Chronic rejection and chronic cyclosporin toxicity in renal allografts (original) (raw)
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Chronic rejection of rat renal allograft
Transplant International, 1992
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 avx) 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 tu-Offprint requests to." E Hfiyry bular 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.
Effect of Cyclosporin A on the in Situ Inflammatory Response of Human Renal Allograft Rejection
Scandinavian Journal of Immunology, 1982
of Cyciosporin A on the in Situ Infiammatory Response of Human AUograft Rejection. A Preliminary Report. Scand. J. Inmimol. 16, 135-149, 1982. Twenty cadaveric kidney aUograft recipients were prerandomized into two groups. Ten patients (control group) were treated postoperatively with azathioprine fAZA) plus methylprednisolone (MP): ihe other ten received cyciosporin A (CyA)as Ihc only imnnino^upprcssive agent. Both groups received MP during rejection. One patient was excluded from the CyA group because of an early postoperative cardiac infarction and death. All iransplants were monitored by alternate-day tine-needle aspiration biopsy and transplant aspiration cytology. Some patients treated wiih CyA had a significant initial decrease in urine output, reaching control values approximately I week postoperatively. Tlie mechanism liehind this deteriorated lenal function is not clear, but it seemed to have been caused by injuries to the kidney tubular component, since a distinct nionocytic-lymphocyiic inflammation and severe cytoiogical changes resembling pronounced acute tubular necrosis were observed concomitantly in transplant aspiration cytology. The CyA-treated patients had normal levels of hlood leucocytes, thrombocytes and lymphocytes but displayed a suong early blood cosinophilia that was absent in the control subjects. During the first . "^0 days after transplantation 15 in situ episodes of inflammation were recorded in the nine transplants treated with CyA, whereas only 6 episodes were found in the 10 transplants receiving AZA +MP(P-,-0.01). The first inflammatory episode in the ( yA-treated Iransplants (leaked between days 5 and 8 after transplantation and was followed by another distinct innammatory episode lietween days I'y and 26. In the AZA-plus MP-treated transplants, only one innammalion episode was observed, with a peak on day 14 posioperatively. The inflammatory cell types most prominently present in the CyA-treated transplants were lymphocytes, B plasniabJasts and monocyte;;. The early inflammatory episodes in the CyA-treated transplants may have been related to the fact that during the initial intramuscular administration, iherapeutie CyA concentrations in patient serum were not achieved until the fourth postoperative day during peroral administration. The onset of transplant function had no impact on the in situ inflammatory response of rejection in the CyA-treated transplants or on the concentration of CyA in patient serum. This indicates that CyA may also be used in initially nonfunctioning transplants, Confirming our earlier results, we were unable to demonstrate the major histocompatibility complex (MHC) antigens on the healthy grafts ireated with AZA plus MP. However, in healthy allografts treated with CyA, both classes of MHC antigens were^ nearly invariably demonstrable on the graft endothelial cell surface. Approximately 60% aUograft survivals were recorded in both groups al 6 months, and all patients with functioning grafts were able to work.
Medical Journal of Australia, 1985
In a prospective randomized clinical trial to compare treatment with cyclosporin A to conventional treatment with azathioprine, prednisone and antithymocyte immunoglobulin in cadaveric renal transplantation, 34 patients were entered into both treatment groups and were examined regularly for seven to 43 months. Renal graft survival at one year was 72% among patients receiving cyclosporin A therapy and 75% among those receiving conventional therapy. Rejection was a frequent complication of both treatments; irreversible rejection occurred in six patients receiving treatment with cyclosporin A and in 10 patients receiving THE SUCCESS of renal transplantation over the last two decades has depended upon the use of azathioprine and corticosteroids to prevent rejection. Antithymocyte immunoglobulin (ATG) has also been used to augment the immunosuppressive potential of these two drugs. Cyclosporin A is the first new immunosuppressive agent in a decade with the potential to prevent graft loss from reiection.':' Since the pioneering work of CaIne et al. in clinical kidney, liver and pancreas transplantation,' cyclosporin A has also been shown to have benefits for heart, lung and bone marrow transplants. 3-5 To evaluate the efficacy of cyclosporin A in renal transplantation, a number of centres around the world have set up clinical, randomized trials. In a Canadian multicentre
Transplantation Proceedings, 2004
The introduction of cyclosporine in kidney transplantation rapidly improved short and medium term graft and patient survival rates. Initially many trials used cyclosporine monotherapy to avoid steroid toxicity, but high acute rejection rates lead to a change in the immunosuppressant scheme. The use of prophylactic steroids significantly decreased acute rejection rates, but the long-term benefit of such a reduction has not been assessed. Methods. Retrospective analysis of the impact of early acute rejection on long-term outcome (10 years) in 264 consecutive renal transplants performed in a single institution between 1986 and 1993 using cyclosporine monotherapy (CM) (n ϭ 139) versus cyclosporine and prednisone (CS) (n ϭ 125). Different protocols were used for elderly or immunological high-risk patients and for transplants with delayed graft function and therefore these patients are not included. The incidence and severity of acute rejection episodes and long-term patient and graft survivals were analyzed. Results. At 1 year, acute rejection episodes showed significantly higher frequency in the CM group than in the CS group (72.66% vs 46.40%). Nevertheless, graft and patient survival rates were similar at 1, 5, and 10 years (Graft: 96.38%, 78.77%, and 59.84% vs 92.59%, 75.62%, and 53.44%; Patient: 99.27%, 95.06%, and 84.76% and 95.9%, 93.09%, and 88.28%). Conclusion. The addition of prophylactic steroids decreases the incidence of acute rejection but does not improve the long-term graft survival. These findings suggest that in an era of new immunosuppressants, fewer acute rejection episodes will be evident requiring more effort to detect and treat subclinical rejections.
