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Fine-Tuning of the Prediction of Mortality in Hemodialysis Patients by Use of Cytokine Proteomic Determination

Stéphanie Badiou^*,, Jean-Paul Cristol^*,, Isabelle Jaussent^,, Nathalie Terrier^*,, Marion Morena^*,, François Maurice, Hélène Leray-Moragues^,||, Jean-Pierre Rivory, Lofti Chalabi, Cécile Delcourt^¶, Bernard Canaud^,||, and Anne-Marie Dupuy^*,

^* CHU Montpellier, Laboratoire de Biochimie, Hôpital Lapeyronie, Université Montpellier I, INSERM, U888, Centre d'Hémodialyse Languedoc Méditerranée, and ^|| CHU Montpellier, Service de Néphrologie, Dialyse et Soins Intensifs, Montpellier, and ^¶ INSERM, U593, and Université Victor Segalen Bordeaux 2, Bordeaux, France

Correspondence: Prof. Jean-Paul Cristol, Biochemistry Laboratory, Lapeyronie University Hospital, 371 Avenue Doyen Gaston Giraud, F34295 Montpellier Cedex 5, France. Phone: 33-0-467-338-314; Fax: 33-0-467-338-393; E-mail: jp-cristol{at}chu-montpellier.fr

Background and objectives: Inflammation-induced atherosclerosis and enhanced susceptibility to infection are linked to immune dysfunction and account for an important part of mortality in hemodialysis patients. This 4-yr prospective study aimed to use cytokine proteomic determination for predicting cardiovascular and noncardiovascular mortality in hemodialysis patients.

Design, setting, participants, & measurements: Levels of 12 cytokines were measured using a proteomic biochip system in 134 patients who were on stable hemodialysis and compared with a control group of 150 healthy volunteers. Cox proportional hazards regression analysis was used to determine the relationship between cytokine and clinical outcome.

Results: A proinflammatory state characterized by decreased anti-/proinflammatory cytokine ratio was evidenced in hemodialysis patients compared with control subjects. After adjustment for age, gender, smoking, and high-sensitivity C-reactive protein levels, IL-6 and (IL-4+IL-10)/IL-6 ratio were associated with a significant and specific enhanced hazard ratio of cardiovascular mortality (hazard ratio 11.32 [95% confidence interval 2.52 to 50.90; P < 0.01] and hazard ratio 3.14 [95% confidence interval 1.20 to 8.22; P < 0.05], respectively, when comparing the third and first tertiles). It is interesting that (IL-4+IL-6+IL-10)/(IL-2+IFN-) ratio, used as a marker of lymphocytes T helper subsets cytokine secretion, was associated only with noncardiovascular mortality (hazard ratio 4.93; 95% confidence interval 1.03 to 23.65; P < 0.05).

Conclusion: Beyond the strong prediction of cardiovascular mortality by IL-6, determination of cytokine ratios can be useful to identify hemodialysis patients with increased noncardiovascular mortality risk.