JCR: Journal of Clinical Rheumatology:
Renal Function in Gout: Long-Term Treatment Effects of Febuxostat
Whelton, Andrew MD*; MacDonald, Patricia A. NP†; Zhao, Lin PhD†; Hunt, Barbara MS†; Gunawardhana, Lhanoo MD, PhD†
From the *Universal Clinical Research Center, Inc, Hunt Valley; and the Johns Hopkins University School of Medicine, Baltimore, MD; and †Takeda Global Research and Development Center, Inc, Deerfield, IL.
This study was funded by Takeda Global Research and Development Center, Inc.
The FOCUS trial was completely funded by TAP Pharmaceutical Products, Inc, which is now a part of Takeda Global Research & Development Center, Inc, Deerfield, IL. It is registered as NCT00174949 on clinicaltrials.gov.
Assistance in manuscript preparation was provided by Meryl Gersh, PhD, of AlphaBioCom, LLC, in Radnor, PA, and was funded by Takeda Global Research & Development Center, Inc.
Dr Whelton has served as a consultant and speaker for Takeda Global Research & Development Center, Inc. Ms MacDonald, Dr Zhao, Ms Hunt, and Dr Gunawardhana currently are all employees of Takeda Global Research & Development Center, Inc.
Correspondence: Andrew Whelton, MD, 1737 Beaver Brook Lane, Hunt Valley, MD 21030-1603. E-mail: email@example.com
Background: The association between hyperuricemia, gout, and impaired renal function has long been recognized. Recent data provide evidence for the causal relationship between elevated serum urate (sUA) and renal changes, leading to declines in glomerular filtration rates. In healthy adults, glomerular filtration rate wanes with age. Urate-lowering therapy (ULT) with allopurinol has been shown to stabilize or reverse this.
Objective: Here we examine the long-term effects of ULT with febuxostat on estimated glomerular filtration rate (eGFR).
Methods: This is a post hoc analysis of the Febuxostat Open-label Clinical trial of Urate-lowering efficacy and Safety study, during which 116 hyperuricemic gout subjects received daily doses of febuxostat (40, 80, or 120 mg) for up to 5 years. sUA concentrations and eGFR were assessed regularly. Results were stratified by mean change in sUA from baseline. Mathematical modeling was used to predict the effect of sUA reduction on eGFR.
Results: Maintenance or improvement in eGFR was inversely correlated with the quantitative reduction in sUA from baseline. For every 1 mg/dL decrease in sUA, the model projected an expected improvement in eGFR of 1 mL/min from the untreated value.
Conclusion: Individuals with the greatest reductions in sUA may experience reduced rates of renal deterioration or even stabilization of renal function. Further studies examining the impact of long-term ULT on renal function in hyperuricemic gout patients are needed to both confirm our results and verify if improvements in renal function are feasible in such patients.
Hyperuricemia, defined as a serum urate (sUA) concentration at or greater than the limit of urate solubility (6.8 mg/dL at 37°C), is common and can manifest clinically as the urate crystal deposition disease, gout.1 The relationship between hyperuricemia, gout, and deterioration of renal function is well known,2-6 along with associations between renal impairment and hypertension,7,8 and between hyperuricemia and hypertension.9,10 Approximately 30% to 60% of patients with gout have some degree of renal impairment,4 defined by an estimated glomerular filtration rate (eGFR) of less than 90 mL/min per 1.73 m2,11 as determined from the Cockcroft-Gault equation12 corrected for ideal body weight. The independent role of hyperuricemia in the production of incident chronic renal failure has also received epidemiologic support in recent reports.13,14 Nonetheless, the causal relationships between hyperuricemia, hypertension, and renal dysfunction require further evaluation.
Management of chronic gout is directed at lowering and maintaining sUA at subsaturating concentrations, usually less than 6.0 mg/dL.15 The 2 available pharmacological methods of urate reduction for the management of gout are xanthine oxidase (XO) inhibition and enhancement of urinary uric acid excretion with a uricosuric agent. Uricosuric agents, such as probenecid, have limited effectiveness in patients with impaired renal function.15 The purine analog XO inhibitor, allopurinol, is currently the most commonly prescribed compound for urate-lowering therapy (ULT).16 Oxypurinol, the active metabolite of allopurinol, is excreted by the kidney, and therefore, allopurinol requires dose reduction in patients with renal impairment.15
Febuxostat (Uloric®; Takeda Pharmaceuticals North America, Inc; Deerfield, IL) is a potent nonpurine selective XO inhibitor approved for use in patients with hyperuricemia and gout.17-19 In the phase 3 clinical development program, febuxostat was shown to be efficacious and well tolerated, with the majority of subjects achieving target sUA of less than 6.0 mg/dL after 2 weeks of treatment.20,21 In addition, febuxostat is comparably efficacious and well tolerated in gout patients with mild or moderate renal impairment (estimated creatinine clearance, 30-89 mL/min).22,23 Patients with severe renal impairment estimated creatinine clearance of less than 30 mL/min were excluded from all trials.
