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.
PREVENTING FLARES BY LOWERING SERUM URATE LEVELS
If tophi are present, if radiography shows evidence of damage, if attacks are frequent or disabling, or if there are relative contraindications to the drugs that would be needed to treat acute attacks, then hypouricemic therapy should be strongly considered to reduce the burden of urate in the body, resorb tophi, and ultimately reduce the frequency of gout flares.20
Although intermittent therapy for attacks or prolonged prophylactic use of colchicine may prevent recurrent episodes of gouty arthritis and may be reasonable for many patients, this approach does not prevent continued urate deposition, with the potential development of bony erosions, tophaceous deposits, and chronic arthritis.
The definitive therapy for gouty arthritis is to deplete the periarticular deposits of urate by maintaining a low serum urate level. Urate-lowering therapy, when indicated, is almost always lifelong.
Four strategies for lowering serum urate
The serum urate concentration can be lowered in four ways:
- Increasing renal uric acid excretion
- Altering the diet
- Decreasing urate synthesis
- Converting urate to a more soluble metabolite.
Increasing uric acid excretion is rarely effective if renal function is impaired
Probenecid, sulfinpyrazone (Anturane), and losartan (Cozaar) modestly increase uric acid secretion and reduce serum urate levels, but they are rarely effective if the creatinine clearance rate is less than 60 mL/minute, and they require significant fluid intake for maximal efficacy.
Uricosuric drugs probably should be avoided in patients who excrete more than 1,000 mg of uric acid per day on a normal diet, since urinary uric acid stones may form. In practice, however, patients are given losartan to treat hypertension without attention to uric acid excretion.
More-potent urocosuric drugs are being tested in clinical trials.
Altering the diet: Traditional advice confirmed
The Health Professionals Follow-up Study27,28 prospectively examined the relation between diet and gout over 12 years in 47,150 men. The study confirmed some long-standing beliefs, such as that consuming meat, seafood, beer, and liquor increases the risk. Other risk factors were consumption of sugar-sweetened soft drinks and fructose, adiposity, weight gain, hypertension, and diuretic use. On the other hand, protein, wine, and purine-rich vegetables were not associated with gout flares. Low-fat dairy products may have a protective effect. Weight loss was found to be protective.
Low-purine diets are not very palatable, are difficult to adhere to, and are at best only minimally effective, lowering serum urate by 1 to 2 mg/dL. Low-protein diets designed to slow progression of CKD will likely also have only a slight effect on serum urate. Dietary change alone is not likely to dramatically lower serum urate levels.
Metabolizing urate with exogenous uricase
Rasburicase (Elitek) effectively converts urate to allantoin, which is more soluble, but rasburicase is fraught with allergic reactions and cannot be used as chronic therapy.
A pegylated intravenous uricase29 has just been approved by the US Food and Drug Administration (FDA); the retail cost is not yet known. It is dramatically effective in those patients able to use it chronically, but it has not been fully evaluated in patients with CKD.
Decreasing urate synthesis with allopurinol
Allopurinol acts by competitively inhibiting xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. The drug, a structural analogue of hypoxanthine, is converted by xanthine oxidase to oxypurinol, which is an even more effective inhibitor of xanthine oxidase than allopurinol.
Allopurinol is metabolized in the liver and has a half-life of 1 to 3 hours, but oxypurinol, which is excreted in the urine, has a half-life of 12 to 17 hours. Because of these pharmacokinetic properties, allopurinol can usually be given once daily, and the dosage required to reduce serum urate levels should in theory be lower in patients with lower glomerular filtration rates.
Allopurinol (100- and 300-mg tablets) is approved by the FDA in doses of up to 800 mg/day to treat hyperuricemia in patients with gout,30 while guidelines from the British Society of Rheumatology advocate a maximum dose of 900 mg/day.31 These maximum doses are based on the limited amount of data with higher doses, not on documented toxicity.
Practice survey data in the United States indicate that most physicians prescribe no greater than 300 mg daily, although this dosage is likely to reduce the serum urate to less than 6 mg/dL—the goal level—in fewer than 50% of patients.20,32 Patients with normal renal function occasionally require more than 1,000 mg daily to reduce the serum urate level to less than 6 mg/dL.
How low should the serum urate level be?
Ideally, therapy should keep the serum urate level significantly below 6.7 mg/dL, the approximate saturation point of urate in physiologic fluids.
Lowering the serum urate level from 10 mg/dL to 7 mg/dL may seem encouraging, and the urate level may be in the laboratory “normal” range; however, urate may continue to precipitate in tissues if the concentration is greater than 6.7 mg/dL. A target of 6 mg/dL, used in clinical studies, is far enough below the saturation level to provide some margin for fluctuations in serum levels. A serum level of 6.0 mg/dL has thus been arbitrarily proposed as a reasonable therapeutic target.
The lower the serum urate level achieved during hypouricemic therapy, the faster the reduction in tophaceous deposits. With adequate urate lowering, tophi can be visibly reduced in less than a year of hypouricemic therapy.33,34
We have as yet no convincing evidence that lowering the serum urate level to less than 6.0 mg/dL is harmful, despite theoretical concerns that urate is a beneficial circulating antioxidant and epidemiologic observations that urate levels have been inversely correlated with progression of Parkinson disease.
