|Year : 2018 | Volume
| Issue : 5 | Page : 1050-1056
|Study of therapeutic efficacy of febuxostat in chronic kidney disease stage IIIA to stage VD
Partha Saradhi Sarvepalli1, Mehruq Fatima2, Abdul Khalid Quadri2, Aliya Raeesa Taher2, Ayesha Habeeb2, Fayeza Amreen2, Badarunnisa Nikhat Parveen3, KG Rajaram4
1 Department of Nephrology, Apollo DRDO Hospital, Hyderabad, Telangana, India
2 Department of Pharmacy Practice, Deccan School of Pharmacy, Hyderabad, Telangana, India
3 Department of Nephrology, Owaisi Hospital and Research Center, Hyderabad, Telangana, India
4 Department of Nephrology, Owaisi Hospital, Deccan College of Medical Sciences, Hyderabad, Telangana, India
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|Date of Submission||05-Sep-2017|
|Date of Decision||16-Dec-2017|
|Date of Acceptance||17-Dec-2017|
|Date of Web Publication||26-Oct-2018|
| Abstract|| |
Hyperuricemia [serum uric acid (SUA) >7.0 mg/dL] which is common in chronic renal diseases is associated with augmented vascular events. In addition to nonpharmacological therapy, hypouricosuric drugs reduce UA levels. The current study was a prospective observational study of six months duration November 2016 to April 2017 done to determine the efficacy of febuxostat in patients with hyperuricemia in chronic kidney disease (CKD) stage G3a to G5 and to correlate any association with reduction of hypertension, improvement in glomerular filtration rate (GFR), and reduction in comorbidities. The study was carried out at the Department of Nephrology, Owaisi Hospital and Research Center, Hyderabad. One hundred and ten patients were screened, of which 53 patients wherein stage G3a to G5 were recruited and SUA levels were obtained after inclusion criteria. SUA >6.0 in females and 7.0 in males were recruited. The drug febuxostat 40 mg was given once day to all patients with stage G3a to G5D with elevate uric acid levels >7.0 in males and more than 6.0 in females and three samples of UA were obtained monthly. The mean of GFR, blood pressure (BP), and SUA levels were obtained before and after the therapy. Of the 53 patients, males were 32 (60.3%), and females were 21 (39.6%). Mean age of the patients were 36.5 years. Mean UA levels before the start of febuxostat therapy were 8.6, and after adding febuxostat, it was 5.10 at the end of the third visit. The mean BP drop was 7.2 ± 2.1 mm in systolic BP (from 154–147 mm Hg) and diastolic BP drop was 93 ± 2.5 mm Hg (5.1 mm Hg). The mean GFR improved from 50.3 to 53.3 mL/min after the start of febuxostat. Febuxostat in asymptomatic CKD patients improves UA levels, BP and estimated GFR at low dose without any adverse events and no cardiac-related events.
|How to cite this article:|
Sarvepalli PS, Fatima M, Quadri AK, Taher AR, Habeeb A, Amreen F, Parveen BN, Rajaram K G. Study of therapeutic efficacy of febuxostat in chronic kidney disease stage IIIA to stage VD. Saudi J Kidney Dis Transpl 2018;29:1050-6
|How to cite this URL:|
Sarvepalli PS, Fatima M, Quadri AK, Taher AR, Habeeb A, Amreen F, Parveen BN, Rajaram K G. Study of therapeutic efficacy of febuxostat in chronic kidney disease stage IIIA to stage VD. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2020 May 26];29:1050-6. Available from: http://www.sjkdt.org/text.asp?2018/29/5/1050/243953
| Introduction|| |
Chronic kidney disease (CKD) is a progressive condition in which progressive loss of renal function occurs over several months to years and is characterized by the gradual replacement of normal kidney architecture with parenchymal fibrosis. In CKD, hyperuricemia is common and associated with intra-arteriolar lesions, vascular endothelial dysfunction and hypertension (HTN) which are contributing to increased burden of cardiovascular disease. Once subjects develop end-stage renal disease, there is a reverse J-curve, in which both high and lower uric acid (UA) levels convey increased cardiovascular risk and mortality.
The prevalence of hyperuricemia rises in parallel with the glomerular filtration rate (GFR) decline, which is present in 40–60% of patients with CKD stages I to III and in 70% of patients with CKD stage IV or stage V. Elevated serum UA (SUA) levels are associated with increased risk of worsening of GFR and augmentation of glomerulosclerosis.
