Uric Acid and Long-term Outcomes in CKD

Article Outline

• Abstract
• Methods
  • Participants and Measurements
  • Outcomes
  • Statistical Analysis
  • Sensitivity Analyses
• Results
  • Baseline Characteristics by Tertile of Uric Acid
  • Uric Acid and All-Cause Mortality
  • Uric Acid and CVD Mortality
  • Uric Acid and Kidney Failure
  • Sensitivity Analyses
• Discussion
• Acknowledgements
• References
• Copyright

Background

Hyperuricemia is prevalent in patients with chronic kidney disease (CKD); however, data are limited about the relationship of uric acid levels with long-term outcomes in this patient population.

Study Design

Cohort study.

Setting & Participants

The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial (N = 840) conducted from 1989 to 1993 to examine the effects of strict blood pressure control and dietary protein restriction on progression of stages 3 to 4 CKD. This analysis included 838 patients.

Predictor

Uric acid level.

Outcomes & Measurements

The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular disease (CVD) mortality, and kidney failure.

Results

Mean age was 52 ± 12 (SD) years, glomerular filtration rate was 33 ± 12 mL/min/1.73 m², and uric acid level was 7.63 ± 1.66 mg/dL. During a median follow-up of 10 years, 208 (25%) participants died of any cause, 127 (15%) died of CVD, and 553 (66%) reached kidney failure. In multivariate models, the highest tertile of uric acid was associated with increased risk of all-cause mortality (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.07 to 2.32), a trend toward CVD mortality (HR, 1.47; 95% CI, 0.90 to 2.39), and no association with kidney failure (HR, 1.20; 95% CI, 0.95 to 1.51) compared with the lowest tertile. In continuous analyses, a 1-mg/dL greater uric acid level was associated with 17% increased risk of all-cause mortality (HR, 1.17; 95% CI, 1.05 to 1.30) and 16% increased risk of CVD mortality (HR, 1.16; 95% CI, 1.01 to 1.33), but was not associated with kidney failure (HR, 1.02; 95% CI, 0.97 to 1.07).

Limitations

Primary analyses were based on a single measurement of uric acid. Results are generalizable primarily to relatively young white patients with predominantly nondiabetic CKD.

Conclusions

In patients with stages 3 to 4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality, but not kidney failure.

Index Words: Kidney disease, uric acid, outcomes, cardiovascular, mortality, kidney failure

Several,¹, ², ³, ⁴ but not all,⁵, ⁶, ⁷, ⁸ studies of the general population have suggested an association between uric acid level and cardiovascular outcomes. Many studies also have shown an association of uric acid level with such established cardiovascular risk factors as hypertension and diabetes.⁹, ¹⁰, ¹¹, ¹² Hyperuricemia is highly prevalent in patients with chronic kidney disease (CKD).¹³

Thus, uric acid may have a role as a uremia-related cardiovascular risk factor in patients with CKD. Although 2 studies of patients with kidney failure found a J-shaped association between uric acid level and all-cause mortality,¹⁴, ¹⁵ this relationship has not been studied in patients in the earlier stages of CKD. It is unclear whether uric acid level is a marker for increased cardiovascular disease (CVD) and all-cause mortality in this patient population and whether the relationship between uric acid level and mortality is independent of traditional CVD risk factors.

Given the interrelationship between CVD and progression of CKD,¹⁶ it is possible that uric acid level also is a risk factor for progression of kidney disease. Existing data about this relationship are contradictory. Although a few studies showed that hyperuricemia was associated with progression of kidney disease,¹³, ¹⁷, ¹⁸, ¹⁹ others failed to show this relationship.²⁰ These studies were limited by imprecise measures of kidney function and lack of data for proteinuria.

Using data from the Modification of Diet in Renal Disease (MDRD) Study randomized cohort, we examined whether uric acid level is an independent risk factor for the development of outcomes during long-term follow-up in patients with predominantly nondiabetic stages 3 to 4 CKD.

