Chronic rejection in renal transplantation

Chronic rejection in renal transplantation is an alloantigen-dependent immune process ultimately leading to graft failure. We reviewed the literature on the basis of the case history of a patient who lost her renal allograft apparently from chronic interstitial rejection. Chronic rejection presents clinically as chronic transplant dysfunction starting at various intervals after transplantation. The histopathologic features consist of chronic allograft nephropathy with or without transplant vasculopathy or glomerulopathy. Chronic rejection should be differentiated from chronic toxicity of calcineurin inhibitors, de novo or recurrent glomerulonephritis, polyoma (BK) virus nephropathy, transplant renal artery stenosis, and nephrosclerosis. Young recipient age, black race, presensitization, histoincompatibility, and acute, especially vascular, and late acute rejection episodes are dominant risk factors, compatible with immunologic mechanisms. Cellular and humoral responses resulting from indirect recognition of alloantigens with subsequent fibrotic sequelae play a central role in the pathogenesis. Circulating donor-specific antibodies and staining for C4d can detect humoral chronic rejection. The prognosis depends on alloreactivity and the presence of progression factors such as old donor age, renal dysfunction, proteinuria, hyperlipidemia, and smoking. A multifactorial approach directed to the risk and progression factors is needed to prevent premature graft loss from chronic rejection.     

慢性排斥反应的病因与病理学分析

为探讨慢性排斥（ＣＲ）的病因与病理学，对１１４１例尸肾移植者中５９例接受治疗的ＣＲ病例进行回顾分析。结果：（１）ＣＲ占总病例的５．２％，平均发生于术后２３个月，有急性排斥（ＡＲ）史者２７．１％，免疫抑制药物服用不足者２５．４％，余为不明原因者。免疫抑制不足者中患者擅自减少剂量者７３．３％，经抗排斥治疗及增加药物剂量后肾功正常或稳定者占１８．６％。（２）ＣＲ表现为间质纤维增殖、小淋巴细胞和浆细胞散在浸润；肾小球基底膜增厚，透明样变，血管内膜增厚。结论：（１）ＡＲ是ＣＲ发生的基础；（２）抗排斥与调整免疫抑制药量可挽救部分ＣＲ；（３）雷公藤、百令胶囊治疗ＣＲ有一定疗效；（４）ＣＲ患者中，淋巴细胞毒性低者肾功能更可能得到控制；（５）长期免疫抑制不足是ＣＲ发生的重要原因，按时按量服药可降低ＣＲ发生率。     

Steroid-resistant acute allograft rejection in renal transplantation

Steroid-resistant rejection after pediatric renal transplantation forms a rare but severe complication with a guarded prognosis particularly if this occurs late after transplantation. There is a paucity of data on how to manage these challenging rejection episodes, particularly in the pediatric literature. Mohan Shenoy et al. published a case series of 15 patients who were treated with anti-thymocyte globulin for steroid-resistant acute allograft rejection over a 15-year period in a single center in this issue of Pediatric Nephrology. While the results for the early rejection group were encouraging, the results in the eight patients with late rejection episodes after transplantation were unfavorable and afflicted with a high incidence of side-effects. Important diagnostic tools such as C4d staining of the renal transplant biopsy and the measurement of donor-specific antibodies were underutilized. The editorial reviews the importance of the differentiation between humoral and cellular rejection and the challenges of treating late antibody-mediated acute rejection in these patients. A multi-center approach is required to establish a registry of these events and ideally prospective randomized interventions should be designed to provide some evidence base for the management of this challenging complication after pediatric renal transplantation.     

