The Study on Serum Urate acid Target for Retarding Renal function to Worse in Diabetes

Background: It’s unclear the exact level of serum urate acid (SUA) which can prevent renal function worse although all internists has been known the target of blood glucose, blood pressure and lipid in diabetes. It’s time to aim for a reasonable SUA target to prevent renal failure in diabetes.. Methods: Using the physical examination results of 3427 diabetic patients in Jiangchuan Community, Shanghai, China, the relationship between SUA and estimated glomerular filtration rate (eGFR) decline was analyzed, and the appropriate cut-off point for SUA to predict eGFR decline was determined. Meanwhile, the population attributable risk proportion (PARP) of eGFR decline in diabetic patients above this SUA cut-off point was calculated. Results: eGFR decreased accompany with the increased SUA level and was negatively associated with the level of SUA significantly. After adjusting for potential confounders, SUA also was an independent risk factor of eGFR decline. The best appropriate SUA point, predicting eGFR decline obtained by ROC curve, was 326.5μmol/L which may prevent from eGFR decline in 33% male patients and 355.5μmol/L which may prevent from eGFR decline in 18% female patients. Compared with SUA>326.5μmol/L male and SUA>355.5μmol/L female group respectively, the relative risk of eGFR decline in SUA≤326.5μmol/L male and SUA≤355.5μmol/L female group is decreased significantly. Conclusions: SUA is an impotant risk factor for eGFR decline in diabetes. 326.5μmol/L in male and 355.5μmol/L in female may be used as the reasonable SUA target to retard renal function to worse in Chinese diabetes. Questionnaire, physical examination and laboratory measurements were completed by professionals. Name, age, gender and history of hypertension were included in the questionnaire. Meanwhile, height, weight, waist circumference, hip circumference and blood pressure of the patients were measured as physical examination. Blood routine, fasting blood sugar (FBG), glycosylated hemoglobin A1c (HbA1c), blood lipids, serum creatinine and urate acid were detected using blood of diabetic patients fasted for 8 hours while urine albumin-to-creatinine ratio (UACR) was detected using urine in the morning.


Background
Impaired renal function, often deteriorating continuously and resulting to end-stage renal disease, is the common chronic complication in diabetes. Diabetic kidney disease (DKD) has become the main cause in patients requiring renal replacement therapy [1,2]. It's important to look for controllable risk factors to take appropriate measures to inhibit diabetic renal function to worse. 3 Previous study has shown that serum urate acid (SUA) is an independent risk factor for renal function damage in new-onset kidney disease [3,4]. However, it is still unknown the SUA concentration target for initiating or continuing treatment to retard renal function to worse and prevent end-stage renal disease in diabetes while all internists know the target of blood sugar, glycosylated hemoglobin A1c (HbA1c) and blood lipid in diabetes [5,6,7]. Therefore, an appropriate target concentration for SUA to prevent renal function worse, assessed by estimated glomerular filtration rate (eGFR), was investigated on the base of the relationship between SUA and eGFR, estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, in diabetic patients via the physical examination data of 3427 diabetic patients in Jiangchuan Community, Shanghai, China, from October 2011 to September 2014. It will help initiate or continue to lower SUA concentration therapy to retard the renal function decline in Chinese diabetes.

Study population
The physical examination is free provided by government in diabetic patient residing in Jiangchuan Community, Minhang District, Shanghai City. From October 2011 to September 2014, 3427 diabetic patients, including 1475 males and 1952 females, with complete information and signed informed consent were included in our study. 4

Research methods
Questionnaire, physical examination and laboratory measurements were completed by professionals. Name, age, gender and history of hypertension were included in the questionnaire. Meanwhile, height, weight, waist circumference, hip circumference and blood pressure of the patients were measured as physical examination. Blood routine, fasting blood sugar (FBG), glycosylated hemoglobin A1c (HbA1c), blood lipids, serum creatinine and urate acid were detected using blood of diabetic patients fasted for 8 hours while urine albumin-to-creatinine ratio (UACR) was detected using urine in the morning.

