Early acute rejection does not affect chronic allograft nephropathy and death censored graft failure

BACKGROUND: Even with the development of modern immunosuppression, an acute rejection episode is a major complication after renal transplantation. Acute rejection episodes have been used as clinical indicators for chronic allograft nephropathy and graft loss. We investigated the timing and frequency of acute rejection episodes in relation to long-term graft survival and chronic allograft nephropathy. METHODS: The Long Term Efficacy and Safety Surveillance study of transplant patients receiving cyclosporin (Neoral) included 1706 adult renal transplants (1995 to 2003) with a functioning graft for at least 1 year. The impact on death-censored long-term graft survival was evaluated for acute rejection episodes (single or multiple) within 3 months, at 3 to 6 months, at 6 to 12 months, or at over 1 year posttransplant. A stepwise binary logistic regression was employed to identify independent risk factors for the time to occurrence of an acute rejection episode. RESULTS: An acute rejection episode occurring within 3 months posttransplantation had no effect on either death-censored long-term graft failure (P=.2157) or chronic allograft nephropathy (P=.9331). However, an acute rejection episode occurring at 1 year or later posttransplantation was significantly associated with death censored long-term graft failure (P <.0001) and chronic allograft nephropathy (P <.0001). The numbers of HLA-DR mismatches and younger recipient ages were independent risk factors for early acute rejection. CONCLUSION: Among patients whose graft survives at least 12 months, an early acute rejection episode within 3 months posttransplant was not associated with either death-censored long-term graft survival or chronic allograft nephropathy among adults treated with cyclosporin. However, an acute rejection episode occurring at 1 year or later posttransplantation showed a positive association with death-censored long-term graft survival or chronic allograft nephropathy. Lower numbers of HLA-DR mismatches sum to reduce the occurrence of acute rejection and the hospitalization time.     

The impact of repeated subclinical acute rejection on the progression of chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is due to both immunologic and non-immunologic factors and results in the development of nonspecific pathologic features that may even be present in long-term well-functioning renal allografts. To investigate the natural history of CAN and potential risk factors associated with progression of these histologic lesions, this study evaluated the of histologic alterations of 124 sequential protocol biopsies performed at 2, 3, and 5 yr after transplantation in 46 patients who exhibited histologic evidence of CAN in the 1-yr biopsy. The occurrence of late acute rejection (AR) greater than 4 mo posttransplant was significantly associated with the development of histologic CAN. In contrast, early clinical AR occurring within 3 mo had no impact on the subsequent development of CAN at 1 yr. Subclinical AR was evident in association with CAN in 50%, 32%, 19%, and 16% of cases with CAN at 1, 2, 3, and 5 yr, respectively. These acute lesions correlated significantly with histologic progression defined as an increased CADI score of the follow-up biopsies. Furthermore, a group of patients who exhibited repeated subclinical AR in the sequential follow-up biopsies had a lower creatinine clearance at 5 yr after transplantation and worse long-term graft survival. In contrast, the absence of evidence of acute inflammation in association with CAN at any time point was associated with minimal deterioration in renal function or progression of renal lesions during the observation period. These results suggest that the persistence of chronic active inflammation may be responsible for the histologic progression of CAN.     

Donor catecholamine use reduces acute allograft rejection and improves graft survival after cadaveric renal transplantation.

BACKGROUND: Epidemiological data implicate that renal transplants from living unrelated donors result in superior survival rates as compared with cadaveric grafts, despite a higher degree of human lymphocyte antigen (HLA) mismatching. We undertook a center-based case control study to identify donor-specific determinants affecting early outcome in cadaveric transplantation. METHODS: The study database consisted of 152 consecutive cadaveric renal transplants performed at our center between June 1989 and September 1998. Of these, 24 patients received a retransplant. Donor kidneys were allocated on the basis of prospective HLA matching according to the Eurotransplant rules of organ sharing. Immunosuppressive therapy consisted of a cyclosporine-based triple-drug regimen. In 67 recipients, at least one acute rejection episode occurred during the first month after transplantation. They were taken as cases, and the remaining 85 patients were the controls. Stepwise logistic regression was done on donor-specific explanatory variables obtained from standardized Eurotransplant Necrokidney reports. In a secondary evaluation, the impact on graft survival in long-term follow-up was further measured by applying a Cox regression model. The mean follow-up of all transplant recipients was 3.8 years (SD 2.7 years). RESULTS: Donor age [odds ratio (OR) 1.05; 95% CI, 1.02 to 1.08], traumatic brain injury as cause of death (OR 2.75; 95% CI, 1.16 to 6. 52), and mismatch on HLA-DR (OR 3.0; 95% CI, 1.47 to 6.12) were associated with an increased risk of acute rejection, whereas donor use of dopamine (OR 0.22; 95% CI, 0.09 to 0.51) and/or noradrenaline (OR 0.24; 95% CI, 0.10 to 0.60) independently resulted in a significant beneficial effect. In the multivariate Cox regression analysis, both donor treatment with dopamine (HR 0.44; 95% CI, 0.22 to 0.84) and noradrenaline (HR 0.30; 95% CI, 0.10 to 0.87) remained a significant predictor of superior graft survival in long-term follow-up. CONCLUSIONS: Our data strongly suggest that the use of catecholamines in postmortal organ donors during intensive care results in immunomodulating effects and improves graft survival in long-term follow-up. These findings may at least partially be explained by down-regulating effects of adrenergic substances on the expression of adhesion molecules (VCAM, E-selectin) in the vessel walls of the graft.     

