H- 01: HLA system
H-09: Immunology
H- 15: Hypertension and CV complications
Alloimmune Responses and Atherosclerotic Disease After Kidney
Transplantation
Ducloux, Didier1,2,3,4,5,6; Courivaud, Cécile1,2,3,4; Bamoulid, Jamal1,2,3,4; Bisaccia, Vincent4; Roubiou,
Caroline1,2,3,4; Crepin, Thomas1,2,3,4; Gaugler, Béatrice1,2,3,6; Laheurte, Caroline1,2,3,6; Rebibou, JeanMichel1,2,3,7; Chalopin, Jean-Marc1,2,3,4,5; Saas, Philippe1,2,3,5,6
Author Information
1
INSERM, UMR1098, FHU INCREASE (Integrated Centre for Research in Inflammatory
Diseases), LabEX LipSTIC, Besançon, France.
2
Université de Franche-Comté, Besançon, France.
3
SFR FED4234, Besançon, France.
4
Department of Nephrology, Dialysis, and Renal Transplantation, CHU Besançon, Besançon,
France.
5
CHU Besançon, CIC-BT 506, Besançon, France.
6
EFS Bourgogne Franche-Comté, CIC-BT 506, Plateforme de Biomonitoring, Besançon, France.
7
Department of Nephrology, Dialysis, and Renal Transplantation, CHU Dijon, FHU INCREASE,
LabEX LipSTIC, Dijon, France.
.
Correspondence: Didier Ducloux, MD, PhD, Inserm, UMR1098, FHU INCREASE (Integrated
Centre for Research in Inflammatory Diseases), LabEX LipSTIC, F-25030 Besançon, France.
(dducloux@chu-besancon.fr)
Journal : Transplantation
Year : 2015 / Month : January
Volume : 99
Pages : 220 - 225
ABSTRACT
Background
Chronic exposure to exogenous antigens causes accumulation of proinflammatory CD57+CD28−
hyperactivated CD8+ T cells that may promote atherosclerosis. We hypothesized that persistent
alloimmune responses may induce immune activation and contribute to posttransplant
atherosclerosis.
Methods
This hypothesis was tested in a single-center cohort of 577 kidney transplant patients. Propensity
score analysis was performed to address potential confounding variables by indication. Immune
exhaustion was studied in subcohort of 103 patients.
Results
Five hundred seventy-seven consecutive renal transplant recipients were included. Seventy-seven
atherosclerotic events (AE) (12.3%) occurred during a mean follow-up of 7 years. The cumulative
incidence of AE increased with the number of human leukocyte antigen (HLA) mismatches (18%,
10%, and 5% in patients with 5–6, 3–4, and 0–2 mismatches, respectively; P=0.012). Human
leukocyte antigen mismatch number (hazards ratio, 1.35; 95% confidence interval, 1.10–1.66, for
each supplementary mismatch; P=0.005) was an independent risk factor for AE. In the propensity
score match analysis, having received a well-matched kidney conferred a reduced risk of AE
(hazards ratio, 0.22; 95% confidence interval, 0.05–0.95; P=0.044).
We observed a significant correlation between HLA mismatch numbers and circulating
CD57+CD28− CD8+ T cells (R=0.31; P=0.017). These CD8+ T cells were more frequent in patients
with more HLA mismatches (P<0.0001).
Conclusion
Overall, our results suggest that chronic allogeneic stimulation participates to accelerated
atherosclerosis observed after transplantation.
COMMENTS
Atherosclerosis is driven by a chronic inflammatory process within the arterial wall initiated mainly
in response to endogenously modified structures, particularly oxidized lipoproteins that stimulate
both innate and adaptive immune responses, leading to further alteration of the vascular wall and
promoting disease progression and complications.The roles of the immune system in therogenesis
are multiple and complex, but resemble in many ways to those described in other chronic
inflammatory diseases.
Renal transplant recipients (RTR) have disproportionately high rates of atherosclerotic outcomes,
and consistent data suggest that vascular inflammation contributes to the pathogenesis of
atherosclerosis in RTR.
The investigators analyzed the impact of HLA mismatch numbers on atherosclerotic events (AE)
after transplantation.
Five hundred seventy-seven patients were included in this study. Mean follow-up was 7±4.6 years.
Seventy-seven AE (12.3%) occurred during follow-up. This corresponds to 19 AE for 1000 patients
per year. Atherosclerotic events were the following: coronary heart disease: myocardial infarction,
33; coronary revascularization without acute coronary syndrome, 4; cerebrovascular disease:
nonhemorrhagic stroke, 16; symptomatic extracranial artery stenosis resulting in carotid
endarterectomy, 2; abdominal aortic or lower extremity arterial disease: lower extremity
revascularization by means of bypass surgery or angioplasty, 18; lower extremity amputation, 4.
The cumulative incidence of AE was higher in patients with more HLA mismatches (18%, 10%, and
5% in patients with 5–6, 3–4, and 0–2 mismatches, respectively; P=0.012)
The number of mismatches was higher in patients who experienced AE than in those without AE
(4.60±1.04 vs. 4.23±1.17; P=0.010). The difference was mainly because of a higher number of
HLA-A mismatches in patients who developed AE (1.54±0.62 vs. 1.33±0.70; P=0.017). The HLADR mismatches were numerically higher in patients with AE, but the difference did not reach
significance (1.38±0.71 vs. 1.24±0.72; P=0.119). The HLA-B mismatches were not different in
patients with or without AE (1.67±0.53 vs. 1.63±0.54; P=0.633).
The Cox regression analysis revealed that age (hazards ratio [HR], 1.05; 95% confidence interval
[95% CI], 1.02–1.07, for each increase in 1 year; P<0.001), a history of CVE (HR, 3.05; 95% CI,
1.72–5.42; P=0.0001), smoking status (HR, 2.35; 95% CI, 1.39–3.97; P =0.001), underweight (HR,
3.06; 95% CI, 1.42–6.61; P=0.005), ATG use (HR, 1.79; 95% CI, 1.02–3.12; P=0.042), and an
increased number of HLA mismatches (HR, 1.34; 95% CI, 1.09–1.65, for each supplementary
mismatch; P=0.005) were independent risk factors for AE. Hypercholesterolemia was marginally
associated with AE (HR, 1.61; 95% CI, 0.98–2.62; P=0.058) .
The present study suggests that allogeneic immune responses promote atherosclerosis. Indeed,
transplanted patients having received a highly mismatched kidney have an increased risk of AE
compared to those having received a more compatible kidney. More precisely, each
supplementary mismatch carries a 34% increase in the risk of AE. This effect was independent of
other known pretransplant cardiovascular risk factors.The underlying mechanism could be related
to the generation of proinflammatory hyperactivated or exhausted CD8+ T cells in response to
chronic antigenic stimulation.
Pr. Jacques CHANARD
Professor of Nephrology