CLINICAL EPIDEMIOLOGY

Association of Incident Gout and Mortality in Dialysis Patients

Scott D. Cohen, Paul L. Kimmel, Robert Neff, Lawrence Agodoa and Kevin C. Abbott
JASN November 2008, 19 (11) 2204-2210; DOI: https://doi.org/10.1681/ASN.2007111256

Abstract

Previous studies have shown that gout is associated with an increased risk for cardiovascular mortality in the general population, but this has not been well studied in patients with ESRD. In this study, the incidence of gout and its association with mortality was evaluated in 259,209 patients in the United States Renal Data System. Overall, the incidence of gout in the first year of dialysis was 5% and in the first 5 yr was 15.4%. Independent risk factors for gout in adjusted analyses included black race, older age, female gender, hypertension, ischemic heart disease, congestive heart failure, and alcohol use. Factors associated with a lower risk for gout included a history of diabetes, smoking, and peripheral vascular disease. Time-dependent Cox regression analysis suggested that an episode of gout was independently associated with a 1.5-fold increase in mortality risk (adjusted hazard ratio 1.49; 95% confidence interval 1.43 to 1.55). The mechanisms underlying this association require further study.

Few studies have evaluated the incidence of gout in dialysis patients.1,2 The available research is limited by small sample sizes. The incidence of gout in dialysis patients is believed to be rare.1,2 A study from Japan revealed a 2.8% frequency of gout after the initiation of renal replacement therapy.2 Ifudu et al.1 reported no new cases of gout after the start of dialysis.

Gout can be defined as the extracellular tissue deposition of uric acid crystals that leads to a debilitating inflammatory arthritis.3 It is believed to be a more frequent occurrence in predialysis patients with chronic kidney disease (CKD) as well as renal transplant recipients compared with patients treated with dialysis. Gout has a significant deleterious effect on patients’ overall functional status and quality of life.4 Singh et al.4 recently found gout to be independently associated with increased hospitalizations and primary care visits using a database of US veterans.

Abbott et al.5 found the incidence of gout to be 7.6% over a 3-yr period in the posttransplantation setting. Other analyses reported the incidence of gout to range between 2 and 13% in transplant recipients.6,7 Hyperuricemia in the setting of transplantation is often secondary to a combination of calcineurin inhibitor use, diuretics, and renal insufficiency including delayed allograft function.6,8 Hyperuricemia may be a marker for progression of renal disease and is associated with worse renal survival in some forms of renal failure.5,9–14 Hyperuricemia has also been associated with decreased patient survival in both general medical and transplant patients.5,15 Nevertheless, preliminary data suggest that the incidence of gout in patients with ESRD may be low, perhaps secondary to clearance of inflammatory mediators on hemodialysis (HD).2

The association of gout with survival and other demographic factors including gender, age, race, and body mass index (BMI) has not been reported in a large population-based study of patients with ESRD. Previous studies of general medical patients showed an increased risk for cardiovascular mortality in patients with a diagnosis of gout.16–18 The purpose of this study was to determine the frequency of gout in dialysis patients in the US Renal Data System (USRDS) database and to evaluate whether incident cases of gout in patients treated with dialysis are associated with decreased survival.

RESULTS

Between January 1, 1999, and December 31, 2003, 259,310 patients started long-term dialysis with Medicare as primary payer (of 450,668 patients total) at the time of the first dialysis session. Of these, 101 had a primary disease coded as ESRD as a result of gouty nephropathy and were excluded from further analysis, leaving 259,209 patients. By logistic regression, factors associated with having Medicare as the primary payer were black race (odds ratio [OR] 1.16; 95% confidence interval [CI] 1.14 to 1.18), male gender (OR 1.03; 95% CI 1.01 to 1.04), increasing age (OR 1.03; 95% CI 1.03 to 1.03), and diabetes (OR 1.04; 95% CI: 1.03 to 1.06). On the basis of Medicare claims data, the incidence of gout in the first year of dialysis was approximately 5.4% after 1 yr, 11.5% by 3 yr, and 15.4% by 5 yr.

Table 1 shows the unadjusted characteristics of patients who had claims for gout after dialysis compared with those who did not. Factors significantly associated with gout in unadjusted analyses were female gender, black race, higher mean age, higher mean BMI, hypertension, ischemic heart disease, higher hematocrit, serum creatinine, use of erythropoietin at the time of initiation of dialysis, and serum albumin. There was a lower risk for gout in patients with a history of peripheral vascular disease, smoking, and diabetes.

View this table:
Table 1.