Chronic rejection of rat renal allograft

Chronic allograft rejection is both a clinical and a histopathological diagnosis. Until recently, the histological definition of chronic renal allograft rejection was based on clinical diagnostic biopsies, where the evidence was partially obscured by recurrence of the original renal disease, and/or by administration of immunosuppressive drugs. In this communication, we present an experimental rat model for chronic renal allograft rejection, devoid of recurrence of the original disease. By comparing allografts to similarly immunosuppressed syngeneic transplants, we define which histological features should be attributed to chronic rejection and which to cyclosporin nephrotoxicity. Rat renal transplants were performed from DA (Ag-B4, RT1^av1) to WF strain (Ag-B2, RT1^u) or, for control, to DA strain, and immunosuppressed for 2 or 3 weeks with cyclosporin using a variety of different dosages. The animals were monitored weekly for serum creatinine levels and for blood cyclosporin concentrations, and core needle biopsies were performed on the grafts at regular intervals. At 3 months post-transplantation the animals were sacrificed and a complete histopathological evaluation was performed. Thirty-one histological variables were scored blindly by two investigators and separately for the graft interstitium, glomeruli, tubuli, and the graft vasculature. The following histological alterations were significantly more prominent in allografts than in similarly immunosuppressed syngeneic transplants: the intensity of interstitial inflammation, particularly the degree of pyroninophilia within the inflammatory cell population; the extent of glomerular mesangial matrix increase, basement membrane thickening, and glomerular sclerosis; the increase in the vascular intimal thickness affecting in particular the first and second order branches of the renal artery; and the obliteration of the graft vasculature. These alterations were considered as being primarily due to chronic rejection. In contrast, the extent of interstitial fibrosis and the extent of tubular changes, including tubular epithelial vacuolation, epithelial atrophy, and tubular basement membrane changes, were not significantly different in the allografts as compared to the syngeneic controls. These alterations were attributed primarily to cyclosporin nephrotoxicity. Serial monitoring of the grafts by needle biopsies clarified the sequence of events in the development of the chronic alterations in the transplant. The first event, as expected, was tubulointerstitial pyroninophilic inflammation, resembling that of acute episodes of rejection. This was significantly stronger and appeared earlier in allografts immunosuppressed for 2 rather than for 3 weeks. Vascular alterations developed next. The last to develop were the glomerular lesions.     

Cytomegalovirus infection and graft rejection in renal transplantation

BACKGROUND: Cytomegalovirus (CMV) infection and CMV disease have been associated with acute and chronic graft rejection. The introduction of the sensitive CMV antigenemia pp65 assay for detection of CMV infection allowed us to study the time course of CMV infection and acute rejection and the long-term outcome in renal transplant recipients with and without a CMV risk constellation. METHODS: Prospective single center study including 48 renal transplant recipients at risk for CMV infection (donor and/or recipient CMV seropositive) and a control group of 36 CMV seronegative recipients of CMV seronegative kidney donors. Evidence of CMV infection was monitored by the CMV antigenemia pp65 assay every 1 to 2 weeks and compared with the occurrence of acute rejection in the posttransplant period and graft function at 5 years. RESULTS: CMV infection developed in 83% (40/48) of patients of the CMV risk group within 4 months posttransplant. A total of 18 of patients experienced an acute rejection episode (control group 16/36; P=0.65). In 12/18 CMV infection followed rejection and in three patients antigenemia preceded the diagnosis of rejection. In three patients CMV antigenemia remained negative. Five-year follow up: Patient survival (44/48 vs. 31/36; P=0.48), graft survival (38/48 vs. 27/36; P=0.79), number of patients with at least one acute rejection episode: CMV risk group: 42.1%, control group 51% (P=0.46), serum creatinine: CMV risk group:130 +/- 66 micromol/iter, control group: 126 +/- 37 micromol/ liter (P=0.56), proteinuria: CMV risk group: 0.02 +/- 0.02 g/mmol creatinine, control group: 0.02 +/- 0.02 g/mmol creatinine (P=1.0). CONCLUSION: CMV infection within 4 months posttransplant, as defined by a positive antigenemia assay was not found to be a risk factor for acute graft rejection or chronic graft dysfunction at 5 years.     

Plasmapheresis--adjunctive treatment for steroid-resistant rejection in renal transplantation

Plasmapheresis was used to treat steroid-resistant rejection in 32 of 154 patients (21.1 per cent) receiving renal allografts during a 3 1/2-year interval. The 2-year actuarial patient and allograft survival rates for the 32 patients were 93.3 plus or minus 5 and 56.9 plus or minus 9 per cent, respectively. Mean patient followup was 18.8 months. No immunologic rebound was noted in any of the 19 patients who responded initially to plasma exchange. Although 14 of these 19 patients had peak creatinine levels of 4 to 14.5 mg. per cent during the rejection reactions significant and sustained improvement in renal function was noted. This was not a controlled trial but the results are sufficiently encouraging to warrant continued evaluation of plasmapheresis as a therapeutic adjuvant in the treatment of humoral or steroid-resistant rejection.     

