Cardiology Research and Practice 1 l iav0.9 v r u s e e f-r0.8 t n e v e VD0.7 C 0.6 CKD−/MetS− CKD+/MetS− CKD−/MetS+ CKD+/MetS+ 0 500 1000 1500 Time (days) 2000 2500 Figure 1: Kaplan-Meier plots showing cumulative CVD event- free survival in participants in four groups divided by presence or absence of CKD and presence or absence of MetS (log-rank test for trend X2 = 114; P < 0.001); CKD: chronic kidney disease; MetS: metabolic syndrome; CVD: cardiovascular disease. three measures of additive interaction between CKD and MetS, there is 2.73 relative excess risk due to the additive interaction, the risk of CVD in individuals who had been exposed to both risk factors (CKD and MetS) is 2.49 times higher than the sum of risks in individuals exposed to a single risk factor alone, and 49% of the incident CVD in individuals exposed to both risk factors is attributable to the additive interaction. 4. Discussion In this ethnically diverse population of 5,163 individuals, aged 44–84, both chronic kidney disease and metabolic syndrome are independent predictors of incident cardio- vascular events. This study identiﬁed a signiﬁcant positive relationship between the cooccurrence of CKD and MetS and risk for CVD events. In a multivariate model, the hazard for incident cardiovascular events was increased due to presence of signiﬁcant additive interaction between CKD and MetS. However, no multiplicative interaction between CKD and MetS was demonstrated. Additionally, the presence of both CKD and MetS conferred a signiﬁcantly higher hazard compared to the presence of each condition separately. From the viewpoint of prevention and clinical practice, additive interaction is more important than multiplicative interaction, as it relates to a higher absolute excess of cases. Deﬁned by cystatin C, CKD [7, 29] has been shown to predict cardiovascular events and mortality in several studies. Ix et al. [7] studied 990 participants in the Heart and Soul Study and demonstrated that compared to participants in the lowest cystatin C quartile, those in the highest quartile (those with CKD) were at increased risk of cardiovascular events (HR, 2.0; 95% CI, 1.0–3.8). Similarly, Deo et al. [29] studied 3,044 older adults ages from 70 to 79 over 6 years in the Health ABC cohort and found that those with CKD had signiﬁcantly higher risk for cardiovascular death (HR, 2.24; 95% CI, 1.30–3.86) compared to those without CKD. This P-value 0.2 0.02 5 Table 3: Estimates of multiplicative and additive interaction (95% conﬁdence interval, CI) controlling for covariates. Parameters Estimate β3 RERI AP SI 0.48 2.73 0.49 2.49 CKD × MetS 95% CI −0.23, 1.28 0.57, 4.85 0.24, 0.74 1.24, 4.98 CKD: chronic kidney disease; MetS: metabolic syndrome; β3: parameter estimate of CKD × MetS testing for multiplicative interaction; RERI: relative excess risk due to additive interaction; AP: attributable portion; SI: synergy index are measures testing for additive interaction. is similar to our ﬁndings where participants with CKD, as deﬁned by eGFRcysC ≤ 60 mL/min/1.73 m2 were at increased risk for CVD events (HR, 2.02, 95% CI, 1.43–2.79) in a multivariate analysis. However, when the CKD only group was compared to participants with no CKD and no MetS, the hazard for CVD events was statistically insigniﬁcant, which is a reﬂection of low statistical power (Table 2). Similarly, MetS has been shown to predict CVD events and mortality [11]. A meta-analysis involving 43 cohorts consisting of 172,573 individuals showed that MetS had a relative risk of cardiovascular events and death of 1.78 (95% CI, 1.58–2.00). In our study, presence of MetS was an independent predictor of CVD events, and when the MetS only group was compared to the group with no CKD/no MetS, the hazard for CVD events remained statistically signiﬁcant (Table 2). Multiple studies [2–4] document the associations between CKD and MetS, and now mechanisms have been postulated that link the two conditions to each other. Recent ﬁndings, suggesting vitamin D being a modulator of both insulin resistance and the renin-angiotensin system [15] and the renin-angiotensin system in local pancreatic islet structure and function [16], suggest that perhaps renal dysfunction and MetS may share common pathological pathways. Clinically, it is seen that individuals with CKD have abnormalities in serum lipid concentrations and distribution (elevated triglycerides and lower high-density lipoprotein), diabetes mellitus, and hypertension [2, 12, 13] which are also part of the MetS construct. Additionally, it has been proposed that the presence of both conditions leads to increased inﬂammation and oxidative stress, increased total peripheral resistance, and impaired left ventricular relaxation which increases the risk for CVD events [30]. This interplay of risk factors and pathological mechanisms implies that perhaps the cooccurrence of CKD and MetS identiﬁes a group of individuals at higher risk for cardiovascular events. A few studies [30, 31] document the role of these two conditions together as it relates to CVD events. Martin et al. [31] studied 13,115 individuals aged ≥35 years from the NHANES III survey and found that the coclustering of CKD and MetS led to a signiﬁcantly higher hazard for CVD mortality (HR, 3.23; 95% CI, 2.56–3.70) when compared with individuals with no CKD and no MetS. Similarly, Iwashima et al. [30] studied 1,160 essential hypertensive