Skip to main content
Top
Published in: BMC Nephrology 1/2017

Open Access 01-12-2017 | Research article

Identification of chronic kidney disease patient characteristics influencing the renoprotective effects of febuxostat therapy: a retrospective follow-up study

Authors: Akinori Yamaguchi, Makoto Harada, Yosuke Yamada, Koji Hashimoto, Yuji Kamijo

Published in: BMC Nephrology | Issue 1/2017

Login to get access

Abstract

Background

The ability of antihyperuricemic therapy to exert renoprotective effects in patients with chronic kidney disease (CKD) is controversial. In the present study, we studied patient characteristics that may mask favorable impact of antihyperuricemic therapy on the progression of CKD.

Methods

This was a single-center, retrospective, follow-up study. One-hundred and seventy-eight CKD patients with hyperuricemia who received febuxostat therapy were included in this study. Mean serum uric acid (mUA) level after treatment and changes in estimated glomerular filtration rate (ΔeGFR) over 6 months were measured and their correlation was examined. Patients were divided into two groups based on mUA, and their ΔeGFR were compared. These analyses were evaluated in various subgroups.

Results

Febuxostat therapy markedly decreased UA level in any CKD stage patients without resulting in serious adverse events. eGFRs of CKD patients in the mUA < 6.0 mg/dl group were maintained, whereas those in the mUA ≥ 6.0 mg/dl group decreased. A significant inverse correlation was observed between mUA and ΔeGFR (r = −0.16, p = 0.019). The renoprotective effects of febuxostat were significant in the following subgroups: male patients, age < 70 years, systolic blood pressure < 130 mmHg, normal cholesterol levels, and absence of diabetes. Coexisting vascular risk factors appear to exert additive masking effects against febuxostat renoprotection.