Lowering of UA by pharmacological and nonpharmacological methods have been associated with improved renal outcomes in regarding improvement in GFR and blood pressure (BP) control, especially in mouse models and in few Korean and Japanese studies. The earlier drug, allopurinol is metabolized by xanthine oxidase to oxypurinol, and both substrates acts to inhibit xanthine oxidase. However, toxicity of allopurinol is more pronounced as estimated glomerular filtration falls as the metabolite oxypurinol is cleared by the kidney.
The novel drug febuxostat, a nonpurine selective xanthine oxidase inhibitor, has been shown to be safe and effective for decreasing SUA levels in CKD when compared to allopurinol. Febuxostat is more potent and less toxic than allopurinol even in hemodialysis (HD) cases as reported in the western literature. This research work is was carried out as there is minimal information available in the Indian context in this aspect of controlling UA levels with the administration of febuxostat in various stages of G 3-G5 CKD patients.
| Aims and Objectives|| |
This study aimed to determine the level of SUA in stage G3a to stage G5D CKD patients (both nondialytic and dialytic) and to study the role of febuxostat in CKD (3–5) in asymptomatic and symptomatic CKD and reduce the burden of HTN, CKD, and hyperuricemic arthritis.
| Materials and Methods|| |
The current study was done at the outpatient renal clinic and HD departments of the division of Nephrology and HTN at Owaisi Hospital and Research Center, a tertiary care teaching hospital for Deccan College of Medical Sciences, Hyderabad, Telangana state, India.
This was a prospective observational study of six months duration from November 2016 – April 2017. Measurement of SUA levels were done in all patients attending the renal clinic on outpatient basis and on HD patients before dialysis randomly. Those individuals who SUA levels were >7.0 mg/dL in males and >6.0 mg/dL in females were counseled about the risks of hyperuricemia and history related to arthritis, HTN, renal colic, and coronary artery disease was obtained. Both symptomatic and asymptomatic patients were screened and were enrolled for the study.
The inclusion criteria were patients who are suffering from CKD Stage 3–5 (dialytic and nondialytic), patients who were willing to participate in the study and expressed a desire to achieve the objective of the study, those who were suffering from primary gout and stopped the treatment. Only patients above 18 years of age were included in the study.
- Patients who were not willing to participate in the study were excluded
- Patients who were already on drugs Losartan and Probenecid were excluded
- Patients who were given Allopurinol were excluded
- Pregnant females were excluded.
All patients who were suffering with CKD were advised to undergo UA level testing. Random UA levels were obtained in non dialytic patients and predialytic UA levels were obtained in CKD stage 5D patients. The automated enzymatic method was used for estimating the UA levels on fasting basis and nondialytic days for dialysis patients. About 2 mL of blood was collected in non heparinized tube and then centrifuged for 20 min, and the serum samples obtained were tested with automated analyzer. (Seimens’ analyzer). SUA was expressed in mg/dL.
| Statistical Analysis|| |
All the patients data were represented as mean and standard deviation. The mean and the standard deviation were calculated and the Chi-square test was done to find the correlation between the SUA levels and the Febuxostat therapy. The mean of GFR, BP, and SUA levels were obtained before and after the therapy. Confidence intervals (CI) were calculated to (95%) were calculated using the standard error and correlation was established. Correlations between continuous variables were assessed using Pearson’s correlation coefficient. Mann–Whitney U-test was used to determine the differences between groups. Statistical analysis was performed with the Statistical Package for Social Sciences (SPSS) version 20.0 for Windows (SPSS Inc., Chicago, IL, USA). P <0.05 was considered statistically significant.
| Results|| |
A total of 110 patients were screened of which 53 patients met the inclusion criteria and were enrolled for febuxostat therapy at a dose of 40 mg per day so as to reduce the SUA levels and all were explained the benefits of lowering of SUA levels and about the risks of febuxostat therapy. All were convinced and informed consent was obtained from them which was approved by the Insitutional Ethics committee.
Out of the 53 patients, males were 32 (60.3%) and females were 21 (39.6%). Mean age of the patients were 36.5 years.
Eighty-five percent of patients were associated with HTN who were on more than four drug therapy including diuretic, 55% of patients were diabetic and 19% were associated with coronary artery disease with status post angioplasty. One patient had rheumatoid arthritis. Eleven percent were smokers and 89% were nonsmokers [Table 1].
