Differential early posttransplant cytokine responses in living and cadaver donor renal allografts

BACKGROUND: Differences in early posttransplant immunologic responses between living donor (LDT) and cadaver donor transplant (CDT) recipients have not been thoroughly studied. This is the first study comparing lymphocyte subpopulations and plasma levels of different cytokines, soluble cytokine receptors, cytokine receptor antagonists, and neopterin during the first 2 posttransplant weeks. PATIENTS AND METHODS: Lymphocyte subpopulations (CD3, CD4, CD8, CD16, CD19, and CD25) and plasma levels of soluble (s) interleukin(IL)-1 receptor antagonist (RA), IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-8, IL-10, transforming growth factor-beta(2), tumor necrosis factor-alpha, interferon-gamma, and neopterin were studied in 52 CDT and 33 LDT recipients 1 to 2, 4 to 6, and 8 to 10 days after transplantation. RESULTS: The most impressive finding was a consistently higher neopterin plasma level in CDT than LDT recipients. Although plasma neopterin decreased during the second posttransplant week in both groups (CDT, P = 0.0001; LDT, P = 0.001), the difference in plasma neopterin levels 8-10 days after transplantation was highly significant (P = 0.005). In contrast, LDT had consistently higher sIL-1RA plasma levels during the first 2 posttransplant weeks. Whereas sIL-1RA plasma levels decreased in both groups during the first posttransplant week (CDT, P = 0.001; LDT, P = 0.005), they increased during the second posttransplant week in LDT (P = 0.02) but remained stable and low in CDT recipients. Eight to ten days after transplantation, the difference was highly significant (P = 0.002). CONCLUSION: These data suggest that transplantation of CDT is associated with strong monocyte-macrophage activation with consistently high neopterin plasma levels, whereas the effect of inflammatory cytokines seems to be down-regulated in LDT recipients by an increased release of antiinflammatory sIL-1RA.     

Identifying risk factors in renal allografts before transplant: machine-measured renal resistance and posttransplant allograft survival

Enhancement of renal allograft function and survival in an era where expanded criteria donors are increasingly used requires validated selection criteria. The goal of this retrospective study was to evaluate the significance of pretransplant donor and allograft parameters to identify risk factors that can be used in a model to predict 1-year allograft outcomes. Donor demographic factors, donor type, and allograft parameters such as biopsy results and machine-measured renal resistance were correlated with 1-year graft outcome. The Kaplan-Meier method was used to estimate graft survival using the categorical predictors of donor type, donor age, and machine measured renal resistance at 1.5, 3, and 5 hours. The log-rank test was used to test the difference in survival curves between cohorts. The Cox regression analysis was used to estimate hazard ratios for machine-measured renal resistance, donor age, donor terminal creatinine level, donor's estimated glomerular filtration rate, cold ischemia time, and percent glomerulosclerosis. The data show that machine-measured renal resistance at 3 and 5 hours has a statistically significant inverse relationship to 1-year graft survival. All other risk factors had no correlation with 1-year graft survival. The machine-measured renal resistance at 3 hours is the earliest significant predictor of 1-year allograft outcome.     

Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation

The long-term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1-year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m(2) , p = 0.035). In conclusion, SCI at 1-year posttransplantation is associated with worsening renal function and is more frequent in SRL-treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.     

L-arginine supplementation improves function and reduces inflammation in renal allografts

Recovery from ischemia/reperfusion and immune-mediated injury in the renal transplant is associated with reduced renal hemodynamics and increased leukocyte infiltration. In diverse models of renal failure, L-arginine supplementation improved hemodynamics and reduced inflammation. However in a proinflammatory environment, L-arginine can worsen renal injury. This study investigated the therapeutic potential of L-arginine supplementation in allogeneic renal transplantation: Brown Norway rat kidneys were transplanted into Lewis rat recipients, with one native kidney remaining. Recipients received low-dose cyclosporin A (2.5 mg/kg per d subcutaneously) to obtain moderate vascular and interstitial rejection, with or without 1% L-arginine in drinking water for 7 d posttransplantation. Transplantation increased renal vasoconstriction (from 16.9 +/- 1.33 to 35.1 +/- 8.6 units; P: < 0.01), thereby reducing GFR (from 0.96 +/- 0.09 to 0.48 +/- 0.10 ml/min; P: < 0.05). Treatment with L-arginine restored renal graft function to levels found in normal donors (renal vascular resistance, 15.7 +/- 1.69 units; GFR, 0.80 +/- 0.06 ml/min). L-arginine significantly reduced vascular occlusion because of less inflammation, endothelial disruption, and thrombosis. L-arginine also decreased tubulitis, interstitial injury, and macrophage infiltration. These protective effects suggest that L-arginine might be useful as additive therapy to conventional immune suppression.     