Conclusions

The results of this study suggest that various vascular risk factors markedly attenuate the renoprotective effects of febuxostat.
Appendix
Available only for authorised users
Literature
1.
go back to reference Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis. 2004;44:642–50.CrossRefPubMed Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis. 2004;44:642–50.CrossRefPubMed
2.
go back to reference Zoppini G, Targher G, Chonchol M, Ortalda V, Abaterusso C, Pichiri I, et al. Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function. Diabetes Care. 2012;35:99–104.CrossRefPubMed Zoppini G, Targher G, Chonchol M, Ortalda V, Abaterusso C, Pichiri I, et al. Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function. Diabetes Care. 2012;35:99–104.CrossRefPubMed
3.
go back to reference Koratala A, Singhania G, Alquadan KF, Shimada M, Johnson RJ, Ejaz AA. Serum uric acid exhibits inverse relationship with estimated glomerular filtration rate. Nephron. 2016;134:231–7.CrossRefPubMed Koratala A, Singhania G, Alquadan KF, Shimada M, Johnson RJ, Ejaz AA. Serum uric acid exhibits inverse relationship with estimated glomerular filtration rate. Nephron. 2016;134:231–7.CrossRefPubMed
4.
go back to reference Ohno I, Hosoya T, Gomi H, Ichida K, Okabe H, Hikita M. Serum uric acid and renal prognosis in patients with IgA nephropathy. Nephron. 2001;87:333–9.CrossRefPubMed Ohno I, Hosoya T, Gomi H, Ichida K, Okabe H, Hikita M. Serum uric acid and renal prognosis in patients with IgA nephropathy. Nephron. 2001;87:333–9.CrossRefPubMed
5.
go back to reference Syrjänen J, Mustonen J, Pasternack A. Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy. Nephrol Dial Transplant. 2000;15:34–42.CrossRefPubMed Syrjänen J, Mustonen J, Pasternack A. Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy. Nephrol Dial Transplant. 2000;15:34–42.CrossRefPubMed
6.
go back to reference Yu MA, Sánchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens. 2010;28:1234–42.PubMed Yu MA, Sánchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens. 2010;28:1234–42.PubMed
7.
go back to reference Tsuda H, Kawada N, Kaimori JY, Kitamura H, Moriyama T, Rakugi H, et al. Febuxostat suppressed renal ischemia-reperfusion injury via reduced oxidative stress. Biochem Biophys Res Commun. 2012;427:266–72.CrossRefPubMed Tsuda H, Kawada N, Kaimori JY, Kitamura H, Moriyama T, Rakugi H, et al. Febuxostat suppressed renal ischemia-reperfusion injury via reduced oxidative stress. Biochem Biophys Res Commun. 2012;427:266–72.CrossRefPubMed
8.
go back to reference Sánchez-Lozada LG, Tapia E, Santamaría J, Avila-Casado C, Soto V, Nepomuceno T, et al. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int. 2005;67:237–47.CrossRefPubMed Sánchez-Lozada LG, Tapia E, Santamaría J, Avila-Casado C, Soto V, Nepomuceno T, et al. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int. 2005;67:237–47.CrossRefPubMed
9.
go back to reference Maejima I, Takahashi A, Omori H, Kimura T, Takabatake Y, Saitoh T, et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 2013;32:2336–47.CrossRefPubMedPubMedCentral Maejima I, Takahashi A, Omori H, Kimura T, Takabatake Y, Saitoh T, et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 2013;32:2336–47.CrossRefPubMedPubMedCentral
10.
go back to reference Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013;14:454–60.CrossRefPubMed Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013;14:454–60.CrossRefPubMed
11.
12.
13.
go back to reference Liu WC, Hung CC, Chen SC, Yeh SM, Lin MY, Chiu YW, et al. Association of hyperuricemia with renal outcomes, cardiovascular disease, and mortality. Clin J Am Soc Nephrol. 2012;7:541–8.CrossRefPubMed Liu WC, Hung CC, Chen SC, Yeh SM, Lin MY, Chiu YW, et al. Association of hyperuricemia with renal outcomes, cardiovascular disease, and mortality. Clin J Am Soc Nephrol. 2012;7:541–8.CrossRefPubMed
14.
go back to reference Shi Y, Chen W, Jalal D, Li Z, Chen W, Mao H, et al. Clinical outcome of hyperuricemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial. Kidney Blood Press Res. 2012;35:153–60.CrossRefPubMed Shi Y, Chen W, Jalal D, Li Z, Chen W, Mao H, et al. Clinical outcome of hyperuricemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial. Kidney Blood Press Res. 2012;35:153–60.CrossRefPubMed
15.
go back to reference Mayer MD, Khosravan R, Vernillet L, Wu JT, Joseph-Ridge N, Mulford DJ. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005;12:22–34.CrossRefPubMed Mayer MD, Khosravan R, Vernillet L, Wu JT, Joseph-Ridge N, Mulford DJ. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005;12:22–34.CrossRefPubMed
16.
go back to reference Levy GD, Rashid N, Niu F, Cheetham TC. Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia. J Rheumatol. 2014;41:955–62.CrossRefPubMed Levy GD, Rashid N, Niu F, Cheetham TC. Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia. J Rheumatol. 2014;41:955–62.CrossRefPubMed
17.
go back to reference Grabowski BA, Khosravan R, Vernillet L, Mulford DJ. Metabolism and excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, in healthy male subjects. J Clin Pharmacol. 2011;51:189–201.CrossRefPubMed Grabowski BA, Khosravan R, Vernillet L, Mulford DJ. Metabolism and excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, in healthy male subjects. J Clin Pharmacol. 2011;51:189–201.CrossRefPubMed
18.
go back to reference Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, Parallel-Group Trial. Arthritis Rheum. 2008;59:1540–8.CrossRefPubMed Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, Parallel-Group Trial. Arthritis Rheum. 2008;59:1540–8.CrossRefPubMed
19.
go back to reference Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12:R63.CrossRefPubMedPubMedCentral Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12:R63.CrossRefPubMedPubMedCentral
20.
go back to reference Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388–93.CrossRefPubMedPubMedCentral Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388–93.CrossRefPubMedPubMedCentral
21.
go back to reference Sircar D, Chatterjee S, Waikhom R, Golay V, Raychaudhury A, Chatterjee S, et al. Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double-blind, randomized, Placebo-Controlled Trial. Am J Kidney Dis. 2015;66:945–50.CrossRefPubMed Sircar D, Chatterjee S, Waikhom R, Golay V, Raychaudhury A, Chatterjee S, et al. Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double-blind, randomized, Placebo-Controlled Trial. Am J Kidney Dis. 2015;66:945–50.CrossRefPubMed
22.
go back to reference Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Palo WA, Eustace D, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005;52:916–23.CrossRefPubMed Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Palo WA, Eustace D, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005;52:916–23.CrossRefPubMed
23.
go back to reference Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. Placebo-controlled double-blind dose-response study of the non-purine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia (including gout patients) in japan: late phase 2 clinical study. J Clin Rheumatol. 2011;17:S35–43.CrossRefPubMed Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. Placebo-controlled double-blind dose-response study of the non-purine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia (including gout patients) in japan: late phase 2 clinical study. J Clin Rheumatol. 2011;17:S35–43.CrossRefPubMed
24.
go back to reference Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450–61.CrossRefPubMed Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450–61.CrossRefPubMed
25.
go back to reference Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. An allopurinol-controlled, multicenter, randomized, open-label, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 2 exploratory clinical study. J Clin Rheumatol. 2011;17:S44–9.CrossRefPubMed Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. An allopurinol-controlled, multicenter, randomized, open-label, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 2 exploratory clinical study. J Clin Rheumatol. 2011;17:S44–9.CrossRefPubMed
26.
go back to reference Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol. 2011;17:S13–8.CrossRefPubMed Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol. 2011;17:S13–8.CrossRefPubMed
27.
go back to reference Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. Multicenter, open-label study of long-term administration of febuxostat (TMX-67) in Japanese patients with hyperuricemia including gout. J Clin Rheumatol. 2011;17:S50–6.CrossRefPubMed Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. Multicenter, open-label study of long-term administration of febuxostat (TMX-67) in Japanese patients with hyperuricemia including gout. J Clin Rheumatol. 2011;17:S50–6.CrossRefPubMed
Metadata
Title
Identification of chronic kidney disease patient characteristics influencing the renoprotective effects of febuxostat therapy: a retrospective follow-up study
Authors
Akinori Yamaguchi
Makoto Harada
Yosuke Yamada
Koji Hashimoto
Yuji Kamijo
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2017
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-017-0572-z

Other articles of this Issue 1/2017

BMC Nephrology 1/2017 Go to the issue