Influence of hypercholesterolemia and acute graft rejection on chronic nephropathy development in renal transplant recipients

Graft endothelial lesions resulting from acute rejection may be sustained by concomitant hypercholesterolemia, thus increasing the risk of chronic graft failure. The present study was undertaken to examine the influence of hypercholesterolemia and acute graft rejection (AGR) episodes on graft function and graft loss due to chronic nephropathy. A cohort of 336 patients transplanted between 1993 and 2000 having graft function at 12 months after transplantation were examined. Immunosuppressive therapy consisted of CsA, azathioprine, and corticosteroids in 90% with 10% of patients receiving mycophenolate mofetil in place of azathioprine. During the first year after transplantation, AGR occurred in 134 (39.8%) and hypercholesterolemia (6.2 mmol/L) in 132 (39.2%) of patients. The population was divided into four groups according to AGR occurrence and cholesterol concentrations during the first year after transplantation for analysis of serum creatinine concentrations and graft loss at 5 years of follow-up. Patients with AGR irrespective of cholesterol levels displayed significantly higher creatinine concentrations. Graft loss in these patients increased over twofold compared to the remaining groups. Patients without hypercholesterolemia and AGR showed normal creatinine concentrations and low graft loss rates during 5 years of follow-up.     

The influence of acute rejection on long-term renal allograft survival: a comparison of living and cadaveric donor transplantation

BACKGROUND: We investigated whether recipients of living donor grafts who suffer an acute rejection progress to graft loss because of chronic rejection at a slower rate than recipients of cadaveric grafts. METHODS: A retrospective review was made of 296 renal transplantations performed at Mount Sinai Hospital. Only grafts functioning for at least 3 months were included in this analysis. Demographic variables of donor and recipient age, race, sex, and serum creatinine at 3 months after transplantation were compared between groups. RESULTS: Among the acute rejection-free cohort, the estimated 5-year graft survival was 90% for those receiving transplants from living relatives and 88% for those receiving cadaveric transplants (P=0.76). However, in grafts with early acute rejection, the 5-year survival was 40% for cadaveric recipients compared with 73% for living related graft recipients (P<0.014). Using the proportional hazards model, cadaveric donor source, older donor age, African American recipient race, and elevated 3-month serum creatinine were independent predictors of long-term graft loss caused by chronic rejection. The severity of acute rejection and recipient age had no impact on the risk of graft loss because of chronic rejection. CONCLUSION: These data indicate that the benefit of living related transplantation results from the fact that a living related graft progresses from acute to chronic rejection at a slower rate than a cadaveric graft. Furthermore, a cadaveric graft that is free of acute rejection 3 months after transplantation has an equal likelihood of functioning at 5 years as that of a graft from a living related donor.     

供者年龄与肾移植慢性排斥反应关系的实验研究

目的 探讨供者的年龄对大鼠同种异体肾移植慢性排斥反应的影响。方法 分别采用3、12、18个月龄的F－344大鼠肾移植给6个月大小的LEW受鼠,以自体肾移植作为对照组,术后检测各组的肾功能和免疫组化的改变,并进行移植肾的组织学观察。结果 18个月龄供肾移植组术后24h尿蛋白含量、移植肾肾小球硬化程度及纤维化程度均较3个月龄及12个月龄组严重,差异有显著性（P＜0.01）;18个月龄的供肾移植组移植肾组织中ED1^＋单核／巨噬细胞、CD4^＋T淋巴细胞及CD8^ 细胞毒性／抑制性T淋巴细胞明显高于3个月龄供肾组,差异有显著性（P＜0.01）。结论 供者的年龄越大,术后移植肾的肾小球硬化及间质纤维化就出现越早,且越严重。     

