Date Published: June 6, 2019
Publisher: Public Library of Science
Author(s): Naoki Sugano, Yukio Maruyama, Satoshi Kidoguchi, Iwao Ohno, Atsushi Wada, Takashi Shigematsu, Ikuto Masakane, Takashi Yokoo, Tatsuo Shimosawa.
Whether higher serum uric acid (UA) values comprise a risk factor for death and whether treatment for high UA is effective in patients undergoing hemodialysis (HD) are essentially unknown. To determine associations between UA and all-cause or cardiovascular (CV) mortality, interactions between UA or medication and effects on mortality, and significance of treatment for hyperuricemia in patients undergoing hemodialysis (HD). We collected the baseline data of 222,434 patients undergoing three HD sessions per week, extracted from a nationwide dialysis registry at the end of 2011 in Japan. Then we evaluated the interaction between serum uric acid level and all-cause and cardiovascular (CV) mortality by the end of 2012. Univariate and multivariate logistic regression and Cox regression analyses found higher all-cause and CV mortality rates among patients with lower, than higher UA values. Hazard ratios (HR) for all-cause and CV mortality were significantly lower in a group with, than without medication for hyperuricemia (HR, 0.837; 95% confidence interval (CI), 0.789–0.889 and HR, 0.830; 95%CI 0.758–0.909, respectively). Lower UA values remained associated with all-cause and CV mortality rates even when in patients taking medication for hyperuricemia. The chief interacting factors for higher mortality rates due to lower UA were higher BMI and diabetes mellitus. In conclusion, lower UA levels were independently associated with higher all-cause and CV mortality among Japanese patients undergoing HD. Intervention for hyperuricemia is considered to improve patient outcomes.
High serum uric acid (UA) values confer risk for gout and kidney damage and comprise a risk factor for cardiovascular (CV) events [1–6] among patients with normal renal function. Although a major antioxidant, UA is involved in hypertension, obesity, kidney and CV diseases, all of which are associated with oxidative stress [7–9]. Several studies have uncovered associations between UA values and all-cause and CV mortality among patients with chronic kidney disease (CKD) who do not undergo dialysis. Higher UA values are associated with higher all-cause and CV mortality rates among patients with stage 3 or 4 CKD . Furthermore, recent studies have associated lower UA values with higher all-cause and CV mortality among patients on hemodialysis (HD) [11–13]. Therefore, relationships between UA values and all-cause and CV mortality seem quite different depending on whether or not patients undergo dialysis. However, these investigations included relatively small numbers of patients. Therefore, the relationship between UA values and all-cause or CV mortality remains uncertain for patients with CKD, especially those undergoing dialysis. Moreover, whether therapy for hyperuricemia is useful for patients with end-stage kidney disease (ESKD) is also uncertain. The Dialysis Outcomes and Practice Patterns Study (DOPPS) associated higher all-cause or CV mortality with lower UA values, but these findings did not change in a model that included medication with allopurinol .
Table 1 shows the baseline characteristics of the 222,434 patients included in this study who underwent three HD sessions per week (mean age, 67 ± 12 years; male, 63.0%; median dialysis duration, 65 months). The underlying pathologies comprised chronic glomerulonephritis (CGN) in 75,974 (34.2%), diabetic nephropathy in 83,736 (37.6%), nephrosclerosis in 17,787 (8.0%), polycystic kidney disease (PKD) in 7,743 (3.5%), and others or unknown in 37,192 (16.7%). The numbers of patients with a history of acute myocardial infarction, cerebral bleeding, cerebral infarction, amputation of an extremity, and gout attacks were 7.8%, 4.9%, 15.3%, 3.0% and 3.3%, respectively. Values among males and females for uric acid were 7.3 ± 1.4 and 7.2 ± 1.4 mg/dL, respectively, and 22.7 ± 4.1 and 21.8 ± 4.5, respectively, for BMI. These values were significantly higher in males than in females (P<0.0001). On the other hand, females were significantly older and had been on dialysis significantly longer than males (age, 68 ± 13 vs. 66 ± 12 y; HD duration, 72 (32–138) vs. 60 (26–118) months). Of the 222,434 patients, 18,775 (8.4%) died within one year (male, 11,941 [8.5%]; female, 6,834 [8.3%]), including 8,094 (3.6%) of CV causes (male, 5,004 [3.6%]; female, 3,090 [3.8%]). We found that lower UA values conferred higher risk for all-cause and CV mortality among patients on HD. Hyperuricemia is a risk factor for developing CKD in normal healthy persons . Patients with reduced renal function have high risk of all-cause and CV mortality . Diabetes mellitus and hypertension frequently cause ESKD, and hyperuricemia is associated with a high incidence of these two conditions . However, the present findings suggested that lower UA is associated with increased risk of all-cause and CV mortality. Even after adjustment for several factors, lower UA remained involved in higher risk of all-cause and CV mortality among males and females. However, Cox regression analyses showed that the effects of UA on mortality were obviously reduced. Uric acid values comprise a surrogate marker of nutritional status, and are associated with inflammation and muscle status . Moreover, the results of stratified analyses for serum albumin, also a surrogate marker of inflammation, were similar to those before stratification. Beberashvili et al. , and the DOPPS study  also found lower UA values in patients on HD; therefore the present results support the previous findings. These studies also noted that lower UA suggests malnutrition and low protein intake. Mortality rates are high for patients on ESKD who also have malnutrition-inflammation-atherosclerosis (MIA) syndrome . Therefore, the present findings suggest that lower UA values represent lower nutritional status and increased mortality. Moreover, the present study included far more patients than previous studies, therefore the data are highly credible. However, some residual confounding factors of nutrition might exist. Source: http://doi.org/10.1371/journal.pone.0217859