Factors assessed in US long-term dialysis patients, April 1, 1999, through December 31, 2003: Medicare as primary payera

Table 2 shows the results of a Cox regression analysis of the factors independently associated with the development of gout after dialysis. Independent factors included female gender, older age (Figure 1), BMI by categories (Figure 2), alcohol use, hypertension, ischemic heart disease, congestive heart failure, and higher hematocrit. Diabetes and smoking were associated with a lower risk for subsequent gout. These results did not significantly change when a repeat analysis was performed accounting for missing values for serum albumin, hemoglobin, and creatinine.

Figure 1.
Figure 1.

Time to gout by age. Line 1, first quintile of age from less than 56.2 yr; line 2, second quintile of age from 56.2 to 68.6 yr; line 3, third quintile of age from 68.6 to 76.8 yr; line 4, fourth quintile of age from greater than 76.8 yr.

Figure 2.
Figure 2.

Time to gout by BMI. Line 1, first quintile of BMI <22.2; line 2, second quintile of BMI from 22.2 to 25.7; line 3, third quintile of BMI from 25.7 to 30.4; line 4. fourth quintile of BMI >30.4.

View this table:
Table 2.

Cox regression analysis of factors associated with Medicare claims for gout after initiation of dialysis, censored for renal transplantationa

The proportion of patients with gout increased according to higher quintiles of BMI (Figure 2). The proportion of patients with gout also increased with advancing age (Figure 1). There was also a higher frequency of gout in black patients compared with other ethnicities. In time-dependent Cox regression analysis (Table 3), an episode of gout was independently associated with subsequent mortality, with an adjusted hazard ratio (HR) of 1.49 (95% CI 1.43 to 1.55). An incident case of gout was also associated with a higher cardiovascular mortality (defined as death as a result of acute myocardial infarction, atherosclerotic heart disease, congestive heart failure, arrhythmia, valvular heart disease, or unspecified cardiac arrest not including cerebrovascular disease) with an adjusted HR of 1.47 (95% CI 1.26 to 1.59). These results did not significantly differ when the cases of gouty nephropathy were included in the analysis (adjusted HR 1.48; 95% CI 1.39 to 1.58). A history of chronic obstructive pulmonary disease, peripheral vascular disease, diabetes, ischemic heart disease, and congestive heart failure was also independently associated with subsequent mortality. As with previous analyses of the USRDS database, black race and increased serum albumin were associated with improved survival on dialysis.

View this table:
Table 3.

Time-dependent Cox regression analysis–adjusted HR for death from a random samplea

Stratified analyses were performed for those with and without diabetes, those with and without hypertension, and between black race and other ethnicities to examine for potential effect modification (Table 4). The adjusted HR for incident cases of gout and all-cause death was significantly higher within all of the subgroups. We also performed analyses including these variables as interaction terms with incident cases of gout. Black race (adjusted HR 1.06, 95% CI 0.96 to 1.18; P = 0.27) and male gender (adjusted HR 0.96, 95% CI 0.88 to 1.06; P = 0.43) were NS interaction terms.

View this table:
Table 4.

Adjusted HR for all-cause death among patients with ESRD and incident cases of gout: A stratified analysisa

DISCUSSION

The true number of patients who have renal disease and a diagnosis of gout and start dialysis is unknown. A review of the USRDS database from 2000 to 2004 revealed a prevalence of 5.9% for patients with a history of gout-related nephrolithiasis or obstruction (all-cause obstruction, not necessarily related to gout) in the ESRD program.19 There was a 0.02% prevalence of patients with a diagnosis of gouty nephropathy in the ESRD program. Our results show that the incidence of gout in patients with ESRD may be similar to that of general medical populations, with a 5% incidence of gout after 1 yr on dialysis and 15.4% incidence after 5 yr. These results contrast with previous smaller and single-center studies that found an infrequent rate of gout in dialysis patients.1,2 The reasons for these disparities are not clear but may be related to the larger number of patients sampled or differences in lifestyle/diet. It is also likely that a significant number of patients with ESRD had a predialysis episode of gout that could not be identified because of the inherent limitations of an observational study. This would serve to overestimate the true incidence of gout among patients in the USRDS.