Cytokine gene polymorphisms and acute human liver graft rejection

Interindividual differences exist in the capacity to produce cytokines. It has been reported that levels of in vitro cytokine production measured after stimulated cell culture are associated with polymorphisms in cytokine genes. Moreover, a correlation between heart, kidney, liver, and lung graft rejection or survival with cytokine gene polymorphisms has been described. In the present study, we analyzed the association of gene polymorphisms in T helper subtype 1 (T_H1-), T_H2-, and regulatory-type cytokines with human liver allograft rejection. Patients who received a primary liver graft from 1992 onward and were seen at the transplant outpatient clinic since then were included on this study (n = 89). Patients were HLA typed routinely. Biopsy-proven acute rejection occurred in 41 of 89 patients. After informed consent, blood was collected and DNA was obtained. Using amplification-refractory mutation system polymerase chain reaction, the following cytokine gene polymorphisms were determined: IL-2+166, IL-2-330, IL-15+13689, IL-15-80, TNF-A-308, TNFd3, IFN-G+874 (T_H1-type cytokines), IL-4+33, IL-4-590, IL-6-174, IL-10-592, IL-10-819, IL-10-1082, IL-13+2043, IL-13-1055 (T_H2 type cytokines), TGF-B1+869, and TGF-B1+915 (regulatory-type cytokines). Univariate analysis showed that polymorphisms of IL-10-1082, TGF-B1+869, and HLA-DR6 were significantly related to liver graft rejection. Multiple logistic regression analysis was used to assess which variables remained significantly predictive of acute rejection. Multivariate analysis showed that TGF-B1+869 and HLA-DR6 were independently associated with the occurrence of acute rejection. These findings suggest a role for the regulatory-type cytokine transforming growth factor-β1 in human liver graft rejection. (Liver Transpl 2002;8:603-611.)     

Peritubular capillaritis in early renal allograft is associated with the development of chronic rejection and chronic allograft nephropathy

Abstract:  Peritubular capillaritis (PTCitis) has been recognized as one form of acute/active allograft rejection, and its relation to humoral immunity has been suggested. However, its mechanisms remain to be fully clarified, and there are no criteria for evaluating the extent of PTCitis in a biopsied allograft. In this study, we first evaluated the extent of PTCitis in early allografts in patients presenting with acute cellular rejection (ACR) and antibody-mediated rejection (AbAR). We also included patients who showed no evidence of ACR and/or AbAR. Next, we investigated whether or not PTCitis persisted and if peritubular capillary basement membrane (PTCBM) thickening was present in their follow-up biopsy specimens. We adopted the scoring system of PTCitis, which was presented at the Seventh Banff Conference on Allograft Pathology in 2003. In total, 53 patients were included in this study. At first biopsy, 17 showed ACR, eight showed AbAR, 16 showed mild PTCitis only, and 14 were without significant pathologic changes. The PTC score was the highest in the AbAR group, and in some patients the score gradually increased during the follow-up period. Similar changes were also observed in the group with mild PTCitis only. In late allografts, half of the patients with AbAR developed chronic rejection (CR), and the PTCBM score was the highest in that group. Surprisingly, CR was present in more than 30% of patients without ACR and/or AbAR but mild PTCitis only. In the control group, only a few showed CR and/or chronic allograft nephropathy (CAN). In conclusion, it became clear that we should carefully monitor for mild PTCitis in early allografts. In addition, our data also proved the usefulness of the PTC score and PTCBM score.     

Immunological factors for chronic rejection and the methods for the prevention of chronic allograft nephropathy

For the prevention of the immunological chronic rejection, HLA-DRB1 allele matching, enough immunosuppression in the induction phase and pathological diagnosis by non-episode and protocol biopsy are the effective methods. For the prevention of the non-immunological chronic rejection, treatments for hypertension, hyperlipidemia and hyperfiltration are the effective treatments.     

Cytokine gene polymorphisms and acute liver graft rejection: a meta-analysis.

