~60 facilities per phase were analyzed. Mortality was compared for patients prescribed (25 %) versus not-prescribed allopurinol using Cox regression, overall, and in patient subgroups. Results Patients prescribed allopurinol were more likely to be younger, male, and non-diabetic, and had higher serum creatinine and lower (treated) serum uric acid levels (mean = 7.0 vs. 8.0 mg/dL, p < 0.001). The inverse association between allopurinol prescription and mortality in unadjusted analyses (HR 0.65, 95 % CI 0.52–0.81) was attenuated by covariate adjustment (HR 0.84, 0.66–1.06). In subgroup analyses, allopurinol was associated with lower mortality among patients with no history of cardiovascular disease (CVD) (HR 0.48, 0.28–0.83), but not among patients with CVD (HR 1.00, 0.76–1.32). A similar pattern was seen outside Japan and for cardiovascular (CV)-related mortality. Conclusions Allopurinol prescription was not significantly associated with case-mix-adjusted mortality in Japanese HD patients overall, but was associated with lower all-cause and CV-related mortality in the subgroup of patients with no prior CVD history. These findings in HD patients may be related to findings in non-dialysis CKD patients showing lower CV event rates and mortality, and improved endothelial function with allopurinol prescription. These results are useful for designing future trials of allopurinol use in HD patients.
    International Urology and Nephrology 06/2014; 46(9). DOI:10.1007/s11255-014-0731-0 · 1.52 Impact Factor
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    • "Correction of hyperuricemia appeared to attenuate ΔeGFR/year, especially for the patients in early CKD stages (1~3a), suggesting that hyperuricemia may influence renal function deterioration in some patients. Although our result is limited by small number of patients and short observation time, this is consistent with the previous finding that allopurinol therapy preserved sCr level and lowered the risk of renal progression in hyperuricemic patients with mild to moderate CKD [18,19]. On the contrary, hypouricemic treatment had no effect on preserving eGFR in patients with CKD stage 3b to 4. This lack of effect may be related to the lower efficacy of uricosuric agents (e.g. "
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    ABSTRACT: 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. 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 m2 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. 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 m2 per year, p = 0.001 by Wilcoxon signed-rank test). 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.
    BMC Nephrology 04/2014; 15(1):63. DOI:10.1186/1471-2369-15-63 · 1.69 Impact Factor
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