It is thought that hyperuricemia might lower the risk of mortality among hemodialysis patients, unlike in the general population, but the evidence is controversial. The aim of the current study was to evaluate the impact of serum uric acid level on the long-term clinical outcomes of hemodialysis patients in Korea.
Retrospective analysis was performed on data from the End-Stage Renal Disease Registry of the Korean Society of Nephrology. This included data for 7,333 patients (mean age, 61 ± 14 years; 61% male) who received hemodialysis from January 2001 through April 2015. Initial laboratory data were used in the analysis.
The mean serum uric acid level in this study was 7.1 ± 1.7 mg/dL. Body mass index, normalized protein catabolic rate, albumin, and cholesterol were positively correlated with serum uric acid level after controlling for age and sex. After controlling for demographic data, comorbidities, and residual renal function, a higher uric acid level was independently associated with a significantly lower all-cause mortality (hazard ratio [HR], 0.90 per 1 mg/dL increase in uric acid level; 95% confidence interval [CI], 0.83–0.97;
Hyperuricemia was strongly associated with a lower risk of all-cause mortality, but there seems to be no significant association between serum uric acid level and cardiovascular mortality among Korean hemodialysis patients with end-stage renal disease.
Uric acid is a product of the metabolic breakdown of purine nucleotides. A high uric acid concentration can result in gout and urolithiasis [
Several studies have shown that elevated serum uric acid level increases the mortality risk among diabetic patients undergoing hemodialysis or peritoneal dialysis [
We conducted a retrospective analysis of patient data from the Korean Society of Nephrology (KSN) registry, which is a nationwide database of the medical records of patients with ESRD, from January 2001 to April 2015. The ESRD registry committee of the KSN launched the official ESRD patient registry in 1985, and collected all registry data by mail until 1994, and subsequently through an internet program that opened in 2001 and was revised in 2013 (
Demographic and clinical data were collected at the time of study enrollment. Age, sex, body mass index, comorbidities, systolic and diastolic blood pressures, presence of residual renal function, duration of dialysis, hemodialysis adequacy (standard Kt/V), normalized protein catabolic rate (nPCR), and laboratory findings were recorded. The presence of residual renal function was defined when urine volume was measurable in maintenance hemodialysis patients. We used the Leypoldt equation for the standard Kt/V calculation [
The primary outcome measure was all-cause mortality, and the secondary outcome was cardiovascular mortality. Of note, there is a possibility of over-estimation of patient survival due to the voluntary nature of registration in the ESRD patient registry, with submission of death reports being easily missed.
Continuous variables are presented as a mean ± standard deviation or median with interquartile range, as appropriate. Categorical variables are presented as number with percentage. We compared the demographic characteristics and covariates using the Pearson chi-square test for categorical variables and one-way analysis of variance for continuous variables. Correlations between univariate variables and serum uric acid level were assessed using Pearson’s correlation coefficients. Partial correlations were used to correct for age and sex. All independent variables in the multiple linear regression were tested for multicollinearity; if the variance inflation factor exceeded 10, the variable was considered to be collinear. Missing data were replaced using multiple imputation analysis [
Demographic and clinical data of our study group are presented in
Serum uric acid was positively correlated with body mass index, nPCR, and levels of albumin, phosphorus, creatinine, and PTH, in both unadjusted models and models adjusted for age and sex. However, standard Kt/V, hemoglobin, and calcium were not correlated with serum uric acid level after adjusting for age and sex (
Among the 7,333 cases included in our analysis, 378 (5.2%) all-cause deaths and 158 (2.2%) cardiovascular deaths were recorded over the follow-up period (
Cox proportional hazards models were used to quantify the associations between serum uric acid level and all-cause and cardiovascular death (
Analysis of imputed datasets (adjusted for missing uric acid level data) in the Cox proportional model yielded survival outcomes comparable to those calculated from the non-imputed data (
We also performed sensitivity analyses to determine the robustness of the association between serum uric acid level and risk of death. All-cause mortality was significantly lower among cases above the serum uric acid (> 5.8 mg/dL) than below (≤ 5.8 mg/dL), after adjustment, with no between-group difference in cardiovascular mortality. When participants were divided into quintiles of serum uric acid level, the HR for all-cause mortality among cases in the highest quintile (≥ 8.5 mg/dL) compared to the lowest quintile (≤ 5.8 mg/dL) was 0.65 (95% CI, 0.42–0.99;
Using data from the KSN registry of ESRD, we found that, among Korean hemodialysis patients, serum uric acid level was correlated with nutritional status indicators, such as body mass index, nPCR, and phosphorus. Moreover, higher uric acid level was associated with lower all-cause mortality in these patients, even after adjustment. However, hyperuricemia could not predict long-term cardiovascular mortality in this population.