In adjusted analyses, we found that independent risk factors for gout included black race, older age, BMI, female gender, hypertension, ischemic heart disease, congestive heart failure, and alcohol use. There was a lower risk for gout in those with a history of diabetes, smoking, and peripheral vascular disease. Risk factors for gout in the general medical population include hyperuricemia, genetic predisposition, obesity, alcohol and purine intake, the metabolic syndrome, age, male gender, hypertension, diuretic therapy, and chronic renal insufficiency.20–22

The reason for the higher risk for gout in women in our cohort is unclear but may be related to the older age and largely postmenopausal status of most of the female dialysis patients. The average age of the dialysis patients with gout was 69.8 ± 12.6 yr; however, gender persisted as a significant risk factor for gout after adjustment for age. Studies in the general medical population have shown a higher risk for gout in older postmenopausal women, as well as women with CKD.23–25 An effect of estrogen to reduce uric acid levels needs further investigation.

Black patients had a higher risk for gout in this cohort. This is consistent with results from the general medical population.26 This may be related to genetic factors predisposing black individuals to hyperuricemia or other dietary factors that may lead to differential rates of gout among ethnic groups. Black individuals have a higher BMI and increased rates of hypertension, which are also predisposing risk factors for developing gout.

Diabetes was associated with a lower risk for developing gout in patients with ESRD. Previous population studies showed diabetes to be associated with incident cases of gout.5,27 Nevertheless, this finding is similar to the results of our previous study of renal transplant recipients in which patients with diabetes also were found to have a decreased incidence of gout.5 It is possible that the different stage of diabetes may explain the disparate results between risk for gout in general medical patients and those with ESRD.5 Patients with diabetes and ESRD are also at increased risk for mortality, which has the potential to modify the risk for the development of gout.

Our analysis showed that incident cases of gout were associated with an increased rate of mortality with an adjusted HR of 1.49. In stratified analyses, the higher adjusted HR for mortality among female patients without diabetes and hypertension and with incident cases of gout most likely reflects fewer competing risks for death within these lower mortality risk groups. This may be secondary to residual confounding from limitations of the USRDS, which has relatively few variables to account for malnutrition, infection, and social circumstances. When we performed analyses including these variables as interaction terms with new-onset gout, black race and male gender were NS interactions. This indicates the differences in relative mortality associated with gout between black and nonblack and between male and female gender, respectively, were not significantly different from what would be expected by chance alone.

These results are similar to the results of other investigators. Hsu et al.28 found that HD patients with the highest percentile of uric acid concentrations had an HR for mortality of 5.67; however, that study evaluated only 146 HD patients from a single center in Taiwan, and, therefore the results are not necessarily generalizable to the United States.

The reasons for the association between incident cases of gout and mortality are not clear. Abbott et al.16 found a 60% increased risk for coronary artery disease in male patients with a diagnosis of gout. On the basis of an analysis of the Multiple Risk Factor Intervention Trial, Krishnan et al.17 found that gout was associated with an approximately 25% increase in the incidence of acute coronary syndrome. Choi et al.18 recently found similar results in an analysis of the Health Professionals Follow-Up Study. Men with a diagnosis of gout and no history of coronary artery disease had a 28% increased risk for mortality, 38% increased risk for cardiovascular mortality, and a 55% increased risk for fatal myocardial events. Cardiovascular disease is the primary cause of mortality among patients with ESRD, which makes these results particularly salient to the results of our analysis.19

Numerous studies showed an association between hyperuricemia and increased risk for cardiovascular deaths in general medicine patients.15,29–37 Although most patients with hyperuricemia do not develop gout, all cases of gout have been associated with hyperuricemia.21 Hyperuricemia may promote atherosclerosis through unknown mechanisms.15 Hyperuricemia has been associated with insulin resistance and, therefore, the metabolic syndrome.38–41 The metabolic syndrome is linked to increased risk for cardiovascular disease and subsequent mortality.42 Our data show a direct relationship between higher BMI and the risk for incident cases of gout, supporting its association with the metabolic syndrome and obesity. Increased uric acid levels may also be a marker of endothelial injury, which may help to promote atherosclerosis.15 Hyperuricemia in patients with ESRD may also be a reflection of the underlying inflammatory state with subsequent increased risk for mortality.43,44 Several studies have shown an association between inflammatory markers such as increased C-reactive protein and hypoalbuminemia and increased mortality.45–48

Other potential mechanisms linking hyperuricemia with mortality include the potential for uric acid to cause platelet aggregation with subsequent higher rates of potential thrombosis.34,49,50 Hyperuricemia is also associated with hypertension through unknown mechanisms but possibly through increased renal tubular sodium reabsorption.51 Uric acid may also play a role in the progression of CKD and congestive heart failure.52,53

