In the present study, we for the first time observed that elevated LAP was positively associated with the risk of prevalent CKD, defined by declined eGFR and/or the presence of albuminuria, in Chinese community adults, and the association between LAP and CKD weakened but retained significance after controlling for confounding factors. Furthermore, stratified analysis revealed that participants with higher LAP were more likely to have increased risk of prevalent CKD than those with lower LAP, especially in women, in subjects who were older, overweight, those with hypertension, NGT, normal PP, LDL-C <3.4 mmol/L, and those without CVD events, no smoking and drinking. Therefore, early prevention and intervention are vital for CKD, and modification of the abnormal fat distribution may contribute to reduced risk of CKD and associated unfavorable health outcomes, especially in women, older subjects, and people with overweight and hypertension.
Accumulating evidence indicates that obesity and CKD have increased in parallel worldwide and are positively correlated [12], and obesity, especially visceral obesity, is an important risk factor for CKD [3, 5, 6, 7]. Visceral obesity has been reported to be associated with IR, dyslipidemia, nonalcoholic fatty liver disease, metabolic syndrome, hyperuricemia, diabetes, hypertension, and CVD events [5, 6, 8, 9], all of which are involved in the pathogenesis of CKD [3, 4, 10]. Direct measurement of visceral adipose tissue by imaging techniques, i.e. computed tomography (CT) and magnetic resonance imaging (MRI) that are considered the gold standards, is not practicable in the routine clinical practice because these imaging techniques are inaccessible, time‐consuming, costly, and radioactive [7]; therefore, surrogate indices have received increasing attention for the assessment of visceral fat distribution. LAP, an emerging surrogate marker, has been suggested as an inexpensive and highly accessible index to assess the visceral adiposity distribution and reflect visceral adiposity dysfunction [9, 10]. Despite the lack of studies evaluating the association between LAP and CKD, defined by declined eGFR and/or the presence of albuminuria, there are several reports regarding the relationship between LAP and eGFR, with conflicting findings [9, 11, 12, 13]. A cross‐sectional study of 4947 Korean subjects aged ≥20 years conducted by Seong et al. showed that the prevalence of declined eGFR was positively associated with the quartiles of LAP in all participants, and the positive association of prevalence of declined eGFR and LAP quartiles was observed only in men but not women, after adjusting for related variables [9]. In another study of 11,192 individuals aged ≥35 years, Dai et al. reported that LAP were significantly associated with CKD, defined by only declined eGFR, in the rural population of northeast China, and LAP can predict CKD only in women [12]. Similarly, data from an observational study from SPECT-China, which included 10,012 subjects aged ≥18 years in East China, demonstrated that LAP strongly associated with eGFR level and declined renal function and could be one of markers for predicting the risk of renal dysfunction [11]. These results are basically consistent with our study showing that participants with CKD, declined eGFR and albuminuria had significantly higher LAP compared to those with non-CKD, declined eGFR and non-albuminuria, respectively. Moreover, we observed that elevated LAP was positively associated with the risk of prevalent CKD, and the association between LAP and CKD weakened but retained significance after controlling for confounding factors. In contrast, results from a prospective study in Iran, consisted of 6693 individuals aged ≥18 years with a mean 8.65 years of follow-up, reported that there was no statistically significant association between the quartiles of LAP and incidence of declined eGFR [13]. The discrepancies between the above mentioned studies may be due to the differences in population characteristics, races, regions, dietary habits, sample size, statistical methods, and confounding factors adjusted in the analyses. More studies are needed before conclusions can be drawn.
