Urate-Lowering Therapy for Preventing Kidney Disease Progression: Are We There Yet?

Related Article, p. 798 Related Article, p. 798 Several epidemiologic studies have established that high serum uric acid levels are associated with the development of new-onset chronic kidney disease (CKD) and progression of CKD to end-stage kidney disease.1Badve S.V. Brown F. Hawley C.M. et al.Challenges of conducting a trial of uric-acid-lowering therapy in CKD.Nat Rev Nephrol. 2011; 7: 295-300Crossref PubMed Scopus (41) Google Scholar However, hyperuricemia is a ubiquitous finding in CKD2Jing J. Kielstein J.T. Schultheiss U.T. et al.Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German Chronic Kidney Disease (GCKD) study.Nephrol Dial Transplant. 2015; 30: 613-621Crossref Scopus (60) Google Scholar and could be a consequence of reduced excretion, diuretic therapy, or oxidative stress. It is not clear whether it plays a causative role or is an indirect marker of kidney function. The current epidemiologic evidence is well supported by preclinical studies, demonstrating a direct pathogenic role for uric acid in the development and progression of CKD.3Kang D.H. Nakagawa T. Feng L. et al.A role for uric acid in the progression of renal disease.J Am Soc Nephrol. 2002; 13: 2888-2897Crossref PubMed Scopus (825) Google Scholar Thus, uric acid has long been considered a potential therapeutic target for slowing the progression of CKD. Our 2014 systematic review of 8 randomized controlled trials involving 476 participants showed that urate-lowering therapy with allopurinol may slow the progression of CKD.4Bose B. Badve S.V. Hiremath S.S. et al.Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis.Nephrol Dial Transplant. 2014; 29: 406-413Crossref PubMed Scopus (160) Google Scholar However, data for the effects of allopurinol on kidney outcomes, mortality, and adverse effects were insufficient to reliably inform medical practice, and no febuxostat trials were identified at that time. Only adequately powered randomized controlled trials can establish causality between uric acid and kidney outcomes. In this issue of AJKD, Kimura et al5Kimura K. Hosoya T. Uchida S. et al.Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial.Am J Kidney Dis. 2018; 72: 798-810Scopus (187) Google Scholar reported results of the Febuxostat Versus Placebo Randomized Controlled Trial Regarding Reduced Renal Function in Patients With Hyperuricemia Complicated by Chronic Kidney Disease Stage 3 (FEATHER). In this double-blind randomized placebo-controlled trial, 443 adult Japanese patients with CKD stage 3 and asymptomatic hyperuricemia (serum uric acid of 7.0-10.0 mg/dL and no history of gout) were randomly assigned to treatment with febuxostat (with a starting dose of 10 mg once daily) or placebo. The febuxostat dose doubled at 4-weekly intervals to the maximum of 40 mg once daily. Two participants were excluded from the analysis. The primary end point was the difference in the slope of annual decline in estimated glomerular filtration rate (eGFR) at 108 weeks, as determined by the Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) eGFR equation. Eighty-two percent of participants completed study follow-up. There was no statistically significant difference in mean eGFR slope (0.70 mL/min/1.73 m2; 95% confidence interval [CI], −0.21 to 1.62) or end-of-study eGFRs (45.3 ± 11.9 vs 44.2 ± 12.5 mL/min/1.73 m2) between the 2 groups. Subgroup analyses showed a significant difference in mean eGFR slope in a subgroup with no evidence of proteinuria on qualitative urine testing, as well as in those with serum creatinine concentrations lower than the median population value. There were no significant differences in systolic or diastolic blood pressures between the febuxostat and placebo groups. Very few participants (8 in the febuxostat group and 13 in the placebo group) experienced “kidney dysfunction” events (defined as doubling of serum creatinine or initiation of dialysis therapy). The incidence of gouty arthritis was significantly lower in the febuxostat group (2/219) than in the placebo group (13/222). Despite being the largest trial evaluating uric acid–lowering therapy in a CKD population reported to date, FEATHER has several limitations. The investigators enrolled a low-risk cohort of patients who had almost no appreciable decline in eGFR over the study duration of 108 weeks. Mean eGFR slopes in the febuxostat and placebo groups were 0.23 ± 5.26 and −0.47 ± 4.48 mL/min/1.73 m2 per year, respectively. Thus, in the placebo group, the mean decline in eGFR over 108 weeks was 1.0%. The inclusion of low-risk cohorts in randomized trials, such as in FEATHER5Kimura K. Hosoya T. Uchida S. et al.Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial.Am J Kidney Dis. 2018; 72: 798-810Scopus (187) Google Scholar and previous nephrology trials, has resulted in low event rates and inadequate statistical power to properly evaluate the prevention of CKD progression. To avoid the risk of being a negative or indeterminate trial, future trials should selectively enroll high-risk cohorts. For a trial with kidney end points, the variability of GFR decline and the uncertainty in predicting it pose challenges in identifying such patients.6Levin A. Djurdjev O. Beaulieu M. Er L. Variability and risk factors for kidney disease progression and death following attainment of stage 4 CKD in a referred cohort.Am J Kidney Dis. 2008; 52: 661-671Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 7Gaspari F. Ruggenenti P. Porrini E. et al.The GFR and GFR decline cannot be accurately estimated in type 2 diabetics.Kidney Int. 2013; 84: 164-173Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Lower eGFRs, higher albuminuria, more rapid past eGFR declines, the presence of diabetes, higher Kidney Failure Risk Equation scores, and larger total kidney volumes in the case of polycystic kidney disease are some of the parameters that could potentially be used in future trials to identify high-risk patients.8Gansevoort R.T. Matsushita K. van der Velde M. et al.Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.Kidney Int. 2011; 80: 93-104Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar, 9Tangri N. Stevens L.A. Griffith J. et al.A predictive model for progression of chronic kidney disease to kidney failure.JAMA. 2011; 305: 1553-1559Crossref PubMed Scopus (719) Google Scholar, 10Irazabal M.V. Rangel L.J. Bergstralh E.J. et al.Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials.J Am Soc Nephrol. 2015; 26: 160-172Crossref PubMed Scopus (326) Google Scholar, 11Grams M.E. Yang W. Rebholz C.M. et al.Risks of adverse events in advanced CKD: the Chronic Renal Insufficiency Cohort (CRIC) Study.Am J Kidney Dis. 2017; 70: 337-346Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 12Kovesdy C.P. Coresh J. Ballew S.H. et al.Past decline versus current eGFR and subsequent ESRD risk.J Am Soc Nephrol. 2016; 27: 2447-2455Crossref PubMed Scopus (61) Google Scholar Conducting trials in CKD progression is also challenging because it often takes many years for CKD to progress to end-stage kidney disease. Therefore, investigators frequently use a composite end point of death, end-stage kidney disease, and serum creatinine level doubling or 40% decline in eGFR, which enables them to conduct trials with smaller sample sizes and shorter follow-up.13Badve S.V. Palmer S.C. Hawley C.M. Pascoe E.M. Strippoli G.F. Johnson D.W. Glomerular filtration rate decline as a surrogate end point in kidney disease progression trials.Nephrol Dial Transplant. 2016; 31: 1425-1436Crossref PubMed Scopus (29) Google Scholar Recently, the National Kidney Foundation (NKF), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) conducted a scientific workshop to determine the validity of GFR slope as a surrogate end point in CKD progression trials. The NKF-FDA-EMA Scientific Workshop Committee’s analyses and conclusions are expected in late 2018. If GFR slope emerges as a valid surrogate end point, we are likely to see more FEATHER-like trials with 2 to 3 years of follow-up in the future. The sample size for FEATHER was calculated assuming an effect size in the mean eGFR decline slope of −2.7 (SD, 7.2) mL/min/1.73 m2 per year.14Hosoya T. Kimura K. Itoh S. et al.The effect of febuxostat to prevent a further reduction in renal function of patients with hyperuricemia who have never had gout and are complicated by chronic kidney disease stage 3: study protocol for a multicenter randomized controlled study.Trials. 2014; 15: 26Crossref PubMed Scopus (53) Google Scholar Without knowing the assumed eGFR decline slope in the control group, this effect size appears to be unrealistically large. Thus, FEATHER, with its sample size of 443 participants, did not have sufficient statistical power to detect a more conservative or biologically plausible difference in eGFR decline slope, let alone in any subgroup analyses. Therefore, the reported subgroup analyses showing a benefit of febuxostat in the subgroups with no proteinuria and those with lower than median serum creatinine values need to be interpreted with caution given that the large number of exploratory data analyses performed increased the likelihood of a statistically significant result occurring due to random chance alone. Furthermore, there is no plausible clinical or mechanistic theory to explain the observed results of these subgroup analyses. Although the efficacy of urate-lowering therapies such as allopurinol and febuxostat remains uncertain, febuxostat was well tolerated in FEATHER. Only 7 (3.2%) participants developed a hypersensitivity reaction (rash or eruption), which was similar to that observed in the placebo group (10 participants [4.5%]). It is also noteworthy that cardiovascular events were experienced by 4 (1.8%) participants in the febuxostat group and 7 (3.2%) in the placebo group. In contrast, the recently published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial involving 6,190 patients with gout and cardiovascular disease showed that