Apoptosis and inflammation in renal reperfusion injury

Ischemia followed by reperfusion (I/R) has cardinal implications in the pathogenesis of organ transplantation and rejection. Apoptosis and inflammation are central mechanisms leading to organ damage in the course of renal I/R. General aspects of apoptosis, morphology, induction, and biochemistry are discussed. Activated caspases, the classical effector enzymes of apoptosis, are able to induce not only apoptosis but also inflammation after I/R in experimental models. This redefines the involvement of apoptosis in I/R injury toward a central and functional role in the development of organ damage. Our purpose is to assess aspects of apoptosis and inflammation in terms of involvement in the pathogenesis of I/R-induced organ damage. Moreover, the implications of recent experimental advances for diagnosis and treatment of renal I/R injury in clinical practice will be discussed.     

Conversion of stable renal allografts at one year from cyclosporin A to azathioprine: a randomized controlled study

Seventy-seven stable, nondiabetic, cadaveric renal transplants were randomized at 1 year to convert from cyclosporin A to azathioprine or to continue on cyclosporin A. Prednisolone was increased twofold during the period of conversion, and there was a 3-week overlap period during which azathioprine and cyclosporin A were given. No grafts were lost due to rejection related to conversion, but 9 of the 33 patients who were randomized to convert experienced rejection episodes and 6 were returned to cyclosporin A. Conversion to azathioprine resulted in a drop in creatinine and improvement in blood pressure control. In the group randomized to stay on cyclosporin A, 6 patients had to be subsequently converted to azathioprine because of cyclosporin A toxicity in spite of well-controlled plasma levels. The creatinine levels after successful conversion remained stable whereas those of the patients continuing on cyclosporin A showed a progressive decline. We conclude that conversion from cyclosporin A to azathiprine can be achieved safely. Progressive deterioration in graft function with continuing cyclosporin A therapy does occur and should be taken as an indication for conversion.     

Rapamycin prevents interstitial fibrosis in renal allografts through decreasing angiogenesis and inflammation

Rapamycin (RPM) has antiangiogenic and antiproliferative effects on cells. The aim of this study was to evaluate the mechanism of RPM as a novel antifibrotic agent by assessing its effect on interstitial fibrosis (IF). Among 60 renal transplant recipients, group 1 patients (n = 20) were treated with RPM and group 2 (n = 40), with cyclosporine. The proportions of infiltrating macrophages and lymphocytes in the interstitium were evaluated in 1-year biopsies. The microvessels were highlightened with CD34. After an initial biopsy, the development of diffuse IF over 18 months was evaluated by follow-up biopsies. The mean microvessel density (MVD) was significantly lower among group 1 (69.3 ± 16) versus group 2 (96.5 ± 30; P < .001). The proportions of macrophages and lymphocytes were lower in group 1 compared to group 2 biopsies (P < .001 for both). Fourteen (35%) group 2 and only 2 (10%) group 1 cases developed IF over 18 months (P < .05). The mean MVD in the initial biopsy was 75.6 ± 18 in cases that did not versus 120 ± 28 among those who did develop IF (P < .001). The amount of interstitial inflammation was greater among patients who did compared with cases who did not develop IF (P < .01). The overall 1-, 3-, and 5-year graft survival rates for group 1 were 95%, 95%, and 89% versus 95%, 65%, and 45% for group 2 patients, respectively (P < .001). RPM-treated patients showed a lower incidence of diffuse IF, which can be explained by antiproliferative and antiangiogenic effects of RPM. In conclusion, RPM therapy displayed an independently positive impact on long-term graft survival.     

缺血预处理在移植肾缺血-再灌注损伤中的应用进展

肾移植相对于其他器官移植术后疗效更为显著,但肾缺血-再灌注损伤（IRI）等术后并发症严重影响受者生存率和生存质量,如何减轻移植肾IRI成为了肾移植领域当前的研究重点。目前认为缺血预处理使移植肾适应缺血是预防IRI发展的有效方法之一,但具体机制尚未完全清楚。本文就缺血预处理在IRI中的应用,缺血预处理对移植肾IRI的调控机制,包括细胞水平的调控和细胞内信号通路的调控,以及缺血预处理的临床应用价值和前景进行综述,以期为改善移植肾IRI,提升肾移植受者和移植肾存活率,改善受者生存质量提供参考。     

Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts

Acute tubular necrosis (ATN), a frequent histopathological feature in the early post–renal transplant biopsy, affects long‐term graft function. Appropriate markers to identify patients at risk of no or incomplete recovery after delayed graft function are lacking. In this study, we first included 41 renal transplant patients whose biopsy for cause during the first month after transplantation showed ATN lesions. Using partial microvasculature endothelial (fascin, vimentin) and tubular epithelial (vimentin) to mesenchymal transition markers, detected by immunohistochemistry, we found a significant association between partial endothelial to mesenchymal transition and poor graft function recovery (Spearman's rho = ?0.55, P = .0005). Transforming growth factor–β1 was strongly expressed in these phenotypic changed endothelial cells. Extent of ATN was also correlated with short‐ and long‐term graft dysfunction. However, the association of extensive ATN with long‐term graft dysfunction (24 months posttransplant) was observed only in patients with partial endothelial to mesenchymal transition marker expression in their grafts (Spearman's rho = ?0.64, P = .003), but not in those without. The association of partial endothelial to mesenchymal transition with worse renal graft outcome was confirmed on 34 other early biopsies with ATN from a second transplant center. Our results suggest that endothelial cell activation at the early phase of renal transplantation plays a detrimental role.     

Early prediction of renal allograft loss beyond one year

Despite significant improvements in the results of renal transplantation since the introduction of cyclosporin, graft loss beyond the 1st year remains a significant and unresolved problem. In a retrospective analysis, 348 cyclosporin-treated renal transplant recipients with a functioning graft at 12 months were studied. Forty-eight patients in whom graft failure occurred in the 2nd and 3rd years were compared to 300 patients who maintained graft function beyond this time. Both groups were comparable with respect to donor and recipient features. Factors reflecting recipient immunological responsiveness —sensitization, previous transplantation and early rejection episodes-continued to affect graft survival beyond the 1st year. Surprisingly, there was a higher incidence of prior transfusion in the group with graft failure in the 2nd and 3rd years than in those with longer function (65% vs 24%). Serum creatinine levels at 3 and 6 months were also predictive of graft loss amongst patients with a functional graft at 1 year. It remains to be answered whether new immunosuppressive drugs and strategies will overcome these risks for late graft loss.     

Flow cytometric crossmatching and outcome one year after renal transplantation

Previous studies have shown that flow cytometric crossmatch assays can identify an at risk population in renal transplantation [1–5]. We used the assay for recipient selection for 1 year. Recipients with donor T cell directed IgG were excluded from transplantation and those with B cell directed IgG were treated with increased immunosuppression. The transplants performed over this period (n = 126) were compared with an earlier series (n = 118) in which flow cytometric crossmatch results did not influence patient management. The results were evaluated for mortality and graft outcome at 3 months and 1 year. In addition, postoperative complications and duration of hospital stay were also assessed.     

Recipient hypertension potentiates chronic functional and structural injury of rat renal allografts

BACKGROUND: Systemic hypertension affects many allograft recipients, is an important risk factor for chronic graft dysfunction, and is linked to reduced graft survival. The condition may up-regulate the expression of inflammatory host cells and their products. These, in turn, may significantly injure vascular endothelium and other components of allografted kidneys. METHODS: Lewis rats received orthotopic F344 renal allografts, a standard model of chronic rejection. Renovascular hypertension was produced by placing a silver clip (0.25 mm) on the renal artery of the retained contralateral native kidney 4 weeks after transplantation. Sham-clipped rats served as normotensive controls. Four recipient groups (Gp) were studied: Gp 1, rats with an allograft plus a clipped native kidney; Gp 2, those with an allograft and a sham-clipped native kidney; Gp 3, isografted animals with a clipped native kidney; and Gp 4, those bearing an isograft and a sham-clipped native kidney. Systolic blood pressure and proteinuria were measured every 2 weeks for 24 weeks. Grafts were assessed serially for morphologic and immunohistologic changes. RESULTS: Systemic blood pressure rose to hypertensive levels in Gps 1 and 3 within a week of clipping but never increased in Gps 2 and 4. Proteinuria developed in hypertensive animals but remained at baseline in normotensive controls. Intimal thickening of allograft arteries progressed to luminal obliteration with extensive perivascular and interstitial fibrosis by 24 weeks. In contrast, vascular changes in isografts of hypertensive hosts were restricted to medial hypertrophy. Tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, platelet derived growth factor (PDGF), endothelin, Il-6, major histocompatibility complex (MHC) class II, and B7 were up-regulated in allografts in hypertensive hosts. Vascular deposition of immunoglobulin (IgG) was increased. These changes were markedly less pronounced in Gp 3 isografts and minimal in the kidneys of the normotensive animals of Gps 2 and 4. CONCLUSIONS: An experimental model is presented that examines the influence of recipient hypertension in the pathogenesis of chronic dysfunction and injury developing in rat renal allografts over time.