Clinical approaches

Once gout has been diagnosed, the cause of the hyperuricemia should be identified. The two most common causes of hyperuricemia are decreased renal elimination of urate and excessive alcohol intake. A basic metabolic panel should be obtained to determine if CKD exists. Potential causes of increased proximal tubular urate reabsorption, such as excessive diuretic usage or congestive heart failure, should be identified. Patients should be questioned about their alcohol intake. In younger individuals with gout, one must consider occult kidney disease. 

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For diagnostic and therapeutic purposes, a 24-hour urine collection for urate can be performed to determine if the patient over-produces urate, under-excretes urate, or both. A 24-hour urate excretion of greater than 700 mg is suggestive of excessive urate excretion but does not rule out that concomitant increased proximal tubular reabsorption is not occurring.24 In one study, in individuals without gout, the fractional excretion of urate was 7.6 ± 1.9% vs. a fraction excretion of 
5.8 ± 1.0% in individuals with gout.24

Acute treatment: Acute treatment is substantially different from chronic prevention. Acute treatment involves decreasing inflammation and pain. Chronic prevention requires lowering serum urate concentrations. In both forms of therapy, one must consider residual renal function.

Local therapy includes the use of ice on the joint, which has been found to decrease pain and swelling compared to no ice.25 An intra-articular glucocorticoid injection is very effective, though requiring an office visit and a physician proficient in the giving these injections. The three major therapeutic medicinal choices for acute gout include colchicine, non-steroidal anti-inflammatory agents (NSAIDs), and glucocorticoid therapy. 

While colchicine has long been used in the treatment of gout, it is associated with significant gastrointestinal toxicity as well as the potential for life-threatening leucopenia. Traditional dosing regimens of 0.6 mg hourly until nausea or diarrhea develops are ill advised. A recent trial showed that colchicine dosed at 
1.2 mg followed by 0.6 mg in one hour was 
as effective as higher dosing (1.2 mg followed by 0.6 mg every hour for six hours) and associated with much less toxicity.26

NSAIDs are very effective agents for the treatment of gout and should be considered in individuals with normal kidney function. Unfortunately, many individuals with gout have renal insufficiency, and the use of NSAIDs may be contraindicated. NSAIDs may be especially contraindicated in individuals receiving ACE inhibitors and diuretics or individuals with kidney failure, liver failure, or heart failure.

A prednisone taper is being used increasingly as a first-line therapy for gout. The major advantages of prednisone are its efficacy and its rapid efficacy. Prednisone also has limited effects on kidney function. A major disadvantage is the effect of prednisone on blood glucose control. Diabetic patients who take a prednisone taper need to monitor their blood glucose concentrations closely.

Chronic treatment: The goal of chronic therapy is to lower the body’s uric acid burden. A goal serum urate level less than 6 mg/dL has been set as a 
target for lowering serum urate levels, as levels below this are associated 
with a low frequency of gout attacks27 and are associated with tophi resolution.This level is only one factor that should be taken into account in the management of the patient with gout.

When serum urate levels are lowered, for an unknown reason, patients have an increased risk of developing a gout attack. A poor understanding of this phenomenon by both patients and 
their physicians has resulted in noncompliance and poor long-term therapy of gout patients. 

Probenecid: Probenecid is a medication that increases renal urate excretion by inhibiting proximal tubular urate uptake. The medication should be considered in individuals with good kidney function whose hyper­uricemia is the result of decreased urate excretion. It is contraindicated 
in individuals with advanced CKD 
and in those with urolithiasis.28 The use of probenecid with penicillin or in patients with renal insufficiency is not recommended, and aspirin may decrease the efficacy of probenecid. Due to drug interactions and the increased urinary uric acid excretion, probenecid is used less commonly than allopurinol. It is important to alert the patient given probenecid to the possible drug interactions that may occur, as the physician prescribing probenecid may not be the sole provider of health care to the patient. 

Allopurinol: Allopurinol is probably the most common medication used in the chronic treatment of gout. It is in general well tolerated by patients. Unfortunately, there is the rare possibility of developing of a severe allergic reaction to allopurinol that can be life-threatening.29, 30 This rare reaction results in a Stevens Johnson rash, elevated liver function tests, and can be associated with fulminant hepatic failure and death. While this reaction is rare, it points to the fact that allopurinol should only be used when a clear indication exists. Patients who have had the severe reaction have typically been older, on a diuretic, and suffering from reduced glomerular filtration rates.30 Patients should be instructed to stop allopurinol immediately if a rash develops and to contact their physician. Close monitoring is especially important in individuals with the risk factors outlined above. For this reason, allopurinol is not recommended in the treatment of asymptomatic hyperuricemia.29 The dosing of allopurinol in CKD remains controversial. Earlier studies suggested that normal doses of allopurinol in patients with CKD resulted in increased accumulation of allopurinol metabolites and placed patients at increased risk of allopurinol hypersensitivity.30 However, these investigations may have been flawed. Despite this, there are no good safety data regarding the correct dosage of allopurinol in CKD.

Febuxostat: Febuxostat is another xanthine oxidase inhibitor that has been found to be more effective in preventing gout attacks and lowering serum urate levels than the traditional doses of allopurinol.4, 31, 32 In clinical trials with febuxostat, no severe allergic reactions have been reported, though in these studies there were also no severe allergic reactions with allopurinol.31, 33

Pegloticase: Pegloticase is a new compound that consists of the enzyme uricase that has been pegylated to decrease immunogenicity. It is indicated for severe gout refractory to other treatments. Pegloticase is given by intravenous infusion and is associated with frequent reactions during infusion. It has been noted to be extremely beneficial in tophaceous gout.

Asymptomatic hyperuricemia: There is no indication for the treatment of asymptomatic hyperuricemia at this time, and this cannot be stressed enough. However, there are a number of studies suggesting that allopurinol may be beneficial in terms of CKD progression and even mortality. In a recent prospective, randomized study,34 113 individuals with an estimated glomerular filtration rate (eGFR) below 
60 mL/min/1.73 m2 were randomized to 100 mg/day allopurinol or placebo. After a median follow-up of almost 
two years, the eGFR decreased by 3.3 mL/min/1.73 m2 in the placebo group and increased by 1.3 mL/min/1.73 m2 in the allopurinol group. Allopurinol was also associated with a 71% reduction in the risk of cardiovascular events during the study. In another study,35 54 hyperuricemic patients with CKD were randomized to receive allopurinol (dosed between 100 and 300 mg/day) and usual therapy for 12 months. Four of 25 patients in the allopurinol group and 12 of 26 in the control group achieved 
the combined end point of significant deterioration of kidney function or 
dialysis dependence.