Original Investigation Relationship Between Serum Uric Acid and All-Cause and Cardiovascular Mortality in Patients Treated With Peritoneal Dialysis Xi Xia, MD,* Feng He, MD,* Xianfeng Wu, MD, Fenfen Peng, MD, Fengxian Huang, MD, PhD, and Xueqing Yu, MD, PhD Background: Although serum uric acid level appears to be associated with mortality in individuals treated with hemodialysis, the relationship between serum uric acid level and death is uncertain in patients treated with peritoneal dialysis (PD). Study Design: Cohort study. Setting & Participants: 985 patients from a single PD center in South China followed up for a median of 25.3 months. Predictor: Serum uric acid level. Outcomes & Measurements: The association of baseline sex-specific uric acid level with all-cause and cardiovascular mortality was evaluated. Models were adjusted for age, body mass index, comorbidity score, residual kidney function, total Kt/V, allopurinol and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, and laboratory test results, including hemoglobin, serum albumin, creatinine, calcium, phosphorus, triglycerides, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. Results: Mean age was 48.3 6 15.4 (SD) years, and 23% had diabetes. Mean uric acid level was 7.0 6 1.3 (range, 3.8-19.8) mg/dL. During follow-up, 144 deaths were recorded, of which 64 were due to cardiovascular events. In multivariable models, the highest sex-specific tertile of uric acid level was associated with increased risk of all-cause mortality (HR, 1.93; 95% CI, 1.27-2.93; P 5 0.004) and cardiovascular mortality (HR, 3.31; 95% CI, 1.70-6.41; P , 0.001) compared to the lowest tertile. Adjusted Cox regression models showed that the HRs per 1-mg/dL higher uric acid level for all-cause and cardiovascular mortality were 1.33 (95% CI, 1.14-1.56; P , 0.001) and 1.44 (95% CI, 1.17-1.77; P 5 0.001) for men and 1.03 (95% CI, 0.86-1.24; P 5 0.8) and 1.16 (95% CI, 0.97-1.38; P 5 0.1) for women, respectively. A formal test for interaction indicated that the association of uric acid level with all-cause and cardiovascular mortality differed by sex (b 5 20.06 [P 5 0.02] and b 5 20.10 [P 5 0.02], respectively). Limitations: Single measurement of uric acid at baseline. Cause of death determined by death certificates and expert consensus. Conclusions: Elevated serum uric acid level is an independent risk factor for all-cause and cardiovascular mortality in men treated with PD. Am J Kidney Dis. -(-):---. Crown Copyright ª 2013 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. INDEX WORDS: Serum uric acid; peritoneal dialysis; all-cause mortality; cardiovascular mortality.
T
he global burden of end-stage renal disease (ESRD) has been increasing steadily. According to the 2011 US Renal Data System report, the total ESRD population increased to more than 570,000 in 2009, of whom 27,522 were on peritoneal dialysis (PD) therapy.1 Of concern, patients with ESRD have an increased risk of mortality; moreover, cardiovascular (CV) disease (CVD) is the leading cause of morbidity and mortality in dialysis patients.2,3 Uric acid is the final product of purine nucleotide metabolism in humans.4 Increased serum uric acid levels have been shown to be related to kidney disease, CVD, hypertension, and metabolic syndrome.5,6 Nevertheless, uric acid’s role as an independent risk factor for mortality and CV risk has been controversial. In the general population, several,7-11 but not all,12-15 studies have suggested a correlation between serum uric acid level and mortality or CV outcomes. For patients with chronic kidney disease (CKD), one Am J Kidney Dis. 2013;-(-):---
study conducted in patients with CKD stages 3-4 found that hyperuricemia appeared to be an independent risk factor for all-cause and CV mortality,16 and another study of patients with CKD stages From the Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. * X.X. and F.H. contributed equally to this work. Received May 6, 2013. Accepted in revised form August 30, 2013. Address correspondence to Fengxian Huang, MD, PhD, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58th, Zhongshan Road II, Guangzhou, 510080 China (e-mail: [email protected]) or Xueqing Yu, MD, PhD, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58th, Zhongshan Road II, Guangzhou, 510080 China (e-mail: [email protected]). Crown Copyright 2013 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.08.027 1
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3-5 also showed that hyperuricemia was a risk factor for all-cause mortality and CV events.17 With regard to patients with ESRD, 4 previous studies examined serum uric acid level as a predictor of mortality. Of these, 3 studies suggested a J-shaped serum uric acid level–mortality relationship.18-20 Additionally, a large multicenter international study (DOPPS [Dialysis Outcomes & Practice Patterns Study]) found that higher uric acid levels were associated with a lower risk of all-cause and CV mortality in the hemodialysis population.21 These 4 studies mainly focused on hemodialysis settings; however, the relationship of serum uric acid level and mortality is uncertain in patients treated with PD. In addition, sex-related differences in serum uric acid level–mortality have been reported, and some studies have shown serum uric acid level to be a predictor of mortality in women only.22-23 However, there is no research available to explore the possibility of sex-related differences in the serum uric acid level–mortality relationship in dialysis patients. Thus, it is unclear whether uric acid level is an independent risk factor for increased all-cause and CV mortality in both male and female patients treated with PD. Therefore, the purpose of this prospective study was to determine the association of serum uric acid levels with all-cause and CV mortality in male and female patients treated with PD.
METHODS Participants From January 1, 2006, to November 30, 2010, a total of 985 consecutive patients were recruited from a single PD center of the First Affiliated Hospital of Sun Yat-sen University. Enrollment included all patients aged 18-80 years who had received continuous ambulatory PD for more than 3 months, except those who had malignant disease or refused to give written consent.
Study Protocol This work was a prospective cohort study conducted in a single PD center. Baseline demographic and clinical data were collected at the initiation of PD therapy. Biochemical parameters were collected 3 months after PD therapy was initiated. Patients who reported current use of insulin or oral hypoglycemic agents and/or who had a clinical diagnosis of type 1 or type 2 diabetes mellitus were considered to have diabetes mellitus. Hypertension was recorded if the patient took antihypertensive drugs or had 2 separate blood pressure measurements $140/90 mm Hg. CVD was defined as history of angina pectoris, myocardial infarction, angioplasty, coronary artery bypass, heart failure, or stroke. The Davies score assigns 1 point for each of the following conditions: ischemic heart disease (defined as prior myocardial infarction, angina, or ischemic changes on electrocardiogram), left ventricular dysfunction (defined as clinical evidence of pulmonary edema not due to errors in fluid balance, or history of congestive heart failure), peripheral vascular disease (includes distal aortic, lower extremity, and cerebrovascular disease), malignancy, diabetes, collagen vascular disease, and other significant pathology (eg, chronic obstructive pulmonary disease).24 The theoretical range is 0-7. Each score was categorized into 4 levels: 0, 1, 2, and .2. 2
Biochemical parameters, including serum uric acid, hemoglobin, serum albumin, serum creatinine, albumin-corrected calcium, serum phosphorus, total triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, and high-sensitivity C-reactive protein, were measured in the First Affiliated Hospital of Sun Yat-sen University. Residual kidney function and total Kt/V were calculated using PD Adequest software 2.0 (Baxter Healthcare Ltd). Residual kidney function, in milliliters per minute per 1.73 m2, was estimated from mean values of creatinine clearance and urea clearance and adjusted for body surface area. Body surface area was calculated by the Gehan and George equation, where RRF equals residual renal function: 1 UrineCrðmmol=LÞ UrineUreaðmmol=LÞ 1 RRF 5 2 SerumCrðmmol=LÞ SerumUreaðmmol=LÞ 3
UrineVolumeðmLÞ 1440
Medicine use was recorded according to prescriptions and adherence of the patient. Patients were required to return to our center at least quarterly for an overall medical evaluation and were interviewed face to face or by telephone monthly by trained nurses to assess for general conditions and concomitant medications. Quarterly visits and monthly telephone contacts were performed for clinical purposes not specifically for this study. The primary outcome of interest was all-cause mortality, and the second outcome of interest was CV mortality. CV events contributing to CV mortality included acute myocardial infarction, atherosclerotic heart disease, cardiomyopathy, cardiac arrhythmia, cardiac arrest, congestive heart failure, cerebrovascular accident (including intracranial hemorrhage), ischemic brain damage, anoxic encephalopathy, and peripheral vascular disease. If the patients died in any hospital, death certificates were referred to for the exact cause of death, and if death occurred outside a hospital, experts would obtain a consensus about the cause of death after a comprehensive consideration of the history, recent situations, signs, and symptoms before and after death from the patient’s medical records in our center and descriptions provided by family members. In this cohort, 101 of 144 (70%) patients died in a hospital. All patients were followed up until death, transfer to hemodialysis therapy, kidney transplantation, transfer of care from our center, or censoring on November 30, 2011. The study protocol was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University. All patients provided informed consent before study entry.
