Prevalence and Correlates of Gout in a Large Cohort of Patients With Chronic Kidney Disease
Prevalence and Correlates of Gout in a Large Cohort of Patients With Chronic Kidney Disease
This study is the first epidemiological investigation of gout prevalence among a large CKD patient population, a high-risk group for gout. The prevalence of gout was 24.3% in the overall GCKD population and increased with lower eGFR from 16.0% (eGFR of ≥60 mL/min/1.73 m) to 35.6% (eGFR <30 mL/min/1.73 m), highlighting the large burden of disease posed by the painful condition of gout and its sequelae. Moreover, we found evidence for significant undertreatment; ~30% of those with gout received no uric acid lowering medication, and among those who are treated almost half remained hyperuricaemic.
The prevalence of gout in this CKD population is about 10 times greater compared with estimates reported from population-based studies and studies of individuals with normal renal function. A study conducted among individuals with CKD identified in the nationally representative population-based National Health and Nutrition Examination Survey (NHANES) found a similar gout prevalence of 35% among those with stage 4 CKD, but lower gout prevalence of 11% among those with stage 3 CKD compared with our estimate of ~25% for CKD stages 3a and 3b. A potential reason for these discrepancies is that a diagnosis of CKD stage 3 based on one measurement of serum creatinine in population-based settings such as the NHANES survey is less valid than the verified presence of CKD in patients under nephrological care, the source population of the GCKD study.
Our results of an inverse relationship between eGFR and gout as well as hyperuricaemia are consistent with other studies, but the association between albuminuria and gout is less clear. In contrast to our study, Juraschek et al. found a graded positive relationship between gout and albuminuria, and Krishnan et al. stated that proteinuria independently associated with increased risk of gout. A potential explanation for this discrepancy is the fact that most GCKD patients were enrolled because of an eGFR <60 mL/min/1.73 m, and the finding that UACR is not an independent correlate of gout in patients with CKD stage 3 or higher may not be representative of the relationship of UACR and gout in healthy reference and/or non-CKD populations. In addition, very high UACR levels in CKD populations are often found in individuals with primary glomerular diseases, who are often younger and have CKD of auto-immune aetiology compared with older individuals with diabetes who typically have high UACR in population-based studies.
The relationship between gout and CKD is bidirectional. Although reduced kidney function can precede the development of gout, gout can also adversely impact renal function. Elevated serum urate concentrations and medication toxicity have been postulated as factors by which these conditions can lead to reduced renal function. In addition, there are numerous shared correlates between the two conditions, with prevalence of 55.4% for obesity, 46.3% for diabetes, 26.7% for CHD and 97.4% for hypertension among the patients with gout in the GCKD study. Prospective studies specifically in CKD populations including different CKD stages and detailed information on medication intake are needed to determine incidence rates and correlates of new-onset gout.
Medication to treat and prevent gout is available, but the treatment of gout was reported to be suboptimal by several studies. The necessity to permanently maintain serum urate levels below its saturation point means that often life-long treatment is required and cost-effective treatments are needed. Typically, the xanthine oxidase inhibitor allopurinol is prescribed as urate-lowering therapy, with other medication having less favourable side effect profiles or higher associated costs. The high proportion of patients with gout that showed hyperuricaemia despite treatment would be even higher if the therapeutic target for urate-lowering therapy (ULT) would be <6 mg/dL, a threshold suggested to be associated with the slowing of CKD progression. This is also illustrated in a recent publication that—using a cut-off of 6 mg/dL in a general population-based sample—reported that half of US Americans with gout on urate-lowering therapy were still hyperuricaemic, a proportion comparable with the one we report in a CKD population using a higher cut-off of >7 mg/dL in men. These numbers clearly illustrate that pharmacologic management of gout in patients with CKD is suboptimal and underscores the need to achieve better urate treatment target rates using available treatment or additional novel urate-lowering therapies. Of note, however, there is a lack of prospective interventional trials in CKD patients assessing the risk benefit relationship of urate-lowering therapy. This lack of evidence may influence treatment decisions and contribute to the relatively large fraction of patients with gout that remain untreated.
The present study has several limitations. First, a gold-standard definition of gout (crystal aspiration or ACR criteria) was not available and should be obtained for future studies of gout risk in patients with CKD. The use of self-reported physician-diagnosed gout may incorporate some misclassification, which may affect prevalence estimates but should not lead to false-positive correlate associations. Second, no data on dietary intake was available, which likewise should be assessed in future studies among CKD patients. Third, our study was based on data collected at the GCKD study enrolment visit, and we can therefore not answer questions related to the temporality of the association between eGFR and gout, or between the presence of gout and incident health outcomes such as renal replacement therapy. However, this will be possible in the future once prospective data become available. Our current study provides information on the prevalence of gout and which correlates to examine, and therefore facilitates future studies on new-onset gout. Our analyses were conducted using an ethnically homogenous German population of patients with mostly stage 3 CKD at enrolment, and our findings may therefore not be generalizable to other ethnic groups or countries or individuals with other CKD stages. Because of the general health-care coverage in Germany, we believe that access to care should have little impact on our findings, which may be different in other settings. A particular strength is that our results are based on one of the largest cohorts of CKD patients worldwide, and the standardized collection of information provides a sound foundation to the evidence reported here. Because of the substantial morbidity associated with gout, our findings are potentially of high clinical relevance and should stimulate and help design future interventional trials.
In conclusion, gout is a highly prevalent comorbidity in patients with CKD, and prevalence increases with lower eGFR. A third of CKD patients with gout are not treated for the condition, and among those who are treated almost half still show hyperuricaemia. CKD patients represent a high-risk population for gout and screening for and treatment of gout in this population deserves special attention.