Acute rejection episodes after renal transplantation in children

46 renal transplants performed in children at the Medizinische Hochschule Hannover between 1975 and 1980 are evaluated for the occurrence of acute rejection episodes. 33 patients received cadaveric donor grafts (CAD) and 13 living donor grafts (LD). Immunosuppression was carried out with prednisone and azathioprine. 14 patients were treated additionally with antilymphocyte globulin (ALG). A total of 68 acute rejection episodes occurred, 38% of them within the first week of transplantation, and the latest 3 years after transplantation. The most important signs of acute rejection were a rise in serum creatinine concentration, a decrease in urine output and fever. Patients with living donor grafts and full-house matched kidneys had fewer reversible and irreversible rejection episodes than did patients with grafts from cadaveric donors and with grafts with 1-4 mismatches. The value of ALG treatment is doubtful: only 1 out of 14 patients who received ALG treatment experienced no rejection episodes compared to 12 out of 33 patients who did not have ALG treatment. 2.4 rejection episodes/patient occurred in patients who had cadaver grafts and had received ALG compared to 1.17 episodes/patient in similar patients who had not received ALG. Irreversible rejection episodes occurred in 4 out of 9 ALG-treated and in 3 out of 23 non-ALG-treated recipients of cadaver grafts.     

Chronic rejection and late renal allograft dysfunction

Renal transplantation is currently standard therapy for end-stage kidney disease for children. Despite the considerable improvement in short-term results, the expected allograft half-life has remained the same. This is due to chronic rejection/late graft dysfunction which has proved resistant to therapeutic attempts. During the last few years the multifactorial pathogenesis of chronic renal allograft rejection has been clarified to some extent. Early injury by immunological and non-immunological mechanisms is followed by vascular remodelling due to repetitive cycles of cytokine release, upregulation of growth factors, and vascular smooth muscle cell proliferation. This leads to typical concentric arteriolosclerosis and ischemia. Secondary kidney-specific mechanisms are initiated by the reduction in functioning renal mass and lead to gradual progression of chronic rejection. There is no single optimal therapy. Several attempts to influence the pathophysiological cascade have been promising. Attention should be focused on minimizing early immunological/non-immunological injury in order to attenuate future progression of chronic rejection. A significant prolongation of allograft half-life may be achieved during the next decade with the introduction of new therapeutic agents and comprehensive approach to treatment. This would be especially beneficial for pediatric recipients, reducing the need for retransplantation in adulthood.     

肾移植慢性排斥的后期药物调整

对２７例术后６个月－８年７个月发生慢性排斥的肾移植患者进行治疗，２１例经治疗后血清肌酐明显下降，并稳定，６例病情有反复。比较不同时期的免疫抑制剂用量，发生稳定组在慢性排斥发生后１、３、６个月时环孢素Ａ、强的松、硫唑嘌呤的用量均明显高于治疗前，而不稳定组在上述时期的免疫抑制用量不高于或于治疗前。认为长期应用较大剂量的免疫抑制剂（尤其是环孢素Ａ）是维持慢性排斥治疗效果的关键，并应充分重视硫唑嘌呤的作用     

肾移植急性排斥反应的早期诊断

自Joseph Murray于1954年完成了首例肾移植,宣布了人类与排斥反应斗争的开始。随着新型免疫抑制剂的不断出现和配型方法的改进,移植排斥发生率显著降低,移植肾存活率大大提高,肾移植已成为终末期肾病的有效治疗手段。然而,急性排斥反应(acute rejection,AR)仍是目前肾移植术后的主要并发症,也是导致慢性排斥反应和移植肾失功的最重要的危险因素。早期诊断、及时干预,可防患于未然,减少危害。一、AR的临床表现及实验室检查肾移植AR可发生于术后任何时间,其中大多数在术后7~90d,发生越早程度越重。其临床表现主要为:①尿量减少:是AR的主要…     