Statistical Analysis Participants were stratified into tertiles of serum uric acid levels, which were calculated separately in men (tertile 1 [lowest], ,6.67; tertile 2 [middle], 6.67-7.56; and tertile 3 [highest], .7.56 mg/dL) and women (tertile 1, ,6.19; tertile 2, 6.19-7.13; and tertile 3, .7.13 mg/dL, respectively). Summary statistics by tertile of uric acid level were presented as percentages for categorical data, mean 6 standard deviation for approximately normally distributed continuous variables, and median (interquartile range) for skewed continuous variables. Differences between the uric acid groups were tested using c2 test for categorical variables, analysis of variance for approximately normally distributed continuous variables, and Kruskal-Wallis test for skewed continuous variables. A logistic regression model was used to examine patient characteristics associated with predictive odds of serum uric acid level in sex-specific tertile 3, which adjusted for covariates listed in Table 1 using a stepwise conditional method (probability for stepwise: entry, 0.1; removal, 0.1). Survival was calculated using Am J Kidney Dis. 2013;-(-):---
Serum Uric Acid and Survival With PD Table 1. Baseline Characteristics by Sex-Specific Tertiles of Uric Acid Tertile 1 (n 5 328)
Tertile 2 (n 5 328)
No. of men/women
192/136
Serum uric acid (mg/dL)
5.8 6 0.6
Demographics Age (y) Body mass index (kg/m2) Comorbid conditions Cardiovascular disease Diabetes mellitus Hypertension Systolic BP (mm Hg) Diastolic BP (mm Hg) Davies score 0 1 2 .2 Laboratory variables Hemoglobin (g/dL) Serum albumin (g/dL) Serum creatinine (mg/dL) Albumin-corrected calcium (mg/dL) Serum phosphorus (mg/dL) Total triglycerides (mg/dL) Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) RKF (mL/min/1.73 m2) hs-CRP (mg/dL) Total Kt/V Treatments Allopurinol Loop diuretic Sodium carbonate ACEi/ARB
Tertile 3 (n 5 329)
P
191/137
192/137
NA
6.9 6 0.3
8.3 6 1.3
NA
51.5 6 15.7 21.0 6 2.9
47.4 6 14.6 21.5 6 3.0
46.1 6 15.4 21.4 6 3.0
,0.001 0.1
34% 35% 66% 137.0 6 22.3 82.5 6 14.9
26% 20% 67% 136.3 6 19.7 85.0 6 13.8
31% 14% 64% 138.0 6 20.4 87.0 6 14.4
0.1 ,0.001 0.8 0.5 ,0.001 0.01
19% 42% 25% 14%
24% 48% 20% 8%
25% 48% 20% 7%
9.9 6 1.7 3.6 6 0.4 9.5 6 3.4 9.4 6 0.7 4.8 6 1.2 144.2 6 91.6 195.0 6 41.9 47.8 6 13.8 111.4 6 28.9 3.3 6 2.5 0.3 [0.5] 2.4 6 0.7
10.2 6 1.5 3.8 6 0.4 10.6 6 3.1 9.3 6 0.6 5.2 6 1.1 159.1 6 96.1 196.8 6 40.3 45.3 6 11.5 114.4 6 28.6 3.5 6 2.5 0.3 [0.6] 2.4 6 0.6
9.8 6 1.7 3.8 6 0.4 10.2 6 3.5 9.2 6 0.7 5.4 6 1.2 159.9 6 113.8 190.3 6 43.8 45.8 6 16.8 108.0 6 32.1 3.7 6 2.5 0.3 [0.5] 2.4 6 0.6
0.001 ,0.001 ,0.001 0.03 ,0.001 0.01 0.1 0.07 0.03 0.1 0.4 0.8
6% 12% 3% 70%
17% 16% 7% 71%
13% 9% 4% 57%
,0.001 0.03 0.08 ,0.001
Note: Values for continuous variables are given as mean 6 standard deviation or median [interquartile range]. Conversion factors for units: creatinine in mg/dL to mmol/L, 388.4; phosphorus in mg/dL to mmol/L, 30.3229; calcium in mg/dL to mmol/L, 30.2495; HDL-C, LDL-C, and total cholesterol in mg/dL to mmol/L, 30.02586; total triglycerides in md/dL to mmol/L, 30.01129; serum uric acid in mg/dL to mmol/L, 359.48. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; HDL-C, highdensity lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; NA, not applicable; RKF, residual kidney function.
the Kaplan-Meier method and differences between distributions of survival were assessed by log-rank test. Figures of log minus log were performed to assess the assumption of proportional hazard, and these checks were satisfied. Cox regression models were used to evaluate the relationship between uric acid tertiles with all-cause mortality and CV mortality, initially without adjustment and subsequently adjusting for several groups of covariates. The multivariate Cox regression model was constructed using eligible covariates that demonstrated significant or near-significant association with mortality (P , 0.2) on bivariable analysis or for importance of clinical concern. 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 higher uric acid level by sex. Moreover, the interaction between sex and serum uric acid level was examined by performing a formal test of interaction. In Cox regression models, time at risk was from study entry until death, transferring to hemodialysis therapy, kidney transplantation, Am J Kidney Dis. 2013;-(-):---
transferring care from our center, or the end of study on November 30, 2011. For primary effects, P , 0.05 was considered statistically significant. For interactions, P , 0.1 was considered significant.25 Statistical analyses were performed using SPSS, version 17.0 for Windows (SPSS Inc).
RESULTS Study Participants Baseline demographic and clinical characteristics of the cohort are given in Table 1, categorized according to sex-specific tertiles of serum uric acid concentration. A total of 985 patients were enrolled in this study (mean age, 48.3 6 15.4 [SD] years; 58% men; 23% with diabetes), with a median follow-up of 25.3 (maximum, 71.8) months. Mean serum uric acid 3
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value was 7.0 (range, 3.8-19.8) mg/dL for all patients, and male patients had a significantly higher mean serum uric acid level than female patients (7.2 6 1.2 vs 6.8 6 1.4 mg/dL, respectively; P , 0.001). A total of 119 patients (12%) were receiving allopurinol at baseline. In the whole process, 140 (14%) patients underwent kidney transplantation after a median of 18.2 months, 65 (7%) were transferred to hemodialysis therapy for any reason after a median of 22.6 months, and 27 (3%) transferred care from our center after a median of 34.0 months. Fatal events were registered during follow-up. A total of 144 deaths (15%) were recorded, of which 64 were due to CV events (Fig 1).
Table 2. Significant Risk Factors for High Serum Uric Acid Levels Adjusted OR (95% CI)
P
Body mass index (per 1-kg/m2 greater)
1.04 (0.99-1.09)
0.1
Diabetes (yes vs no) Hemoglobin (per 1-g/dL greater)
0.41 (0.27-0.62) 0.90 (0.81-0.99)
,0.001 0.02
Serum albumin (per 1-g/dL greater)
1.62 (1.09-2.41)
0.02
Serum creatinine (per 1-mg/dL greater)
0.89 (0.84-0.94)
,0.001
Serum phosphorus (per 1-mg/dL greater)
1.50 (1.28-1.75)
,0.001
Risk Factors for Higher Uric Acid Levels
LDL-C (per 1-mg/dL greater)
1.00 (0.99-1.00)
0.06
Table 2 lists significant risk factors for patients with higher serum uric acid levels in sex-specific tertile 3 by adjusting for covariates listed in Table 1 and with a stepwise selection procedure. Higher serum uric acid level was associated with absence of diabetes; lower hemoglobin level, higher serum albumin level, lower serum creatinine level, higher serum phosphorus level, and no use of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blocker (ARBs).
