Case: new treatment approach

Mr. M and the clinician agree that treatment of his acute gout symptoms with an intra-articular corticosteroid is a sensible approach, eliminating concerns about compliance to an oral regimen or systemic effects of steroids. 

Mr. M returns one month later, his acute flare resolved. The clinician 
discusses changing Mr. M’s medications in order to reduce his serum uric 
acid level to the goal of 6 mg/dL.5 The thiazide diuretic in his combination antihypertensive decreases distal sodium reabsorption, which is compensated for by increased proximal tubular sodium and, secondarily, urate reabsorption.

Thus, thiazide diuretics increase serum urate levels.8 Changing to another antihypertensive agent may help to lower his serum urate level. As the patient has not been compliant with his allopurinol in the past, they consider beginning allopurinol again for chronic treatment of his symptomatic hyperuricemia.

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Discussion: long-term management 

There are several considerations for pharmacologic management of hyperuricemia in patients with CKD (Table). Long-term therapy is recommended for patients with >2 gout flares per year and for those with tophi. A serum urate goal of <6 mg/dL is associated with a marked reduction in acute gout flares.5

Initiation of allopurinol or febuxostat can mean increased likelihood of an acute gout flare. Prophylaxis with NSAIDs or colchicine can prevent flares, but they may be contraindicated in patients with kidney failure or used with extreme caution if there are no alternatives. Low-dose prednisone may prevent acute flares but is associated with long-term toxicity.

Another option is to provide patients with a glucocorticoid dose pack to take in anticipation that they may develop an acute gout attack. Patients must understand that they should continue with their allopurinol or febuxostat during the flare. If they do not experience rapid improvement, they should contact their physician to rule out septic arthritis. 

Allopurinol is effective in both overproducers (10%) and underexcreters (90%) of urate (Table).5,8,19 Allopurinol is considered a first-line therapy because it has a simple dosing regimen, is relatively inexpensive, and is generally well tolerated. Allopurinol is metabolized to the liver to its active metabolite, oxypurinol, which inhibits xanthine oxidase, thus blocking the conversion of hypoxanthine to xanthine to uric acid to decrease serum and urinary levels of urate.

One should monitor for GI intolerance, headache, and leukopenia, the most frequent toxicities associated with allopurinol therapy. Patients affected with allopurinol hypersensitivity syndrome, the most dreaded complication of allopurinol usage, develop a rash consistent with Stevens-Johnson syndrome. Hepatic failure may develop, and the condition can be fatal. Patients starting allopurinol should be advised to stop the medication and call their clinician immediately if 
they develop a rash.

Earlier studies linked allopurinol hypersensitivity syndrome to kidney impairment and diuretic usage, though these studies may have been flawed, so it remains unclear what factors are likely triggers for this syndrome. Allopurinol interacts with several drugs, including azathioprine, theophylline, warfarin, and thiazide diuretics. 

Some patients with CKD, especially those with tophi, may require higher doses of allopurinol than those recommended to meet the serum uric acid goal.20 A study of allopurinol administered at 300 mg/day for 6 weeks in patients with CKD found that patients had oxypurinol concentrations higher than the recommended therapeutic range. There was a linear correlation between oxypurinol levels and changes in serum uric acid levels, with a higher proportion of patients meeting the serum uric acid goal of 6 mg/dL.

None of the patients experienced a significant change in creatinine clearance rate or serum albumin level, developed a rash, or experienced allopurinol hypersensitivity syndrome or other serious adverse events, though this study did not have the power to detect these events.20 Allopurinol should not be given with azathioprine or 6-mercaptopurine because both drugs are metabolized by xanthine oxidase.

Another trial found that a daily 
100-mg dose of allopurinol for 24 months in patients with CKD slowed progression of kidney disease and reduced CV risk compared with placebo.12 At the end of the study, serum uric acid levels had decreased from 7.8 to 6.0 mg/dL in the allopurinol group but showed no change in the placebo group (P=0.016). In addition, the eGFR increased by 1.3 mL/min/1.73 m2 in the allopurinol group but decreased by 
3.3 mL/min/1.73 m2 in the placebo group (P=0.018), indicating that allopurinol slowed the progression of kidney disease.

In addition, allopurinol reduced C-reactive protein levels compared to both baseline (P=0.04) and placebo (P=0.018), reducing CV risk (P=0.039) in 71% of patients. Effective treatment of gout will reduce the need for analgesic use, which may also slow the decline of renal function.

Probenecid is a uricosuric agent that acts at the level of urate anion transporter 1 (URAT1) in the kidney proximal tubule to increase urinary urate excretion.5 Probenecid loses its effectiveness if the GFR is <50 mL/min (Table). As this agent increases urinary urate excretion, it should not be used in patients with already high levels of urinary uric acid (ie, >800 mg/day). Probenecid use may increase the frequency of both uric acid and calcium oxalate kidney stones, so patients should increase their fluid intake to prevent the development of renal calculi. There are potential interactions with azathioprine, rifampin, salicylates, heparin, penicillins, and indomethacin.

Febuxostat is an orally administered, nonpurine, selective xanthine oxidase inhibitor.21,22 Because it undergoes nearly complete hepatic metabolism, there is no need to adjust febuxostat dosing in patients with mild-to-
moderate kidney impairment. In a head-to-head clinical trial, febuxostat 80 or 120 mg/day was more effective than allopurinol 300 mg/day in achieving a serum urate level of 6 mg/dL after 3 months.5 Like allopurinol, febuxostat may induce gout flares on initiation of therapy (an indication of its effectiveness), warranting prophylaxis with an anti-inflammatory agent.

Pegloticase, the most recent addition to the antihyperuricemic armamentarium, is a polyethylene glycol-mammalian recombinant uricase indicated for treatment-refractory gout.16,23 Pegloticase is administered by intravenous infusion every 2 weeks and requires no dose adjustment for patients with kidney impairment. Gout flare prophylaxis with an NSAID or colchicine should begin 1 week before initiating pegloticase and continue for 6 months unless contraindicated or not tolerated.

This biological agent is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency due to a risk for methemoglobinemia and hemolysis. The development of antibodies against pegloticase is common and is associated with failure to maintain normalized serum uric acid levels and infusion reactions. Data from 26-week, placebo-controlled trials of pegloticase showed that 42% of patients achieved a serum urate level <6 mg/dL and 40% had complete dissolution of tophi. Acute gout flares were highest in the first 3 months of treatment with pegloticase (77%) and decreased by 6 months (41%), compared with an occurrence in 81% of patients in the placebo group.

Serious adverse events (flares and infusion reactions) occurred in one-quarter to one-third of patients. No overall differences in efficacy were noted between patients with CKD and patients with normal kidney function.16 Pegloticase is a promising agent, especially for individuals with tophaceous gout who cannot take allopurinol or febuxostat. This agent has resulted in dramatic resolution of tophi in a number of patients. Given the high risk of allergic reactions, it may be advisable to refer patients requiring pegloticase to clinicians with expertise in its use.