In the present study, the prevalence of the metabolic syndrome and its components, measured individually or in combination, was analysed in a comprehensive cohort of haemodialysed patients in Alsace. The analysis also assessed whether the metabolic syndrome or various combinations of its components were associated with cardiovascular history and comorbidities, as compared with BMI and diabetes.
Our multicentre study in 753 patients comprised a representative proportion of the regional haemodialysis population (75%). Of note, half of the non-included patients were excluded because WC measurements were deemed unfeasible due to the inability to stand up. To our knowledge, the present patient population represents the largest studied cohort of patients treated on maintenance haemodialysis and dealing with MetS.
Irrespective of the criteria used, a high prevalence of MetS was observed, present in more than half of the patients. Abdominal obesity (increased waist circumference) was also prevalent, particularly in women. These data reflect the exceedingly high prevalence of diabetes and obesity in the general Alsatian population, which also explains diabetic nephropathy as the leading cause of end-stage renal failure in this region (30).
As expected, the relationships between obesity, diabetes, metabolic syndrome and high WC were strong. The metabolic syndrome is a complex entity involving several criteria for its definition, which has evolved over time. The present study used the criteria from the latest 2009 classification (HMetS 2009), which appear better suited to haemodialysis patients (15).
In our population, however, not all criteria had the same positive predictive value (PPV), as high WC, hypo-HDLaemia and hypertriglyceridaemia were identified as the most specific. Unsurprisingly, an increased waist circumference, a marker of abdominal adiposity, was the single most potent factor associated with the metabolic syndrome in our cohort. In contrast, the “high blood pressure” criteria was less specific, likely because hypertension could result from a number of other causes in this dialysis population, including arterial stiffness and volume overload.
In this cross-sectional study, more than 50% of the patients exhibited at least one cardiovascular comorbidity, confirming the high burden of cardiovascular comorbidities in this population. However, in the present haemodialysis cohort, metabolic syndrome was strongly and independently associated with major cardiovascular events (coronary artery disease, peripheral arteriopathy, stroke or congestive heart failure), with this association persisting after adjustment for other cardiovascular risk factors, including diabetes and BMI. This association was even more robust with certain specific complications, namely coronary heart disease and congestive heart failure.
The strength of this association may, however, have been underestimated due to the cross-sectional nature of the analysis. Indeed, patients with MetS, who faced a higher risk, could have died prematurely after starting haemodialysis. Also, most of the patients in whom measurement of WC was impossible were more likely to be arteriopathic amputees or post-stroke hemiplegics.
As expected, diabetes was strongly associated with MACE in our cohort. In the general population, the relationship between diabetes and metabolic syndrome is strong (31). In our cohort, however, the harmful effect of the metabolic syndrome persisted after adjustment for diabetes, demonstrating an independent prognostic impact. An analysis excluding diabetics further confirmed a significant association between the metabolic syndrome and MACE, confirming previous reports in the general population (32). Nevertheless, in the subgroup analysis studying diabetic patients, there was no significant association between metabolic syndrome and MACE. A study with more power would probably prove a statistical link between MS and MACE in diabetic patients. In contrast, neither WC alone nor BMI were associated with cardiovascular history in multivariate analysis, thereby corroborating the data observed for BMI in the general population.
More surprisingly, statin treatment was associated with a 2.7-fold higher risk of cardiovascular complications. In our study, 60% of the patients were on statin treatment, including a majority of patients with MetS. Unlike LDL-cholesterol, both HDL-cholesterol and triglycerides were ostensibly relatively uninfluenced by the statin treatment. Although randomised trials have failed to find any apparent benefits of statins in dialysis patients, a direct deleterious effect of statin is seemingly unlikely, this paradox likely reflecting an indication bias, since statins are prescribed preferentially in individuals at high risk or with a history of cardiovascular complications.
When analysing the cardiovascular events individually, the association with metabolic syndrome was significant for coronary heart disease and congestive heart failure but not for peripheral arteriopathy or stroke.
There are sparse data in the literature on the metabolic syndrome in dialysis patients, with data applicable to European populations being particularly scarce. Moreover, studies have yielded conflicting results. A prospective Tunisian study in 200 haemodialysis patients found an association between the metabolic syndrome and cardiovascular events (18). Another Iranian retrospective study conducted in 300 haemodialysis patients showed an increased risk of coronary heart disease associated with the metabolic syndrome (19). In contrast, the prospective study of Tsangalis et al. in 102 patients in Greece did not find an association between metabolic syndrome and MACE (20). These authors suggested a survival bias in explaining these results since patients with metabolic syndrome could have been the first to die before inclusion in the study. In a prospective Chinese study, 157 patients exhibited no association between metabolic syndrome, CVD, and mortality (21). In these two last studies, MetS was associated with a better nutritional status, a possible confounding factor. Of note, we did not find any difference in serum albumin levels in patients with or without the metabolic syndrome.
