Risk of chronic kidney disease in patients with gout and the impact of urate lowering therapy: a population-based cohort study

Gout is the most prevalent inflammatory arthritis, affecting 2.5% of adults in the UK and 3.9% in the USA [1, 2]. Chronic kidney disease (CKD) is also a common problem, with the global prevalence of CKD stages 3–5 (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m²) estimated to be 10.6% [3]. An association between gout and CKD has been recognised for many years [4–6].

CKD can progress to end-stage renal disease (ESRD) and can lead to premature mortality [7]. The rate of progression to renal replacement therapy (RRT) or death over 5 years in patients with CKD stage 3 is 1.3% and 24.3%, respectively, and with stage 4 it is 19.9% and 45.7%, respectively [8]. In our recent systematic review and meta-analysis, 24% of people with gout had CKD stage ≥ 3 [9]. The association between hyperuricaemia, gout and CKD is thought to be bidirectional, with CKD known to be an independent risk factor for gout [10–13] and gout potentially predisposing to CKD by a number of mechanisms including hyperuricaemia, chronic inflammation and drug therapy with non-steroidal anti-inflammatory drugs (NSAIDs). In addition, hypertension, diabetes mellitus and obesity are highly prevalent in gout [14] and CKD, and are risk factors for CKD [15]. Our systematic review identified only two cohort studies investigating the risk of CKD in people with gout. Although large, both examined risk of ESRD rather than the earlier stages of CKD and neither used data from Europe [16, 17]. Better understanding of the risk of earlier stages of CKD in people with gout would help guide screening and the management of associated comorbidities and could aid the early identification or possible prevention of CKD in gout.

Urate-lowering therapy (ULT) should be considered for all patents with gout, in particular those with recurrent flares or tophi [18–20]. Data from randomised trials suggests that ULT in patients with CKD can slow the rate of decline of eGFR and reduce risk of progression to ESRD [21]. However, these trials were largely conducted in individuals without gout and the impact of ULT on development of CKD in people with gout remains unclear. The aim of this study was to quantify the risk of developing CKD stage ≥ 3 among patients with incident gout and assess the impact of ULT on this risk.

In the stratified analyses, for both exposed and unexposed patients, the absolute rate of development of CKD stage ≥ 3 was greater in women and increased with age. The adjusted HRs remained largely consistent between genders and across all age groups and IMD quintiles (Table 2). Risk of development of CKD stage ≥ 3 was found to be higher within the first 2 years of gout diagnosis (adjusted HR 2.20 95% CI 2.07 to 2.36) compared to 6–10 years following diagnosis (adjusted HR 1.45 95% CI 1.29 to 1.63). Figure 2 describes the development of CKD stage ≥ 3 in patients with gout and patients without gout during follow up.

In the landmark analysis, patients with gout were excluded due to either death, developing CKD or transfer from general practice within 1 year (n = 1962) or 3 years (n = 12,947) of gout diagnosis. Of the remaining patients with gout, 4198 (10.6%) in the 1-year landmark analysis and 4793 (16.8%) in the 3-year landmark analysis were receiving ULT (Additional file 1: Figure S1).

This retrospective cohort study, set in a large UK primary care population, compared the risk of developing CKD stage ≥ 3 in those with gout versus those without gout. Following adjustment for age, gender, comorbidities, deprivation, NSAID use, frequency of hospital admission and GP attendance, patients with gout had 78% increased risk of development of CKD stage ≥ 3 compared to patients without gout. Risk of CKD development was highest in the first 2 years following gout diagnosis. Following adjustment patients with gout exposed to at least 6 months ULT had no increased risk of developing CKD compared to those not exposed, in all analyses apart from analysis in women receiving ULT within 3 years of diagnosis.

This study has a number of strengths. Participants were from primary care where the majority of patients with gout are managed, thus aiding generalisability. The sample size was large and the median follow up was 6 years, which should be sufficient for development and ascertainment of CKD stage ≥ 3. Ascertainment of the primary outcome required either a clinical diagnostic code or two consecutive eGFR measurements < 60 mL/min/1.73m². Utilising biochemical data and Read codes should aid completeness compared to using codes alone, as GP coding of CKD has been shown to capture only 72% of those with biochemically evident disease [32]. Previous cohort studies examining gout and renal disease used either record linkage or diagnostic codes alone and examined either the severest form of CKD (ESRD) [16, 17] or “renal diseases” [25], which would include a large number of heterogenous conditions. This is the first study to the best of our knowledge to examine risk of earlier stages of CKD and to use biochemical data, which is an additional strength. Immortal time bias, which could have resulted in lower observed risk of CKD associated with ULT exposure, was addressed with the use of landmark analysis, which is also a strength of this study.

