Gouty arthritis (gout) is relatively common in the general population, with an estimated prevalence of 4%, and it is associated with approximately 3.9 million ambulatory care visits per year [1, 2]. Chronic kidney disease (CKD) is also common, affecting approximately 26 million adults in the United States over the age of 20 [3, 4]. Specific lifestyles choices can influence the risk of gout, but lifestyle changes may not be sufficient to manage disease after the onset of gout [5].

Gout patients typically exhibit increased levels of serum uric acid. It is recommended that serum uric acid levels be lowered to a target of < 6 mg/dL to better manage gout symptoms, and to reduce synovial MSU crystals and acute gout attacks [6]. Uric acid is excreted primarily through the kidney, and any impairment of kidney function can result in hyperuricemia. Even among individuals with normal renal function, the presence of hyperuricemia has been correlated with future incidence of renal impairment and increased healthcare utilization and costs [7, 8]. Treatment of gout in patients with CKD is complicated because full dosing of allopurinol, the uric acid-reducing medicine, requires adequate renal function to clear oxypurinol, its active metabolite [9]. It is recommended that patients with renal impairment should receive reduced doses of allopurinol, as they may be at increased risk for allopurinol-related toxicity [9]. However, suboptimal uric acid control has been associated with worsening renal function [10–12].

Studies suggest that the prevalence of both gout and CKD are likely to increase over time [3, 4]. Although the vast majority of patients with gout in the United States seek treatment from primary care physicians [2], most studies of CKD in gout patients have been performed in other settings such as rheumatology clinics [12–15], dialysis databases [16], and renal transplant centers [17, 18]. In the present study, a retrospective analysis was performed using a large US health plan database (and associated lab data) containing detailed information on gout diagnosis, urate-lowering therapy usage, and serum uric acid (sUA) levels. The objectives of this study were to determine the prevalence of CKD among a general population of gout patients in a normal practice setting, and to investigate the impact of CKD on allopurinol dosing and uric acid control.

The prevalence of CKD in the US general population is approximately 13% [3]. This retrospective study reveals a very high prevalence of CKD (approximately 40%) among gout patients in the US. A previous smaller study of gout patients in New Zealand found a level of CKD prevalence similar to what is reported here [25]. In the present study, gout patients with severe renal disease were somewhat older and more likely to be female and to have a greater overall comorbidity burden. As expected, serum uric acid concentrations were higher among those with worse renal disease. Although individuals with CKD were treated more frequently, they received lower initial doses of allopurinol. Over time, the average allopurinol dose among patients with gout increased regardless of the presence or severity of renal disease. The magnitude of increase among those with renal disease was smaller but statistically indistinguishable from those with normal renal function. Thus, the treatment received by those with normal renal function was not substantially more aggressive than the treatment received by those with impaired renal function.

Within each cohort, patients who used allopurinol had lower serum uric acid levels than patients who did not use allopurinol. However, a significant finding of this study was the relatively low proportion of patients treated with allopurinol who achieved a serum uric acid concentration of < 6 mg/dL (25.6% of patients without CKD, 23.3% of those with Stage 2 CKD, 20.2% of those with Stage 3 CKD, and 18.8% of those with Stage 4 CKD). Although goal attainment was low among all patient cohorts, presence of CKD decreased the likelihood of meeting this benchmark even further. Further, a low percentage of patients with CKD (only about 16%) had their allopurinol dosage titrated. These findings highlight the therapeutic challenge of balancing the risks and benefits of administering allopurinol to patients with impaired renal function.

Appropriate dosing of allopurinol when CKD is present is an important yet controversial topic. The US Food and Drug Administration has approved the following dosing regimen for gout without concurrent renal disease [26]: Start with a dose of 100 mg/day and increase by 100 mg/day at weekly intervals until the desired therapeutic response is achieved. A maximum dose of 800 mg/day is permitted. However, in a Japanese study, patients achieved a therapeutic serum concentration of oxypurinol (> 4.6 mcg/mL) and a clinical response rate of > 90% at an allopurinol dose of just 100-200 mg/day [27]. Dosing in this study was based on levels of serum creatinine, not on eGFR. Others have raised concerns about the safety of higher doses of allopurinol, and using serum creatinine as an index for allopurinol dosing has been shown to be less safe than using eGFR [28]. Adhering to the current guidelines for dosing allopurinol based on eGFR, on the other hand, does not necessarily result in desired uric acid control [9, 29, 30]. The results of the managed care analysis performed here reflect this therapeutic challenge.

