Repercussions of renal dosing of allopurinol for suboptimal gout care

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Repercussions of renal dosing of allopurinol for suboptimal gout care

The authors of ‘2016 updated the European League Against Rheumatism (EULAR) evidence-based recommendations for the management of gout’ were commended to advocate the use of allopurinol at a lower dose in patients with normal renal function. Specially, this help understand an approach to potentially decrease the risk of precipitating flares of gout early in the course of urate lowering, and perhaps to decrease the risk of severe cutaneous reactions (SCARs) compared with higher initial doses of allopurinol. It was also noted that the authors did not furnish a recommendation on starting dose for patients with renal impairment, the patient group most likely to get advantage from starting at a much lower dose of allopurinol.

Another point of concern is, recommendation #9, which advocates restricting the maximal dose of allopurinol based on creatinine clearance (CrCL). It has already been discussed that such practices induces suboptimal management of hyperuricaemia in the majority of gout patients. Since this scheme was published in 1984, clinging to the CrCL-based allopurinol dosing has been a major contributing factor to the under-treatment of gout. As per the authors, there is data supporting careful dose escalation in those with renal impairment. However, authors also had a view that the low incidence of SCARs makes it strenuous to quantify this risk and therefore, advise against a dose-escalation approach. After starting allopurinol, soon after the allopurinol hypersensitivity syndrome/SCAR occurs. As renal impairment is a main risk factor for allopurinol hypersensitivity syndrome/ SCAR, there is no proof that long-term restriction of allopurinol dose according to CrCL lowers this risk in patients with low starting doses of allopurinol. The approach recommended by the EULAR panel could guide to a clinical situation where patients may be exposed to potential risks of allopurinol, without the benefits achieved by careful dose escalation to obtain serum urate target. By pivoting on the maximum dose of allopurinol rather than the starting dose in patients with renal dysfunction, a key safety point has been missed. This may inadvertently reinforce fears of prior decades about allopurinol use in patients with renal dysfunction where more recent data has revealed that allopurinol can be safely used in patients with renal impairment.

Recommendation #9 is also likely to reduce the quality of care for the many people with gout. This happens in regions with restricted access to urate-lowering therapies other than allopurinol. Also,  recommending febuxostat if renally dosed allopurinol is niggardly for gout management elevates potential concern for patients with renal impairment. The studies depicting  the safety and efficacy of febuxostat in people with gout and comorbid renal impairment have been limited. Only 266 subjects with chronic kidney disease (CKD) stage 3 were randomised to febuxostat in the CONFIRMS clinical trial, and only 19 subjects with CKD stage 4 randomised to febuxostat in another recent trial. This is significant, as febuxostat itself has been linked to SCARs, inculcating in patients with renal impairment and/or previous hypersensitivity to allopurinol, causing the European Medical Agency and Health Canada to issue warnings concerning this issue. Currently, it is not known if this represents a true cross-reactivity or rather an individual’s propensity to undergo a drug reaction.

For the future prospects, the lack of clarity in the optimal management of hyperuricaemia in patients with gout and renal impairment should be regarded as a crucial topic. About half of all gout patients  suffer from moderate-to-severe CKD and the limited treatment options are available in this setting. A major knowledge gap and unmet needs remain the optimal means of curbing these challenges. We realize that a large, well-designed study will likely be required, keeping in mind the low incidences of allopurinol hypersensitivity syndrome (AHS)/SCAR reactions. Nonetheless, advocating allopurinol dosing as per CrCL in the absence of evidence to support this practice will not ameliorate the historically poor management of gout in patients with renal disease.



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Original title of article:

Renal dosing of allopurinol results in suboptimal gout care


Tuhina Neogi  et al.

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