The limitations of this study include the retrospective study design with the known potentials for biases. Causality between incident cases of gout and mortality cannot be inferred. There is the potential for misclassification with this type of analysis; therefore, the diagnosis of gout may be over- or underestimated. Outcomes cannot be independently verified by investigators. We cannot be certain that preexisting claims for gout were completely excluded because of the inherent limitations of a database. This may have accounted for the larger than expected incidence of gout. Harrold et al.54 addressed this concern of validity of gout diagnoses using large administrative databases in a recent study. Nevertheless, the data are significant because they highlight the importance of finding surrogate markers for inflammation in dialysis patients that may be associated with mortality. Gout also has a significant impact on patient morbidity and quality of life.4,55 A recent study showed that a diagnosis of gout had an adverse impact on worker productivity.55 The management of gout is often more complicated in patients with CKD compared with the general population56; therefore, an appreciation that gout may be more common in patients with ESRD than previously reported is clinically important even if many of the cases are recurrent instead of incident cases.

This is the largest study to evaluate the associations of incident cases of gout in dialysis patients on a population level. Additional prospective studies are needed to confirm the potential association between incident cases of gout and mortality. Research is also needed to elucidate the precise mechanisms underlying this association.

CONCISE METHODS

A national registry (the USRDS) was analyzed in a historical cohort study of the rate, risk factors, and mortality associated with gout in patients who had ESRD and were on dialysis therapy.19 The variables included in the USRDS standard analysis files (SAF), as well as data collection methods and validation studies, are listed at the USRDS web site under Researcher's Guide, Appendix D and E, Contents of all of the SAF's, and published by the USRDS (http://www.usrds.org). The demographics of the dialysis population have been previously described (2002 USRDS report). The files SAF.PATIENTS were used as the primary data set, including cause of renal disease (PDIS) and cause and date of patient death. SAF.MEDEVID was used for additional information coded in the medical evidence form starting in 1999 and has been validated for use in research57; therefore, patients who presented with ESRD between January 1, 1999, and December 31, 2003, were selected for the study and followed through December 31, 2005. Study eligibility was restricted to patients with evidence of Medicare or Medicaid as primary payer as indicated from the PAYHIST file. Patients were excluded from the analysis when the cause of their ESRD was coded as gouty nephropathy.

Outcomes included Medicare claims for gout. Other outcomes included death from any cause. Time to Medicare claims for gout was defined as the time from the first dialysis session until the date of Medicare Claim for gout (International Classification of Diseases, Ninth Revision code 274.x), with patients censored for death or the end of the study period (December 31, 2004), whichever came first. Time to death was defined as time after the date of first dialysis until death, censored for the end of the study period, in this case considered December 31, 2005.

All analyses were performed using SPSS 12.0 (SPSS, Chicago, IL). Files were merged and converted to SPSS files using DBMS/Copy (Conceptual Software, Houston, TX). Statistical significance was defined as P < 0.05. Univariate analysis was performed with χ2 testing for categorical variables (Fisher exact test for violations of Cochran assumptions) and t test (Mann-Whitney for non-normal distributions) for continuous variables. Variables with P < 0.10 in univariate analysis for a relationship with gout (including age; gender; year of first dialysis session; and history of transplant, diabetes, or gout as cause of ESRD) were entered into multivariate analysis as covariates. An exception was made for factors with a potential biologic relationship with gout.58 These additional variables include race, BMI, smoking status, hypertension, use of erythropoietin at the time of dialysis initiation, hematocrit at time of dialysis initiation, and history of alcoholism.

Cox regression models were performed to test associations with gout, using covariates as specified previously. Patient survival curves were calculated using life-table analysis with patients censored at time of loss to follow-up. Time to gout was calculated as the time from the date of dialysis initiation until the diagnosis date of gout, censored for death, end of the study period, loss to follow-up, or renal transplantation. Survival was calculated from the date of gout diagnosis until death, censored for last follow-up visit, or loss to follow-up occurring after diagnosis. The association of gout with survival was calculated as a time-dependent variable in Cox regression, with all values before gout coded as 0 (including patients who never received a diagnosis of gout, all values after diagnosis as 1).

DISCLOSURES

None.

Acknowledgments

S.D.C. has been supported by a research fellowship award from the National Kidney Foundation.

This work was presented as a poster presentation at the annual meeting of the American Society of Nephrology; San Francisco, CA; November 2 through November 5, 2007.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • The opinions are solely those of the authors and do not represent an endorsement by the Department of Defense or the National Institutes of Health.

  • This is a US government work. There are no restrictions on its use.

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Association of Incident Gout and Mortality in Dialysis Patients
Scott D. Cohen, Paul L. Kimmel, Robert Neff, Lawrence Agodoa, Kevin C. Abbott
JASN Nov 2008, 19 (11) 2204-2210; DOI: 10.1681/ASN.2007111256
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