Several studies have described an association between serum uric acid concentration and mortality among patients on maintenance hemodialysis or peritoneal dialysis [
The mechanism underlying the paradoxical association between serum uric acid level and all-cause mortality among dialysis patients has not been clearly elucidated and is multifactorial in nature. Several possible explanations could be proposed based on previous studies and our findings. First, serum uric acid level could be considered an indicator of nutritional status among patients on dialysis. In fact, serum uric acid level is significantly associated with handgrip strength, geriatric nutritional risk index, and malnutrition-inflammatory score, which are useful tools for monitoring nutritional status in hemodialysis patients [
Although low uric acid level might be associated with all-cause mortality in dialysis patients, it is important to clarify whether hyperuricemia
The present study did not find an association between serum uric acid level and cardiovascular mortality, even after adjustment of the models. Similarly, a longitudinal cohort study on maintenance hemodialysis patients indicated that a longitudinal increase in serum uric acid level over time was correlated with better all-cause mortality but not cardiovascular mortality or first cardiovascular event [
The limitations of the current study must be acknowledged. First, because of the retrospective design, a substantial number of patients with unavailable serum uric acid data were excluded from our cohort. Patients included in the analysis had lower all-cause and cardiovascular mortality compared to the excluded patients. Thus, selection bias might have affected the generalization of our findings to the maintenance hemodialysis population. Nevertheless, a multiple imputation model was used to estimate missing values, and similar results were obtained using the resulting dataset. Second, the rate of mortality in our cohort could have been underestimated because death reports are collected voluntarily, and the causes of death were extracted from patient records. Third, we could not exclude the possibility of residual confounding factors and the presence of unmeasured confounders, such as uric acid-lowering agents, despite our best efforts to adjust for significant confounding factors, including residual renal function that can influence serum uric acid level and standard Kt/V as a marker of hemodialysis adequacy. Despite these limitations, the strength of our study is that it used data from a nationwide Korean ESRD registry with a large number of patients undergoing maintenance hemodialysis and long-term follow-up, up to 14 years.
In conclusion, our study demonstrated that higher serum uric acid level at the commencement of dialysis was strongly associated with a lower risk of all-cause mortality, except for cardiovascular mortality, in Korean patients undergoing hemodialysis. These findings suggest the need for simple laboratory tests to estimate serum uric acid level in order to identify disease prognosis and the requirement for nutritional interventions. Further studies are also needed to evaluate and determine the precise mechanisms behind our findings.
This study was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning (2015R1C1A1A01051769) and by the Basic Science Research Program through the NRF, funded by the Ministry of Science, ICT, and Future Planning (2016R1A2B4007870). The authors would like to thank all medical doctors and nurses of dialysis centers in Korea who participated in this registry and the ESRD Registry Committee of the Korean Society of Nephrology.
All authors have no conflicts of interest to declare.
Futher detailes are presented in the online version of this article (available at
Mean, 7.12 mg/dL; standard deviation, 1.71 mg/dL.
(A) All-cause mortality and (B) cardiovascular mortality. Q1 (≤ 5.8 mg/dL), Q2 (5.9–6.6 mg/dL), Q3 (6.7–7.4 mg/dL), Q4 (7.5–8.4 mg/dL), and Q5 (≥ 8.5 mg/dL).