Our findings do not indicate that initial daily dose of allopurinol is prescribed in a manner that correlates with published guidelines sensitive to renal function. The original guidelines for allopurinol dosing were based on an extensive review of severe adverse reactions to allopurinol and a small de novo study of 40 patients [9]. That study calculated that renal clearance of oxypurinol was directly proportional to the creatinine clearance, which was calculated using the Cockroft-Gault formula. The recommended dosing levels were based on achieving a target serum oxypurinol level of 30-100 mmol/L and not on avoiding any toxicity threshold. In another study based on data from a rheumatology practice, there were modest correlations between allopurinol doses and plasma oxypurinol concentrations, and between creatinine clearance and plasma oxypurinol [30]. However, there was no correlation between plasma oxypurinol and plasma uric acid, and only 50% of patients within the therapeutic range of plasma oxypurinol had a plasma uric acid level < 0.42 mmol/L [30]. Collectively, these findings suggest that there is considerable heterogeneity in drug handling, and future studies need to test the underlying assumption that oxypurinol is the sole active metabolite responsible for therapeutic efficacy and toxicity. Concerns regarding adverse events in particular may influence the aggressiveness of current treatment regimens. Cutaneous adverse reactions to allopurinol occur in approximately 7.7 per 1000 recipients [31], and the incidence of allopurinol hypersensitivity syndrome is about 2-3 times higher among renally impaired patients compared to non-renally impaired patients [32]. However, the relationship between adverse events and allopurinol dosing is still not fully understood. Previous studies have shown that patients receiving doses of allopurinol above the recommended dose (as based on the creatinine clearance rate) did not exhibit increased toxicity [33, 34]. Other studies have indicated that specific genetic markers may influence the risk of experiencing severe cutaneous adverse reactions following allopurinol treatment [35].

A few caveats must be considered when interpreting the results of the present study: (1) The approach used to identify gout patients from claims data is subject to misclassification errors. This problem was addressed by performing sensitivity analyses that specified different combinations of coding, medications, and laboratory criteria as alternate selection criteria. The resulting patient populations varied in terms of size and other characteristics, but the fundamental findings in this analysis held. (2) Because of the requirement of availability of a serum creatinine test, the current study population may have been less renally healthy than other populations of gout patients. This factor could reduce the generalizability of the findings. (3) The authors studied patients with gout seeking medical care, thereby potentially selecting those with more severe or frequent flare-ups of gout; this, in turn, may have overestimated the prevalence of CKD among gout patients. (4) The multivariate model examining allopurinol dose change did not distinguish between dose increases or decreases. This would be a valuable direction for future research. (5) A limitation of claims analysis is that we are only able to measure prescribed doses, which may differ from the dose that a patient actually took.

In this study a high prevalence of CKD was observed among gout patients. Serum uric acid goal attainment was low among patients treated with allopurinol, and poorest among those with CKD. The findings suggest that poor outcomes among gout patients with CKD are partly due to clinicians' reluctance to prescribe higher doses of allopurinol to patients with impaired renal function. The benefits and risks of allopurinol treatment must be weighed carefully in patients with CKD, and alternate treatment approaches are needed to improve the prognosis of these patients. Future research should address at least three additional issues: (1) the role of non-oxypurinol metabolites of allopurinol in efficacy and toxicity, (2) more sophisticated pharmacogenomics-based studies of allopurinol dosing in the presence of CKD, and (3) development of urate-lowering drugs that are not renally cleared. Additionally, our results suggest a need to raise awareness among physicians regarding the importance of titrating therapy to reach uric acid goals.