Recent development of rat models in which hyperuricemia is induced with administration of oxonic acid, an inhibitor of uricase, has allowed for investigation into the impact of elevated sUA on hypertension and renal function.24,25 In these models, hyperuricemia leads to elevated blood pressure, activation of the renin-angiotensin system, decreased creatinine clearance, alterations in renal cellularity, and development of severe arteriolopathy of the afferent arteriole.24-29 Allopurinol and febuxostat, when used in the rat model before the development of irreversible vascular and glomerular histological damage, can reverse these effects, thereby preventing hypertension and decreased renal function.28-30
There are few studies examining the effects of ULT upon renal function in gouty or hyperuricemic patients.31-33 We report here our observations on changes in renal function via eGFR in a cohort of subjects with gout who were treated with febuxostat in an open-label study for 5 years. In addition, based on the estimated annual linear physiological decrease in renal function in healthy male adults of 0.8 mL/min,34 and data collected from investigations reported here, we have put forth a mathematical model to illustrate the impact of lowering sUA on eGFR in patients with gout.
Of 145 hyperuricemic gout subjects completing a 28-day, double-blind, placebo-controlled trial,35 116 enrolled in the long-term, open-label, 5-year Febuxostat Open-label Clinical trial of Urate-lowering efficacy and Safety (FOCUS) study (ClinicalTrial.gov identifier NCT00174949).36 Before any study-related procedure, all subjects provided written informed consent and Health Insurance Portability and Accountability Act authorization. Data from the "final visit" (day 28) in the preceding double-blind study35 were considered day 1 data for the long-term extension study. Baseline sUA was defined as the value obtained 2 days before the start of the 28-day, double-blind study period. Uric acid production status of each subject (overproduction [>800 mg/24 hours] vs. impaired renal uric acid excretion [<800 mg/24 hours]) was determined at the time of entering the 28-day study by measurement of 24-hour urinary uric acid excretion.
Inclusion criteria included enrollment and completion of the 28-day phase 2 study.35 Subjects had to be 18 to 85 years of age with a history or presence of gout, defined by the American College of Rheumatology,37 and no history of active liver disease or any other significant medical condition, no change in thiazide diuretic or steroid therapy within 1 month of study enrollment, and no chronic nonsteroidal anti-inflammatory drug (NSAID) use. Subjects with mild or moderate renal impairment, defined as serum creatinine (sCr) of greater than 1.5 mg/dL or creatinine clearance of greater than 50 to less than 80 mL/min, were included. Further details on inclusion and exclusion criteria have been described elsewhere.35,36
Subjects initially received febuxostat 80 mg/d; between weeks 4 to 24, the dose could be titrated to 40 or 120 mg/d to maintain a sUA between less than 6.0 mg/dL but not lower than 3.0 mg/dL. By week 28, subjects were required to have been receiving a stable dose for at least 4 weeks. All subjects were provided with colchicine prophylaxis (0.6 mg twice daily) for the first 4 weeks of this open-label study. sUA, sCr, and blood pressure were assessed at every visit, which occurred every 4 weeks during year 1, and then every 8 weeks and at year end for years 2 through 5.36
Efficacy and safety analyses were carried out on all subjects who received at least 1 dose of febuxostat. The primary efficacy endpoint was the proportion of subjects who achieved and maintained sUA of less than 6.0 mg/dL.36
As previously described, safety was monitored regularly during the 5-year duration of the FOCUS study via the assessment of adverse events (AEs), laboratory tests, physical examinations, and vital signs.36 The severity of reported AEs was estimated by the investigators, along with their potential relationship to the study drug.36
Renal Function Analyses
Initially, eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation: 186 × C−1.154 × A−0.203 × R × S; where C = sCr (mg/dL), A = age (in years), R = 1.210 if subject is black and 1 otherwise, and S = 0.742 if subject is female and 1 otherwise.38 Subsequently, we also determined eGFR using the newly developed Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.39 eGFR = 141 × min (sCr/κ, 1)α × max (sCr/κ, 1)−1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black], where κ is 0.7 for females and 0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of sCr κ or 1, and max indicates the maximum of sCr/κ or 1.