Components and simplified MetS
The current definition of the metabolic syndrome is somewhat complex as it involves parameters requiring a strictly fasting measurement (blood glucose, HDL-cholesterol, triglycerides) or potentially associated with high variability (blood pressure). This may hinder the evaluation of MetS and raises the question of whether a simple measurement of waist circumference could provide similar prognostic information.
In the present study, we found no significant association between high waist circumference (MsWC) and history of MACE, after adjustment for diabetes and BMI. These results are inconsistent with those of a prospective Italian study of the CREDIT registry (Calabria Registry of Dialysis and Transplantation) (16), which analysed the effect of waist circumference on global and cardiovascular mortality in 537 haemodialysis patients. In this south-Italian cohort, the prevalence of obesity and MsWC was much lower (12% and 39% respectively) comparatively to the present cohort. While BMI was inversely correlated with mortality, the increase in WC was directly associated with an increased risk of overall and cardiovascular death. Moreover, after adjusting for other risk factors, a 10 cm higher WC was found to increase overall mortality and cardiovascular mortality by 26% and 38%, respectively. Among all the other risk factors (cardiovascular history, age, duration of dialysis, haemoglobin, CRP), only the presence of diabetes increased the risk of overall (OR 2.73) and cardiovascular (OR 2.88) mortality. Unfortunately, this Italian study did not investigate the prognostic value of the full-blown metabolic syndrome on cardiovascular mortality.
In Japan, an association between directly CT-measured abdominal adiposity and cardiovascular disease, including stroke and coronary artery disease was observed in a small cohort of haemodialysis patients (17-26).
These findings, however, have not been consistent. In Taiwan, another prospective study in 91 patients found more cardiovascular events associated with the metabolic syndrome and increased WC (28), but no association with mortality (22). These authors also found that abdominal obesity was correlated with PAD, independently of other factors related to MetS and inflammation (23).
BMI is a global parameter that does not dissociate abdominal adiposity (visceral white fat), which has harmful metabolic effects, from muscle mass and brown fat which, conversely, are protective factors (5, 33). However, WC does not differentiate visceral adiposity which is more strongly associated with the risk of diabetes (34, 35), dyslipidaemia (36), hypertension (37) and CV complications (5, 38), from subcutaneous adiposity, which is potentially more metabolically benign. Visceral obesity can be better quantified using CT scans of L4-L5 (5, 24, 25, 39), although this technique is poorly suitable for epidemiological studies. Some authors have proposed the concept of "hypertriglyceridaemic waist", associating a high waist circumference and an increase in serum triglycerides. This syndrome has even been found more strongly correlated with visceral obesity (5, 35) and cardiovascular diseases (40).
In the dialysis population, hypertension is prominent, although its association with cardiovascular morbidity and mortality remains controversial (41). Since hypertension results from multiple mechanisms in haemodialysis patients (42), its integration into the definition of the metabolic syndrome is hence debatable.
Furthermore, our findings show that the combinations of MsWC + MsTG or MsWC + MsTG + MsHDL were those most significantly associated with cardiovascular complications. Indeed, the addition of a 4th or 5th parameter (either blood glucose or high blood pressure) did not yield any additional prognostic information. Our results thus support the use of the "hypertriglyceridaemic waist" as a marker of cardiovascular risk in haemodialysis patients.
Finally, only MetS and low serum albumin were associated with heart failure in multivariate analysis. In haemodialysis patients, low serum albumin is frequent and strongly associated with both cardiac and overall mortality (43-45). Nevertheless, the significance of low serum albumin is multiple, including malnutrition but also chronic inflammation (IL6-dependent liver synthesis), as well as haemodilution related to volume overload.
The strengths of the study include the relatively large homogeneous cohort, representative of a contemporary European population. We also used a harmonised coding system nested in the regional REIN registry. Finally, the WC measurement was standardised across all participating centres.
Some limitations of the study should bear in mind. Although the cohort was representative, nearly 25% of the patients were excluded from the analysis, some of whom could have provided valuable information. Collection of MACE was performed retrospectively at the time of initiation of maintenance dialysis and inclusion in the REIN registry, and yearly thereafter. On the other hand, chart history during pre-dialysis follow-up was available in a vast majority of patients. Finally, this study was cross-sectional with the inherent limitations due to surviving bias, and statistical associations cannot be ascertained as being causative.