Notably, we found that female participants with higher LAP were more likely to have increased risk of prevalent CKD than those with lower LAP, but no statistically significant association between LAP quartiles and prevalence of CKD after adjustment for confounding factors in men, which was consistent with previous studies [12], suggesting significant gender difference in the relationship of LAP and CKD. The mechanisms underlying the gender-specific difference are unclear. We speculate that this may be due to differences in sex hormones, the distribution of fat, and lifestyles in men and women. In our study, only participants aged ≥40 years with a mean age of 58 years were included, of whom the majority of women were postmenopausal. It is well known that estrogens could regulate adipose deposition and function [9], and estrogen exerts renoprotective effects [22]. Therefore, postmenopausal females tended to deposit more abdominal visceral adipose tissue and lost estrogen renal protection partly due to the rapid decline in estrogens [5, 9]. On the other hand, males tended to be physically active and consumed more tea, especially green tea, both of which may make males have a lower distribution of abdominal fat compared to females of the same ages who were less active and consumed less tea [23, 24, 25]. It is recognized that abdominal visceral adipose tissue as a metabolically active endocrine organ is a source of various bioactive adipocytokines and inflammatory proteins such as adiponectin, visfatin, omentin-1, leptin, resistin, IL-6, tumor necrosis factor-α, CRP, and plasminogen activator inhibitor-1 [26, 27]. A growing number of studies have shown that altered cytokines levels are closely linked with change in renal hemodynamics, renal vascular damage, glomerular sclerosis, renal fibrosis, proteinuria, reduced eGFR, and CKD [6, 28, 29]. Age is an important factor for determining the prevalence of CKD, and eGFR decreased steadily as age increased [9]. In general, age is also a crucial cause of CKD-inducing diseases such as diabetes, hypertension, dyslipidemia, and hyperuricemia. In the present study, we observed a positive association between the quartiles of LAP and prevalence of CKD in subjects aged ≥60 years, and no statistically significant association in subjects aged <60 years, which was similar to a previous study [22], suggesting that age over 60 years is a strong risk factor for CKD. We also found that age, BMI, and WC were positively correlated with the prevalence of CKD in univariate analysis, and the association between the quartiles of LAP and CKD was attenuated after adjusting for gender and age in Model 2, while the association increased after further adjustment for BMI in Model 3, indicating that the risk of prevalent CKD may increase in women and subjects aged ≥60 years, and older age and women may be two stronger factors than obesity for CKD. Thus, it is of great importance to early screen for CKD among women and subjects aged ≥60 years, and such populations should monitor the LAP early, make lifestyle changes and take necessary treatment.
Emerging epidemiologic studies suggested that hypertension commonly complicates CKD, and hypertension was a leading cause of incidence, prevalence, and progression of CKD [1, 3, 4, 22], which might lead to deleterious metabolic and cardiovascular consequences [3, 10]. Whether LAP is an effective maker for CKD that could be applied in the Chinese hypertensive population remains unknown. Previous studies showed that obesity is closely associated with CKD in the hypertensive population from different countries [30-33]. Lea et al. showed that metabolic syndrome associated with abdominal obesity is associated with proteinuria in hypertensive African Americans [30]. Results from the renal sub-study of the China Stroke Primary Prevention Trial (CSPPT) in China, a prospective cohort study of 12 672 hypertensive patients with over a median follow-up of 4.4 years, reported that higher BMI was significantly associated with an increased risk of CKD development in hypertensive patients with normal kidney function [31]. Similar results have been obtained from another two recent cross-sectional studies of hypertensive patients [32, 33]. Our study provided further evidence that supported the potential role of hypertension in the development of CKD, since we found that patients with CKD had significantly higher SBP and DBP, while SBP and DBP were positively correlated with the prevalence of CKD in univariate analysis. Moreover, the association between LAP quartiles and CKD was attenuated after further adjusting for blood pressure in Model 5, suggesting that hypertensive may increase the risk of prevalent CKD. Further, a stratified population study showed that participants with higher quartiles of LAP had significantly increased risk of prevalent CKD in people with hypertension, however, no correlation was found between LAP quartiles and increased risk of prevalent CKD, which also indicated that hypertension plays an important role in the development of CKD. Thus, not only modification of visceral fat distribution but also the early identification and management of established risk factors in such people are of great importance to reduce the additive risk of CKD.