The long-term effect of sUA reduction upon renal function (using MDRD-calculated eGFR) was sequentially evaluated by dividing the study cohort into 5 groups representing the spectrum of chronic reduction of sUA from baseline values. Specifically, the study groups, based on mean reduction of sUA from baseline values, were (A) 3.0 mg/dL or less; B) >3.0 to 4.0 mg/dL or less; (C) greater than 4.0 to 5.0 mg/dL or less; (D) greater than 5.0 to 6.0 mg/dL or less; and (E) greater than 6.0 mg/dL. In addition, the relationship between final absolute sUA and mean change eGFR was examined.
Concomitant Medication Use
The use of concomitant medications known to affect renal function was evaluated during the study observation period. Specifically, we assessed the balance in the quantitative use of NSAIDs, angiotensin-converting enzyme inhibitors (ACEIs), and diuretic compounds in each of the study groups A through E.
Based on our study results, we developed a mathematical model to predict the deterioration of renal function in this cohort should hyperuricemia be left untreated. The model determined the relationship between the change in sUA from baseline and eGFR over time. For each year, the eGFR selected for model analysis was the one nearest to the end of the year interval. For example, for year 1, it would be the eGFR closest to, but not greater than, 365 days from first dose of study drug. Average sUA on treatment was determined from postbaseline sUA concentrations. The predictors (time [year], average sUA on study drug, baseline eGFR, and sUA change from baseline) were evaluated for a relationship to eGFR change from baseline using a repeated-measures linear model. Backward selection (P = 0.1) was used to reduce the model down to those predictors that best explained the eGFR change from baseline. Because it is known that healthy adults between the ages of 30 and 80 years manifest an annual physiological reduction in glomerular filtration rate of 0.8 mL/min, we added this physiological decrement in renal function into the mathematical model.34
Baseline characteristics and comorbidities recorded before treatment in the 28-day double-blind study35 are presented in Table 1. Most subjects were male, white, obese (body mass index, ≥30 kg/m2), and hypertensive. The average duration of gout at baseline was 11.9 years. Seventy-six percent (88/116) of subjects were underexcretors.
Most subjects achieved a sUA of less than 6.0 mg/dL within 2 weeks of ULT and maintained this throughout the duration of the 5-year study.36 As the study progressed, the incidence of reported gout flares requiring treatment steadily declined to zero by the fifth year.36
Measures of renal function (eGFR and sCr averaged across all subjects) were stable over the 5-year study period (Table 2). eGFR values estimated by either MDRD or CKD-EPI formulas were similar.
The eGFR mean change from baseline in the 5 subgroups of study participants is presented in Table 3 and Figure 1. In these 5 subject groups, maintenance or improvement in eGFR was inversely correlated with the quantitative reduction in sUA from baseline to the final visit. Those subjects who manifested the greatest persistent reduction in sUA were those who demonstrated the best quantitative retention of eGFR. No correlation was observed between the mean change from baseline in eGFR and final sUA when study subjects were grouped by final sUA as follows: <4 mg/dL (n = 22), 4 or greater to less than 5 mg/dL (n = 38), 5 or greater to less than 6 mg/dL (n = 31), and 6 mg/dL or greater (n = 24). In addition, when final sUA was stratified by less than 5.5 mg/dL (69% of the study group) or 5.5 mg/dL or greater (31% of the study group), mean change in eGFR was similar between the 2 groups throughout the 5 years of observation.
The predictive model developed for this study identified a statistically significant (P = 0.02) inverse correlation between change in sUA and eGFR values over 5 years. This model projected that if our study subjects were not treated to reduce their elevated sUA, they would have manifested an eGFR reduction of 7 mL/min at the end of 5 years. The model then projected that for every 1 mg/dL reduction in sUA, an improvement of 1 mL/min from this untreated value could be expected. Hence, a gout patient with a baseline eGFR of approximately 65 mL/min and a sustained decrease of 7 mg/dL in sUA after 5 years would manifest as having no decrease in eGFR.
