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CCR5 Deletion Protects Against Inflammation-Associated Mortality in Dialysis Patients

Friso L.H. Muntinghe^*, Marion Verduijn, Mike W. Zuurman^*, Diana C. Grootendorst, Juan Jesus Carrero, Abdul Rashid Qureshi, Karin Luttropp, Louise Nordfors, Bengt Lindholm, Vincent Brandenburg, Martin Schalling, Peter Stenvinkel, Elisabeth W. Boeschoten^||, Raymond T. Krediet^¶, Gerjan Navis^* and Friedo W. Dekker

^* University Medical Center Groningen, Internal Medicine, Nephrology, Groningen, The Netherlands; Leiden University Medical Center, Clinical Epidemiology, Leiden, The Netherlands; Karolinska Institutet, University Hospital at Huddinge, Department of Renal Medicine, Institution of Molecular Medicine, Stockholm, Sweden; University Hospital Aachen, Department of Nephrology, Aachen, Germany; ^|| Hans Mak Institute, Naarden, The Netherlands; ^¶ Academic Medical Center, Nephrology, Amsterdam, The Netherlands

Correspondence: Friso L.H. Muntinghe, University Medical Center Groningen, Department of Internal Medicine, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, The Netherlands. Phone: 31-50-3616161; Fax: 31-50-3619069; E-mail: f.l.h.muntinghe{at}int.umcg.nl

Received for publication April 28, 2008. Accepted for publication February 21, 2009.

The CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR532) leads to deficiency of the receptor. We hypothesized that CCR532 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP 10 mg/L (n = 225), those carrying the deletion allele with hsCRP 10 mg/L (n = 55) had similar mortality, and those carrying the wild-type genotype with hsCRP > 10 mg/L (n = 108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP > 10 mg/L (n = 25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR532 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673