Use of ACEi/ARB (yes vs no)
0.64 (0.47-0.85)
0.003
Uric Acid and All-Cause and CV Mortality Associations of sex-specific tertiles of serum uric acid concentration with all-cause and CV mortality with defined models (with the lowest tertile as the reference group) are listed in Table 3. Regardless of the adjustment method used, the highest tertile (tertile 3) was associated significantly with higher all-cause and CV mortality compared to the lowest tertile (tertile 1). However, the risk of all-cause and CV
Figure 1. Study flow, including patient enrollment, and outcomes. Abbreviation: CVD, cardiovascular disease. 4
Risk Factors
Note: High serum uric acid refers to sex-specific tertile 3. Data adjusted for covariates listed in Table 1 (high-sensitivity C-reactive protein was log-transformed, stepwise conditional adjustment). Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; OR, odds ratio.
mortality in the middle tertile (tertile 2) did not statistically significantly differ from the lowest tertile (tertile 1). In model 4, which was a maximally adjusted model including age, body mass index, Davies comorbidity score, hemoglobin level, serum albumin level, serum creatinine level, albumincorrected calcium level, serum phosphorus level, total triglyceride level, LDL cholesterol level, residual kidney function, log-transformed high-sensitivity C-reactive protein level, total Kt/V, use of allopurinol, use of loop diuretics, and use of ACE inhibitors/ARBs, adjusted HRs for all-cause and CV mortality were 1.93 (95% confidence interval [CI], 1.27-2.93; P 5 0.004) and 3.31 (95% CI, 1.70-6.41 P , 0.001), respectively, when serum uric acid level increased from tertile 1 to tertile 3. Figure 2 shows Kaplan-Meier survival curves of sex-specific tertiles. In crude analysis, a significant difference between tertiles of serum uric acid and their association with all-cause and CV mortality was found, with the lowest survival in patients with serum uric acid concentration in the highest tertile (tertile 3; log-rank test P 5 0.006 and P 5 0.03, respectively). Associations of serum uric acid concentration with all-cause and CV mortality for men and women were studied by Cox regression models after adjustment for age, body mass index, Davies comorbidity score, hemoglobin level, serum albumin level, serum creatinine level, albumin-corrected calcium level, serum phosphorus level, total triglyceride level, LDL cholesterol level, residual kidney function, logtransformed high-sensitivity C-reactive protein level, Am J Kidney Dis. 2013;-(-):---
Serum Uric Acid and Survival With PD Table 3. Relationship Between Sex-Specific Tertiles of Uric Acid and All-Cause and CV Mortality Tertile 2 (n 5 328) HR (95% CI)
Pa
Tertile 3 (n 5 329) HR (95% CI)
Pa
All-cause mortality Unadjusted Model 1b Model 2c Model 3d Model 4e
0.62 0.80 0.83 1.22 1.28
(0.41-0.95) (0.52-1.22) (0.54-1.28) (0.77-1.92) (0.81-2.02)
Unadjusted Model 1b Model 2c Model 3d Model 4e
0.97 1.26 1.32 1.97 1.96
(0.50-1.86) (0.65-2.45) (0.68-2.57) (0.97-4.01) (0.96-4.00)
0.06 0.6 0.8 0.8 0.6
1.23 1.70 1.76 1.91 1.93
(0.84-1.79) (1.16-2.51) (1.19-2.59) (1.26-2.89) (1.27-2.93)
0.6 0.01 0.008 0.004 0.004
CV mortality 1.0 1.0 0.8 0.1 0.1
1.89 2.70 2.78 3.38 3.31
(1.04-3.44) 0.08 (1.46-5.00) 0.004 (1.50-5.15) 0.002 (1.75-6.54) ,0.001 (1.70-6.41) ,0.001
Note: Reference group is tertile 1 of serum uric acid level (n 5 328). Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio. a P value had been multiplied by 2 for multiple comparisons. b Adjusted for age and body mass index. c Adjusted for model 1 covariates and Davies comorbidity score. d Adjusted for model 2 covariates and hemoglobin, serum albumin, serum creatinine, albumin-corrected calcium, serum phosphorus, total triglyceride, and low-density lipoprotein cholesterol levels; residual kidney function; log-transformed high-sensitivity C-reactive protein level; and total Kt/V. e Adjusted for model 3 covariates and use of allopurinol, loop diuretics, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker.
total Kt/V, use of allopurinol, use of loop diuretics, and use of ACE inhibitors/ARBs (Table 4). With each 1mg/dL increase in serum uric acid level, adjusted HRs of all-cause and CV mortality were 1.33 (95% CI, 1.141.56; P , 0.001) and 1.44 (95% CI, 1.17-1.77; P 5 0.001) for men and 1.03 (95% CI, 0.86-1.24; P 5 0.8) and 1.16 (95% CI, 0.97-1.38; P 5 0.1) for women, respectively. As further support of this apparent difference by sex, we tested the interaction between sex and serum uric acid level on all-cause and CV mortality among all participants and observed a significant interaction (b 5 20.06; [P 5 0.02] and b 5 20.10 [P 5 0.02], respectively). Additional analysis was performed based on those without use of allopurinol. Adjusted HRs of all-cause and CV mortality for a 1-mg/dL increase in serum uric acid concentration were 1.30 (95% CI, 1.10-1.56; P 5 0.002) and 1.36 (95% CI, 1.09-1.70; P 5 0.006) for men and 1.04 (95% CI, 0.87-1.24; P 5 0.7) and 1.17 (95% CI, 0.98-1.40; P 5 0.08) for women, respectively. Again, the interaction term suggested differences by sex to be statistically significant (b 5 20.06 [P 5 0.04] and b 5 21.04 [P 5 0.02], respectively). Am J Kidney Dis. 2013;-(-):---
DISCUSSION Results of this study indicate that elevated serum uric acid levels are associated with higher all-cause and CV mortality only in male patients treated with PD, independent of several potential confounders (eg, demographic characteristics, Davies comorbidity score, laboratory values, and treatments). Adjusted HRs per 1-mg/dL increase in serum uric acid level for all-cause and CV mortality were 1.33 (95% CI, 1.141.56; P , 0.001) and 1.44 (95% CI, 1.17-1.77; P 5 0.001) for men. Excluding 119 patients who received allopurinol did not substantively alter the findings. Moreover, all-cause and CV mortality were significantly higher in those in the sex-specific highest tertile (tertile 3) compared with the lowest tertile (tertile 1) of serum uric acid. Whether elevated serum uric acid concentration is an independent risk factor for mortality and CV risk or it represents a surrogate marker for decreased kidney function, hypertension, and/or CVD has been a matter of some debate. This controversy persists regarding those in the general population7-15 and patients with specific conditions such as diabetes26-28 and hypertension.22,29 Conflicting results also exist regarding the role of serum uric acid level as a risk factor in patients with ESRD.18-21 To date, 4 studies have explored the relationship of serum uric acid level and mortality in dialysis patients, of which 3 found a J-shaped relationship between serum uric acid level and all-cause mortality.18-20 Each of these 3 studies had sample sizes of fewer than 300 patients, and they did not investigate CV mortality specifically. Furthermore, 2 of the 3 investigations were retrospective studies,19,20 and 2 were restricted to incident dialysis patients only, with serum uric acid levels having been obtained before dialysis treatment was initiated.18,20 In addition, the DOPPS (a large multicenter study of 4,637 patients who had baseline serum uric acid levels available [median follow-up, 23 months]) found that serum uric acid level was reversely and independently related to all-cause and CV mortality; as for this unexpected result, it was explained in part that higher serum uric acid concentration was a marker for better nutritional status.21 Nevertheless, 4 articles did not evaluate the clinical impact of serum uric acid level on patients who had undergone PD or analyze potential differences in male and female patients. In our study, sex-related differences were found that showed that elevated serum uric acid level was associated independently with higher all-cause and CV mortality in only male patients treated with PD. Although men have significantly higher serum uric acid levels than women, whether serum uric acid level had a sex-related difference on mortality or clinical outcomes has been uncertain. 5
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Figure 2. Crude analyses of all-cause and cardiovascular mortality between sex-specific tertiles of serum uric acid levels. KaplanMeier estimates of (A) all-cause and (B) cardiovascular mortality.