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Methods 

Participants and Measurements 

Details of the MDRD Study have been described previously.²¹ The MDRD Study was a randomized controlled trial conducted from 1989 to 1993 that tested the effect of dietary protein restriction and strict blood pressure control on the rate of progression of kidney disease in 840 individuals. Baseline entry criteria included age of 18 to 70 years and serum creatinine level of 1.2 to 7 mg/dL in women and 1.4 to 7 mg/dL in men. Exclusion criteria were pregnancy, type 1 diabetes, insulin-dependent type 2 diabetes, glomerulonephritis caused by autoimmune diseases, obstructive uropathy, renal artery stenosis, proteinuria with protein greater than 10 g/d, mean arterial pressure greater than 125 mm Hg, and prior kidney transplantation. Glomerular filtration rate (GFR) was measured by using iothalamate clearance. In study A (GFR, 25 to 55 mL/min/1.73 m²), patients were prescribed a usual- or low-protein diet. In study B (GFR 13 to 24 mL/min/1.73 m²), patients were prescribed 1 of 2 low-protein diets: the same-low protein diet as in study A or a very low-protein diet supplemented with a mixture of ketoacids and amino acids. Studies A and B were combined for the present analysis, which includes 838 patients with baseline uric acid measurements. Uric acid was measured at baseline at the MDRD Study Central Biochemistry Laboratory (Department of Biochemistry, Cleveland Clinic Foundation, Cleveland, OH).

Outcomes 

We assessed 3 outcomes: all-cause mortality, CVD mortality, and kidney failure (defined as requirement for dialysis or transplantation). Survival status and cause of death through December 31, 2000, were ascertained by review of death certificates using the National Death Index. A death was ascribed to CVD if the primary cause of death was CVD (International Classification of Diseases, Ninth Revision [ICD-9] codes 390 to 459) or kidney disease or diabetes was listed as the primary cause of death and CVD (ICD-9 codes 390 to 459) was the secondary cause of death. Diabetes was defined as ICD-9 codes 250.0 to 250.9. Death caused by kidney disease was defined as ICD-9 codes 580 to 599 and 753.1. Kidney failure outcomes were obtained from the US Renal Data System through December 31, 2000. Data collection procedures were approved by the Cleveland Clinic and Tufts-New England Medical Center Institutional Review Boards.

Statistical Analysis 

Distribution and normality of variables of interest were evaluated by using box plots and histograms. Summary statistics by tertiles of uric acid are presented as percentages for categorical data, mean ± SD for approximately normally distributed continuous variables, and median and interquartile range for skewed continuous variables. Differences between uric acid groups were tested by using χ² test for categorical variables, analysis of variance for approximately normally distributed continuous variables, and Kruskall Wallis test for skewed continuous variables.

Cox proportional hazards models stratified by study were used to evaluate the relationship between uric acid tertiles and all-cause mortality, CVD mortality, and kidney failure, initially without adjustment and subsequently adjusting for several groups of covariates. Covariates were selected for inclusion in the model for P less than 0.1 in univariate analysis (Table 1). Model 1 adjusted for randomization assignments to protein diets and blood pressure strata, age, and sex. Model 2 adjusted for traditional CVD risk factors, including history of CVD, diabetes, body mass index, and high-density lipoprotein cholesterol level in addition to the variables in model 1; systolic blood pressure was forced into the model given its known association with uric acid level and the outcomes of interest. Model 3 adjusted for variables in model 2 and kidney disease factors: GFR, serum albumin level, and diuretic use, with additional adjustment for cause of kidney disease and log-transformed proteinuria for the kidney failure outcome, and model 4 adjusted for model 3 covariates plus allopurinol use. Proportional hazards assumptions were tested by using log minus log survival plots and plots of Schoenfeld residuals versus survival time.

