Article

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

ABSTRACT

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 was clearly associated with the increasing incidence and progression of CKD (Mok et al., 2012; Obermayr et al., 2008) and end stage renal disease (ESRD) (Iseki et al., 2004; Ishani et al., 2006). In addition, it was reported that lowering uric acid (UA) levels could protect CKD from progression (Goicoechea et al., 2010; Sakai et al., 2014). However, meta-analyses of uratelowering therapy showed inconsistent results (Bose et al., 2014; Wang et al., 2013). "
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    ABSTRACT: Uric acid has emerged as a novel and potential modifiable risk factor for the incidence and progression of kidney diseases, however, the deteriorate effect of uric acid on renal mesangial cells remains unclear. The present study is to examine the immune activation of soluble and crystal forms of uric acid in human mesangial cells. We stimulated primary human mesangial cells (HMCs) with increasing concentrations (from 50 to 200μg/ml) of soluble monosodium urate (MSU) or MSU crystals. We examined interleukin (IL)-1β protein expression levels in cell culture by ELISA. The stimulated HMCs were further stimulated with soluble MSU or MSU crystals at 200μg/ml with or without the pre-incubation of toll like receptor (TLR) 4 inhibitor TAK242 (1μM). TLR4, nod-like receptor protein (NLRP3, also known as NALP3), IL-1β, human leukocyte antigen (HLA)-DR and CD40 were examined by Realtime-PCR, Western blot and ELISA, respectively. We found that both soluble MSU and MSU crystals increased IL-1β protein expression levels in dose-dependent fashion. Soluble MSU significantly enhanced the expression of TLR4, NLRP3, IL-1β, HLA-DR and CD40 while MSU crystals only upregulated the expression of TLR4 and IL-1β. TLR4 inhibitor TAK242 significantly blocked the up-regulation of NLRP3, IL-1β, HLA-DR and CD40 induced by soluble MSU while no TAK242 suppression effect on MSU crystals induced IL-1β up-regulation was found. Our results suggested that soluble MSU, but not MSU crystals, induce NLRP3, IL-1β, HLA-DR and CD40 upregulation in a TLR4-dependent manner. These findings indicate that soluble MSU may play a pathological role in hyperuricemia induced renal mesangial injury. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Aug 2015 · Molecular Immunology
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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.
    Full-text · Article · Nov 2014 · Nutrition, metabolism, and cardiovascular diseases: NMCD
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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.
    Full-text · Article · Jun 2014 · International Urology and Nephrology
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