Many cross‐sectional and prospective studies have reported significant relationships between CKD, CVD events, diabetes, dyslipidaemia and arterial stiffness [3, 4, 19, 34], which might partially explain the association between LAP and CKD in our study. It is recognized that LDL-C is causally associated with a high risk of coronary artery disease, and high LDL-C was observationally and genetically associated with high risk of CKD in the general population [35]. There is mounting evidence that elevated PP, a surrogate measure of arterial stiffness, was demonstrated to be a well-known predictor of CVD events, such as CHD, stroke and heart failure, and cardiovascular mortality [20, 36], and also reported to be associated with increased risk of albuminuria [19] either in general or hypertensive populations. In general, patients with CKD had high prevalence of CVD, and progressive CVD and progressive declined kidney function do have a number of common risk factors [37], including hypertension and diabetes, which were the main causes of CKD. Our study provided further evidence that supported the potential role of CVD events, diabetes, dyslipidaemia and arterial stiffness in the development of CKD, since we found that patients with CKD had significantly higher CVD events and its components, including MI, CHD and PAD, blood glucose parameters (FBG, PBG, and HbA1c), prevalence of T2DM, users of hypoglycemic drugs, blood lipids parameters (TG, TG, and lower HDL-C), and PP. Moreover, the prevalence of CKD was positively correlated with prevalence of CVD and T2DM, users of hypoglycemic drugs, TG, TG, and PP, and negatively with HDL-C in univariate analysis. Further, the association between LAP and CKD was attenuated gradually but retained significance after further adjusting for prevalence of T2DM and CVD events, hypoglycemic drugs, LDL-C, and PP and in Model 4 and Model 5, suggesting that CVD events, diabetes, dyslipidaemia and arterial stiffness may increase the risk of prevalent CKD. Unexpectedly, stratified populations study showed that significant associations between higher LAP quartiles and CKD were detected only in people who had NGT, LDL-C < 3.4 mmol/L, normal PP, and those without CVD events, however, no correlations were found between LAP quartiles and CKD in participants with prediabetes, T2DM, LDL-C ≥ 4.1 mmol/L, high pulse pressure, and CVD events. The possible reason of lacking significant associations between LAP and CKD in participants with prediabetes and T2DM, at least in part, might be due to the populations of prediabetes and T2DM may be aware of the importance of glycemic control and the improvement of fat distribution, therefore, possibly had better compliance with medical orders and more physical activities, and kept a more healthy diet habit, all of which contributed to the favorable effect of CKD. Additionally, in participants with CVD events, LDL-C ≥ 4.1 mmol/L, and high pulse pressure, no associations were also found between LAP and CKD, which may be due to that the small case numbers and large 95% Cls in certain subgroups led to the not available data or imprecise estimation. Further research in larger population is needed to verify our speculation.
Our study has several potential limitations that merit comment. First, the cross-sectional design of the current study precluded conclusions on the temporal relationship of LAP with elevated risk of CKD. Thus, further large-scale prospective studies are needed to determine the role of LAP in the early identification of CKD in Chinese adults with different characteristics. Second, imaging techniques, such as CT and MRI, are considered the gold standards for determining the extent of visceral fat area, but these imaging techniques are inaccessible, time‐consuming, costly, and radioactive, and therefore are not suitable for large-scale epidemiological investigations. Instead, increasing evidence suggests that LAP is considered as a useful clinical indicator of visceral adiposity distribution and could reflect visceral adiposity dysfunction due to its inexpensiveness, accessibility and reliability. Third, despite we excluded subjects who used ACEI/ARB and lipid-lowering drugs, and after adjusting for hypoglycemic drugs in the current analysis, there is still the possibility that other medications may partially affect the association of LAP with CKD. Fourth, our study population included only middle-aged and elderly subjects in five communities of Luzhou city, located in South China, and therefore our findings may not be generalizable to participants of different ages, North China population, and other ethnic populations. More studies are needed to confirm this relationship of LAP with CKD in such populations. Fifth, although many traditional risk factors were adjusted, residual confounding variables and unmeasured factors, such as dietary factors, cannot be excluded from the current study, which may affect the exact association of LAP with CKD. Despite these limitations, the current study is not without strengths, including a large sample size, use of a standardized method at a single center, and a comprehensive adjustment for major traditional risk factors, and represented middle-aged and elderly population from different communities across Luzhou, which can raise the reliability of our findings. Moreover, our study, to our knowledge, provides first clinical evidence on a potential link between LAP and CKD, defined by declined eGFR and/or the presence of albuminuria, in Chinese community adults.