Impact Of HLA And MICA Antibodies On Renal Transplant Patients

Despite the progress in renal transplantation,acute rejection and graft failurestill occur and chronic rejection continues to be the main problem in long-termallograft survival.Alloantibodies are now appreciated as important mediators of acuteand chronic rejection,differing in pathogenesis from T cell-mediated rejection.Alloantibodies preferentially attack a different"location,"namely the peritubular andglomerular capillaries.In contrast to T cells,which characteristically infiltrate tubulesand arterial endothelium,antibody-mediated rejection generally has a worse prognosisand requires a different form of therapy than the usual T cell-mediated acute rejection.Our aim here was to conduct a systematic study of antibodies against HLA,MICA inpatients who had received a renal transplant within the past 10 years and to evaluatethe effect of these antibodies on graft survival.Furthermore,the current study alsoused clinically-indicated biopsies to investigate the histological changes,theirprognosis and possible association with alloantibodies.First of all,we prospectively examined the sera of 92 patients who had undergonea first-kidney transplantation performed in the past 10 years.All patients werefollowed one year.The average number of months between the sample collection dateand the transplant date was 36.5 months.Testing for anti-HLA and anti-MICAantibodies was performed by Luminex methods,using LABScreen(?) assays.Amongthe 92 patients,58.7% had anti-HLA antibodies,25% had anti-MICA antibodies.Anti-HLA antibodies had no correlation with the anti-MICA antibodies.Femalegender was associated with the presence of anti-HLA class I antibodies and theoverall frequencies of anti- HLA classâ… antibodies was found to increase with time.Patients who used ATG as induction therapy had less frequencies of anti- HLAantibodies.With respect to anti-MICA antibodies,recipient age or gender,immunosuppressive agents,months on dialysis before transplantation,type of dialysisdid not differ between the positive patients and the negative ones.Graft functiondeterioration was associated with anti-HLA classâ…¡antibodies,but not with thepresence of only anti-HLA classâ… antibodies.There was no association between thepresence of antibodies and patient death.Regarding MICA antibodies,patients withMICA antibodies had a more rapid renal deterioration compared to patients withoutMICA antibodies (p=0.016).Graft survival was analyzed by the Cox regression model.The results showed anti-HLA class antibodies had the strongest effect withhazard ratio (HR) of 7.9,and anti-HLA classâ…¡antibodies had a HR of 5.7.MICAantibodies had a HR of 2.04,but the P value was greater than 0.05.In conclusion,thepresence of anti-HLA classâ…¡antibodies conferred a risk for graft loss before adecline in renal function and increased the risk of graft failure.Secondly,we retrospectively investigated the influence of antibodies on differenttransplant patients.We selected all renal transplants patients from 1990 to 2008 whohad a functioning graft for at least 6 months and a clinically indicated graft biopsywith CAN and acute rejection(AR).We studied the presence of anti-HLA antibodiesand anti-MICA antibodies in the last serum taken while the graft was functioning anddivided them into two groups including 23 CAN ones and 35 AR ones.We alsoselected 32 comparable normal cases as control group.The frequencies of anti- HLAantibodies detected in CAN group and AR group were higher compared to normalgroup,but there was no significant difference within the three groups in terms ofMICA antibodies In group AR,patients with anti-HLA antibodies showeddeteriorating renal function compared to negative ones(p=0.011),but MICAantibodies did not show the similar phenomenon.In contrast,patients with anti-HLAantibodies in CAN group did not reveal difference of renal function with negativeones,but we found good association between MICA antibodies and renal dysfunction(p=0.012).Regarding normal group,HLA and MICA antibodies both did not showaggravating influence on transplant kidneys.Lastly,we evaluated the relationship of histomorphology and C4dimmunostaining in indicated renal allograft biopsies with antibodies.52 patients whohad complete medical materials were included.Cryostat-monoclonalantibody-immunofluorescence technique on C4d stains was used.Overall,theprevalence of C4d positivity was 51.9% (27of 52).C4d was found to have correlationwith HLA antibodies,the incidence of HLA antibodies in the C4d-positive cases was89%,compared to 40% in the C4d-negative cases (p=0.003).Although there was nosignificant association between C4d and MICA antibodies,the presence of MICAantibodies was more frequent among the C4d-positive group (33%) than in the C4dnegative group (24%).In this study,we also found associations of histologicalfeatures of AMR with C4d staining and HLA antibodies.Polymorphs in glomeruli (glomerulitis) were more common in the C4d-positive group,transplant arteriopathyand fibrin thrombi in capillaries/vessels were more common in the HLA antibodiespositive group,but we did not found correlation between histological features andMICA antibodies.There was no difference in the changes of renal function betweenC4d-positive and C4d-negative cases,but the patients with C4d positivity andantibodies showed bad outcome,this suggests it is the serologic one rather than theimmunohistologic finding to be a key point of graft survival.