Efficacy and safety of urate-lowering therapy in people with kidney impairment: a GCAN-initiated literature review

Abstract

Objectives The aim was to evaluate the efficacy, defined as achieving target serum urate <6.0 mg/dl, and safety of urate-lowering therapies (ULTs) for people with gout and chronic kidney disease (CKD) stages 3–5. Methods PubMed, The Cochrane Library and EMBASE were searched from 1 January 1959 to 31 January 2018 for studies that enrolled people with gout, who had an estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) of <60 ml/min and exposure to allopurinol, febuxostat, probenecid, benzbromarone, lesinurad or pegloticase. All study designs other than case reports were included, except for people on dialysis, for whom we did include case reports. Results There were 36 reports with an analysis of efficacy and/or safety based upon renal function: allopurinol (n = 12), febuxostat (n = 10), probenecid (n = 3), benzbromarone (n = 5), lesinurad (n = 5) and pegloticase (n = 1). There were 108 reports that involved people with gout and renal impairment but did not contain any analysis on efficacy and/or safety based upon renal function: allopurinol (n = 84), febuxostat (n = 14), benzbromarone (n = 1), lesinurad (n = 3) and pegloticase (n = 6). Most studies excluded people with more severe degrees of renal impairment (eGFR or CrCl of <30 ml/min). For allopurinol, in particular, there was significant variability in the dose of drug used and the efficacy in terms of urate lowering, across all levels of renal impairment. Conclusion There is a lack of evidence regarding the efficacy and/or safety of currently used ULTs according to different levels of renal function. Future studies should include patients with CKD and should report study outcomes stratified by renal function.

Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities

“…G-CAN therefore endorsed systematic reviews of the evidence for the use of medications to manage gout flares as well as ULTs. These reviews 33 , 34 form the basis for this Consensus Statement and provide the evidence to support key areas for research in each section. People with gout were not directly involved in this Consensus Statement.…”

“…As mentioned above, systematic literature reviews on the safety and efficacy of pharmacological therapies for gout in people with CKD were conducted to identify knowledge gaps and research priorities. The systematic literature review of ULTs 33 was led by L.K.S. in conjunction with the fellows H.F. and A.B.V.-S., and the systematic literature review of therapies for gout flares and prophylaxis 34 was led by A.L.G.…”

“…Two reviewers independently screened the full texts to identify eligible studies for data extraction; any discrepancy identified during the screening phase was discussed by the two reviewers to reach consensus. Detailed methods and results of the literature reviews have been previously reported 33 , 34 .…”

“…Even when people with CKD were enrolled in clinical trials, few studies reported the out comes stratified by kidney function. For example, only 12 of 96 articles reporting 91 original studies of allopu rinol and 20 of 41 articles reporting 34 original studies with febuxostat in people with CKD and gout reported data according to renal function 33 . As a consequence, it is not possible to draw specific conclusions about the efficacy and safety of drugs used for gout in CKD.…”

“…Whether the combination of xanthine oxidase inhibitors (XOIs; allopurinol or febuxostat) with uricosurics (such as probenecid) is a viable strategy in people with gout and CKD is unknown as these combinations share the same limitations of uricosurics by themselves, and evidence that is even more limited. Pegloticase is largely under-studied although the available data suggest it has similar efficacy and safety in those with impaired kidney function and those with normal kidney function 33 . As there are some data indicating that the frequency of gout flares decreases with advancing CKD and after dialysis, it is plausible that some patients with mild hyperuricaemia or normouricaemia and no flares will not require ULT 57 .…”