Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis

We included studies if their selection criteria specified estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² or their baseline mean eGFR or serum creatinine were <60 ml/min/1.73 m² or >137 μmol/L for men, and >104 μmol/L for women, respectively (>1.55 mg/dL for men and >1.18 mg/dL for women) [29]. Any pharmacologic therapy given to lower uric acid was considered a suitable intervention. These included allopurinol, febuxostat, probenecid, sulfinpyrazone, benzbromarone, pegloticase and rasburicase. We included studies in which the comparator was placebo, usual therapy or an alternative drug. Outcomes of greatest interest were: serum creatinine level, eGFR, proteinuria, incidence of ESRD, incidence of cardiovascular events and cardiovascular mortality. Other outcomes were: serum uric acid level, blood pressure (diastolic and systolic), markers of inflammation (C-reactive protein levels), all-cause mortality, adverse events and serious adverse events. We included only RCTs and quasi-RCTs. We accepted any estimate of GFR, whether derived from serum creatinine and demographic variables, or from directly-measured creatinine or isotope clearance. We followed a prespecified protocol but this was not registered.

In the primary search, citations were compiled from the following electronic databases: Ovid MEDLINE (1966-June 2013), Ovid EMBASE (1980-June 2013), CENTRAL (June 2013) and Web of Science (June 2013) using search strategies detailed in the Additional file 1. We reviewed the Cochrane Collaboration’s protocol and adapted some of their search terms [30]. The first arm of our search strategy included terms such as: kidney disease, renal insufficiency and renal replacement therapy as well as further synonyms and key words. These were combined with the second arm of our strategy comprising of terms such as allopurinol, gout suppressants, urate oxidase and further descriptors related to ULT. The citations were downloaded into Endnote, version X7 (Thompson ISI Research-Soft, Philadelphia, PA) and duplicate citations removed.

To further identify relevant studies, a secondary search was performed, making use of reference lists of previous narrative reviews [31-33] and of studies identified in the primary search, PubMed ‘Related Articles’ feature, published abstracts from two recent American Society of Nephrology (2010-2012) and International Society of Nephrology meetings (2010-2012), internet searches using Google Scholar, and trial registers from National Institute of Health and Current Controlled Trials. We also identified seven studies [34-40] from two recently published systematic reviews on a similar question [41,42].

Two authors (TK, MG) completed the first phase of screening using titles and abstracts (kappa of 0.84). Agreement for the second phase of screening, using full-text manuscripts, was lower at a kappa of 0.41. All disagreements for both phases were resolved by consensus.

Two authors (TK and MG) independently extracted data for each included study using standardized forms. Subsequently, quality assessment was also completed in duplicate (TK, MG) using the Cochrane Collaboration’s Higgins Risk of Bias Assessment Tool [43]. Disagreements from both data abstraction and quality assessment were resolved through consensus. All the non-English language studies were written in Chinese; data was extracted and quality assessed by one author (TK), with the assistance of a translator.

Given the heterogeneity in duration of follow up and study comparators, we decided to meta-analyze studies greater than 3 months in duration that compared allopurinol to inactive control [34,36-40,44-48].

We used a random-effects model within Comprehensive Meta-analysis (Englewood NJ). Two of the studies did not report GFR estimates [46,48]: we used serum creatinine and demographic information from the studies, to estimate mean eGFR. The equations utilized were Modification of Diet in Renal Disease (MDRD) with Chinese coefficients where appropriate [49].

The 19 studies, published between 1998 and 2012, randomized 992 participants with duration of follow-up ranging from 2 days to 24 months; 16 were parallel group and 3 were crossover design (Table 1). The studies originated from 10 different countries, including the United States, United Kingdom, Iran, France, Italy, Greece, Spain and China. Most were single-centre and had relatively small sample sizes with short duration of follow up. Populations were variable and half the studies did not report usage of baseline renin-angiotensin-aldosterone system (RAAS) blockade (Table 2).

Pooled estimate of eGFR was in favour of allopurinol with a mean difference (MD) of 3.2 ml/min/1.73 m², 95% confidence interval (CI) 0.16-6.2 ml/min/1.73 m², p = 0.039. Heterogeneity was measured with a Q-value of 6.95 and I² of 42.5, p = 0.138. We performed a sensitivity analysis excluding studies in which we had calculated eGFR from serum creatinine: in this analysis, the tendency was in the same direction but the results did not meet formal statistical significance. Pooling of serum creatinine also favoured allopurinol with a mean difference of 0.63 mg/dL, 95% CI 0.43-0.83 mg/dL. As expected, a statistically significant reduction in serum uric acid was found with a MD of 2.8 mg/dL, 95% CI 2.3-3.4 mg/dL, p < 0.001. Notably reductions were found for both pooled estimates of systolic (MD 6.6 mmHg, 95% CI 2.0-11.1 mmHg) and diastolic blood pressure (MD 2.1 mmHg, 95% CI 0.50-3.7 mmHg). Proteinuria showed a tendency towards benefit, again favouring allopurinol (Figure 2). A funnel plot was completed for serum creatinine, which showed mild asymmetry consistent with publication bias (Figure 3).

We did not meta-analyze trials of less than three months’ duration, because we thought it biologically implausible that effects would be observable so rapidly. Three trials with less than one month of follow up did not show statistically significant differences in renal function [50-53]. There were three studies of between one and three months’ duration: uricosuric amlodipine compared to tertatolol showed higher eGFR in the group treated with amlodipine [54]; creatinine clearance improved following a single dose infusion of rasburicase compared to placebo [55]; and there was a tendency towards higher eGFR in a comparison of benzbromarone to allopurinol [56].

There were insufficient data on adverse events, incidence of ESRD and cardiovascular events for meta-analysis. One study reported cardiovascular event rates finding a statistically significant reduction in cardiovascular risk comparing allopurinol to usual therapy after 24 months of follow-up (HR 0.29, 95% CI 0.09-0.86, p = 0.026) [44]. No serious adverse events were noted in any of the included studies, specifically allopurinol hypersensitivity syndrome, toxic epidermal necrolysis or Steven-Johnson syndrome.

Overall, study quality was variable (Figure 4). The internal validity of the included RCTs was difficult to assess as most studies omitted important methodological details. Notably, some studies did not use an intention-to-treat analysis. We were not able to report quality features in one study as it was available in abstract form only [34]. Although a few of the studies were not placebo-controlled, we did not assess this as a high risk of bias per se since our outcomes of interest were objective.