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.
FEBUXOSTAT, AN ALTERNATIVE TO ALLOPURINOL
Febuxostat is an oral nonpurine inhibitor of xanthine oxidase.43 Approved by the FDA in 2009, it is available in 40- and 80-mg tablets.
Unlike allopurinol, febuxostat is metabolized primarily by hepatic glucuronide formation and oxidation and then excreted in stool and urine,44 making it in theory an attractive agent in patients with renal insufficiency, bypassing the controversial dose-adjustment issue with allopurinol.
In the Febuxostat Versus Allopurinol Controlled Trial (FACT),20 a 52-week randomized, double-blind study in hyperuricemic patients with gout, serum urate levels were reduced to less than 6.0 mg/dL in over 50% of patients receiving febuxostat 80 mg or 120 mg once daily, while only 21% of patients receiving 300 mg of allopurinol achieved this goal. This does not imply that allopurinol at higher doses, as should be used in clinical practice,45 would not be equally effective. Patients with CKD were not included in this trial.
In the study by Schumacher et al,33 febuxostat 80, 120, or 240 mg once daily reduced serum urate. A small subset (35 patients) had mild to moderate renal insufficiency (serum creatinine 1.5–2 mg/dL).33 The number of patients with renal insufficiency who achieved the primary end point of a serum urate level lower than 6 mg/dL was 4 (44%) of 9 in the febuxostat 80-mg group, 5 (46%) of 11 in the 120-mg group, and 3 (60%) of 5 in the 240-mg group, while none of the 10 patients in the dose-adjusted allopurinol group achieved the primary end point (P < .05). Of note, 41% of the patients with normal renal function who received allopurinol achieved the primary end point.33 As proposed above, if the allopurinol dose had been slowly increased in the patients with renal insufficiency, it might have been equally effective.
Febuxostat has not been thoroughly evaluated in patients with severe CKD or in patients on hemodialysis.
A presumed niche indication of febuxostat is in patients allergic to allopurinol, since the drugs are not similar in chemical structure. However, at present, experience with this use is limited. Allopurinol-allergic patients were excluded from the clinical trials; thus, if there is any allergic overlap, it would not likely have been recognized in those studies. The FDA has received reports of patients who were allergic to allopurinol also having reactions to febuxostat, and it is currently evaluating these reports (personal communication).
Concern was raised over cardiovascular adverse events in patients treated with febuxostat during clinical trials. In the FACT trial, two patients died of cardiac causes.20 In the study by Schumacher et al,33 11 of 670 patients experienced cardiac adverse events in the febuxostat group vs 3 of 268 in the allopurinol group. Events included atrial fibrillation, chest pain, coronary artery disease, and myocardial infarction. However, this difference was not statistically significant.
Febuxostat costs much more than allopurinol. Currently, patients pay $153.88 for 1 month of febuxostat 40 or 80 mg from Cleveland Clinic pharmacy; 1 month of allopurinol costs $17.45 (300 mg) or $14.00 (100 mg). We believe febuxostat should be reserved for patients with documented intolerance to allopurinol in effective doses.
Monitoring serum urate levels is important in all patients on hypouricemic therapy so that dosage adjustments can be made until the target serum urate concentration is reached. In patients failing to meet target serum urate levels, patient adherence with the prescribed dosing should be specifically addressed because as many as 50% of patients do not adhere to their prescribed regimen.
DOES URATE-LOWERING THERAPY HAVE BENEFITS BEYOND GOUT?
Despite experimental animal data and a strong epidemiologic association between hyperuri-cemia and hypertension,46 metabolic syndrome, and rates of cardiovascular and all-cause mortality,47 the evidence from interventional trials so far does not support the routine use of hypo-uricemic therapy to prevent these outcomes.
Similarly, hyperuricemia has long been associated with renal disease, and there has been debate as to whether hyperuricemia is a result of kidney dysfunction or a contributing factor.46,48–51 A few studies have documented improvement of renal function after initiation of hypouricemic therapy.52 However, treating asymptomatic hyperuricemia to preserve kidney function remains controversial.
A recent study indicates that lowering the serum urate level with allopurinol can lower the blood pressure in hyperuricemic adolescents who have newly diagnosed primary hypertension.53 This does not indicate, however, that initiating hypouricemic therapy in patients with preexisting, long-standing hypertension will be successful.
RECOMMENDED FOR OUR PATIENT
As for our diabetic patient with an acute gout flare and creatinine clearance rate of 45 mL/minute, we would recommend:
- Aspirating the knee, sending the fluid for bacterial culture, and then treating it with a local glucocorticoid injection
- Starting colchicine 0.6 mg every day, with frequent monitoring for signs of toxicity (muscle pain, weakness, leukopenia, and elevations of creatine kinase and aspartate aminotransferase)
- Increasing his allopurinol dose by 100 mg every 2 to 4 weeks until the target serum urate level of less than 6.0 mg/dL is reached
- If he cannot tolerate allopurinol or if the target serum urate level is not achieved despite adequate doses of allopurinol (about 800 mg), we would switch to febuxostat 40 mg and increase the dose as needed to achieve the desired urate level.
