The chemokine receptor 5 Delta32 mutation is associated with increased renal survival in patients with IgA nephropathy.
BACKGROUND
Chemokine receptor 5 (CCR5) plays an important role in the recruitment of monocytes and T cells in inflammation and experimental studies suggest that CCR5 might be involved in the pathogenesis of IgA nephropathy. A mutation in the CCR5 gene (CCR5 Delta32), leading to a nonfunctional receptor, was recently described. We therefore evaluated the potential role of this mutation on renal survival in patients with IgA nephropathy.


METHODS
The distribution of the CCR5 Delta32 genotype was determined by polymerase chain reaction (PCR) analysis in 228 patients with biopsy-proven IgA nephropathy. In 190 patients with available demographic and clinical follow-up data, the effect of the mutation on the clinical outcome was analyzed using the Log-rank test and the Cox proportional hazard model. In vitro, the influence of the CCR5 Delta32 genotype on the chemotactic response of monocytes was assessed.


RESULTS
Of the 190 patients, 158 (83.2%) had a CCR5 wild-type genotype, 29 (15.3%) were heterozygous, and three patients had a homozygous CCR5 Delta32 genotype (1.6%). Renal survival was significantly longer in patients with the CCR5 Delta32 genotype than in the wild-type group (Log-rank P < 0.001). Using the multivariate Cox proportional hazard model, the CCR5 Delta32 genotype was identified as an independent factor associated with a lower risk to develop end-stage renal disease (ESRD) [hazard ratio (HR) 0.23, 95% CI 0.09 to 0.57, P= 0.002]. In vitro analysis of monocytes from CCR5 Delta32 carriers showed a reduced chemotactic response to CCR5 ligands in vitro.


CONCLUSIONS
Our study demonstrates an independent role of the CCR5 Delta32 genotype for the clinical outcome in IgA nephropathy. In vitro experiments revealed a reduced chemotactic response of monocytes from CCR5 Delta32 carriers, thus pointing out a possible pathophysiologic explanation for the beneficial effect of the CCR5 Delta32 genotype.
Panzer
Ulf
U
Medizinische Klinik IV, Universitätsklinikum Hamburg Eppendorf, Germany.
Schneider
André
A
Steinmetz
Oliver M
OM
Wenzel
Ulrich
U
Barth
Petra
P
Reinking
Rüdiger
R
Becker
Jan U
JU
Harendza
Sigrid
S
Zahner
Gunther
G
Fischereder
Michael
M
Krämer
Bernhard K
BK
Krämer
Bernhard H
BH
Schlöndorff
Detlef
D
Ostendorf
Tammo
T
Floege
Jürgen
J
Helmchen
Udo
U
Stahl
Rolf A K
RA
D000483:Alleles; D001483:Base Sequence; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D005922:Glomerulonephritis, IGA / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000517:prevention & control; D008024:Ligands; D009000:Monocytes / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics*; D012307:Risk Factors; D017384:Sequence Deletion
D008024:Ligands; D019713:Receptors, CCR5; D004247:DNA