Chronic renal allograft rejection: Pathophysiologic considerations
Kidney International, 2005
Chronic rejection is currently the most prevalent cause of renal transplant failure. Clinically, chronic rejection presents by chronic transplant dysfunction, characterized by a slow loss of function, often in combination with proteinuria and hypertension. The histopathology is not specific in most cases but transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified such as young recipient age, black race, presensitization, histoincompatability, and acute rejection episodes, especially vascular rejection episodes and rejections that occur late after transplantation. Chronic rejection develops in grafts that undergo intermittent or persistent damage from cellular and humoral responses resulting from indirect recognition of alloantigens. Progression factors such as advanced donor age, renal dysfunction, hypertension, proteinuria, hyperlipidemia, and smoking accelerate deterioration of renal function. At the tissue level, senescence conditioned by ischemia/reperfusion (I/R) may contribute to the development of chronic allograft nephropathy (CAN). The most effective option to prevent renal failure from chronic rejection is to avoid graft injury from both immune and nonimmune mechanism together with nonnephrotoxic maintenance immunosuppression.
Immunosuppression and transplant vascular disease: benefits and adverse effects
Pharmacology & Therapeutics, 2003
Cardiac allograft vasculopathy (CAV) occurs within 5 years of transplantation surgery and represents the main cause of death in long-term heart transplant survivors. The detailed pathogenesis of CAV is unknown, but there are strong indications that immunologic mechanisms, which are regulated by nonimmunologic factors, are the major cause of this phenomenon. Cyclosporine A (CsA) is a frequently used immunosuppressive agent in transplant medicine to prevent rejection. The mechanism of action of CsA involves initial binding to cyclophilin to form a complex that then inhibits calcineurin (CN), leading to reduced interleukin (IL)-2 production as part of the signal transduction pathway for the activation of B-lymphocytes and T-lymphocytes. Based on this proposed mechanism, it was expected that CsA should be an effective strategy in attenuating the host immune response against transplanted allograft tissue; however, CsA has not changed the outcome of CAV. Several mechanisms have been suggested for the ineffectiveness of CsA in long-term prevention of CAV. For example, routine therapeutic doses of CsA may block CN incompletely (50%), whereas complete blockade requires doses that are not clinically tolerable. Another explanation is the possible activation of T-cell receptors directly (CN independent) by the immune response, which induces protein kinase C u (PKCu) and leads to IL-2 production and immune rejection. Moreover, there may be a role for nonimmunologic mechanisms, such as complement, which cannot be controlled by CsA, or CsA may cause hypercholesterolemia or induce overexpression of transforming growth factor-h (TGF-h). This review also compares the effect of CsA with other immunosuppressants in allograft artery preservation and their clinical efficacy. D
Transplant International, 1990
We have investigated the impact of triple drug immunosuppression on the occurrence of early inflammatory episodes, as detected by fine needle aspiration biopsy, and of episodes of clinical rejection during the immediate postoperative period. The prospective component of this study includes 128 consecutive first cadaveric renal transplant recipients receiving triple drug treatment consisting of azathioprine (Aza), cyclosporin (CyA) and methylprednisolone (MP). For controls we have used three historical groups: one immunosuppressed with Aza and MP (group A), another with CyA monotherapy (group B), and the third with CyA together with MP (group C) in equivalent drug dosages. On the average, 0.8 episodes of inflammation per patient were recorded during the immediate postoperative period of 30 days with triple drug treatment. This was significantly less than the 1.3 episodes in patients receiving Aza and MP (P less than 0.01), the 1.7 episodes in patients on CyA monotherapy (P less than 0.001), or the 1.6 episodes in patients receiving CyA together with MP (P less than 0.001). Although the first episode of inflammation commenced concurrently in each group and the peak intensity of inflammation was the same, the mean duration of inflammation was significantly shorter--2.7 days--under triple drug treatment than the 7.8-11.7 days for controls (P less than 0.001). The frequency of rejection episodes under triple treatment was also significantly lower--0.2 per patient--than the 0.8 per patient in controls (P less than 0.001). The first rejection episode occurred later in the triple drug treatment group--on the average, on day 15.2--than in the historical controls (on days 7.7-11.7).(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic rejection in renal transplantation
Transplantation Reviews, 2004
With renal transplantation, chronic rejection is currently the most prevalent cause of late transplant failure. Clinically, chronic rejection presents as chronic transplant dysfunction, characterized by a slow loss of function, often in combination with hypertension and proteinuria. Transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic for chronic rejection. Risk factors have been identified and include young recipient age, black race, presensitization, histoincompatibility, and acute rejection episodes, especially vascular rejection episodes and rejections that occur late after transplantation. Chronic rejection develops in grafts that undergo intermittent or persistent damage from cellular and humoral immune responses resulting from indirect recognition of alloantigens. Progression factors such as advanced donor age, renal dysfunction, hypertension, proteinuria, hyperlipidemia, and smoking play an important role. At the tissue level, senescence conditioned by ischemia/reperfusion may contribute to the development of chronic rejection. The most effective option to prevent renal failure from chronic rejection is to avoid graft injury from both immune and nonimmune mechanism together with nonnephrotoxic maintenance immunosuppression.