Metabolic syndrome and concomitant diabetes mellitus are associated with higher risk of cardiovascular comorbidity in patients with primary glomerular diseases: A retrospective observational study

Abstract Background Metabolic syndrome (MS) and diabetes mellitus (DM) are risk factors for cardiovascular diseases in general population. However, there was a paucity of studies investigating their impact in primary glomerular diseases (PGD). Hypothesis MS and concomitant DM are associated with higher risk of cardiovascular comorbidity in PGD. Methods In a retrospective observational design, we analyzed 3622 hospitalized adult PGD patients and compared the prevalence of cardiovascular comorbidity in non‐MS, MS with and without DM. Risk factors for cardiovascular comorbidity were identified using univariate and multivariate logistic regression. Results Among 3622 PGD patients, 308 (8.5%) cases accompanied with MS, including 180 (5.0%) patients with DM and 128 (3.5%) without DM. One hundred and sixty four (4.5%) cases coexisted with cardiovascular comorbidity. Patients with MS and concomitant DM exhibited a higher prevalence of cardiovascular comorbidity than those without MS stratified by estimated glomerular filtration rate and pathological types. Logistic regression showed that MS and concomitant DM (OR: 2.496, 95% CI: 1.600‐3.894, P < .001), older age (OR: 1.060, 95% CI: 1.047‐1.074, P < .001), male (OR: 1.536, 95% CI: 1.072‐2.200, P = .019), higher level of serum ti (OR: 1.002, 95% CI: 1.001‐1.003, P < .001), hyperuricemia (OR: 1.901, 95% CI: 1.327‐2.725, P < .001), idiopathic membranous nephropathy (OR: 2.874, 95% CI: 1.244‐6.640, P < .001) and focal segmental glomerulosclerosis (OR: 2.906, 95% CI: 1.147‐7.358, P < .001) were independently associated with a higher risk for cardiovascular comorbidity. Conclusions In PGD patients, MS and concomitant DM are associated with an increased risk for cardiovascular comorbidity. More evidence for the causal link between MS/DM and cardiovascular outcomes is needed to be clarified.


| INTRODUCTION
Metabolic syndrome (MS) was widely prevalent and characterized by a cluster of cardiovascular risk factors, including impaired glucose metabolism, dyslipidemia and hypertension. Previous meta-analysis had found that MS was associated with a twofold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality in general population. 1 Chronic kidney disease (CKD) was another cardiovascular risk factor, which remained a worldwide public health problem and had dramatically increased. It was estimated that the prevalence of CKD was 8% to 16% 2 in the world and was 10.8% in China. 3 Chronic Kidney Disease Prognosis Consortium had found that estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m 2 and albumin creatine ratio greater than 1.1 mg/mmol (10 mg/g) were independent predictors of all-cause mortality and cardiovascular mortality. 4 Previous epidemiological studies had reported an increased prevalence of MS in CKD, which was associated with higher risk for disease progression . 5 The overall prevalence of MS was 30.5% in stages 4 and 5 CKD patients. 6 MS portends a higher CVD risk in CKD population. Primary glomerular disease (PGD), as one of the leading causes of CKD, was considered to increase cardiovascular comorbidity and mortality, especially in those with lower eGFR. 7 The vast majority of PGD were in early stage of CKD and the prevalence of MS in PGD had not been investigated before. In addition, PGD patients were characterized by glomerular leakage of albuminuria and susceptible to insulin resistance or hyperglycemia, dyslipidemia and hypertension. 8 Therefore, PGD and MS may share some common metabolic characteristics. However, it remained unclear whether MS was independently associated with higher cardiovascular risk in PGD patients.
Diabetes mellitus (DM) was another independent risk factor for cardiovascular disease and was frequently seen in PGD patients.
Among a Chinese CKD cohort study, DM was independently associated with higher prevalence of cardiovascular disease. 9   identified based on reported history and discharge diagnosis. Hypertension was defined as a systolic blood pressure 140 mmHg or more, diastolic blood pressure 90 mmHg or more, or treatment with antihypertensive medicine. Hyperlipidemia was defined as blood triglyceride ≥1.70 mmol/L and/or total cholesterols ≥5.18 mmol/L. Hyperuricemia was defined as a serum uric acid level ≥420 μmol in males or ≥360 μmol in females or based on the use of urate-lowering medications. Anemia was defined as hemoglobin <120 g/L in women and <130 g/L in men. Microscopic hematuria was defined as three or more red blood cells per high-power field on at least two different occasions.

