This national population-based study supported a direct association between SUA and the development of CKD, with no mediating effect of dyslipidemia, hypertension or hyperglycemia. The potential mechanisms for the direct effect of SUA are as follows. First, RAS would be activated by high-level SUA,26 thereby increasing the glomerular pressure and generating direct fibrogenic effect on renal cells which could lead to kidney disease.27 Second, an animal study indicated SUA could stimulate the proliferation of VSMC by uric acid-mediated COX-2 dependent pathway, thereby inducing preglomerular vasculopathy, vascular injury and renal dysfunction.28 Third, SUA probably had a direct effect on renal tubular cells through the induction of phenotypic transition of cultured renal tubular cells (i.e., epithelial-to-mesenchymal transition, EMT),29 and EMT is an important contributor to the pathogenesis of renal fibrosis.30 Fourh, SUA may also induce CKD via the decrease of NO production and induction of oxidative stress.28
As hypertension, hyperglycemia and dyslipidemia are risk factors of CKD16 and also related to high-level SUA,7 it is possible that the association between SUA and CKD could be explained by the mediating effect of these cardiometabolic risk factors. However, the result of the mediation analysis indicated that there was no mediating effect of hypertension, hyperglycemia or dyslipidemia on the association between SUA and CKD. The possible explanations are as follows. First, although high-level SUA could increase the risk of hypertension, hyperglycemia and dyslipidemia, the strong direct damage effect of SUA on CKD may be more potent than the effect of hypertension, hyperglycemia or dyslipidemia on renal function in the initial stage of CKD. Also, the sample size in our study can ensure us to exclude the contribution of each mediator to the indirect effect, which only made up less than 5% of the total effect. Second, the marker of early renal damage from hyperglycemia and hypertension is microalbuminuria,31,32 and only with disease progressing, high-level blood pressure and high-level blood glucose could cause obvious damage to eGFR. The study period in our study was only five years; therefore, the effect of hypertension or hyperglycemia on the decline of eGFR may be weak in the initial stage of CKD.
The significant relationship between SUA and the development of hyperglycemia observed in this study was consistent with previous studies.14,33,34 The positive association between SUA and hyperglycemia can be explained by nitric oxide reduction induced by hyperuricemia.35 The decrease of nitric oxide lowers insulin-stimulated glucose intake in skeletal muscle and prompts insulin resistance,36 thereby leading to hyperglycemia. The association between SUA and the development of dyslipidemia found in this study was also consistent with some previous studies.7,34 However, other studies indicated that there was no relationship between SUA and the development of dyslipidemia.37,38 Therefore, the role of SUA in the pathogenesis of dyslipidemia is still controversial and future work in this regard is warranted.
We also observed the positive relationships between SBP, DBP or blood glucose and eGFR. This phenomenon could be explained by glomerular hyperfiltration in initial stage of hypertension and hyperglycemia,13,39,40 since the glomerular hyperfiltration in those with hyperglycemia and hypertension may be caused by improper vasodilation of afferent arteriole39 and increased glomerular hydraulic pressure, respectively.41 It was noticeable that there was a significant negative dose-response relationship between HDL-C and eGFR. One study suggested that lower HDL-C was related to higher eGFR in individuals without kidney disease.42 One explanation is that individuals with high-level HDL-C may also have high-level TC and high-level LDL-C which are also negatively associated with eGFR as observed in our study and other previous studies.43,44 Therefore, HDL-C may not have a protective effect on kidney function. However, another study reported that HDL-C was critical for the protection against renal dysfunction.45 Also, it was found that high-level HDL-C was not related to reduced mortality risk in individuals with kidney dysfunction.46 These conflicting results probably indicated that the effect of HDL-C could be heterogeneous; therefore, the mechanisms of how HDL-C influence the development of CKD remains unclear.
This longitudinal study utilized the nationally representative data to explore whether SUA has a direct effect on the development of CKD among Chinese middle-aged and older population. But this study still has limitations. First, no data on albuminuria were included, which is an important factor for the definition of CKD. However, the definition of CKD using eGFR < 60 mL/min per 1.73 m2 is well-accepted and acknowledged in population-based studies.47,48 Second, in CHARLS, the identification of hyperglycemia and hypertension depended on not only the data from blood test and physical examination, but also self-reported physician diagnosis. But according to previous validation studies, the self-reports of common chronic diseases were accurate and well-accepted.49,50 In addition, many published high-quality studies based on CHARLS also used such self-reported physician diagnosis, which confirmed the reliability and accurancy of the data.