Chronic cyclosporine nephrotoxicity in renal transplantation

Although extensively studied, the pathophysiologic characteristics of chronic cyclosporine (CsA) nephrotoxicity are still far from being completely understood. The recognition of chronic CsA nephrotoxicity in allografted kidneys is hampered by a lack of easily assessable sensitive and specific markers. Long-term results of CsA withdrawal trials and trials that evaluated CsA sparing or withdrawal after the diagnosis of chronic allograft nephropathy (CAN) have shown that chronic CsA nephrotoxicity has a more important role in the etiology of late transplant dysfunction than appreciated before. Various hypotheses have explained the renal structural changes of chronic CsA nephrotoxicity including ischemia, cellular toxicity, and the stimulation of renal fibrosis by growth factors or cytokines. Possible ways to prevent chronic CsA nephrotoxicity include improved therapeutic drug monitoring and CsA withdrawal or avoidance. Patients with aspecific CAN in late biopsy may benefit from withdrawal of CsA or a reduction of its dose. Current knowledge is being discussed. It is concluded that in the near future more strategies are likely to be used to prevent loss of allograft function as a result of drug toxicity.     

Chronic rejection in single-lung transplantation manifested by obliterative bronchiolitis

Chronic rejection of the lung in patients with heart-lung transplants has most often been associated with the development of obliterative bronchiolitis. Previously only one patient receiving a single-lung transplant suffered from the development of this problem. We describe a patient whose obliterative bronchiolitis developed 9 months after single-lung transplantation. Progressive deterioration occurred until his death from obliterative bronchiolitis at 21 months after transplantation. The functional and histologic changes are described and the possible mechanisms discussed.     

Early versus late acute rejection episodes in renal transplantation

BACKGROUND: Acute rejection is a major complication after renal transplantation and the most important risk factor for chronic rejection. We investigated whether the timing of the last treated acute rejection episode (ARE) influences long-term outcome and compared the risk profiles of early versus late ARE. METHODS: A cohort of 654 patients who underwent cadaveric renal transplants (1983-1997) that functioned for more than 6 months was studied. In 384 of 654 transplant recipients, one or more treated AREs were documented; the last ARE occurred in 297 of 384 transplant recipients within 3 months and in 87 of 384 after 3 months. Applying multivariate logistic regression analysis, we compared the predictor variables of the two groups with transplants without AREs. RESULTS: Ten-year graft survival rates censored for causes of graft loss other than chronic rejection were 94%, 86%, and 45% for patients without ARE, with early ARE, and with late ARE, respectively. Delayed graft function, odds ratio (OR) 2.37 (1.55-3.62), and major histocompatibility complex (MHC) class II incompatibility, OR 2.28 (1.62-3.20) per human leukocyte antigen (HLA)-DR mismatch, were independent risk factors for early ARE. In contrast, recipient age, OR 0.75 (0.61-0.93) per 10-year increase, donor age, OR 1.28 (1.07-1.53) per 10-year increase, female donor gender, OR 1.74 (1.03-2.94), and MHC class I incompatibility, OR 1.35 (1.07-1.72) per mismatch of cross reactive groups, were associated with late ARE. CONCLUSIONS: Late ARE has a detrimental impact on long-term graft survival and is associated with MHC class I incompatibility, whereas early ARE is correlated with HLA-DR mismatches and has a better prognosis. These data are consistent with the role of direct and indirect allorecognition in the pathophysiology of early and late ARE, respectively.     

Antithymocyte treatment of steroid-resistant acute rejection in renal transplantation

To evaluate the outcome of early (ER <3 months) and late (LR >3 months) episodes of corticosteroid resistant acute allograft rejection (CRR) treated with anti-thymocyte globulin (ATG) in pediatric renal allograft recipients. Retrospective study of 15 children, mean age 13.2y, who received ATG for the treatment of biopsy proven CRR over a 15 year period. Seven children received ATG for ER (median 26 days post transplantation) and 8 for LR (median 763 days). There was a significant improvement in the 3 month eGFR (70.3 ml/min/1.73m², SD 22.3, p = 0.018) when compared with the value prior to ATG treatment (23.3 ml/min/1.73m², SD 10.2) in the ER group. In the LR group (4 DSA positive) there was no improvement in the eGFR at 3 months (42 ml/min/1.73m², SD 10.5, p = 0.32) when compared with the value prior to ATG (38 ml/min/1.73m², SD 9.7). At final review, eGFR in the ER group was 72.3 ml/min/1.73m² (SD 33) vs. 37.7 ml/min/1.73m² (SD 17.9) in the LR group after a mean follow up of 10.4y and 1.2y, respectively. ATG therapy in CRR is associated with reversal of rejection and excellent graft outcome in children with ER. The benefits remain uncertain in LR, the etiology of which is multifactorial.