An important caveat is gout ascertainment based on GP-coded diagnoses alone, risking misclassification bias, although gout diagnoses have been validated in CPRD and have a positive predictive value of 90% [26]. Ascertainment bias is a possible limitation of this study as patients with gout presented more frequently to their GP and hospital and had higher prevalence of hypertension and diabetes mellitus, which could have prompted more frequent renal function testing. GP consultation rates during follow up were adjusted for in the statistical analysis but may not completely address this issue. Furthermore, it was not possible to account for patient ethnicity or the severity of comorbidities. Regarding ULT prescription data, prescriptions do not necessarily equate to dispensing of ULT and it was not possible assess adherence.

In this study, those with CKD stage ≥ 3 or RRT occurring pre-index or within 1 year of gout diagnosis were excluded. Despite this, the possibility of reverse causation could still potentially underlie an association between gout and CKD e.g. undiagnosed or mild renal dysfunction leading to hyperuricaemia, thus conferring risk of gout development, with later progression to CKD [33]. It is possible that our finding of the risk of CKD development being highest within 2 years of gout diagnosis reflects this. It is also of note that nine genetic loci associated with both CKD and serum urate concentration, with varying direction of effect, have been identified by genome-wide association studies, which could further complicate the relationship between gout and CKD [34].

The prevalence of CKD stage ≥ 3 in gout was found to be 24% in our recent systematic review and meta-analysis [9]. We identified only two other prospective studies examining the risk of CKD associated with gout. These studies reported an increased risk of ESRD of 57% [17] and 80% [16], in keeping with our risk estimate for CKD stage ≥ 3. One study published subsequent to our systematic review found three times increased risk of “renal diseases” (defined using Read codes rather than eGFR) following gout diagnosis but did not differentiate between acute or chronic forms [25]. In our study allopurinol accounted for 99% of all ULT prescriptions. We did not find clear evidence that ULT exposure influenced the risk of developing CKD. Risk was greater in those exposed to ULT, but those exposed were older and more frequently had diabetes mellitus and hypertension and these factors appeared to explain the ULT-CKD association in our data. In previous studies examining the association between ULT and renal disease, benefits were noted to be greatest in those taking higher doses of ULT [35] or reaching target SUA levels [36]. It is of note, however, that patients with gout often remain on lower doses of allopurinol and the majority do not reach target SUA levels [37, 38]. This study has not explored whether target SUA levels were reached and our finding of no association may reflect suboptimal urate-lowering rather than the true effect of ULT.

Women who develop gout are typically older, have more comorbidities such as hypertension, diabetes mellitus and obesity and receive ULT less frequently than men [39]. Possible explanations for our finding of increased risk of CKD associated with ULT in women in the 3-year analysis include women prescribed ULT potentially having more severe gout and therefore possibly conferring greater risk of CKD, incomplete adjustment for comorbidities or medications or ascertainment bias, as comorbid women taking allopurinol may have more frequent renal function testing. It is possible that allopurinol has deleterious effects on renal function in women with gout but to the best of our knowledge this has not been found in previous studies. The finding of increased risk was not replicated in the 1-year analysis, however, suggesting the finding in the 3-year analysis could be related to chance.

Whilst it is not possible to make causal inferences from this observational study, it is worth considering the potentially plausible mechanisms for the association between gout and CKD. Renal damage could result from comorbid hypertension, diabetes mellitus, obesity or use of nonsteroidal anti-inflammatory drugs. Hyperuricaemia-mediated endothelial dysfunction has been suggested to lead to renovascular disease [40], although Mendelian randomisation studies have not found an association between urate and CKD [34]. Inflammation in gout is increasingly recognised to persist in the intercritical period between acute attacks [41, 42], raising the possibility that inflammatory mechanisms contribute to increased risk. Activation of the NLRP3 inflammasome and subsequent production of interleukin-1β is a key inflammatory process in gout [43]. This is of note as renal NLRP3 expression is significantly increased in CKD and it has been suggested that this and interleukin-1β contribute to progression of CKD [44, 45]. We are unable to make comparisons to previous cohort studies, as they have used different outcome measures and, as discussed above, the possibility of reverse causation complicates temporal inferences from this study. As also noted previously, a number of conditions associated with gout are also risk factors for CKD and incomplete adjustment for these could result in residual confounding.

This study has demonstrated gout to be a risk factor for incident CKD stage ≥ 3, after adjustment for age, gender, comorbidities, deprivation, NSAID use, frequency of hospital admission and GP attendance. In clinical practice, renal function monitoring is often suboptimal in gout [36] suggesting an area for improvement. Further research examining the mechanisms by which gout may increase risk of CKD is suggested, including the role of hyperuricaemia and possible linked inflammatory processes. Due to high prevalence of CKD in gout, further research into whether optimal use of ULT can reduce the risk or progression of CKD in patients with gout would also be of value.