Table 1. Baseline Characteristics by Tertiles of Uric Acid

	Tertile 1 (1.7-6.9 mg/dL) (n = 276)	Tertile 2 (7.0-8.3 mg/dL) (n = 288)	Tertile 3 (8.4-15.6 mg/dL) (n = 274)	P
Uric acid (mg/dL)	5.8±0.9	7.6±0.4	9.5±0.9
Demographic factors
Age(y)	53.0±11.5	52.1±12.3	50.2±13.2	0.03
Men(%)	50	41	27	<0.001
White(%)	84	88	83	0.3
Current smoker(%)	9	10	10	0.8
Cardiovascular risk factors
Diabetes(%)	6	7	3	0.06
History of coronary artery disease(%)	13	6	10	0.03
Systolic blood pressure(mm Hg)	131.2±16.7	133.4±18.5	131.2±17.4	0.3
Diastolic blood pressure(mm Hg)	80.4±9.5	81.2±9.5	81.3±11.2	0.5
Body mass index(kg/m2)	26.7±4.5	27.1±4.5	27.6±4.4	0.04
Total cholesterol(mg/dL)	213.8±46.8	217.9±43.2	218.4±45.8	0.4
Low-density lipoprotein cholesterol(mg/dL)	145.8±42.9	149.0±40.3	147.7±40.7	0.7
High-density lipoprotein cholesterol(mg/dL)	42.4±15.1	40.4±13.8	36.8±13.3	<0.001
C-Reactive protein(mg/dL)	0.2(0.5)	0.2(0.5)	0.3(0.5)	0.3
Kidney disease factors
Glomerular filtration rate(mL/min/1.73 m2)	34.2±12.5	32.6±12.2	30.6±10.9	<0.001
Albumin(g/dL)	4.0±0.3	4.0±0.4	4.1±0.3	<0.001
Proteinuria(g/d)	0.2(1.1)	0.4(1.7)	0.3(1.5)	0.2
Cause of kidney disease(%)
Polycystic kidney disease	38	29	33
Glomerular disease	34	35	34	0.3
Other	28	36	33
Medications
Allopurinol(%)	33	10	8	<0.001
Diuretics(%)	33	34	46	0.01

Note: Data expressed as mean±SD or median(interquartile range). Conversion factors for units: uric acid in mg/dL to μmol/L, ×59.48; total, high-density lipoprotein, and low-density lipoprotein cholesterol in mg/dL to mmol/L, ×0.02586; glomerular filtration rate in mL/min/1.73 m² to mL/s/1.73 m², ×0.01667; and albumin in g/dL to g/L, ×10.

To maximize statistical power to examine the relationship between uric acid level and mortality, continuous variable analyses were conducted with hazard ratios (HRs) presented per 1-mg/dL greater uric acid level. We performed 2 multivariable models corresponding to the previously described models 3 and 4.

Finally, because high uric acid levels may lead to hypertension and hypertension may be in the causal pathway between uric acid level and the outcomes, fully adjusted models for all-cause and CVD mortality and kidney failure were repeated without adjustment for systolic blood pressure.

Models for the mortality outcomes included patients who developed kidney failure and were censored only at death or the end of follow-up, whereas models for kidney failure were censored at kidney failure, death, or the end of follow-up.

Sensitivity Analyses 

Because allopurinol decreases uric acid levels, individuals treated with allopurinol may be misclassified in the low uric acid level group despite having been exposed to high uric acid levels for extended periods. We therefore repeated the analyses by: (1) categorizing the sample into 2 groups based on the presence of hyperuricemia, defined as either allopurinol use or serum uric acid level greater than 9 mg/dL (men) or greater than 8 mg/dL (women); this definition was based on analyses from the Atherosclerosis Risk in Communities (ARIC) Study⁶; and (2) excluding the 143 participants who reported allopurinol use. Cox proportional hazards models stratified by study were used to evaluate the relationship of uric acid tertiles excluding patients on allopurinol therapy and hyperuricemia with all-cause and CVD mortality, initially without adjustment and subsequently adjusting for the following covariates selected on the basis of P less than 0.1 in univariate analysis: age, sex, blood pressure and dietary protein randomization assignments, history of CVD and diabetes, body mass index, high-density lipoprotein and low-density lipoprotein cholesterol levels, log-transformed C-reactive protein level, GFR, serum albumin level, diuretic use, and allopurinol use. We also adjusted for log-transformed proteinuria and cause of kidney disease for the kidney failure and composite outcome.