association also existed in most men.9,22 To our knowledge, our study is the first to examine the relationship of serum uric acid level and all-cause and CV mortality by sex in patients with ESRD. Furthermore, serum uric acid level is related to menopausal status in female patients,32 and this may influence the relationship of serum uric acid level and all-cause and CV mortality. In our patients, women younger than 45 years had a significantly higher mean serum uric acid level than those 45 years or older (6.95 6 1.30 vs 6.67 6 1.40 mg/dL; P 5 0.04). When we examined the impact of serum uric acid concentration on
Some studies suggested that higher serum uric acid concentration was an independent risk factor for mortality or disease progression in both male and female populations,9,11 some observed this relationship only in women,22,23 and others, only in men.30,31 These inconsistent results may be due to differences in the populations studied and follow-up periods. A follow-up study using the same cohort as the previous one but with longer follow-up (18.5 vs 13.5 years) not only confirmed the result of the earlier study—that higher serum uric acid level was associated with CV mortality in women—but also extended that the
Table 4. All-Cause and CV Mortality for Each 1-mg/dL Increase in Serum Uric Acid Level by Sex
Men Group
Total cohorta Excluding patients using allopurinola
Sex * SUA Interaction
Women
HR (95% CI)
P
All-cause
1.33 (1.14-1.56)
,0.001
1.03 (0.86-1.24)
0.8
20.06
0.02
CV
1.44 (1.17-1.77)
0.001
1.16 (0.97-1.38)
0.1
20.10
0.02
All-cause
1.30 (1.10-1.56)
0.002
1.04 (0.87-1.24)
0.7
20.06
0.04
CV
1.36 (1.09-1.70)
0.006
1.17 (0.98-1.40)
0.08
21.04
0.02
HR (95% CI)
P
b
Mortality Outcome
P
Note: P , 0.05 for main effect, P , 0.1 for interactions. Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio; SUA, serum uric acid. a Adjusted for age, body mass index; Davies comorbidity score; hemoglobin, serum albumin, serum creatinine, albumin-corrected calcium, serum phosphorus, total triglyceride, and low-density lipoprotein cholesterol levels; residual kidney function; logtransformed high-sensitivity C-reactive protein level; total Kt/V; and use of allopurinol, loop diuretics, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker. 6
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Serum Uric Acid and Survival With PD
all-cause mortality in the 2 different age groups of female patients separately, the association did not show statistical significance (data not shown). Previous reports suggest that higher serum uric acid levels are related closely to other established risk factors, such as male sex, hypertension, and metabolic syndrome; thus, elevated serum uric acid concentration may contribute to increased mortality risk indirectly. Meanwhile, higher serum uric acid level may be considered a surrogate for better nutritional status, which is expected to decrease mortality in dialysis patients. Age, prevalence of diabetes, diastolic blood pressure, comorbidity score, hemoglobin level, serum albumin level, serum creatinine level, albumincorrected calcium level, serum phosphorus level, LDL cholesterol level, and treatments (allopurinol, loop diuretics, and ACE inhibitors/ARBs) varied among patients in sex-specific tertiles of serum uric acid levels. Higher serum uric acid level has a positive association with higher serum phosphorus and serum albumin concentrations, which may be evidence of better nutritional status. Moreover, higher serum uric acid level also was associated inversely with diabetes, which is consistent with the finding in a hemodialysis study and a previous study at our center.20,21,33 However, some studies in CKD or PD settings did not find that the prevalence of diabetes differed among various levels of serum uric acid,16,34 and some showed that the prevalence of diabetes was significantly higher in hyperuricemic patients (serum uric acid .7.0 mg/dL).35 Diabetes may be associated with lower uric acid levels because of poorer nutrition and increasing excretion of uric acid.36 In our study, serum albumin levels were significantly lower in individuals with versus without diabetes (3.5 6 0.4 vs 3.8 6 0.4 mg/dL, respectively; P , 0.001), but fractional excretion of uric acid was not measured. It was reported that serum uric acid level negatively correlates with hemoglobin A1c or fructosamine level, suggesting a relationship between glycemic control and serum uric acid level.36,37 However, hemoglobin A1c level was not correlated with serum uric acid level in patients from our cohort with diabetes (r 5 0.05; P 5 0.5). More studies are needed to determine the effects of diabetes on serum uric acid concentrations in patients with ESRD and explain the plausible mechanisms. In short, our study showed that higher serum uric acid levels are associated with increased risks of all-cause and CV mortality independent of potential risk factors, suggesting that higher serum uric acid level might lead to excess risk above that expected from the established risk factors. The underlying mechanisms connecting serum uric acid level with all-cause and CV mortality in patients treated with PD are still far from being well understood. However, some published data may Am J Kidney Dis. 2013;-(-):---
help establish some potential explanations. For example, a Korean study that followed up 134 incident patients treated with PD with residual urine volumes .200 mL/ d up to a maximum of 24 months showed that hyperuricemia was associated significantly with the rate of decline in residual kidney function, after adjusting for demographic data, comorbid conditions, body mass index, baseline residual kidney function, and medications (P 5 0.001).35 Furthermore, evidence indicated that higher serum uric acid level may play a role in endothelial dysfunction. For instance, serum uric acid levels were found to be associated with a reduction in nitric oxide levels, with resultant endothelial dysfunction in both cultured endothelial cells and experimental animals.38 Moreover, in a study applying the flow-mediated dilatation test as a current standard for noninvasive assessment of endothelial function, an independent correlation between serum uric acid level and degree of endothelial dysfunction was found in patients treated with long-term PD.34 The strengths of our study are as follows: (1) this is a prospective cohort study having a large number of patients treated with PD in a single center, (2) the correlation between serum uric acid level and mortality was examined for both overall patients and by sex, and (3) we completed a detailed assessment and adjustment for metabolic and CV risk factors. Our study also has some limitations. In analysis, only baseline data were used, which did not cover the change in serum uric acid levels during the observation period. Moreover, the reliance on death certificates and expert consensus for determining cause of death may lead to misclassification. Last, all recruited patients were mainly from South China, which means our study may lack generalization to other ethnic populations. In conclusion, our study explored the relationship between serum uric acid level and all-cause and CV mortality in patients treated with PD both for overall patients and by sex. We found that higher serum uric acid concentrations are associated with higher all-cause and CV mortality only in male patients treated with PD. The association remained robust despite adjustment for metabolic and CV risk factors. Further studies will be necessary not only to determine whether uric acid– lowering regimens improve survival in patients treated with PD, but also to clarify the underlying mechanisms.
