Clinically significant chronic kidney disease (CKD) is defined as a glomerular filtration rate (GFR) below 60ml/min/1.73m2 present for >3 months.1 It is estimated that CKD affects 15% of the adult population in the United States, and between 8% and 16% of the population worldwide, which is a challenge for health services.1–3

The kidneys are responsible for excreting two-thirds of uric acid circulating in the blood. Thereby, hyperuricemia is among CKD complications.4 The prevalence of hyperuricemia is 20.1% in the United States general population and it has increased over several decades, reaching 38% among CKD patients.5,6

Hyperuricemia, defined as a plasma uric acid levels >6.8mg/dl,7 is the primary precursor of gout and it is involved in the pathogenesis of different diseases, such as hypertension, obesity, hypercholesterolemia, atherosclerosis, metabolic syndrome, and chronic heart failure.8

The association of hyperuricemia with the risk of progression of CKD has been shown in some studies,9–12 which has led to clinical trials to assess the association between acid uric-lowering therapy and CDK progression with diverging results. Thus, this study aimed to perform a systematic review to evaluate the association of urate-lowering treatments and CKD progression.

This systematic review was conducted according to the Preferred Items guidelines for Reporting for Systematic Reviews and Meta-Analysis (PRISMA). This study was not registered.

This study is a systematic review followed by a meta-analysis evaluating a possible association between XO inhibitors as uric acid-lowering therapies and the progression of CKD with the largest number of patients involved.

This study showed a significant difference in the change of GFR of the treated group compared to the control group, combining all therapies. Likewise, CKD patients who received uric acid-lowering treatment had a substantial decrease in serum uric acid, serum creatinine and proteinuria. However, there was no difference in the GFR and creatinine between the groups when analyzed by individual therapies. For uACR and uPCR outcomes, febuxostat and topiroxostat treatment decreased proteinuria, while the allopurinol treatment group showed did not difference compared to the control group.

Some hypotheses will be discussed below that may explain our results. Due to the insidious nature of CKD, one hypothesis is the follow-up time required to demonstrate the benefit in GFR. For example, urate promotes kidney damage with long-term exposure. Thus, the follow-up may be an essential factor in the trials that studied the association between uric acid-lowering and renal outcomes.24,35 Sato et al. showed that among trials in which patients in the control group experienced progressive deterioration of kidney function was typically in studies with 6 months to 2 years of follow-up.52

For this reason, we performed a subgroup analysis of the change in GFR by follow-up time. Studies with 6 months or more of follow-up showed a significant difference in GFR of the treated patients compared to the control groups, while the results of pooled studies with less than 6 months no difference were found between the treatment and control groups.

The sample size of the selected studies could also help to explain the divergence of the results between the analyses of individual and pooled therapies. Serdar et al. report that for minor effects size or if the variability of this effect on the population for extensive, it is necessary to increase the sample size.36 When we separated the studies by drugs, this led to a reduction in the sample size in subgroups, and this may mean that the benefit of uric acid-lowering therapy in GFR exists, but the effect is small.

Another vital aspect being discussed is the result of the analysis by CKD stage of the patients included in the studies. When the studies were pooled according to the risk of CKD progression, it was observed that uric acid-lowering therapy attenuated the decline in the GFR in low-risk CKD patients, but not in patients with an elevated risk of CKD progression. One hypothesis to explain the difference in the effect of uric acid-lowering treatments in the patients at low and high risk of CKD progression is that hyperuricemia may be just one of the factors that cooperate for the progression of CKD, and uric acid-lowering therapies may not be enough to attenuate the disease in the presence of the other causes that may be intensified.

Recent studies with allopurinol found no benefit in reducing CKD progression with the use of hypoglycemic therapies, which generated scepticism on the part of the nephrological community.16,24,37 However, the Preventing Early Renal Loss in Diabetes (PERL) and the Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase (CKD-FIX) studies recruited subjects irrespective of their serum uric acid concentration. For example, PERL study included patients with serum urate starting at 4.5mg/dl, and the mean serum urate in both treated and placebo groups was 6.1mg/dl. The association between serum uric acid levels and CKD development is not linear but increases exponentially for values of serum uric acid >7mg/dl.38

In this line of reasoning, also in a recently published cohort single-center prospective study involving 411 hypertensive, non-diabetic, Chinese patients with a median follow up of 4 years, Huang et al.39 found that only uric acid level above 7.5mg/dl was independently associated with time-dependent reduction of patients’ GFR and the authors suggested that this cut-off value is of clinical importance. Piani et al.38 address that the controversy between studies on uric acid-lowering therapy and CKD progression could be explained by selection bias due to the heterogeneity of the hyperuricemic population, which could also explain the persistent heterogeneity in our analysis.

Lastly, CKD-FIX study involved stage 3 and 4 CKD patients with evidence of a reduction of at least 3ml/min/1.73m2 in the previous year. The follow up was two years. Due to a decision made by the trial steering committee, only 60% of the intended number of patients were enrolled, which may have affected the results.