Baseline clinical characteristics of the study population according to quintile of serum uric acid level
Variable | Serum uric acid level (mg/dL) | |||||
---|---|---|---|---|---|---|
| ||||||
≤ 5.8 (n = 1,506) | 5.9–6.6 (n = 1,365) | 6.7–7.4 (n = 1,502) | 7.5–8.4 (n = 1,528) | ≥ 8.5 (n = 1,432) | ||
Age (yr) | 64.5 ± 13.3 | 62.1 ± 13.2 | 61.3 ± 13.5 | 59.1 ± 13.6 | 58.0 ± 13.1 | < 0.001 |
Male | 827 (54.9) | 794 (58.2) | 885 (58.9) | 976 (63.9) | 989 (69.1) | < 0.001 |
SBP (mmHg) | 141.5 ± 19.7 | 142.6 ± 19.6 | 141.9 ± 19.7 | 141.6 ± 19.1 | 142.0 ± 19.4 | 0.273 |
DBP (mmHg) | 77.4 ± 12.0 | 78.0 ± 11.7 | 77.9 ± 11.8 | 78.8 ± 11.3 | 78.9 ± 11.9 | 0.002 |
Diabetes | 822 (54.6) | 722 (52.9) | 774 (51.5) | 745 (48.8) | 616 (43.0) | < 0.001 |
Hypertension | 280 (18.6) | 286 (21.0) | 324 (21.6) | 313 (20.5) | 327 (22.8) | 0.017 |
Body mass index (kg/m2) | 21.8 ± 15.4 | 22.0 ± 3.4 | 22.4 ± 4.8 | 23.0 ± 14.8 | 22.8 ± 5.3 | 0.009 |
Dialysis time/session (min) | 235 ± 20 | 238 ± 19 | 237 ± 19 | 237 ± 17 | 236 ± 20 | < 0.001 |
nPCR (g/kg/day) | 0.92 ± 1.00 | 1.03 ± 1.20 | 1.22 ± 1.79 | 1.10 ± 1.46 | 1.32 ± 2.29 | 0.002 |
Standard Kt/V | 2.11 ± 0.49 | 2.14 ± 0.39 | 2.12 ± 0.40 | 2.10 ± 0.36 | 2.07 ± 0.39 | < 0.001 |
Hemodialysis duration (y) | 2.80 ± 2.52 | 2.92 ± 2.53 | 3.00 ± 2.54 | 3.01 ± 2.59 | 2.87 ± 2.49 | 0.163 |
Presence of RRF | 45 (3.0) | 37 (2.7) | 30 (2.0) | 38 (2.5) | 34 (2.4) | 0.259 |
Hemoglobin (g/dL) | 10.2 ± 1.2 | 10.3 ± 1.5 | 10.4 ± 1.2 | 10.4 ± 1.1 | 10.5 ± 1.2 | < 0.001 |
Hematocrit (%) | 31.2 ± 4.4 | 31.3 ± 3.9 | 31.6 ± 3.7 | 31.4 ± 3.8 | 31.4 ± 4.0 | 0.002 |
Albumin (g/dL) | 3.7 ± 0.7 | 3.8 ± 0.6 | 3.8 ± 0.6 | 3.9 ± 0.5 | 3.9 ± 0.5 | < 0.001 |
Calcium (mg/dL) | 8.72 ± 0.90 | 8.67 ± 0.89 | 8.67 ± 0.86 | 8.67 ± 0.91 | 8.63 ± 0.89 | 0.074 |
Phosphorus (mg/dL) | 4.1 ± 1.5 | 4.6 ± 1.4 | 4.9 ± 1.5 | 5.2 ± 1.7 | 5.5 ± 1.7 | < 0.001 |
Baseline creatinine (mg/dL) | 6.9 ± 3.0 | 7.8 ± 2.8 | 8.6 ± 2.9 | 9.3 ± 3.1 | 9.7 ± 3.6 | < 0.001 |
Uric acid (mg/dL) | 4.9 ± 1.0 | 6.3 ± 0.2 | 7.1 ± 0.2 | 7.9 ± 0.3 | 9.6 ± 1.1 | < 0.001 |
PTH (pg/mL) | 145 ± 155 | 180 ± 184 | 191 ± 213 | 208 ± 226 | 220 ± 203 | < 0.001 |
Cholesterol (mg/dL) | 142.8 ± 42.0 | 145.6 ± 40.5 | 144.6 ± 40.5 | 145.2 ± 39.5 | 144.7 ± 40.7 | 0.417 |
All-cause death | 121 (8.0) | 83 (6.1) | 66 (4.4) | 60 (3.9) | 48 (3.4) | < 0.001 |
Cardiovascular death | 45 (3.0) | 40 (2.9) | 27 (1.8) | 26 (1.7) | 20 (1.4) | < 0.001 |
Values are presented as mean ± standard deviation or number (%).