| Statistical analysis
All data were analyzed using SPSS statistical software for Windows, version 23.0 (SPSS, Inc., Chicago, IL). Measurement data with a normal distribution are expressed as the mean ± SD, and differences among groups were compared using one-way ANOVA followed by a Bonferroni post hoc test. The measurement data discordant with a normal distribution are expressed as medians (25th, 75th percentiles), and differences between two groups were compared using the Mann-Whitney U test. Categorical data are expressed as cases (percentages), and differences between groups were compared using the χ 2 test. Logistic regressions were performed to analyze risk factors for cardiovascular comorbidity, and odds ratios (ORs) and 95% confidential intervals (95% CIs) were calculated. The adjusted variables were selected into the multivariate regression model (forward selection stepwise; P < .05 criterion for variable retention) based on the univariate regression analyses. Two-tailed tests were used for all comparisons, and P < .05 was considered to be statistically significant.

| Clinical characteristics of PGD patients with and without cardiovascular comorbidity
The prevalence of cardiovascular comorbidity was 4.5% (164/3622) in PGD. Compared with non-cardiovascular comorbidity, more patients with cardiovascular comorbidity were male and elder, and presented with higher levels of serum creatine, 24 hours proteinuria, uric acid, TG and LDL-C. Additionally, they exhibited lower levels of eGFR, serum albumin and hemoglobin but a higher proportion of hypertension, diabetes, hyperuricemia and hyperlipidemia (Table S1).

| Prevalence of MS and cardiovascular comorbidity stratified by eGFR and pathological types
The pathological composition of 3622 PGD patients are provided in  Figure 1B).
Clinical baseline characteristics of primary glomerular diseases patients with and without metabolic syndrome    20 According to the baseline characteristics in our research, MS was more likely to occur in elder PGD patients and coexisted with higher levels of serum creatine, proteinuria, uric acid and lower levels of eGFR. These findings suggested that MS was associated with severe renal insufficiency and metabolic disorder in PGD.
In addition, age, proteinuria, uric acid, triglyceride, proportion of hypertension, hyperuricemia, and hyperlipidemia were significantly higher in subjects with MS and DM compared to MS alone. Therefore, DM with MS may be a marker of high risk for future cardiovascular events at baseline rather than MS alone.
The other important finding of our study is that patients with MS and DM presented with higher prevalence of cardiovascular comorbidity compared with non-DM stratified by eGFR and pathological types. we did not observe an association between MS without DM and cardiovascular comorbidity after adjustment for other predictors. Several researches had also found that MS without DM was not a predictor for cardiovascular events. 24,25 Although some reviews 1 had concluded that MS was associated with a significantly increased risk of cardiovascular comorbidity, these analyses included many MS patients with concomitant DM and could not determine whether MS represented an independent risk beyond its component factors. 25 In several retrospective and prospective studies, MS had been significantly associated with the development and progression of CKD [26][27][28]  with quantitative proteinuria greater than 1.0 g/24 hours was higher than those with quantitative proteinuria less than 1.0 g/24 hours (2.94% vs 1.45%, χ 2 = 4.110, P = .043). Therefore, for IgAN with massive proteinuria, cardiovascular comorbidity risk still deserves equal attention during follow-up. In addition, although proteinuria was a proved risk factor for cardiovascular diseases, we did not demonstrate it in PGD population.
Distinct quantitative proteinuria and clinical manifestation were found in different pathological types of PGD, which may confound the impact of proteinuria on cardiovascular risks in this study.
Importantly, our study for the first time explored the joint association between MS accompanying DM and cardiovascular comorbidity in large Chinese PGD population. However, our study still had several limitations. Firstly, due to the retrospective nature and the lack of longterm follow-up, we could not explore that the presence of MS and concomitant DM at baseline were risk factor for developing subsequent cardiovascular diseases in PGD. In addition, there were several definitions of MS including world health organization (WHO) and the NCEP adult treatment panel (ATP) III. 35 The definition of MS we applied 10 did not include elevated waist due to lack of waist circumference index, which may underestimate the prevalence of MS in PGD population.

| CONCLUSIONS
In PGD patients, MS and concomitant DM were associated with an increased risk for cardiovascular comorbidity. IMN and FSGS were also independent predictors for higher cardiovascular risk in PGD. The