Serum leptin level and incidence of CKD: a longitudinal study of adult enrolled in the Korean genome and epidemiology study(KoGES)

The Korean Genome and Epidemiology Study (KoGES) is a population-based prospective cohort in South Korea which is conducted in the Korean general population by the Korea National Institute of Health (KNIH). The participants have been followed-up every 2 years. The health check-up and measurements of biomarkers are carried out at each visit to identify risk factors for the development of chronic disease (e.g., hypertension, diabetes, osteoporosis, and cardiovascular disease), diet profile, lifestyle (e.g., alcohol intake, smoking, and exercise) and diverse environmental factors. The study was based on data Korean Genome and Epidemiology Study on the Atherosclerosis Risk of Rural Areas in the Korean General Population (KoGES-ARIRANG), part of the KoGES which included participants from 40–70 years of age who resided in the Wonju and Pyengchang areas of the Republic of Korea. In this study, 6,444 Korean adults aged 40–69 years were recruited from two Korean cities (Wonju and Pyeongchang), and were followed up biennially over a 7-year period [11‐13]. The study was conducted in accordance with the Declaration of Helsinki. Informed written consent was obtained from all participants. Demographic information was collected at the baseline and follow-up examination using a standard questionnaire that was administered during face-to-face interviews. The study was approved by the institutional review board of Yonsei University Wonju College of Medicine (IRB No. 2020–02-0018).

We used data from KoGES-ARIRANG to assess the incidence and risk factors of chronic kidney disease as per serum leptin level. Adults aged 40–70 years from the rural areas of Wonju and Pyeongchang were enrolled where demographic shifts are infrequent and high long-term follow up rates are expected. All study participants which did not done the first follow-up survey were first excluded. And individuals whose leptin levels were not evaluated at baseline, and whose GFR was less than 60 mL/min/1.73m² also excluded.

The endpoint was the development of CKD at the follow-up visit, defined based on the National Kidney Foundation KDOQI definition for chronic kidney disease (eGFR of < 60 mL/min/1.73m2). eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation (eGFR = 186 × [serum Cr]-1.154 × [age]—0.203 × [0.742 if women]) which is known to be more accurate than other Equation [14].

The data were expressed as means, medians, and frequencies. A t-test or Mann–Whitney U test was conducted to compare continuous variables. Meanwhile, the chi-square test was performed to compare categorical variables. All analyses were performed separately according to sex. Analysis of variance was performed to check the differences in the variables between the three groups. Multivariate logistic regression analysis was used to assess independent associations with incident CKD as the dependent variable in tertiles of leptin values. The potential confounder included age and baseline eGFR. No imputation was used for missing values as any subject with missing leptin and eGFR at baseline and follow-up were excluded during participant selection. The tertile cut-off points were 1.69 and 2.91 ng/mL for men (n = 1,039) and 6.08 and 9.89 ng/mL for women (n = 1,409). Results were expressed as odds ratios (ORs) along with their corresponding 95% confidence intervals (CIs). Age-adjusted ORs were first calculated (model 1), and the results were further adjusted for baseline eGFR (model 2). The results were further adjusted for age and baseline eGFR as continuous variables (model 3).

The baseline survey, carried out from November 2005 to February 2012, included 6,444 adults (2,563 men and 3,881 women) aged 40—70 years. All study participants were invited to the first follow-up survey (May 2008 to October 2017) and 4,859 (75.4%) attended. We excluded 2,051 individuals whose leptin levels were not evaluated at baseline, and 162 whose GFR was less than 60 mL/min/1.73m². A total of 2,646 individuals were included in the final analysis (1100 men and 1546 women) (Fig. 1).

Table 1 shows the clinical and biochemical features of the study cohort. The mean age of the study population was 56.20 (standard deviation[SD]: 8.04) years for men and 54.14 (SD 8.18) years for women. The mean eGFR were 78.38 ± 10.81 mL/min/1.73m² and 74.55 ± 8.86 mL/min/1.73m² in men and women, respectively. The average BMI were 24.33 kg/m² in men and 24.88 kg/m² in women. The median leptin level in women (9.04 ng/mL, SD 2.04) was significantly higher than that in men (2.74 ng/mL, SD 5.64)(P < 0.001).

The patients’ characteristics were divided in to three groups based on tertiles of leptin values; since leptin values differ according to sex, analysis were performed separately. (Table 2) For all populations, age, hypertension history, smoking history, BMI, fasting glucose levels, waist circumference, LDL-cholesterol levels, and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), baseline eGFR were different among the groups. In the male population, significant differences were observed in history of diabetes mellitus, history of dyslipidemia, systolic and diastolic blood pressure history of diabetes mellitus, history of hypertension, HbA1c and triglyceride levels, in addition to the aforementioned variables. In the female population, significant differences were observed in history of dyslipidemia, BMI, waist circumference, systolic and diastolic blood pressure, LDL-cholesterol levels, triglyceride levels, HOMA-IR, and hs-CRP level.

In the multivariate logistic regression models, individuals in the highest serum leptin tertile showed significant associations with CKD risk after adjustment compared with those in the lowest tertiles in the population. The odds ratio for trend was 1.15(P = 0.394) (Table 3). More pronounced tendency was observed in men. The odds ratio for trend was 3.19 after adjusting for age in men and statistical significance was noted (P = 0.002). Model 2 showed same tendency after adjusting eGFR. (OR for trend = 2.13, P > 0.049) Analyses after additionally adjusting for age and eGFR showed correlation with statistical significance between serum leptin and CKD risk (OR for trend = 2.25, P = 0.037). The same trends were also observed in women but no statistical significance was found.