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Results 

Mean age of the study cohort was 52 ± 12 years, 85% were white, 61% were men, and 5% had diabetes. Mean GFR and uric acid levels were 33 ± 12 mL/min/1.73 m² and 7.63 ± 1.66 mg/dL, respectively. A total of 143 patients (17%) were on allopurinol therapy at baseline.

Baseline Characteristics by Tertile of Uric Acid 

Patients in the highest tertile of uric acid were more likely to be women and younger and have greater body mass index, greater serum albumin level, lower high-density lipoprotein cholesterol level, and lower GFR (Table 1). Prevalences of coronary artery disease, diabetes, and allopurinol use were greatest in the lowest tertile of uric acid.

Uric Acid and All-Cause Mortality 

Twenty-five percent (n = 208) of participants died during a median follow-up of approximately 10 years. Crude all-cause mortality rates were 23%, 25%, and 27% in uric acid tertiles 1, 2, and 3, respectively (Fig 1). In unadjusted Cox models, there was no association between tertiles of uric acid and all-cause mortality. This relationship became significant after adjustment for demographic factors, dietary intervention, CVD risk factors, kidney disease risk factors, and diuretic and allopurinol use (Table 2). We believe the discrepancy between the unadjusted and adjusted models reflects the younger age, higher numbers of women, and lower prevalence of diabetes mellitus and CVD in the highest tertile of uric acid, as listed in Table 1. Of note, the prevalence of allopurinol use was greatest in the lowest tertile, suggesting that treated patients with hyperuricemia were included in this lower tertile, thus accounting for the worse CVD risk profile in this group. HRs did not change appreciably when systolic blood pressure was excluded from the model (HR for tertile 2 versus tertile 1, 1.26 [95% confidence interval (CI), 0.89 to 1.79]; HR for tertile 3 versus tertile 1, 1.54 [95% CI, 1.07 to 2.20]).

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• Figure 1. 

  Crude rates of clinical outcomes by uric acid tertiles. Abbreviation: CVD, cardiovascular disease.

Table 2. Relationship Between Tertiles of Uric Acid and All-Cause Mortality, Cardiovascular Disease Mortality, and Kidney Failure

	Tertile 1 (1.7-6.9 mg/dL) (n = 276)	Tertile 2 (7.0-8.3 mg/dL) (n = 288)	Tertile 3 (8.4-15.6 mg/dL) (n = 274)
All-cause mortality
Unadjusted	1.00(reference)	1.13(0.81-1.59)	1.20(0.86-1.69)
Model 1⁎	1.00(reference)	1.21(0.86-1.69)	1.34(0.95-1.88)
Model 2†	1.00(reference)	1.29(0.91-1.86)	1.53(1.08-2.18)
Model 3‡	1.00(reference)	1.22(0.86-1.73)	1.50(1.05-1.90)
Model 4§	1.00(reference)	1.27(0.88-1.84)	1.57(1.07-2.32)
Cardiovascular disease mortality
Unadjusted	1.00(reference)	0.88(0.57-1.35)	0.97(0.64-1.48)
Model 1⁎	1.00(reference)	0.93(0.61-1.43)	1.09(0.71-1.67)
Model 2†	1.00(reference)	0.98(0.63-1.52)	1.33(0.86-2.08)
Model 3‡	1.00(reference)	0.94(0.60-1.46)	1.28(0.82-2.00)
Model 4§	1.00(reference)	1.05(0.66-1.68)	1.47(0.90-2.39)
Kidney failure
Unadjusted	1.00(reference)	1.23(0.99-1.51)	1.16(0.94-1.43)
Model 1⁎	1.00(reference)	1.21(0.98-1.49)	1.08(0.87-1.33)
Model 2†	1.00(reference)	1.18(0.96-1.46)	1.10(0.89-1.36)
Model 3‡	1.00(reference)	1.11(0.90-1.37)	1,12(0.90-1.39)
Model 4§	1.00(reference)	1.18(0.94-1.47)	1.20(0.95-1.51)

Note: Values expressed as hazard ratio(95% confidence interval).