Serum uric acid levels and stages of chronic kidney disease
Out of 53 patients, five patients were in stage IIIA (9.4%), nine patients were in stage IIIB (16.9%), stage IV were seen in nine patients (16.9%) and stage VD was seen in 30 patients (56.6%). Overall, mean UA levels before the start of febuxostat therapy was 8.6 (CI 8.24–9.14 (95%) and after adding febuxostat, it was 5.10 at the end of the third visit. (CI 4.71–5.49 95% limit) [Table 2].
|Table 2: Mean SUA level in CKD Stage G3a-G5 patient's prior and after febuxostat therapy.|
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Variations in each stage of chronic kidney disease before and after febuxostat therapy
In stage IIIA, the mean SUA levels before the start of therapy were 8.74 (CI 95% interval - 7.36–10.11). After therapy, the mean SUA levels reduced to 5.78 (CI 5.29–6.26). In Stage IIIB, the mean SUA levels reduced from 7.91 (CI 7.22–8.59) to 4.86 at the end of therapy (CI 4.25–5.48 (95% limits). In stage IV, the mean SUA levels were 8.46 (CI 7.59–9.33 (95% limits) before febuxostat and after therapy SUA reduced to 5.23 mg/dL (CI 3.77–6.68 (95% limits). In stage VD, we noticed that the mean SUA levels before therapy were 8.99 (CI 8.31–9.67 (95% limits) and mean UA levels reduced to 5.02 after therapy (CI is 4.515.53–95% limits) [Table 3].
|Table 3: Mean and 95% confidence interval of SUA level in patients with CKD stage G3a-G5 prior and after febuxostat therapy.|
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Blood pressure levels before the start of febuxostat therapy
Of the 53 patients the mean BP levels were systolic 154.2 ± 2.4 mm Hg and diastolic was 98.3 ± 2.4 mm Hg. In stage 3 CKD mean BP was 155.5 ± 3.5 mm Hg and 88.5 ± 2.4 mm Hg. In stage IV CKD mean systolic BP (SBP) was 152.5 ± 3.5 mm Hg and diastolic BP (DBP) was 86.4 ± 2.4 mm Hg. In HD patients the mean BP was 160.3 ± 2.4 mm Hg and DBP was 98.4 ± 2.6 mm Hg [Table 4] and [Table 5].
|Table 4: Mean SBP variation in patients with CKD stage G3a-G5 prior and after febuxostat therapy.|
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|Table 5: Mean DBP variation in patients with CKD stage G3a–G5 prior and after febuxostat therapy.|
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Blood pressure levels after start of febuxostat therapy
The mean BP drop was 7.2 ±2.1 mm in overall study in systolic group (from 154 to 147 mm Hg) and DBP drop was 3.75 ± 2.25 mm Hg (6.1). In patients with G3a CKD the mean SBP drop was 8.3 mm Hg, in G3b CKD the drop was 8.3 ± 1.3 mm Hg, in G4 CKD it was 6.4 ± 0.4 mm Hg and in G5HD-CKD the drop was 6.3 ± 0.9 mm Hg.
In the DBP the drop was significantly noted from all stages of CKD, in G3a CKD it was 3.6 ± 0.6 mm Hg, in G3b CKD it was 2.9 ± 0.5 mm Hg, in stage G4 CKD the drop was 2.2 ± 0.6 mm Hg and in patients on HD the drop was 5.2 ± 0.4 mm Hg at the final visit of febuxostat therapy. There was a significant correlation between the BP drop and the usage of febuxostat therapy in both levels of BP (P <0.0041, in SBP and 0.0062 in DBP group) [Table 4] and [Table 5].
Uric acid levels and glomerular filtration rate variation
The mean GFR before the start of the febuxostat therapy in nondialytic CKD was 50.5 mL/min/m2 and after three months of therapy of febuxostat the GFR improved to 53.3 mL/min/m2. There was no change in the GFR on dialysis therapy. In CKD IIIa, the mean GFR was 52.2 ± 3.2 mL/min/m2 prior to febuxostat and after therapy it improved to 53.2 ± 1.3 mL/min/m2. In CKD stage IIIB, the mean GFR was 38.3 ± 2.4 mL/min/ m2 before febuxostat and after therapy it was 39.4 ± 2.2 mL/min/m2. In stage IV CKD, the mean GFR was 24.6 ± 1.6 mL/min/m2 prior to febuxostat therapy and postfebuxostat the GFR improved to 25.4 ± 1.8 mL/min/m2 [Table 6].
|Table 6: GFR improvements in CKD stage G3a to G4 patients before and after febuxostat therapy.|
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| Discussion|| |
UA is a product of purine metabolism with excretion rate of 800 mg/day in healthy adults. Being excreted predominantly by the kidneys, UA accumulation is associated with renal and extrarenal complications. In the current study of the 53 patients who had hyperuricemia there was a reduction in the mean SUA levels from 8.69 to 5.10 mg/dL in following therapy with febuxostat of 40 mg per day in any stage of CKD and none of them had any adverse events with febuxostat therapy. The mean UA levels was directly associated with the fall in BP with P <0.05.