ACKNOWLEDGEMENTS Support: This work was supported by grants from the National Key Basic Research Program of China (grant 2011CB504005), the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (grant 2011BAI10B05), the National Natural Science Foundation of China (grant 81170765), and the Guangdong Natural Science Foundation (grant S2011020002359). Financial Disclosure: The authors declare that they have no other relevant financial interests. 7
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REFERENCES 1. Collins AJ, Foley RN, Chavers B. United States Renal Data System 2011 annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. Am J Kidney Dis. 2012;59(1)(suppl 1):e1-e420. 2. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296-1305. 3. Cheung AK, Sarnak MJ, Yan G, et al. HEMO Study Group: cardiac diseases in maintenance hemodialysis patients: results of the HEMO Study. Kidney Int. 2004;65(6):2380-2389. 4. Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids. 2008;27(6):608-619. 5. Nakagawa T, Kang DH, Feig D, et al. Unearthing uric acid: an ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int. 2006;69(10):1722-1725. 6. Ford ES, Li C, Cook S, Choi HK. Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents. Circulation. 2007;115(19):2526-2532. 7. Bengtsson C, Lapidus L, Stendahl C, et al. Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand. 1988;224(6):549-555. 8. Liese AD, Hense HW, Löwel H, et al. Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg cohort. World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases. Epidemiology. 1999;10(4):391-397. 9. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality: the NHANES I epidemiologic follow-up study, 19711992. National Health and Nutrition Examination Survey. JAMA. 2000;283(18):2404-2410. 10. Niskanen LK, Laaksonen DE, Nyyssönen K, et al. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med. 2004;164(14):1546-1551. 11. Holme I, Aastveit AH, Hammar N, et al. Uric acid and risk of myocardial infarction, stroke and congestive heart failure in 417,734 men and women in the Apolipoprotein Mortality RISk study (AMORIS). J Intern Med. 2009;266(6):558-570. 12. Reunanen A, Takkunen H, Knekt P. Hyperuricemia as a risk factor for cardiovascular mortality. Acta Med Scand Suppl. 1982;668:49-59. 13. Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart disease events. Heart. 1997;78(2):147-153. 14. Culleton BF, Larson MG, Kannel WB, et al. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131(1):7-13. 15. Moriarity JT, Folsom AR, Iribarren C, et al. Serum uric acid and risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol. 2000;10(3):136-143. 16. Madero M, Sarnak MJ, Wang X, et al. Uric acid and longterm outcomes in CKD. Am J Kidney Dis. 2009;53(5):796-803. 17. Liu WC, Hung CC, Chen SC, et al. Association of hyperuricemia with renal outcomes, cardiovascular disease, and mortality. Clin J Am Soc Nephrol. 2012;7(4):541-548. 18. Suliman ME, Johnson RJ, García-López E, et al. J-Shaped mortality relationship for uric acid in CKD. Am J Kidney Dis. 2006;48(5):761-771. 19. Hsu SP, Pai ME, Peng YS, et al. Serum uric acid levels show a ‘J-shaped’ association with all-cause mortality in haemodialysis patients. Nephrol Dial Transplant. 2004;19(2):457-462. 8
20. Lee SM, Lee AL, Winters TJ, et al. Low serum uric acid level is a risk factor for death in incident hemodialysis patients. Am J Nephrol. 2009;29(2):79-85. 21. Latif W, Karaboyas A, Tong L. Uric acid levels and allcause and cardiovascular mortality in the hemodialysis population. Clin J Am Soc Nephrol. 2011;6(10):2470-2477. 22. Freedman DS, Williamson DF, Gunter EW, et al. Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1995;141(7):637-644. 23. Skak-Nielsen H, Torp-Pedersen C, Finer N, et al. Uric acid as a risk factor for cardiovascular disease and mortality in overweight/obese individuals. PLoS One. 2013;8(3):e59121. 24. Davies SJ, Russell L, Bryan J, Phillips L, Russell GI. Comorbidity, urea kinetics, and appetite in continuous ambulatory peritoneal dialysis patients: their interrelationship and prediction of survival. Am J Kidney Dis. 1995;26(2):353-361. 25. Fleiss JL, Levin BA, Paik MC. Statistical Methods for Rates and Proportions. 3rd edition. Hoboken, NJ: J. Wiley; 2003. 26. Zoppini G, Targher G, Negri C. Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients. Diabetes Care. 2009;32(9):1716-1720. 27. Ong G, Davis WA, Davis TM. Serum uric acid does not predict cardiovascular or all-cause mortality in type 2 diabetes: the Fremantle Diabetes Study. Diabetologia. 2010;53(7):1288-1294. 28. Ford ES. Uric acid and mortality from all-causes and cardiovascular disease among adults with and without diagnosed diabetes: findings from the National Health and Nutrition Examination Survey III Linked Mortality Study. Diabetes Res Clin Pract. 2011;93(2):e84-e86. 29. Verdecchia P, Schillaci G, Reboldi G, et al. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension: the PIUMA Study. Hypertension. 2000;36(6):1072-1078. 30. Schwarzschild MA, Schwid SR, Marek K, et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol. 2008;65(6):716-723. 31. Paganoni S, Zhang M, Quiroz Zárate A, et al. Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol. 2012;259(9):1923-1928. 32. Levine W, Dyer AR, Shekelle RB, Schoenberger JA, Stamler J. Serum uric acid and 11.5-year mortality of middle-aged women: findings of the Chicago Heart Association Detection Project in Industry. J Clin Epidemiol. 1989;42(3):257-267. 33. Yang X, Yi C, Liu X, et al. Clinical outcome and risk factors for mortality in Chinese patients with diabetes on peritoneal dialysis: a 5-year clinical cohort study. Diabetes Res Clin Pract. 2013;100(3):354-361. 34. Tang Z, Cheng LT, Li HY, et al. Serum uric acid and endothelial dysfunction in continuous ambulatory peritoneal dialysis patients. Am J Nephrol. 2009;29(5):368-373. 35. Park JT, Kim DK, Chang TI, et al. Uric acid is associated with the rate of residual renal function decline in peritoneal dialysis patients. Nephrol Dial Transplant. 2009;24(11):3520-3525. 36. Gołembiewska E, Ciechanowski K, Safranow K, Kedzierska K, Kabat-Koperska J. Renal handling of uric acid in patients with type 1 diabetes in relation to glycemic control. Arch Med Res. 2005;36(1):32-35. 37. Yuan HJ, Yang XG, Shi XY, Tian R, Zhao ZG. Association of serum uric acid with different levels of glucose and related factors. Chin Med J (Engl). 2011;124(10):1443-1448. 38. Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67(5): 1739-1742. Am J Kidney Dis. 2013;-(-):---
T
he global burden of end-stage renal disease (ESRD) has been increasing steadily. According to the 2011 US Renal Data System report, the total ESRD population increased to more than 570,000 in 2009, of whom 27,522 were on peritoneal dialysis (PD) therapy.1 Of concern, patients with ESRD have an increased risk of mortality; moreover, cardiovascular (CV) disease (CVD) is the leading cause of morbidity and mortality in dialysis patients.2,3 Uric acid is the final product of purine nucleotide metabolism in humans.4 Increased serum uric acid levels have been shown to be related to kidney disease, CVD, hypertension, and metabolic syndrome.5,6 Nevertheless, uric acid’s role as an independent risk factor for mortality and CV risk has been controversial. In the general population, several,7-11 but not all,12-15 studies have suggested a correlation between serum uric acid level and mortality or CV outcomes. For patients with chronic kidney disease (CKD), one Am J Kidney Dis. 2013;-(-):---
study conducted in patients with CKD stages 3-4 found that hyperuricemia appeared to be an independent risk factor for all-cause and CV mortality,16 and another study of patients with CKD stages From the Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. * X.X. and F.H. contributed equally to this work. Received May 6, 2013. Accepted in revised form August 30, 2013. Address correspondence to Fengxian Huang, MD, PhD, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58th, Zhongshan Road II, Guangzhou, 510080 China (e-mail: [email protected]) or Xueqing Yu, MD, PhD, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58th, Zhongshan Road II, Guangzhou, 510080 China (e-mail: [email protected]). Crown Copyright 2013 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.08.027 1
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3-5 also showed that hyperuricemia was a risk factor for all-cause mortality and CV events.17 With regard to patients with ESRD, 4 previous studies examined serum uric acid level as a predictor of mortality. Of these, 3 studies suggested a J-shaped serum uric acid level–mortality relationship.18-20 Additionally, a large multicenter international study (DOPPS [Dialysis Outcomes & Practice Patterns Study]) found that higher uric acid levels were associated with a lower risk of all-cause and CV mortality in the hemodialysis population.21 These 4 studies mainly focused on hemodialysis settings; however, the relationship of serum uric acid level and mortality is uncertain in patients treated with PD. In addition, sex-related differences in serum uric acid level–mortality have been reported, and some studies have shown serum uric acid level to be a predictor of mortality in women only.22-23 However, there is no research available to explore the possibility of sex-related differences in the serum uric acid level–mortality relationship in dialysis patients. Thus, it is unclear whether uric acid level is an independent risk factor for increased all-cause and CV mortality in both male and female patients treated with PD. Therefore, the purpose of this prospective study was to determine the association of serum uric acid levels with all-cause and CV mortality in male and female patients treated with PD.
METHODS Participants From January 1, 2006, to November 30, 2010, a total of 985 consecutive patients were recruited from a single PD center of the First Affiliated Hospital of Sun Yat-sen University. Enrollment included all patients aged 18-80 years who had received continuous ambulatory PD for more than 3 months, except those who had malignant disease or refused to give written consent.