In the field of liver transplantation, 7 reports have been published investigating the association between polymorphisms in cytokine genes and the occurrence of acute rejection in liver graft recipients. However, most of the individual studies lack the statistical power to detect a small-to-moderate effect of cytokine gene polymorphisms on the acute rejection rate. To overcome this problem, we performed a quantitative meta-analysis of 7 gene-association studies that were comparable with regard to definition of acute rejection and the type of immunosuppression used. In the overall analysis, the interleukin (IL)-10 polymorphism at position -1082 was identified as a genetic risk factor for acute liver graft rejection; liver transplant recipients carrying the IL-10 -1082.A allele displayed a lower rejection rate (common odds ratio [OR], .6; 95% confidence interval [CI], .4-.9). For the tumor necrosis factor (TNF)-A -308 polymorphism, a common OR could not be calculated due to significant heterogeneity of ORs between the studies (mean OR, 1.4; 95% CI, .8-2.6). No associations were found between acute liver graft rejection and single nucleotide polymorphisms in the IL-6 (position -174) and transforming growth factor (TGF)-beta1 (positions +869 and +915) genes. In conclusion, results from this meta-analysis suggest a role for the IL-10 -1082 polymorphism in human liver graft rejection.     

Sex hormones and gender-related differences: their influence on chronic renal allograft rejection

BACKGROUND: Renal hemodynamics and immune responses differ between males and females. Thus, sex hormones and genetically determined gender differences may determine the process of chronic rejection to some extent. METHODS: Female (F) or male (M) F344 kidneys were orthotopically transplanted into ovariectomized female Lewis recipients and were treated for 16 weeks with either estradiol, testosterone, or vehicle. RESULTS: Testosterone treatment resulted in increased urinary protein excretion independently of the donor gender, as well as extended glomerular sclerosis, interstitial fibrosis, and severe vascular lesions. Additionally, mononuclear cell infiltration was most pronounced in these animals, in parallel to an increased expression of intercellular adhesion molecule-1 (ICAM-1), fibronectin, laminin, and transforming growth factor-beta (TGF-beta) in the grafts. Estradiol treatment resulted in an improved graft function, reduced glomerular sclerosis, and a diminished cellular infiltration, in parallel to a reduced ICAM-1, fibronectin, laminin, and TGF-beta expression. In animals treated with vehicle, the gender of the donor influenced the outcome. Grafts of male origin had good graft function and histology, whereas grafts from female donors developed severe proteinuria and glomerular, interstitial, and vascular damage. CONCLUSIONS: These results suggest that a protective effect of estradiol on the progression of chronic rejection exists that is independent of donor gender. Additionally, a male kidney may benefit from the absence of testosterone, whereas the function of a female kidney deteriorates in the absence of estradiol.     

Absence of donor MHC antigen expression ameliorates chronic kidney allograft rejection

BACKGROUND: In previous studies, we have demonstrated that a subset of mouse kidney allografts has prolonged survival without any immunosuppressive treatment. Chronic rejection (CR) develops in these long surviving grafts. The pathologic features of CR in this model are similar to CR in human kidney grafts. METHODS: To explore the role of donor major histocompatibility complex (MHC) antigens in the development of CR, we performed vascularized kidney transplants using kidneys from donor mice that lack expression of both MHC class I and II antigens (MHC-/-). RESULTS: Survival was significantly improved in recipients of MHC-/- allografts. This enhanced survival was associated with higher glomerular filtration rate (GFR) in MHC-/- allografts (4.92 +/- 0.54 cc/min/kg) compared to controls (2.19 +/- 0.63 cc/min/kg; P = 0.004). The typical histologic features of CR were markedly reduced in MHC-/- allografts. Semiquantitative histopathological scores for MHC-/- grafts (13.3 +/- 2.1) were significantly lower than in control allografts (19.0 +/- 1.0; P = 0.04). Along with this improvement in structural abnormalities, significantly fewer CD4+ T (38.3 cells/mm(2) vs. 75.0 cells/mm(2); P = 0.008), CD8+ T cells (38.7 vs. 96 cells/mm(2), respectively; P = 0.008) and macrophages (60 vs. 134 cells/mm(2), respectively; P = 0.04) infiltrated MHC-/- allografts compared to controls. The levels of intragraft cytokine mRNA expression also were reduced in MHC-/- allografts compared to control allografts. Finally, serum alloantibodies were virtually undetectable in recipients of MHC-/- kidney allografts. CONCLUSIONS: Cell surface expression of donor MHC antigens promotes the development of CR. Donor antigen expression promotes the accumulation of infiltrating cells in the graft and the development of donor specific alloantibodies. Abrogation of these responses is associated with improved graft survival and reduced CR in MHC-/- grafts.