febuxostat increased the risks for both all-cause death (hazard ratio [HR], 1.22; 95% CI, 1.01-1.47) and cardiovascular death (HR, 1.34; 95% CI, 1.03-1.73) compared to allopurinol.15White W.B. Saag K.G. Becker M.A. et al.Cardiovascular safety of febuxostat or allopurinol in patients with gout.N Engl J Med. 2018; 378: 1200-1210Crossref PubMed Scopus (462) Google Scholar However, with respect to cardiovascular risk, it should be noted that the FEATHER population was a relatively low-risk cohort (only 7.5% of participants had ischemic heart disease at baseline), such that clinicians should continue to exercise caution while prescribing febuxostat as outlined in the safety announcement recently issued by the FDA.16FDA. Drug Safety Communication: FDA to evaluate increased risk of heart-related death and 19 death from all causes with the gout medicine febuxostat (Uloric). https://www.fda.gov/downloads/drugs/drugsafety/ucm584803.pdf, Accessed July 11, 2018.Google Scholar Another interesting finding of FEATHER was that fewer participants in the febuxostat group developed gouty arthritis compared to the placebo group (0.9% vs 5.9%, respectively). Gout is highly prevalent in CKD, affecting 23% to 28% of patients with CKD stage 3 and 36% of patients with CKD stage 4/5.2Jing J. Kielstein J.T. Schultheiss U.T. et al.Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German Chronic Kidney Disease (GCKD) study.Nephrol Dial Transplant. 2015; 30: 613-621Crossref Scopus (60) Google Scholar The incidence of gout increases with worsening kidney function.17Tan V.S. Garg A.X. McArthur E. Lam N.N. Sood M.M. Naylor K.L. The 3-year incidence of gout in elderly patients with CKD.Clin J Am Soc Nephrol. 2017; 12: 577-584Crossref Scopus (11) Google Scholar Although the 2012 American College of Rheumatology guidelines recommend that urate-lowering therapy should only be started after an individual has experienced symptomatic hyperuricemia,18Khanna D. Fitzgerald J.D. Khanna P.P. et al.2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.Arthritis Care Res (Hoboken). 2012; 64: 1431-1446Crossref PubMed Scopus (1223) Google Scholar the FEATHER findings of appreciable gout prevention and acceptable safety profile pose the intriguing question of whether asymptomatic hyperuricemia should be treated with urate-lowering therapy in patients with CKD to reduce the incidence of gout, regardless of whether it has any additional renoprotective benefits. As for the question of whether we now have sufficient evidence to either confirm or rule out the role of urate-lowering therapy in preventing CKD progression, the answer is that we do not. The mentioned limitations of FEATHER, taken in conjunction with the present low-certainty evidence from previous trials, mean that there should be no change to the current KDIGO (Kidney Disease: Improving Global Outcomes) guideline clinical practice recommendation that, “there is insufficient evidence to support or refute the use of agents to lower serum uric acid concentrations in people with CKD and either symptomatic or asymptomatic hyperuricemia in order to delay progression of CKD.”19Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Chapter 3: management of progression and complications of CKD.Kidney Int Suppl. 2013; 1: 73-90Google Scholar More information is also required regarding the cardiovascular safety of febuxostat, such that clinicians and patients should heed the FDA’s plea to report side effects involving febuxostat.16FDA. Drug Safety Communication: FDA to evaluate increased risk of heart-related death and 19 death from all causes with the gout medicine febuxostat (Uloric). https://www.fda.gov/downloads/drugs/drugsafety/ucm584803.pdf, Accessed July 11, 2018.Google Scholar Currently, there are 2 ongoing, government-funded, noncommercial, randomized, placebo-controlled trials that are evaluating whether urate-lowering therapy with allopurinol slows the decline in GFR, either estimated using the CKD Epidemiology Collaboration (CKD-EPI) equation in a high-risk cohort of people with stage 3 or 4 CKD (Australian New Zealand Clinical Trials Registry identifier, ACTRN12611000791932) or measured using iohexol clearance in patients with type 1 diabetes mellitus, micro- or macroalbuminuria, and hyperuricemia (ClinicalTrials.gov identifier, NCT02017171).20Maahs D.M. Caramori L. Cherney D.Z. et al.Uric acid lowering to prevent kidney function loss in diabetes: the Preventing Early Renal Function Loss (PERL) allopurinol study.Curr Diabetes Rep. 2013; 13: 550-559Crossref PubMed Scopus (117) Google Scholar The results of these 2 ongoing trials are expected in late 2019 and will hopefully shed much needed light on the efficacy, safety, and merit of urate-lowering therapy as a renoprotective strategy in patients with CKD. Febuxostat Therapy for Patients With Stage 3 CKD and Asymptomatic Hyperuricemia: A Randomized TrialAmerican Journal of Kidney DiseasesVol. 72Issue 6PreviewEpidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. Full-Text PDF Open Access