Preliminary observations on the association between serum IL-6 and hydration status and cardiovascular risk in patients treated with peritoneal dialysis
Introduction
Cardiovascular disease remains the commonest cause of death for patients on peritoneal dialysis (PD). In addition to traditional cardiovascular risk factors that affect the general population, PD patients are exposed to risks related to the underlying kidney disease and the dialysis procedure itself [1]. Inflammation, invariably present in PD patients, is thought to confer increased cardiovascular risk through its contribution to atherosclerosis, endothelial dysfunction and malnutrition [2]. Inflammation in PD occurs both in the systemic and intraperitoneal compartments, being a result of uraemia, co-morbidities, and peritonitis. While systemic and intraperitoneal inflammation appears to be independent entities, it has been hypothesized that the membrane compartment can add to the systemic response by spilling inflammatory cytokines into the circulation [3]. In this respect, it has been demonstrated that intraperitoneal concentrations of interleukin-6 (IL-6) are higher than those in the systemic compartment [4]. Nevertheless, the recent large multi-centre Global Fluid study has shown that this is systemic inflammation, as defined by elevated plasma IL-6, that is a strong independent predictor of patient survival [4]. This finding is in keeping with the previously reported relationship between genetic polymorphisms associated with high IL-6 production and an increased mortality risk [5]. It also strongly supports the existence of a long-postulated link between IL-6 and mortality [6].
The meta-analysis of 10 studies in haemodialysis and PD patients has suggested that elevated IL-6 may be associated with increased mortality from cardiovascular causes [7]. The balANZ study addressed the issue specifically in the PD population and demonstrated for the first time that systemic IL-6 was indeed a significant independent predictor of cardiovascular events in incident PD patients [8].
Introduction of bioimpedance analysis (BIA) has made it possible to assess fluid status in PD patients more accurately [9]. Large cross-sectional studies have revealed that BIA-determined overhydration is common in PD patients and associated with loss of residual renal function, malnutrition, and inflammation [10], [11]. Importantly, increasing evidence suggests that overhydration predicts both all-cause and cardiovascular mortality [12]. The assessment of hydration status in PD patients may be further aided by the measurement of biochemical markers of plasma volume and cardiac function [9].
In the present study we wished to explore whether there exists a particular “phenotype” associated with high serum IL-6 that characterizes PD patients in terms of their fluid status and cardiac parameters.
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Patients
This was an investigator-initiated cross-sectional study. Prevalent patients undergoing PD in 3 regional dialysis centres between 2011 and 2014 were assessed for eligibility. Inclusion criteria were (i) age ⩾ 18 years, (ii) time on PD ⩾ 3 months, (iii) informed consent. Patients with (I) any acute inflammatory disease within 12 weeks prior to enrolment, (II) amputated limbs, (III) cardiac pacemakers or implantable cardioverter defibrillators were excluded. Eventually, 57 patients of the Caucasian
Patient characteristics according to serum IL-6
Serum IL-6 concentrations in the group of patients studied ranged from 0.39 to 2.34 pg/ml (median value 0.94 pg/ml, coefficient of variation 49%). They were correlated across the population with selected parameters (Fig. 1). In addition, patients were divided into tertiles according to their IL-6 levels and analyzed in detail (Table 1). Thus, patients with high serum IL-6 were older, more often diabetic, and treated with PD for longer. They did not differ in residual urine output, peritoneal
Discussion
The main observation of the present study is that high systemic IL-6 identifies a PD patient phenotype that is associated with increased cardiovascular risk. This increased burden is likely to be related to overhydration, the magnitude of which (as assessed by BIA) correlates significantly with serum IL-6. Given a cross-sectional observational design of the study, one may only speculate on the nature of the association between IL-6 and overhydration. Elevated systemic IL-6 typically reflects
Conclusions
Taken together, our data indicate that the measurement of systemic IL-6 may contribute to the more accurate assessment of cardiovascular risk in PD patients. In this respect, it has recently been demonstrated that even in patients with early stages of chronic kidney disease, high serum IL-6 is associated with both past and future cardiovascular events [34]. There are some obvious limitations of the present study. They include a cross-sectional design, the relatively small sample size and
Conflict of interest
No conflict of interest has been declared by the authors.
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