Study Protocol This work was a prospective cohort study conducted in a single PD center. Baseline demographic and clinical data were collected at the initiation of PD therapy. Biochemical parameters were collected 3 months after PD therapy was initiated. Patients who reported current use of insulin or oral hypoglycemic agents and/or who had a clinical diagnosis of type 1 or type 2 diabetes mellitus were considered to have diabetes mellitus. Hypertension was recorded if the patient took antihypertensive drugs or had 2 separate blood pressure measurements $140/90 mm Hg. CVD was defined as history of angina pectoris, myocardial infarction, angioplasty, coronary artery bypass, heart failure, or stroke. The Davies score assigns 1 point for each of the following conditions: ischemic heart disease (defined as prior myocardial infarction, angina, or ischemic changes on electrocardiogram), left ventricular dysfunction (defined as clinical evidence of pulmonary edema not due to errors in fluid balance, or history of congestive heart failure), peripheral vascular disease (includes distal aortic, lower extremity, and cerebrovascular disease), malignancy, diabetes, collagen vascular disease, and other significant pathology (eg, chronic obstructive pulmonary disease).24 The theoretical range is 0-7. Each score was categorized into 4 levels: 0, 1, 2, and .2. 2
Biochemical parameters, including serum uric acid, hemoglobin, serum albumin, serum creatinine, albumin-corrected calcium, serum phosphorus, total triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, and high-sensitivity C-reactive protein, were measured in the First Affiliated Hospital of Sun Yat-sen University. Residual kidney function and total Kt/V were calculated using PD Adequest software 2.0 (Baxter Healthcare Ltd). Residual kidney function, in milliliters per minute per 1.73 m2, was estimated from mean values of creatinine clearance and urea clearance and adjusted for body surface area. Body surface area was calculated by the Gehan and George equation, where RRF equals residual renal function: 1 UrineCrðmmol=LÞ UrineUreaðmmol=LÞ 1 RRF 5 2 SerumCrðmmol=LÞ SerumUreaðmmol=LÞ 3
UrineVolumeðmLÞ 1440
Medicine use was recorded according to prescriptions and adherence of the patient. Patients were required to return to our center at least quarterly for an overall medical evaluation and were interviewed face to face or by telephone monthly by trained nurses to assess for general conditions and concomitant medications. Quarterly visits and monthly telephone contacts were performed for clinical purposes not specifically for this study. The primary outcome of interest was all-cause mortality, and the second outcome of interest was CV mortality. CV events contributing to CV mortality included acute myocardial infarction, atherosclerotic heart disease, cardiomyopathy, cardiac arrhythmia, cardiac arrest, congestive heart failure, cerebrovascular accident (including intracranial hemorrhage), ischemic brain damage, anoxic encephalopathy, and peripheral vascular disease. If the patients died in any hospital, death certificates were referred to for the exact cause of death, and if death occurred outside a hospital, experts would obtain a consensus about the cause of death after a comprehensive consideration of the history, recent situations, signs, and symptoms before and after death from the patient’s medical records in our center and descriptions provided by family members. In this cohort, 101 of 144 (70%) patients died in a hospital. All patients were followed up until death, transfer to hemodialysis therapy, kidney transplantation, transfer of care from our center, or censoring on November 30, 2011. The study protocol was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University. All patients provided informed consent before study entry.
Statistical Analysis Participants were stratified into tertiles of serum uric acid levels, which were calculated separately in men (tertile 1 [lowest], ,6.67; tertile 2 [middle], 6.67-7.56; and tertile 3 [highest], .7.56 mg/dL) and women (tertile 1, ,6.19; tertile 2, 6.19-7.13; and tertile 3, .7.13 mg/dL, respectively). Summary statistics by tertile of uric acid level were presented as percentages for categorical data, mean 6 standard deviation for approximately normally distributed continuous variables, and median (interquartile range) for skewed continuous variables. Differences between the uric acid groups were tested using c2 test for categorical variables, analysis of variance for approximately normally distributed continuous variables, and Kruskal-Wallis test for skewed continuous variables. A logistic regression model was used to examine patient characteristics associated with predictive odds of serum uric acid level in sex-specific tertile 3, which adjusted for covariates listed in Table 1 using a stepwise conditional method (probability for stepwise: entry, 0.1; removal, 0.1). Survival was calculated using Am J Kidney Dis. 2013;-(-):---
Serum Uric Acid and Survival With PD Table 1. Baseline Characteristics by Sex-Specific Tertiles of Uric Acid Tertile 1 (n 5 328)
Tertile 2 (n 5 328)
No. of men/women
192/136
Serum uric acid (mg/dL)
5.8 6 0.6
Demographics Age (y) Body mass index (kg/m2) Comorbid conditions Cardiovascular disease Diabetes mellitus Hypertension Systolic BP (mm Hg) Diastolic BP (mm Hg) Davies score 0 1 2 .2 Laboratory variables Hemoglobin (g/dL) Serum albumin (g/dL) Serum creatinine (mg/dL) Albumin-corrected calcium (mg/dL) Serum phosphorus (mg/dL) Total triglycerides (mg/dL) Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) RKF (mL/min/1.73 m2) hs-CRP (mg/dL) Total Kt/V Treatments Allopurinol Loop diuretic Sodium carbonate ACEi/ARB
Tertile 3 (n 5 329)
P
191/137
192/137
NA
6.9 6 0.3
8.3 6 1.3
NA
51.5 6 15.7 21.0 6 2.9
47.4 6 14.6 21.5 6 3.0
46.1 6 15.4 21.4 6 3.0
,0.001 0.1
34% 35% 66% 137.0 6 22.3 82.5 6 14.9
26% 20% 67% 136.3 6 19.7 85.0 6 13.8
31% 14% 64% 138.0 6 20.4 87.0 6 14.4
0.1 ,0.001 0.8 0.5 ,0.001 0.01
19% 42% 25% 14%
24% 48% 20% 8%
25% 48% 20% 7%
9.9 6 1.7 3.6 6 0.4 9.5 6 3.4 9.4 6 0.7 4.8 6 1.2 144.2 6 91.6 195.0 6 41.9 47.8 6 13.8 111.4 6 28.9 3.3 6 2.5 0.3 [0.5] 2.4 6 0.7
10.2 6 1.5 3.8 6 0.4 10.6 6 3.1 9.3 6 0.6 5.2 6 1.1 159.1 6 96.1 196.8 6 40.3 45.3 6 11.5 114.4 6 28.6 3.5 6 2.5 0.3 [0.6] 2.4 6 0.6
9.8 6 1.7 3.8 6 0.4 10.2 6 3.5 9.2 6 0.7 5.4 6 1.2 159.9 6 113.8 190.3 6 43.8 45.8 6 16.8 108.0 6 32.1 3.7 6 2.5 0.3 [0.5] 2.4 6 0.6
0.001 ,0.001 ,0.001 0.03 ,0.001 0.01 0.1 0.07 0.03 0.1 0.4 0.8
6% 12% 3% 70%
17% 16% 7% 71%
13% 9% 4% 57%
,0.001 0.03 0.08 ,0.001
Note: Values for continuous variables are given as mean 6 standard deviation or median [interquartile range]. Conversion factors for units: creatinine in mg/dL to mmol/L, 388.4; phosphorus in mg/dL to mmol/L, 30.3229; calcium in mg/dL to mmol/L, 30.2495; HDL-C, LDL-C, and total cholesterol in mg/dL to mmol/L, 30.02586; total triglycerides in md/dL to mmol/L, 30.01129; serum uric acid in mg/dL to mmol/L, 359.48. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; HDL-C, highdensity lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; NA, not applicable; RKF, residual kidney function.
the Kaplan-Meier method and differences between distributions of survival were assessed by log-rank test. Figures of log minus log were performed to assess the assumption of proportional hazard, and these checks were satisfied. Cox regression models were used to evaluate the relationship between uric acid tertiles with all-cause mortality and CV mortality, initially without adjustment and subsequently adjusting for several groups of covariates. The multivariate Cox regression model was constructed using eligible covariates that demonstrated significant or near-significant association with mortality (P , 0.2) on bivariable analysis or for importance of clinical concern. 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 higher uric acid level by sex. Moreover, the interaction between sex and serum uric acid level was examined by performing a formal test of interaction. In Cox regression models, time at risk was from study entry until death, transferring to hemodialysis therapy, kidney transplantation, Am J Kidney Dis. 2013;-(-):---
transferring care from our center, or the end of study on November 30, 2011. For primary effects, P , 0.05 was considered statistically significant. For interactions, P , 0.1 was considered significant.25 Statistical analyses were performed using SPSS, version 17.0 for Windows (SPSS Inc).
RESULTS Study Participants Baseline demographic and clinical characteristics of the cohort are given in Table 1, categorized according to sex-specific tertiles of serum uric acid concentration. A total of 985 patients were enrolled in this study (mean age, 48.3 6 15.4 [SD] years; 58% men; 23% with diabetes), with a median follow-up of 25.3 (maximum, 71.8) months. Mean serum uric acid 3
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value was 7.0 (range, 3.8-19.8) mg/dL for all patients, and male patients had a significantly higher mean serum uric acid level than female patients (7.2 6 1.2 vs 6.8 6 1.4 mg/dL, respectively; P , 0.001). A total of 119 patients (12%) were receiving allopurinol at baseline. In the whole process, 140 (14%) patients underwent kidney transplantation after a median of 18.2 months, 65 (7%) were transferred to hemodialysis therapy for any reason after a median of 22.6 months, and 27 (3%) transferred care from our center after a median of 34.0 months. Fatal events were registered during follow-up. A total of 144 deaths (15%) were recorded, of which 64 were due to CV events (Fig 1).