Analyses were repeated with uric acid level as a continuous variable. There was no association in unadjusted analysis (HR per 1-mg/dL greater uric acid level, 1.07; 95% CI, 0.99 to 1.16); however, in the fully adjusted model, a 1-mg/dL greater uric acid level was associated with 17% increased risk of all-cause mortality (HR, 1.17; 95% CI, 1.05 to 1.30). As with the categorical analyses, differences in sex distribution, age, and CVD risk profile appear to account for the differences between univariate and multivariable associations.

Uric Acid and CVD Mortality 

Fifteen percent (n = 127) of participants died of CVD during a median follow-up of approximately 10 years. Crude CVD mortality rates were 16%, 14%, and 15% in uric acid tertiles 1, 2, and 3, respectively (Fig 1). In unadjusted Cox models, there was no association between tertiles of uric acid and CVD mortality (Table 2). In multivariate Cox models adjusting for demographic factors, dietary intervention, CVD risk factors, kidney disease risk factors, and diuretic and allopurinol use, there was a trend toward increased risk in the relationship between uric acid level and CVD mortality that did not reach statistical significance. HRs did not change appreciably when systolic blood pressure was excluded from the model (HR for tertile 2, 1.00; 95% CI, 0.65 to 1.56; HR for tertile 3, 1.33; 95% CI, 0.85 to 2.09).

Analyses were repeated with uric acid level as a continuous variable. Although high levels of uric acid were not associated with increased risk of CVD mortality in unadjusted analysis (HR per 1-mg/dL greater uric acid level, 1.02; 95% CI, 0.92 to 1.14), adjustment for covariates resulted in a significant relationship (HR, 1.16; 95% CI, 1.01 to 1.33). As stated, we believe the discrepancy between unadjusted and adjusted models reflects the more favorable CVD profile in the highest tertile group.

Uric Acid and Kidney Failure 

Sixty-six percent (n = 553) of participants reached kidney failure during a median follow-up of approximately 6 years. Crude kidney failure rates were 63%, 66%, and 69% in uric acid tertiles 1, 2, and 3, respectively (Fig 1). In unadjusted Cox models, there was no association between tertiles of uric acid and kidney failure. After adjustment for demographic factors, dietary intervention, CVD risk factors, kidney disease risk factors, and diuretic and allopurinol use, there was no association between uric acid level and the development of kidney failure (Table 2). HRs did not change appreciably when systolic blood pressure was excluded from the model (HR for tertile 2, 1.15; 95% CI, 0.93 to 1.42; HR for tertile 3, 1.13; 95% CI, 0.91 to 1.41).

Analyses were repeated with uric acid level as a continuous variable. Greater levels of uric acid were not associated with increased risk of kidney failure in unadjusted analysis (HR per 1-mg/dL greater uric acid level, 1.04; 95% CI, 0.99 to 1.09) or fully adjusted models (HR per 1-mg/dL greater uric acid level, 1.02; 95% CI, 0.97 to 1.07).

Sensitivity Analyses 

We repeated the analyses categorizing the sample into 2 groups based on the presence of hyperuricemia defined as either allopurinol use or serum uric acid level greater than 9 mg/dL (men) or greater than 8 mg/dL (women; Table 3). Forty-one percent (n = 340) of participants had hyperuricemia at baseline. Unadjusted rates of all-cause mortality, CVD mortality, and kidney failure were 28%, 19%, and 69% in the hyperuricemia group versus 23%, 12%, and 64% in the normal uric acid level group. Hyperuricemia was associated with a 51% increased risk of CVD mortality in unadjusted models and 59% in adjusted Cox models; there was no association with all-cause mortality or kidney failure in unadjusted or adjusted models. Results in the subgroup not using allopurinol were consistent with results of primary analyses (data not shown).