Regarding uACR and uPCR, sensitive markers of kidney damage, they may reflect that proteinúria can present a faster response to therapy and risk of CKD progression than the GFR measurement.40 Our study showed, in the uACR/uPCR analysis, that there was a benefit in the uric acid-lowering therapy group. Proteinuria and albuminúria are known to be independent predictors of CDK progression. Therefore, reducing albuminuria and proteinuria is a target for renoprotection in patients with CKD. Zeeuw et al.41 showed that for every 50% reduction in proteinuria in patients with type 2 diabetic nephropathy, there was a 45% reduction in ESRD risk.

Some hypotheses have been described linking hyperuricemia with CKD progression. Many studies have suggested that hyperuricemia is an independent risk factor for renal disease and has a role in the pathogenesis of kidney injury in CKD patients. Thus, it is possible that uric acid-lowering treatment may delay the progression of CKD, at least in patients with hyperuricemia and low risk of CKD progression.

Hyperuricemia patients may have the deposition of monosodium urate crystals in the tubules or interstitium in the kidney that leads to chronic inflammation and tubular damage.42 Although urate crystal deposition in the kidney might be expected to be higher in patients with gout, people with asymptomatic hyperuricemia may have silent crystal deposition in the kidney.38

Mild hyperuricemia also has been associated with an increased risk of developing hypertension, diabetes and metabolic syndrome, factors that contribute to the development and progression of renal dysfunction.43 Hyperuricemia has also been associated with endothelial dysfunction, resulting in thickening of the afferent arterioles and decreased vasodilation, factors involved in the kidney injury.44,45 Tsuruta et al.46 showed in their trial that hemodialysis patients with hyperuricemia treated with febuxostat had a significant reduction in their endothelial dysfunction and oxidative stress.

Even a slight increase in serum uric acid levels may cause mitochondrial dysfunction, activate the renin–angiotensin–aldosterone-system (RAAS) and promote salt sensitivity.43 Besides, high serum uric acid levels are linked with the proliferation of vascular smooth muscle, which causes an increase in glomerular hydrostatic pressure.47 Furthermore, uric acid may stimulate the synthesis of IL-6, and tumor necrosis factor α, through contributing to the development of vascular diseases and CKD.48,49

This review selected studies contained 3 different therapies: allopurinol, febuxostat and topiroxostat. These drugs are XO inhibitors.50–53 The xanthine oxidase has a role in catalyzing hypoxanthine's oxidation to xanthine and xanthine to uric acid, which is why these drugs promote the reduction of uric acid synthesis.54 Additionally, reactions promoted by xanthine oxidase generate reactive oxygen species, superoxide anion and hydrogen peroxide, which may cooperate for oxidative stress, a common event in patients with CKD and considered to be an important pathogenic mechanism to the progression of CKD.55,56 Therefore, uric acid-lowering may slow CKD progress by inhibiting reactive oxygen species and suppressing RAAS activity, leading to increased glomerular perfusion.50 Yang et al.57 showed benefits in oxidative stress markers with allopurinol therapy in rabbits with diabetes.

The findings of this systematic review corroborate with other studies. Liu et al.58 showed that the risk of worsening kidney function, ESRD or death was significantly decreased in the allopurinol group compared to the control group. Kanji et al.59 evaluated all urate-lowering therapies on CKD progression, and the GFR mean difference founding favored treatment.

In the analysis of the effect of uric acid-lowering therapy in changes in serum uric acid after treatment, our study showed that patients treated with febuxostat reduced their serum uric acid to a significantly lower level than patients treated with allopurinol (−3.22mg/dl versus −2.37mg/dl). Sezai et al.60 found in cardiac surgery patients with hyperuricemia that febuxostat reduced uric acid earlier than allopurinol, which had a more substantial renoprotective effect than allopurinol, and had superior antioxidant and anti-inflammatory properties.

This study has several strengths. To our knowledge, this is the first meta-analysis that assessed uACR and uPCR as outcomes and includes topiroxostat treatment. This study informs physicians regarding the effect of XO inhibitors therapy on CKD progression. Despite the few published clinical trials, the studies selected in this systematic review added up 2463 patients, with the most significant number of patients involved.

Some limitations of our study were the small number of randomized trials on the use of topiroxostat in patients with CKD patients, different follow-up times between the studies, three studies did not report on the use of renin-angiotensin system inhibitors,18,27,31 studies performed without blinding,17,22,23,27,28,31 and substantial heterogeneity. Differences in population characteristics, study designs, sample sizes, and follow-up time may have contributed to high heterogeneity.

These results suggest that uric acid-lowering treatment with XO inhibitors may slow the progress of CKD and reduce proteinuria. Nevertheless, these findings should be interpreted considering the study limitations. Large and powered randomized clinical trials, with adequate follow-up time and with specific CKD populations (by the risk of CKD progression and with hyperuricemia), are needed to assess the effects of uric acid-lowering therapies in GFR and proteinuria of CKD patients.

The authors declare that they have no conflict of interest.