Table 2. Significant Risk Factors for High Serum Uric Acid Levels Adjusted OR (95% CI)
P
Body mass index (per 1-kg/m2 greater)
1.04 (0.99-1.09)
0.1
Diabetes (yes vs no) Hemoglobin (per 1-g/dL greater)
0.41 (0.27-0.62) 0.90 (0.81-0.99)
,0.001 0.02
Serum albumin (per 1-g/dL greater)
1.62 (1.09-2.41)
0.02
Serum creatinine (per 1-mg/dL greater)
0.89 (0.84-0.94)
,0.001
Serum phosphorus (per 1-mg/dL greater)
1.50 (1.28-1.75)
,0.001
Risk Factors for Higher Uric Acid Levels
LDL-C (per 1-mg/dL greater)
1.00 (0.99-1.00)
0.06
Table 2 lists significant risk factors for patients with higher serum uric acid levels in sex-specific tertile 3 by adjusting for covariates listed in Table 1 and with a stepwise selection procedure. Higher serum uric acid level was associated with absence of diabetes; lower hemoglobin level, higher serum albumin level, lower serum creatinine level, higher serum phosphorus level, and no use of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blocker (ARBs).
Use of ACEi/ARB (yes vs no)
0.64 (0.47-0.85)
0.003
Uric Acid and All-Cause and CV Mortality Associations of sex-specific tertiles of serum uric acid concentration with all-cause and CV mortality with defined models (with the lowest tertile as the reference group) are listed in Table 3. Regardless of the adjustment method used, the highest tertile (tertile 3) was associated significantly with higher all-cause and CV mortality compared to the lowest tertile (tertile 1). However, the risk of all-cause and CV
Figure 1. Study flow, including patient enrollment, and outcomes. Abbreviation: CVD, cardiovascular disease. 4
Risk Factors
Note: High serum uric acid refers to sex-specific tertile 3. Data adjusted for covariates listed in Table 1 (high-sensitivity C-reactive protein was log-transformed, stepwise conditional adjustment). Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; OR, odds ratio.
mortality in the middle tertile (tertile 2) did not statistically significantly differ from the lowest tertile (tertile 1). In model 4, which was a maximally adjusted model including age, body mass index, Davies comorbidity score, hemoglobin level, serum albumin level, serum creatinine level, albumincorrected calcium level, serum phosphorus level, total triglyceride level, LDL cholesterol level, residual kidney function, log-transformed high-sensitivity C-reactive protein level, total Kt/V, use of allopurinol, use of loop diuretics, and use of ACE inhibitors/ARBs, adjusted HRs for all-cause and CV mortality were 1.93 (95% confidence interval [CI], 1.27-2.93; P 5 0.004) and 3.31 (95% CI, 1.70-6.41 P , 0.001), respectively, when serum uric acid level increased from tertile 1 to tertile 3. Figure 2 shows Kaplan-Meier survival curves of sex-specific tertiles. In crude analysis, a significant difference between tertiles of serum uric acid and their association with all-cause and CV mortality was found, with the lowest survival in patients with serum uric acid concentration in the highest tertile (tertile 3; log-rank test P 5 0.006 and P 5 0.03, respectively). Associations of serum uric acid concentration with all-cause and CV mortality for men and women were studied by Cox regression models after adjustment for age, body mass index, Davies comorbidity score, hemoglobin level, serum albumin level, serum creatinine level, albumin-corrected calcium level, serum phosphorus level, total triglyceride level, LDL cholesterol level, residual kidney function, logtransformed high-sensitivity C-reactive protein level, Am J Kidney Dis. 2013;-(-):---
Serum Uric Acid and Survival With PD Table 3. Relationship Between Sex-Specific Tertiles of Uric Acid and All-Cause and CV Mortality Tertile 2 (n 5 328) HR (95% CI)
Pa
Tertile 3 (n 5 329) HR (95% CI)
Pa
All-cause mortality Unadjusted Model 1b Model 2c Model 3d Model 4e
0.62 0.80 0.83 1.22 1.28
(0.41-0.95) (0.52-1.22) (0.54-1.28) (0.77-1.92) (0.81-2.02)
Unadjusted Model 1b Model 2c Model 3d Model 4e
0.97 1.26 1.32 1.97 1.96
(0.50-1.86) (0.65-2.45) (0.68-2.57) (0.97-4.01) (0.96-4.00)
0.06 0.6 0.8 0.8 0.6
1.23 1.70 1.76 1.91 1.93
(0.84-1.79) (1.16-2.51) (1.19-2.59) (1.26-2.89) (1.27-2.93)
0.6 0.01 0.008 0.004 0.004
CV mortality 1.0 1.0 0.8 0.1 0.1
1.89 2.70 2.78 3.38 3.31
(1.04-3.44) 0.08 (1.46-5.00) 0.004 (1.50-5.15) 0.002 (1.75-6.54) ,0.001 (1.70-6.41) ,0.001
Note: Reference group is tertile 1 of serum uric acid level (n 5 328). Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio. a P value had been multiplied by 2 for multiple comparisons. b Adjusted for age and body mass index. c Adjusted for model 1 covariates and Davies comorbidity score. d Adjusted for model 2 covariates and hemoglobin, serum albumin, serum creatinine, albumin-corrected calcium, serum phosphorus, total triglyceride, and low-density lipoprotein cholesterol levels; residual kidney function; log-transformed high-sensitivity C-reactive protein level; and total Kt/V. e Adjusted for model 3 covariates and use of allopurinol, loop diuretics, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker.
total Kt/V, use of allopurinol, use of loop diuretics, and use of ACE inhibitors/ARBs (Table 4). With each 1mg/dL increase in serum uric acid level, adjusted HRs of all-cause and CV mortality were 1.33 (95% CI, 1.141.56; P , 0.001) and 1.44 (95% CI, 1.17-1.77; P 5 0.001) for men and 1.03 (95% CI, 0.86-1.24; P 5 0.8) and 1.16 (95% CI, 0.97-1.38; P 5 0.1) for women, respectively. As further support of this apparent difference by sex, we tested the interaction between sex and serum uric acid level on all-cause and CV mortality among all participants and observed a significant interaction (b 5 20.06; [P 5 0.02] and b 5 20.10 [P 5 0.02], respectively). Additional analysis was performed based on those without use of allopurinol. Adjusted HRs of all-cause and CV mortality for a 1-mg/dL increase in serum uric acid concentration were 1.30 (95% CI, 1.10-1.56; P 5 0.002) and 1.36 (95% CI, 1.09-1.70; P 5 0.006) for men and 1.04 (95% CI, 0.87-1.24; P 5 0.7) and 1.17 (95% CI, 0.98-1.40; P 5 0.08) for women, respectively. Again, the interaction term suggested differences by sex to be statistically significant (b 5 20.06 [P 5 0.04] and b 5 21.04 [P 5 0.02], respectively). Am J Kidney Dis. 2013;-(-):---
DISCUSSION Results of this study indicate that elevated serum uric acid levels are associated with higher all-cause and CV mortality only in male patients treated with PD, independent of several potential confounders (eg, demographic characteristics, Davies comorbidity score, laboratory values, and treatments). Adjusted HRs per 1-mg/dL increase in serum uric acid level for all-cause and CV mortality were 1.33 (95% CI, 1.141.56; P , 0.001) and 1.44 (95% CI, 1.17-1.77; P 5 0.001) for men. Excluding 119 patients who received allopurinol did not substantively alter the findings. Moreover, all-cause and CV mortality were significantly higher in those in the sex-specific highest tertile (tertile 3) compared with the lowest tertile (tertile 1) of serum uric acid. Whether elevated serum uric acid concentration is an independent risk factor for mortality and CV risk or it represents a surrogate marker for decreased kidney function, hypertension, and/or CVD has been a matter of some debate. This controversy persists regarding those in the general population7-15 and patients with specific conditions such as diabetes26-28 and hypertension.22,29 Conflicting results also exist regarding the role of serum uric acid level as a risk factor in patients with ESRD.18-21 To date, 4 studies have explored the relationship of serum uric acid level and mortality in dialysis patients, of which 3 found a J-shaped relationship between serum uric acid level and all-cause mortality.18-20 Each of these 3 studies had sample sizes of fewer than 300 patients, and they did not investigate CV mortality specifically. Furthermore, 2 of the 3 investigations were retrospective studies,19,20 and 2 were restricted to incident dialysis patients only, with serum uric acid levels having been obtained before dialysis treatment was initiated.18,20 In addition, the DOPPS (a large multicenter study of 4,637 patients who had baseline serum uric acid levels available [median follow-up, 23 months]) found that serum uric acid level was reversely and independently related to all-cause and CV mortality; as for this unexpected result, it was explained in part that higher serum uric acid concentration was a marker for better nutritional status.21 Nevertheless, 4 articles did not evaluate the clinical impact of serum uric acid level on patients who had undergone PD or analyze potential differences in male and female patients. In our study, sex-related differences were found that showed that elevated serum uric acid level was associated independently with higher all-cause and CV mortality in only male patients treated with PD. Although men have significantly higher serum uric acid levels than women, whether serum uric acid level had a sex-related difference on mortality or clinical outcomes has been uncertain. 5
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Figure 2. Crude analyses of all-cause and cardiovascular mortality between sex-specific tertiles of serum uric acid levels. KaplanMeier estimates of (A) all-cause and (B) cardiovascular mortality.