Table 3. Hyperuricemia and All-Cause Mortality, Cardiovascular Disease Mortality, and Kidney Failure

	All-Cause Mortality	Cardiovascular Disease Mortality	Kidney Failure
Unadjusted⁎	1.21(0.92-1.59)	1.51(1.06-2.13)	1.04(0.88-1.23)
Adjusted⁎
Model 1†	1.20(0.91-1.58)	1.52(1.07-2.16)	1.02(0.86-1.21)
Model 2‡	1.20(0.89-1.61)	1.68(1.15-2.46)	1.02(0.85-1.22)
Model 3§	1.16(0.86-1.56)	1.59(1.09-2.34)	1.06(0.88-1.28)

Note: Values expressed as hazard ratio (95% confidence interval). The reference group is normal uric acid level (n = 499) versus hyperuricemia (n = 340), defined as allopurinol use or uric acid level greater than 9 mg/dL in men and greater than 8 mg/dL in women.

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Discussion 

In this cohort of patients with predominantly nondiabetic CKD, hyperuricemia appears to be associated with increased risk of CVD and all-cause mortality, but not kidney failure, in long-term follow-up.

Several studies have evaluated uric acid level as a CVD risk factor in the general population with contradictory results. In a population-based study of epidemiological follow-up data from 5,926 participants in the National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-up Study, uric acid level was an independent predictor of CVD mortality.³ The relationship between uric acid level and increased risk of CVD also was observed in cohorts of healthy men,²² women,¹ the elderly,² and individuals at high risk of coronary disease.²³

In contrast, in 6,763 participants from the Framingham Heart Study, uric acid level did not increase the risk of coronary heart disease, CVD mortality, or all-cause mortality in adjusted analyses.⁵ Similarly, 2 other population-based cohorts, the ARIC Study⁶ and the British Regional Heart Study,⁷ failed to find an association between uric acid level and CVD outcomes.

Hyperuricemia is highly prevalent in patients with CKD, raising interest in it as a potentially modifiable CVD risk factor in this high-risk patient population. Two studies have examined the relationship between uric acid level and CVD in patients with kidney failure treated by means of dialysis. In a cohort of 294 incident patients with CKD stage 5, there was a J-shaped association of uric acid level with all-cause mortality.¹⁵ Similar results were seen in a cohort of 146 patients on long-term hemodialysis therapy in which the lowest and highest quintiles of uric acid level had greater risks of all-cause mortality.¹⁴

Data about the relationship between uric acid level and CVD outcomes in patients in the earlier stages of CKD before reaching kidney failure are limited. In a recent analysis examining the impact of nontraditional CVD risk factors on CVD outcomes in 1,678 patients with estimated GFR less than 60 mL/min/1.73 m², uric acid level was not an independent predictor of a composite outcome of myocardial infarction, stroke, and all-cause mortality.²⁴ In contrast, in a cohort of individuals with normal kidney function, baseline uric acid level was associated with the composite outcome of death and incident CKD.²⁵

In the MDRD Study randomized cohort, increased uric acid levels were independently associated with increased risk of all-cause and CVD mortality after adjustment for traditional CVD risk factors. Our results were unchanged by adjustment for blood pressure, suggesting that perhaps the increased risk was independent of a relationship between uric acid level and blood pressure and may involve other mechanisms. Putative mechanisms include inflammation,²⁶ endothelial dysfunction,²⁷ and vascular smooth muscle proliferation.²⁸ However, we acknowledge that blood pressure was closely targeted during the trial and we are not able to adjust for changes in blood pressure through extended follow-up.