DBP, diastolic blood pressure; nPCR, normalized protein catabolic rate; PTH, parathyroid hormone; RRF, residual renal function; SBP, systolic blood pressure.
Significant correlations of several variables with serum uric acid level in the study population
Variable | Serum uric acid level | |||
---|---|---|---|---|
| ||||
Unadjusted | Adjusted for age and sex | |||
|
| |||
Age (yr) |
−0.166 | < 0.001 | – | – |
Body mass index (kg/m2) | 0.036 | 0.002 | 0.097 | < 0.001 |
Dialysis time/session (min) | 0.007 | 0.532 | 0.025 | 0.290 |
nPCR (g/kg/day) | 0.069 | 0.001 | 0.069 | 0.004 |
Standard Kt/V | −0.045 | < 0.001 | −0.031 | 0.194 |
Hemodialysis duration (y) | 0.017 | 0.167 | 0.017 | 0.477 |
Hemoglobin (g/dL) | 0.066 | < 0.001 | 0.040 | 0.089 |
Albumin (g/dL) | 0.124 | < 0.001 | 0.146 | < 0.001 |
Calcium (mg/dL) | −0.034 | 0.004 | −0.016 | 0.511 |
Phosphorus (mg/dL) | 0.308 | < 0.001 | 0.252 | < 0.001 |
Baseline creatinine (mg/dL) | 0.300 | < 0.001 | 0.188 | < 0.001 |
PTH (pg/mL) | 0.130 | < 0.001 | 0.084 | < 0.001 |
Cholesterol (mg/dL) | 0.013 | 0.266 | 0.032 | 0.184 |
nPCR, normalized protein catabolic rate; PTH, parathyroid hormone.
For adjusted values, partial correlations were used.
Hazard ratio of all-cause mortality associated with continuous, dichotomous, and quintiles of serum uric acid level in unadjusted and multivariable-adjusted Cox proportional hazards models using multiple imputation
Variable | Non-imputated data | Multiple imputation (pooling) | ||||||
---|---|---|---|---|---|---|---|---|
|
| |||||||
Event | Unadjusted | Multivariable adjusted |
Events | Multivariable adjusted |
||||
All-cause mortality |
378/7,333 (5.2) | 0.786 (0.734–0.841) | < 0.001 | 0.900 (0.834–0.973) | 0.008 | 8,837/42,791 (20.7) | 0.916 (0.855–0.982) | 0.013 |
Binary uric acid level (mg/dL) | ||||||||
B1 (≤ 5.8) | 121/1,501 (8.1) | Reference | Reference | 2,426/10,234 (23.7) | Reference | |||
B2 (> 5.8) | 257/5,822 (4.4) | 0.430 (0.339–0.545) | < 0.001 | 0.662 (0.509–0.859) | 0.002 | 6,411/32,557 (19.7) | 0.662 (0.513–0.854) | 0.002 |
Quintile of uric acid level (mg/dL) | ||||||||
Q1 (≤ 5.8) | 121/1,506 (8.0) | Reference | Reference | 2,426/10,234 (23.7) | Reference | |||
Q2 (5.9–6.6) | 83/1,365 (6.1) | 0.560 (0.406–0.773) | < 0.001 | 0.685 (0.480–0.977) | 0.037 | 1,675/7,789 (21.5) | 0.715 (0.504–1.014) | 0.060 |
Q3 (6.7–7.4) | 66/1,502 (4.4) | 0.447 (0.321–0.622) | < 0.001 | 0.646 (0.451–0.925) | 0.017 | 1,559/7,790 (20.0) | 0.627 (0.440–0.894) | 0.010 |
Q4 (7.5–8.4) | 60/1,528 (3.9) | 0.390 (0.277–0.550) | < 0.001 | 0.667 (0.463–0.961) | 0.030 | 1,559/8,164 (19.1) | 0.661 (0.462–0.945) | 0.023 |
Q5 (≥ 8.5) | 48/1,432 (3.4) | 0.336 (0.230–0.490) | < 0.001 | 0.648 (0.423–0.992) | 0.046 | 1,618/8,814 (18.4) | 0.636 (0.422–0.959) | 0.031 |
Values are presented as number (%) of events or hazard ratio (95% confidence interval).