Concomitant medications were assessed for each study subject throughout his/her participation in the study. The use of chronic NSAIDs was exclusionary in this study; therefore, the use of NSAIDs was acute in nature with short therapeutic courses, averaging approximately 6 days. For treatment-response groups A through E, the mean duration of NSAID exposure was comparable. The use of diuretics and ACEIs was also comparable between treatment-response groups. The use of acetaminophen was common and comparable in groups A through E.
Rates of most frequent AEs (≥5 per 100 subject-years of exposure) and all reported serious AEs are provided in Table 4. Ninety-one percent (106/116) of subjects reported at least 1 AE during the study. Serious AEs were reported by 18% (21/116) of subjects. No subjects died during the study. Primary reasons for premature discontinuation from the study included personal reason(s) (n = 22), AEs (n = 13), gout flare (n = 8), lost to follow-up (n = 5), and other (withdrew consent, noncompliance, protocol violation, sUA >6.0 mg/dL; n = 10).36 The most common AEs that led to withdrawal from the study were abnormal liver function tests (n = 3), cancers (n = 3), and increased sCr (n = 2).
Primary gout, a systemic metabolic disorder, is the clinical manifestation of hyperuricemia. In humans, uric acid is the end product of purine catabolism and the activity of XO. Hyperuricemia results from the underexcretion or overproduction of urate. For most gout patients, their hyperuricemia is the result of renal underexcretion.25,40 The molecular bases for this dysfunction are just beginning to be understood with the recent identification and characterization of a series of genes and their related protein transporters involved in urate handling in the proximal tubule.41-44
Renal impairment has long been associated with hyperuricemia and gout. In patients with immunoglobulin A nephropathy, sUA is significantly associated with glomerulosclerosis, tubular atrophy, interstitial fibrosis, interstitial inflammation, hyaline arteriolosclerosis, and arterial intimal fibrosis.45 The Vienna Health Screening Project, a longitudinal, population-based study, followed more than 17,000 subjects for a median of 7 years and assessed risk factors for the development of chronic kidney disease (CKD; eGFR <60 mL/min per 1.73 m2).46 An increase in sUA by 2 mg/dL was independently associated with a 69% increased risk for new-onset CKD. Hyperuricemia is also independently associated with the risk of developing end-stage renal disease.6
Increases in plasma renin activity, plasma aldosterone concentrations, and urine K+ and Na+ ratio (increased K+ excretion and reduced Na+ excretion) have been observed in rats in which hyperuricemia was induced with administration of oxonic acid (an inhibitor of uricase).27 Induced sUA elevations also lead to inhibition of intrarenal nitric oxide synthase 1 expression,24,25 along with arteriolopathy in the afferent artiole.26,28,29 Thickening of the vascular wall can then lead to a collapse of the lumen with resulting ischemia, stimulating tubulointerstitial inflammation and fibrosis, along with arterial hypertension.24,28,29 Treatment with both allopurinol28 and febuxostat29,30 in these rat models has led to alleviation of the arteriolopathy and reductions in glomerular hypertension. Whereas hyperuricemia has been shown to induce intrarenal oxidative stress and endothelial dysfunction,47 some data suggest that independent of the sUA-lowering effect, the benefit of an XO inhibitor could also lie in the inhibition of XO activity that leads to free-radical production.48
The FOCUS trial is the longest, to date, assessing febuxostat in gout patients. In this study, maintenance of sUA at less than 6.0 mg/dL for 5 years led to overall stabilization of renal function as reflected in mean eGFR and sCr. Our statistical model predicts that in gout subjects, of the demographics noted in our investigation and receiving ULT over 5 years, every 1 mg/dL decrease in sUA will lead to a 1 mL/min increase in or stabilization of eGFR versus no ULT. Individuals with the greatest reductions in sUA could be expected to experience reduced rates of renal deterioration or even stabilization of renal function. Additional studies examining the impact of long-term ULT in gout patients on renal function are needed to both confirm our clinical observations and the projections of our statistical model to determine if improvements in renal function are achievable. In particular, studies will be needed to further characterize the slope of progression of renal function, correlated with long-term quantitative reduction of sUA, so that the nature of the curves of potential improvement, stabilization, or decrease in renal function may be identified.