Statistical analysis
All data were analysed by SPSS version 22. The categorical variables were expressed as composition ratio (%).The difference between groups was performed by Chi-square test. The Linear correlation was performed by Pearson correlation analysis.
The risk factor analysis was performed by unconditional binary logistic regression.
The receiver operating characteristic curve (ROC) analysis was used to determine the appropriate cut-off point of SUA as a reference indicator for indicating eGFR decline.

Analysis of the linear correlation between SUA and eGFR
The results from Pearson correlation analysis show that SUA was positively correlated with age, TG and Leukocyte, but negatively correlated with e GFR, FBG, HDL-C and HbA1c (Table 2). Furthermore, SUA was most closely associated with eGFR (male r=-0.377; female r=-0.419). The results suggested a linear negative correlation between SUA and eGFR significantly.  Table 3). The results suggested that SUA is an independent risk factor for eGFR decline in both male and female patients.

Discussion
Diabetes, a chronic systemic metabolic disease characterized by long-term hyperglycemia, leads to glomerular filtration rate (GFR) decline via continuous impairment of renal function and has been the main cause in end stage renal disease (ERSD) [8]. The GFR decline still hasn't been inhibited though the treatment has been actively used in controlling risk factors such as blood sugar, blood pressure, blood lipid and the renin-angiotensin system [9][10][11][12].
Previous studies have shown that hyperuricemia is an independent risk factor for renal dysfunction [13]. But it's still unknown the SUA target concentration to prevent renal function worse although all internists has been known the target of blood glucose, blood pressure and lipid in diabetes. It's time to aim for a reasonable serum urate target to retard renal function to worse in diabetes.
Therefore, the physical examination data from diabetic patients in Jiangchuan community, Shanghai City, China, were used to find out the SUA reasonable target on 14 the base of the relationship between SUA and eGFR in this study. It is the first time to elaborate the appropriate SUA target for treatment to retard eGFR decline in Chinese diabetic patients.
The results from this study showed that the overall prevalence of eGFR decline in the patients with diabetes was 38.97%, including 46.51% for men and 34.17% for women. These results show that the SUA was an independent risk factor for eGFR decline and negative linear correlated with eGFR in diabetic patients. Higher urate acid is associated with lower eGFR in Chinese diabetes. It supports that we should find out the reasonable SUA target for treatment to protect the renal function in diabetes.
Initial threshold of treatment for reducing urate acid remains controversial in asymptomatic CKD patients with hyperuricemia [18,19]. Moreover, the appropriate target level of SUA to prevent renal function worse in diabetic patients is still unknown. Therefore, we further explored the appropriate cut-off point of SUA on the 16 base of the relationship between SUA and eGFR via ROC curve according to male and female patients respectively. The eGF R decline was predicted by different SUA cut-off points. SUA cut-off point 326.5μmol/L in male and 355.5μ mol/L in female were corresponded to the shortest distance of the ROC curves respectively. It indicated that the cut-off points of SUA had the greatest significance for predicting eGFR decline in male and female patients respectively. Therefore, SUA 326.5μmol/L in male and 355.5μmol/L in female may be used as the SUA target.
In addition, a large proportion of menopausal female patients over 65 years in which lower estrogen levels reduced SUA excretion [20] may be the reason why the SUA target level in female is higher than that in male.
Furthermore, the percentage of the population attributable risk proportion (PARP) at SUA 326.5μmol/L in male and 355.5μmol/L in female was calculated. The results show that 33.799% of eGFR decline could be inhibited after the level of SUA was under 326.5μmol/L in male while 18.943% of eGFR decline could be prevented after SUA below 355.5μ mol/L in female. Subsequently, using 326.5μmol/L in male and 355.5μmol/L in female as SUA target, the relative risk of eGFR decline in SUA≤326.5μmol/L in male and SUA≤355.5μmol/L in female group was decreased significantly. It supported to use SUA≤326.5μmol/L in male and SUA≤355.5μmol/L in female as the SUA target which could protect renal function significantly in diabetes. Intervention treatment should to be considered for inhibiting renal function 17 decline if the level of SUA is higher than 326.5μmol/L in male and 355.5μ mol/L in female diabetic patient.

Conclusions
Our study show that there is a significant negative linear correlation between the levels of SUA and eGFR, and SUA is an independent risk factor for eGFR decline in