In a study done by Akimoto et al, febuxostat lowered the SUA levels (8.9 ± 1.0 at baseline) significantly from one month after the initiation of the treatment and the target SUA level (6.0 mg/dL) was achieved in 12 patients (70.5%) after one month of treatment, compared to 13 (76.4%) and 14 (82.3%) patients after three and six months of treatment, respectively. In this study, the SUA levels were reached within one month of initiation of therapy both in dialysis and nondialysis CKD.
In the current study, there was a significant improvement in the estimated GFR (eGFR) who were on febuxostat therapy in stage III and IV CKD at the end of the follow-up with a mean decline in creatinine of 0.3 mg equivalent to GFR improvement of 3 mL/min/m2. This can be compared to Sircar et al who randomised 108 CKD patients to febuxostat 40 mg versus placebo. Six months of treatment with febuxostat was associated with a stronger reduction in UA levels (from 9.0 ± 2.0 to 5.2 ± 1.5 mg/dL) and with improvement of GFR (+3.2 mL/min/1.73 m2) compared with that observed with allopurinol by Goicoechea et al. In another study done by Kim et al at Korea a four weeks therapy of febuoxostat versus allopurinol in gouty men found that at the end of four weeks therapy of allopurinol and febuxostat was associated with decline in DBP in allopurinol group and serum creatinine levels in Febuxostat group.
There was a significant reduction in mean SBP after the initiation of therapy with febuxostat. This can be compared to Sircar et al study where average BP in the febuxostat group was 149.5/85.4 mm Hg, which decreased to 136.6/80.0 mm Hg at six months. Average BP in the placebo group was 138.5/80.5 mm Hg at baseline and decreased to 134.4/ 82.9 mm Hg at six months.
UA reduces nitric oxide synthesis and increases endothelin activation. Hence, lowering the SUA levels was associated with reduction in the BP of these patients. Moreover, the requirement of drug therapy was reduced in 11 out of the 53 patients on non-HD population group (20.75%).
eGFR improved steadily in all cases of nondialytic CKD which indicates that the strong endothelial dysfunction associated with hyperuricemia. Hyperuricemia, when treated with febuxostat, improved GFR in Sircar et al study also where there was 10% improvement in eGFR over baseline compared with 26 of 48 (54%) from the placebo group (P <0.004). Hence, our study has a direct correlation with improvement in GFR when SUA level reached <6.0 mg/dL (P <0.001). This can be compared to the febuxostat/allopurinol Comparative Extension Long-term (EXCEL) Study where patients treated with febuxostat had greater continued reductions in SUA levels was associated with less decline in kidney function (P <0.001) by statistical modeling. There was long-term reduction in SUA level in persons with gout, 1.2 mL/min/1.73 m2 of eGFR for every 1 mg reduction in SUA. In another study done on febuxostat and severe renal impairment in gout, febuxostat was efficacious, but there was no change in serum creatinine levels at the end of the study. In our study, no adverse events were reported with 40 mg of febuxostat therapy. In a comparative study done between febuxostat and allopurinol the number of gouty flare-ups were reduced in the febuxostat group when compared to Allopurinol group and prevention of tophi deposition. In the CKD BHPHD study done by Weng et al febuxostat improved eGFR and also reduced hyperuricemia with better improvement in renal outcomes.
| Limitations of the study|| |
This study was of limited sample size and was done for a short duration. Large cohort are required before we conclude that febuxostat has to be given asymptomatically hyperuricemic patients.
| Conclusions|| |
Nonpharmacological and drug therapy with febuxostat at a low dose of 40 mg in moderate renal insufficiency (CKD stage G3–G4) improved GFR, reduction in BP and in dialysis patients improvised the BP and reduced the risk of vascular events. In patients with elevated UA >7.0 even though asymptomatic we recommend using low dose febuxostat of 40 mg per day in any stage of CKD which is economical and has minimal adverse effects to prevent vascular events.
Conflict of interest: None declared.
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Dr. Partha Saradhi Sarvepalli
Department of Nephrology, Apollo DRDO Hospital, Hyderabad, Telangana
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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