Most long-term studies of gout treatment have not examined the effect of ULT upon renal function.49,50 However, our data are supported by the few studies in both gout and nongout hyperuricemic subjects that have assessed renal function.31-33,51 Gibson et al.31 reported that in 22 gouty subjects, 2 years of ULT with allopurinol and colchicine anti-inflammatory prophylaxis led to stabilization of eGFR, whereas subjects treated with colchicine only experienced significant declines in eGFR. In nongout hyperuricemic, hypertensive subjects, Kanbay et al.32 reported that 3 months of allopurinol treatment led to significant improvements in eGFR and blood pressure control. In a cohort of subjects with mild to moderate renal impairment, Siu et al.33 randomly assigned hyperuricemic patients to allopurinol treatment, 100 (sCr > 1.7 mg/dL) or 200 mg (sCr ≤ 1.7 mg/dL) or usual care (control group) and examined sUA and renal function (by sCr, need for dialysis, or death) at 3, 6, and 12 months. Mean baseline sCr concentration for the allopurinol group (n = 25; data were not reported for individual doses) was 1.64 (SD, 0.63) and 1.86 (SD, 0.69) mg/dL for the control group (n = 26). The allopurinol group experienced significant decreases in mean sUA and no change in sCr, whereas the control group had no improvements in sUA and declines in renal function, which became significant by 3 months and continued throughout the duration of the study.33 Within the allopurinol group, 84% of subjects maintained stable renal function, whereas 16% had worsening of renal function. In contrast, 54% of subjects in the control group had stable renal function, whereas 46% deteriorated.33 The difference between the 2 groups in the percentage of subjects with worsening renal function was significant (P = 0.015). Talaat and el-Sheikh51 reported that the withdrawal of allopurinol therapy from 50 patients with CKD who were on chronic allopurinol therapy for the treatment of mild hyperuricemia (mean sUA before treatment was 9.6 mg/dL) led to significant worsening of hypertension and significant accelerated deterioration of renal function during 12 months of follow-up. These changes were observed within 2 weeks of allopurinol withdrawal.
There are limitations to this study. Primarily, this is a post hoc analysis of the FOCUS trial data; the study was not designed to assess improvements in renal function as an efficacy endpoint and was not powered to statistically determine if observed changes within and between our study groups were significant. However, our mathematical model, along with prior studies examining the impact of ULT on renal function, lends support to the idea that sUA and renal function are intimately related. When this analysis was initiated, the CKD-EPI formula for the estimation of eGFR was not yet available. Thus, the model is based on eGFR values that may not be as accurate for this population.39 However, mean eGFR levels calculated by either MDRD or CKD-EPI provided in Table 2 are similar, suggesting that the overall implications of this analysis would not be affected.
An additional limitation lies in the open-label, extension design of the trial, in which subjects received febuxostat only.36 As such, we cannot make any comparisons between febuxostat and allopurinol, nor do we have a placebo group to determine patterns in eGFR in subjects not receiving febuxostat.
As previously discussed in the original FOCUS analyses,36 half of the subjects prematurely withdrew from the study. Although this reduction likely reduces the power of this post hoc analysis, it may very well be a reflection of the challenge of retaining subjects in a long-term follow-up study. Prospective studies with greater numbers of subjects are needed to confirm our observations of maintenance or improved renal function in patients with gout and in hyperuricemic patients with renal impairment.
Finally, it is possible that our results are not a simple reflection of lowering sUA, but may reflect the interaction between ULT and the concomitant use of medications that affect sUA and renal function. Thiazide and loop diuretics and β-blockers increase sUA, whereas certain ACEIs (captopril, enalapril, and ramipril) along with angiotensin receptor-blocking agents, such as losartan, decrease sUA.52 This study was not designed to examine changes in the use of such agents in relation to changes in sUA, eGFR, or blood pressure. However, we do show that use of these agents was similar across groups A through E, suggesting that the primary influence on observed changes in eGFR was due to long-term decreases in sUA and not concomitant medication use. It will be of importance to adequately power and prospectively evaluate the long-term effect of reducing sUA (<6.0 mg/dL) on renal function, both in hyperuricemic gout patients and in individuals with hyperuricemia and concurrent renal impairment. Until such studies are completed, our trial data in gout patients strongly support the clinical desirability of maintaining sUA of less than 6.0 mg/dL inasmuch as this will be persistently below the systemic saturation point of urate.
Use of long-term ULT may lead to stabilization or even improvement of renal function in hyperuricemic gout patients.
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