Managing gout: How is it different in patients with chronic kidney disease?
ABSTRACTMany patients with gout have comorbidities, including hypertension and chronic kidney disease (CKD). The goals when treating gout are no different in these patients, but the choice and dosage of drugs may need to be modified.
KEY POINTS
- Owing to concerns about using colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with CKD, glucocorticoids (local injections or systemic therapy) are often used to treat acute attacks. Corticotropin (Acthar), anti-tumor necrosis factor agents, and interleukin 1 antagonists are effective but expensive.
- Colchicine can be used in low doses as prophylaxis, with caution and appropriate monitoring. NSAIDs should be avoided, and glucocorticoids may not be effective for this purpose.
- Whether the dosage of allopurinol should be lower in patients with CKD remains controversial. We start with a low dose and slowly increase it, with a goal serum urate level of less than 6.0 mg/dL.
- Febuxostat (Uloric), like allopurinol, is a xanthine oxidase inhibitor, but the elimination of the active drug is not by the kidney. Nevertheless, we try allopurinol in escalating doses first, due to major cost differences.
Start low, go slow to avoid a flare
Rapid reduction of the serum urate level in a patient with chronic hyperuricemia and gout is likely to induce an acute flare.20 We have traditionally used a “start low and increase slowly” approach to escalating hypouricemic therapy in hopes of reducing the likelihood of causing a gout flare.
Without anti-inflammatory prophylaxis, acute flares associated with urate-lowering are extremely likely. In a 28-week trial of allopurinol, febuxostat, and placebo by Schumacher et al,33 during the first 8 weeks, when prophylaxis against gout flare was provided with either colchicine 0.6 mg once daily or naproxen (Naprosyn) 250 mg twice daily, the proportion of patients requiring treatment of gout flares was still 23% to 46%. When prophylaxis was stopped, the flare rate increased further.33
IS IT NECESSARY TO ADJUST THE ALLOPURINOL DOSE IN CHRONIC KIDNEY DISEASE?
In 1984, Hande et al35 proposed that allopurinol doses be lower in patients with renal insufficiency, with a dosage scale based on creatinine clearance.
Their thoughtful proposal was based on data from six of their own patients and 72 others with severe allopurinol toxicity, mainly allopurinol hypersensitivity syndrome, reported in the literature.
Perez-Ruiz et al36 noted that patients who had experienced adverse effects from allopurinol in their series were likely to have had received “higher” doses of allopurinol, if the dosage was corrected for reduced oxypurinol elimination based on their estimated creatinine clearance.
However, most of these reactions occurred soon after initiating therapy, a temporal pattern more typical of non-dose-dependent allergic reactions. Additionally, allopurinol hypersensitivity has been linked to T-cell-mediated immune reactions to oxypurinol,37 a mechanism not likely linked to drug levels.
Arguments against dose adjustment
Despite the compelling information that allopurinol reactions are more common in CKD, adjusting the dosage of allopurinol has not been clearly shown to reduce the frequency of these reactions.
In a small retrospective analysis, Vázquez-Mellado et al38 reported that adjusting the allopurinol dosage according to creatinine clearance did not decrease the incidence of allopurinol hypersensitivity.
In a study in 250 patients, Dalbeth et al39 showed that the overall incidence of hypersensitivity reaction was 1.6%, and the incidence of allergic reactions did not decrease when allopurinol was given according to the dosing guidelines proposed by Hande et al.35 However, it is worth noting that, of the patients who received the recommended lower doses, only 19% achieved the target serum urate level of 6 mg/dL.39
Silverberg et al40 found that of 15 patients who developed hypersensitivity reactions to allopurinol, 10 had received doses that were low or appropriate according to the guidelines of Hande et al.35
More recently, Stamp et al41 found that gradually increasing the allopurinol dose above the proposed creatinine clearance-based dose was safe and effective. Thirty-one (89%) of the 35 patients who completed the study achieved the target serum urate level of 6 mg/dL, while only 3 of 45 who started the study developed rashes, which were not serious.
The small number of patients in these studies limits any strong conclusion, but at present there is no interventional study showing that allopurinol dosing adjustment based on glomerular filtration rate is effective or safer than dosing based on the serum urate level.
Our view on allopurinol dosing adjustment
We believe the initial observations of Hande et al35 and the subsequent meticulous data from Perez-Ruiz et al36 suggest a relationship between CKD and the occurrence of severe allopurinol reactions. However, these observations do not prove that dose adjustment will prevent these reactions.
In patients with normal kidney function, the FDA30 and the European League Against Rheumatism (EULAR)42 recommend slow upward titration, starting with 100 to 200 mg/day, which we agree should decrease the frequency of acute gout flares. The dose is increased by increments of 100 mg/day at intervals of 1 week (FDA recommendation) or 2 to 4 weeks (EULAR recommendation) until the serum urate level is lower than 6 mg/dL.
We believe the optimal approach to allopurinol dosing in patients with CKD remains uncertain. We generally escalate the dose slowly, with ongoing frequent laboratory and clinical monitoring, and we do not limit the maximal dose as suggested by Hande et al.35
An alternative strategy is to use the newer, far more expensive xanthine oxidase inhibitor febuxostat in patients with CKD, since it is not excreted by the kidney. We usually first try escalating doses of allopurinol.