association also existed in most men.9,22 To our knowledge, our study is the first to examine the relationship of serum uric acid level and all-cause and CV mortality by sex in patients with ESRD. Furthermore, serum uric acid level is related to menopausal status in female patients,32 and this may influence the relationship of serum uric acid level and all-cause and CV mortality. In our patients, women younger than 45 years had a significantly higher mean serum uric acid level than those 45 years or older (6.95 6 1.30 vs 6.67 6 1.40 mg/dL; P 5 0.04). When we examined the impact of serum uric acid concentration on
Some studies suggested that higher serum uric acid concentration was an independent risk factor for mortality or disease progression in both male and female populations,9,11 some observed this relationship only in women,22,23 and others, only in men.30,31 These inconsistent results may be due to differences in the populations studied and follow-up periods. A follow-up study using the same cohort as the previous one but with longer follow-up (18.5 vs 13.5 years) not only confirmed the result of the earlier study—that higher serum uric acid level was associated with CV mortality in women—but also extended that the
Table 4. All-Cause and CV Mortality for Each 1-mg/dL Increase in Serum Uric Acid Level by Sex
Men Group
Total cohorta Excluding patients using allopurinola
Sex * SUA Interaction
Women
HR (95% CI)
P
All-cause
1.33 (1.14-1.56)
,0.001
1.03 (0.86-1.24)
0.8
20.06
0.02
CV
1.44 (1.17-1.77)
0.001
1.16 (0.97-1.38)
0.1
20.10
0.02
All-cause
1.30 (1.10-1.56)
0.002
1.04 (0.87-1.24)
0.7
20.06
0.04
CV
1.36 (1.09-1.70)
0.006
1.17 (0.98-1.40)
0.08
21.04
0.02
HR (95% CI)
P
b
Mortality Outcome
P
Note: P , 0.05 for main effect, P , 0.1 for interactions. Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio; SUA, serum uric acid. a Adjusted for age, body mass index; Davies comorbidity score; hemoglobin, serum albumin, serum creatinine, albumin-corrected calcium, serum phosphorus, total triglyceride, and low-density lipoprotein cholesterol levels; residual kidney function; logtransformed high-sensitivity C-reactive protein level; total Kt/V; and use of allopurinol, loop diuretics, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker. 6
Am J Kidney Dis. 2013;-(-):---
Serum Uric Acid and Survival With PD
all-cause mortality in the 2 different age groups of female patients separately, the association did not show statistical significance (data not shown). Previous reports suggest that higher serum uric acid levels are related closely to other established risk factors, such as male sex, hypertension, and metabolic syndrome; thus, elevated serum uric acid concentration may contribute to increased mortality risk indirectly. Meanwhile, higher serum uric acid level may be considered a surrogate for better nutritional status, which is expected to decrease mortality in dialysis patients. Age, prevalence of diabetes, diastolic blood pressure, comorbidity score, hemoglobin level, serum albumin level, serum creatinine level, albumincorrected calcium level, serum phosphorus level, LDL cholesterol level, and treatments (allopurinol, loop diuretics, and ACE inhibitors/ARBs) varied among patients in sex-specific tertiles of serum uric acid levels. Higher serum uric acid level has a positive association with higher serum phosphorus and serum albumin concentrations, which may be evidence of better nutritional status. Moreover, higher serum uric acid level also was associated inversely with diabetes, which is consistent with the finding in a hemodialysis study and a previous study at our center.20,21,33 However, some studies in CKD or PD settings did not find that the prevalence of diabetes differed among various levels of serum uric acid,16,34 and some showed that the prevalence of diabetes was significantly higher in hyperuricemic patients (serum uric acid .7.0 mg/dL).35 Diabetes may be associated with lower uric acid levels because of poorer nutrition and increasing excretion of uric acid.36 In our study, serum albumin levels were significantly lower in individuals with versus without diabetes (3.5 6 0.4 vs 3.8 6 0.4 mg/dL, respectively; P , 0.001), but fractional excretion of uric acid was not measured. It was reported that serum uric acid level negatively correlates with hemoglobin A1c or fructosamine level, suggesting a relationship between glycemic control and serum uric acid level.36,37 However, hemoglobin A1c level was not correlated with serum uric acid level in patients from our cohort with diabetes (r 5 0.05; P 5 0.5). More studies are needed to determine the effects of diabetes on serum uric acid concentrations in patients with ESRD and explain the plausible mechanisms. In short, our study showed that higher serum uric acid levels are associated with increased risks of all-cause and CV mortality independent of potential risk factors, suggesting that higher serum uric acid level might lead to excess risk above that expected from the established risk factors. The underlying mechanisms connecting serum uric acid level with all-cause and CV mortality in patients treated with PD are still far from being well understood. However, some published data may Am J Kidney Dis. 2013;-(-):---
help establish some potential explanations. For example, a Korean study that followed up 134 incident patients treated with PD with residual urine volumes .200 mL/ d up to a maximum of 24 months showed that hyperuricemia was associated significantly with the rate of decline in residual kidney function, after adjusting for demographic data, comorbid conditions, body mass index, baseline residual kidney function, and medications (P 5 0.001).35 Furthermore, evidence indicated that higher serum uric acid level may play a role in endothelial dysfunction. For instance, serum uric acid levels were found to be associated with a reduction in nitric oxide levels, with resultant endothelial dysfunction in both cultured endothelial cells and experimental animals.38 Moreover, in a study applying the flow-mediated dilatation test as a current standard for noninvasive assessment of endothelial function, an independent correlation between serum uric acid level and degree of endothelial dysfunction was found in patients treated with long-term PD.34 The strengths of our study are as follows: (1) this is a prospective cohort study having a large number of patients treated with PD in a single center, (2) the correlation between serum uric acid level and mortality was examined for both overall patients and by sex, and (3) we completed a detailed assessment and adjustment for metabolic and CV risk factors. Our study also has some limitations. In analysis, only baseline data were used, which did not cover the change in serum uric acid levels during the observation period. Moreover, the reliance on death certificates and expert consensus for determining cause of death may lead to misclassification. Last, all recruited patients were mainly from South China, which means our study may lack generalization to other ethnic populations. In conclusion, our study explored the relationship between serum uric acid level and all-cause and CV mortality in patients treated with PD both for overall patients and by sex. We found that higher serum uric acid concentrations are associated with higher all-cause and CV mortality only in male patients treated with PD. The association remained robust despite adjustment for metabolic and CV risk factors. Further studies will be necessary not only to determine whether uric acid– lowering regimens improve survival in patients treated with PD, but also to clarify the underlying mechanisms.
ACKNOWLEDGEMENTS Support: This work was supported by grants from the National Key Basic Research Program of China (grant 2011CB504005), the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (grant 2011BAI10B05), the National Natural Science Foundation of China (grant 81170765), and the Guangdong Natural Science Foundation (grant S2011020002359). Financial Disclosure: The authors declare that they have no other relevant financial interests. 7
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