Despite multiple epidemiological and prospective studies, the role of uric acid in the progression of kidney disease and development of kidney failure remains controversial. Two studies showed that hyperuricemia was an independent risk factor for progression of immunoglobulin A nephropathy.¹⁸, ²⁹ In a study of 6,400 individuals with normal kidney function at baseline, uric acid levels greater than 8.0 mg/dL were associated with 2.9- and 10-fold increased risks of developing CKD (defined as creatinine level > 1.2 mg/dL in women and > 1.4 mg/dL in men) within 2 years in men and women, respectively.¹⁷ A recent study, including 13,338 individuals with normal kidney function based on estimated GFR, evaluated the relationship between uric acid level and incident kidney disease (defined as GFR decrease ≥ 15 mL/min/1.73 m² with final GFR < 60 mL/min/1.73 m²). During follow-up of 8.5 years, each 1-mg/dL greater uric acid level at baseline was associated with an approximately 10% increase in risk of incident kidney disease in multivariable adjusted models.²⁵ A randomized trial of allopurinol versus placebo in 54 patients with stages 3 to 4 CKD found slower progression (defined as creatinine level increase > 40% of baseline or need for replacement therapy) in the allopurinol group during a 1-year follow-up.³⁰ In a population-based study from Japan, hyperuricemia, defined as serum uric acid level of 6.0 mg/dL or greater, was an independent risk factor for kidney failure.³¹ In contrast, in an analysis that included 5,808 participants from the Cardiovascular Health Study (CHS), although there was a modest association between uric acid level and progression of CKD (defined as decrease in GFR > 3 mL/min/1.73 m²/y), there was no association between uric acid level and incident CKD (defined as estimated GFR < 60 mL/min/1.73 m²).¹³

In our study cohort of patients with predominantly nondiabetic stages 3 to 4 CKD, uric acid level was not an independent risk factor for the development of kidney failure. There are a few potential explanations for our findings. First, we adjusted for iothalamate GFR as a measure of level of kidney function. It is possible that other studies may have been limited by residual confounding from using less precise measures of kidney function. Second, most other studies looked at incident CKD in a cohort with normal kidney function at baseline. It is possible that uric acid level may not be an important contributor to progression in patients with established kidney disease, especially in the presence of such powerful risk factors for the progression of CKD as proteinuria and high blood pressure. Third, in the MDRD Study, patients were randomly assigned to 2 different targets of blood pressure control. In long-term follow-up of the study, patients randomly assigned to the low blood pressure group had delayed onset of kidney failure.³² If hypertension is in the pathway relating uric acid to progression of kidney disease, the strict blood pressure control could have blunted the effect of hyperuricemia on the development of hypertension and subsequent kidney failure. However, our results did not change with exclusion of systolic blood pressure from the models.

There are a few limitations to this study. First, a single baseline measurement of uric acid was used to predict events several years in the future. However, there is a precedent for this, and several previous studies have used this approach.³, ¹⁷, ²⁵ Second, it is possible that we failed to observe a significant relationship with CVD mortality in the tertile analyses because of inadequate statistical power. However, the additional analyses are consistent with this increased risk. It is important to acknowledge that the results are primarily generalizable to relatively young white patients with predominantly nondiabetic CKD. It is possible that measures of association between uric acid level and CVD are even greater in other populations in which excess adiposity and diabetes are prevalent. However, this is a large cohort of patients with stages 3 to 4 CKD with a wide range of kidney function ascertained by using iothalamate GFR. Participants are not diabetic and neither appreciably malnourished nor acutely ill. This minimizes the limitation of confounding caused by such comorbid conditions as malnutrition, diabetes, and preexisting CVD.

In conclusion, hyperuricemia in persons with CKD appears to be associated with increased risk of all-cause and CVD mortality, but not kidney failure. Uric acid level may represent an important therapeutic target for mitigating CVD risk in patients with CKD.

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Acknowledgements 

Support: This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) Grants K23 DK067303, K23 DK02904, K24 DK078204, and UO1 DK35073, and TAP Pharmaceutical Products Inc.

Financial Disclosure: None.

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