Discussion
This study is the first epidemiological investigation of gout prevalence among a large CKD patient population, a high-risk group for gout. The prevalence of gout was 24.3% in the overall GCKD population and increased with lower eGFR from 16.0% (eGFR of ≥60 mL/min/1.73 m) to 35.6% (eGFR <30 mL/min/1.73 m), highlighting the large burden of disease posed by the painful condition of gout and its sequelae. Moreover, we found evidence for significant undertreatment; ~30% of those with gout received no uric acid lowering medication, and among those who are treated almost half remained hyperuricaemic.
The prevalence of gout in this CKD population is about 10 times greater compared with estimates reported from population-based studies and studies of individuals with normal renal function. A study conducted among individuals with CKD identified in the nationally representative population-based National Health and Nutrition Examination Survey (NHANES) found a similar gout prevalence of 35% among those with stage 4 CKD, but lower gout prevalence of 11% among those with stage 3 CKD compared with our estimate of ~25% for CKD stages 3a and 3b. A potential reason for these discrepancies is that a diagnosis of CKD stage 3 based on one measurement of serum creatinine in population-based settings such as the NHANES survey is less valid than the verified presence of CKD in patients under nephrological care, the source population of the GCKD study.
Our results of an inverse relationship between eGFR and gout as well as hyperuricaemia are consistent with other studies, but the association between albuminuria and gout is less clear. In contrast to our study, Juraschek et al. found a graded positive relationship between gout and albuminuria, and Krishnan et al. stated that proteinuria independently associated with increased risk of gout. A potential explanation for this discrepancy is the fact that most GCKD patients were enrolled because of an eGFR <60 mL/min/1.73 m, and the finding that UACR is not an independent correlate of gout in patients with CKD stage 3 or higher may not be representative of the relationship of UACR and gout in healthy reference and/or non-CKD populations. In addition, very high UACR levels in CKD populations are often found in individuals with primary glomerular diseases, who are often younger and have CKD of auto-immune aetiology compared with older individuals with diabetes who typically have high UACR in population-based studies.
The relationship between gout and CKD is bidirectional. Although reduced kidney function can precede the development of gout, gout can also adversely impact renal function. Elevated serum urate concentrations and medication toxicity have been postulated as factors by which these conditions can lead to reduced renal function. In addition, there are numerous shared correlates between the two conditions, with prevalence of 55.4% for obesity, 46.3% for diabetes, 26.7% for CHD and 97.4% for hypertension among the patients with gout in the GCKD study. Prospective studies specifically in CKD populations including different CKD stages and detailed information on medication intake are needed to determine incidence rates and correlates of new-onset gout.
Medication to treat and prevent gout is available, but the treatment of gout was reported to be suboptimal by several studies. The necessity to permanently maintain serum urate levels below its saturation point means that often life-long treatment is required and cost-effective treatments are needed. Typically, the xanthine oxidase inhibitor allopurinol is prescribed as urate-lowering therapy, with other medication having less favourable side effect profiles or higher associated costs. The high proportion of patients with gout that showed hyperuricaemia despite treatment would be even higher if the therapeutic target for urate-lowering therapy (ULT) would be <6 mg/dL, a threshold suggested to be associated with the slowing of CKD progression. This is also illustrated in a recent publication that—using a cut-off of 6 mg/dL in a general population-based sample—reported that half of US Americans with gout on urate-lowering therapy were still hyperuricaemic, a proportion comparable with the one we report in a CKD population using a higher cut-off of >7 mg/dL in men. These numbers clearly illustrate that pharmacologic management of gout in patients with CKD is suboptimal and underscores the need to achieve better urate treatment target rates using available treatment or additional novel urate-lowering therapies. Of note, however, there is a lack of prospective interventional trials in CKD patients assessing the risk benefit relationship of urate-lowering therapy. This lack of evidence may influence treatment decisions and contribute to the relatively large fraction of patients with gout that remain untreated.
The present study has several limitations. First, a gold-standard definition of gout (crystal aspiration or ACR criteria) was not available and should be obtained for future studies of gout risk in patients with CKD. The use of self-reported physician-diagnosed gout may incorporate some misclassification, which may affect prevalence estimates but should not lead to false-positive correlate associations. Second, no data on dietary intake was available, which likewise should be assessed in future studies among CKD patients. Third, our study was based on data collected at the GCKD study enrolment visit, and we can therefore not answer questions related to the temporality of the association between eGFR and gout, or between the presence of gout and incident health outcomes such as renal replacement therapy. However, this will be possible in the future once prospective data become available. Our current study provides information on the prevalence of gout and which correlates to examine, and therefore facilitates future studies on new-onset gout. Our analyses were conducted using an ethnically homogenous German population of patients with mostly stage 3 CKD at enrolment, and our findings may therefore not be generalizable to other ethnic groups or countries or individuals with other CKD stages. Because of the general health-care coverage in Germany, we believe that access to care should have little impact on our findings, which may be different in other settings. A particular strength is that our results are based on one of the largest cohorts of CKD patients worldwide, and the standardized collection of information provides a sound foundation to the evidence reported here. Because of the substantial morbidity associated with gout, our findings are potentially of high clinical relevance and should stimulate and help design future interventional trials.
In conclusion, gout is a highly prevalent comorbidity in patients with CKD, and prevalence increases with lower eGFR. A third of CKD patients with gout are not treated for the condition, and among those who are treated almost half still show hyperuricaemia. CKD patients represent a high-risk population for gout and screening for and treatment of gout in this population deserves special attention.
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