B, binary; Q, quintile.
Models are adjusted for the factors of age, sex, body mass index, primary renal disease (history of hypertension and diabetes mellitus), systolic blood pressure, diastolic blood pressure, albumin, presence of residual renal function, and standard Kt/V;
Continuous per 1 mg/dL increase in uric acid.
Hazard ratio of cardiovascular mortality associated with continuous, dichotomous, and quintiles of serum uric acid level in unadjusted and multivariable-adjusted Cox proportional hazards models using multiple imputation
Variable | Non-imputated data | Multiple imputation (pooling) | ||||||
---|---|---|---|---|---|---|---|---|
|
| |||||||
Event | Unadjusted | Multivariable adjusted |
Event | Multivariable adjusted |
||||
Cardiovascular mortality |
158/7,333 (2.2) | 0.810 (0.729–0.900) | < 0.001 | 0.901 (0.802–1.012) | 0.078 | 3,231/42,791 (7.6) | 0.903 (0.813–1.003) | 0.057 |
Binary of uric acid level (mg/dL) | ||||||||
B1 (≤ 5.8 ) | 45/1,501 (3.0) | Reference | Reference | 860/10,234 (8.4) | Reference | |||
B2 (> 5.8 ) | 113/5,822 (1.9) | 0.533 (0.365–0.777) | 0.001 | 0.745 (0.498–1.115) | 0.152 | 2,371/32,557 (7.3) | 0.724 (0.491–1.067) | 0.103 |
Quintile of uric acid level (mg/dL) | ||||||||
Q1 (≤ 5.8 ) | 45/1,506 (3.0) | Reference | Reference | 860/10,234 (8.4) | Reference | |||
Q2 (5.9–6.6 ) | 40/1,365 (2.9) | 0.752 (0.463–1.222) | 0.250 | 0.830 (0.489–1.407) | 0.488 | 613/7,789 (7.9) | 0.839 (0.495–1.421) | 0.513 |
Q3 (6.7–7.4 ) | 27/1,502 (1.8) | 0.565 (0.340–0.940) | 0.028 | 0.785 (0.466–1.324) | 0.365 | 574/7,790 (7.4) | 0.738 (0.440–1.240) | 0.251 |
Q4 (7.5–8.4 ) | 26/1,528 (1.7) | 0.453 (0.264–0.777) | 0.004 | 0.697 (0.401–1.213) | 0.202 | 575/8,164 (7.0) | 0.672 (0.388–1.165) | 0.157 |
Q5 (≥ 8.5 ) | 20/1,432 (1.4) | 0.382 (0.211–0.693) | 0.002 | 0.631 (0.328–1.212) | 0.167 | 610/8,814 (6.9) | 0.603 (0.317–1.145) | 0.122 |
Values are presented as number (%) of events or hazard ratio (95% confidence interval).
B, binary; Q, quintile.
Models are adjusted for the factors of age, sex, body mass index, primary renal disease (history of hypertension and diabetes mellitus), systolic blood pressure, diastolic blood pressure, albumin, presence of residual renal function, and standard Kt/V;
Continuous per 1 mg/dL increase in uric acid.