A recent consensus statement identified knowledge gaps and areas of research regarding the management of gout in patients with chronic kidney disease (CKD). The full guidance was published in Nature Reviews Rheumatology.
The prevalence of gout ranges from 0.1% to 10%. According to the Gout, Hyperuricemia, and Crystal-Associated Disease Network (G-CAN), the definition of gout requires current or prior clinically evident symptoms or signs resulting from monosodium urate crystal deposition.
Kidney impairment is common in patients with gout and previous studies have reported that up to 70% of patients with gout have an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2, and approximately one-quarter have an eGFR of less than 30 mL/min/1.73 m2. It has also been reported that CKD is associated with an increased risk for gout; one-quarter of patients with an eGFR less than 60 mL/min/1.73 m2 have gout.
The objective of the current consensus statement from G-CAN was to summarize the available evidence on the management of gout in patients with CKD and to identify important gaps in knowledge and associated areas for research.
Identification of Research Areas and Proposal of Priorities
Researchers at G-CAN conducted a systematic literature review to identify articles in PubMed, the Cochrane Library, and EMBASE databases on the safety and efficacy of pharmacologic therapies for patients with gout and CKD.
Issues related to the natural history and study-related issues in gout in patients with CKD and were the 2 main areas of concern identified.
Data on the natural history of gout are limited and it remains unknown whether the presymptomatic phase is more common in those with CKD and whether the rate of progression to symptomatic gout is different in patients with CKD. While results of a study suggested potential improvement in kidney function with urate-lowering therapy (ULT) in patients with gout, additional research is needed to confirm this association.
In light of the existing gaps in general research areas, the G-CAN researchers proposed several research priorities for patients with gout and CKD, including studies to assess the natural history of gout in individuals with CKD, trials to identify potential predictors of topahceous or erosive disease, and studies to determine the impact of a treat-to-target paradigm on progression of CKD.
For study-related issues, the exclusion of patients with substantial kidney impairment from clinical trials and limited data on the clinical trials outcomes stratified by kidney function were noted to be the most important factors that limited the ability to draw specific conclusions about the safety and efficacy of pharmacologic interventions for gout in patients with CKD.
Drugs Used in the Management of Gout
Drugs used to manage gout flares include nonsteroidal anti-inflammatory drugs (NSAID), colchicine, corticosteroids, and interleukin (IL)-1 inhibitors.
While NSAIDs are generally contraindicated in patients with CKD; however, these drugs may be used for a short period in patients with end-stage kidney disease.
Data on colchicine in patients with CKD are limited and largely empirical, with pharmacokinetic studies reporting decreased colchicine clearance in individuals with significant kidney impairment.
Corticosteroids are a safe treatment option for gout flares in those with CKD. While data on IL-1 antagonist in patients with CKD are limited, since the clearance of anakinra is directly related to renal function, it is suggested the drug should be administered every other day in those with significant kidney impairment.
Drugs Used for Gout Flare Prophylaxis
Drugs used for gout flare prophylaxis are typically administered at lower doses and for longer durations than in gout management. There has been much controversy on the appropriate use of urate-lowering therapy (allopurinol, febuxostat, probenecid, benzbromarone, lesinurate, and pegloticase) in patients with gout and CKD, with different recommendations published by the relevant medical groups.
However, all current guidelines recommend ULT in patients with CKD and gout as an alternative to long-term corticosteroids that are associated with morbidity.
While the data are scarce, febuxostat was found to be more acceptable than allopurinol for use in patients with eGFR less than 30 mL/min/1.73 m2, due to the risk for allopurinol hypersensitivity syndrome. There are conflicting data on the efficacy of probenecid in patients with eGFR less than 50 mL/min/1.73 m2. Although benzbromarone is effective in patients with an eGFR of 20 mL/min/1.73 m2, the risk for hepatotoxicity has limited its use in many countries. Evidence regarding the use of pegloticase in patients with gout and CKD is also limited.
Of note, several studies have shown that gout flares are less frequent with advanced CKD and after dialysis, suggesting that some patients may not require ULT.
The G-CAN researchers proposed several requirements for pharmacologic gout studies, among which are the inclusion of patients with all stages of CKD in clinical trials, reporting outcomes stratified by CKD stage, and adherence to standardized reporting outcome measures to allow for data comparison between studies and data collection for meta-analyses.
Data on the safety and efficacy of ULT in patients receiving hemodialysis or peritoneal dialysis have been limited to case reports and cases series.
Safety of Xanthine Oxidase Inhibitors (XOIs)
The risk for allopurinol hypersensitivity syndrome has caused significant controversies regarding the dosing of allopurinol in CKD. Researchers noted that it was acceptable to initiate allopurinol at a low dose and gradually increase dose; however, the benefits of this approach have yet to be confirmed.
Data on febuxostat in patients with CKD are limited, but a study reported that treatment with a daily dose of 60 to 80 mg of febuxostat may be safe and effective, without a decline in kidney function. Treatment with febuxostat has known to cause hypersensitivity reactions.
The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial raised issues about the safety of allopurinol and febuxostat in patients with gout and cardiovascular disease (CVD), resulting in a black box warning for febuxostat use. However, the Febuxostat versus Allopurinol Streamlined Trial (FAST), a randomized controlled trial that compared the cardiovascular safety of febuxostat and allopurinol in patients with gout, found the febuxostat was not associated with an increased risk for CVD and all-cause death.
Overall, several research priorities for gout drugs in CKD were proposed by G-CAN, including safe and effective colchicine use, the short- and long-term use of NSAID in patients with end-stage kidney disease, safe dosing and treatment duration of corticosteroids, and the safety of IL-1 inhibitors in patients with kidney impairment.
The researchers also called for studies on allopurinol, to assess the impact of initiating treatment at a lower dose on the risk for allopurinol hypersensitivity syndrome and to understand the effect of gradually increasing the dose on the risk for flares and the need for flare prophylaxis. They added that the effect of febuxostat on cardiovascular risk in patients with gout should be explored in patients with CKD and CVD, and additional studies are needed to determine whether febuxostat is safer than allopurinol in CKD.
“This consensus statement is not intended as a guideline for the management of gout in CKD; rather, it analyses the available literature on the safety and efficacy of drugs used in gout management to identify important gaps in knowledge and associated areas for research,” the authors concluded.
Disclosure: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Stamp LK, Farquhar H, Pisaniello HL, et al. Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities. Nat Rev Rheumatol. Published online July 30, 2021. doi:10.1038/s41584-021-00657-4