Chronic Graft Dysfunction Research Articles

Cyclosporine versus tacrolimus in kidney transplantation: are there differences in nephrotoxicity?

Cyclosporine and tacrolimus, two calcineurin inhibitors, show different side effects and toxicities. The data concerning their nephrotoxicity are few and conflicting. A retrospective study was performed in 2 groups of renal transplant recipients treated with cyclosporine or tacrolimus to evaluate graft function and side effects. All patients had completed at least 6 months of follow-up before inclusion in the study. Group I included 10 patients who were converted from cyclosporine to tacrolimus, due to cosmetic problems or due to chronic graft dysfunction with creatinine values <3 mg/dL. After conversion, there was a significant reduction in creatinine values (from 2.43 ± 1.21 to 1.86 ± 0.72 mg/dL; P = .023) and an improvement in creatinine clearance (from 47.5 ± 19.2 to 56.1 ± 18.9 mL/min; P = .047). The lipid profile did not change, but there was a trend to better blood pressure control with less antihypertensive drugs. Group II compared 2 subgroups of patients receiving kidneys from the same donor, one treated with cyclosporine and the other with tacrolimus. Tacrolimus patients showed better renal function; namely, creatinine was 1.15 ± 0.27 versus 1.44 ± 0.33 mg/dL ( P = .029) and creatinine clearance was 87.7 ± 27.1 versus 60.3 ± 25.9 mL/min ( P = .043). Lipid and blood pressure values were not different between the 2 subgroups, but tacrolimus patients tended to need a lower number of antihypertensive medications. The incidence of de novo diabetes mellitus was approximately 20% among patients using tacrolimus. We concluded that tacrolimus may be less nephrotoxic than cyclosporine. Tacrolimus patients showed better graft function and easier blood pressure control, but a high incidence of posttransplantation diabetes mellitus.

Chronic renal allograft dysfunction: the role of T cell-mediated tubular epithelial to mesenchymal cell transition.

Chronic graft dysfunction is now the leading clinical problem after renal transplantation. The principal histopathologic lesion seen in this disease is tubular loss with concurrent interstitial fibrosis. Although the severity of acute rejection often correlates with that of subsequent chronic dysfunction, a direct link between these processes has remained elusive. This study was designed to test the hypothesis that intraepithelial T cells recruited to the renal tubules during acute rejection can directly induce fibrosis by causing tubular epithelial cells to undergo transformation to produce a motile population of activated fibroblasts. A study of renal allograft tissue sections showed the presence of the S100A4 marker of epithelial to mesenchymal transition in some tubular epithelial cells; the expression of this antigen was heterogeneous both within and between individual tubular cross-sections. Significantly, S100A4-expressing epithelial cells were frequently associated with infiltrating CD8+ T cells, and many coexpressed the Ki67 marker of proliferation. A parallel study of human renal cortical epithelial cells in primary culture demonstrated that S100A4 was induced by stimulation for 72 h with TGF-beta(1) and by direct contact with membrane-associated TGF-beta on MOLT-16 cells, a model intraepithelial T-cell line. Further experiments demonstrated that induction of transition coincided with a significantly increased potential for human renal epithelial cells to invade the tubular basement membrane. These data are consistent with a model in which intratubular T cells can present TGF-beta and directly induce adjacent tubular epithelial cells to transform to proliferating fibroblasts that migrate across the tubular basement membrane, producing fibrotic lesions within the renal interstitium.

Experience with cyclosporine: approaching the therapeutic window for C2 levels in maintenance kidney transplant recipients

This study was aimed to evaluate the clinical benefit of C 2 monitoring in 191 stable renal transplant patients previously monitored by C 0. All patients had been transplanted for at least 1 year and received cyclosporine (CsA)-based immunosuppression since the start. At the inceptions C 0 levels were significantly correlated with C 2 values ( P < .0001). Patients with starting C 2 levels >1000 ng/mL showed significantly higher levels of serum creatinine (sCr) both at inception (1.66 ± 0.50 vs 1.44 ± 0.41 mg/dL; P = .0021) and at the end of a 2-year follow-up (1.84 ± 0.80 vs 1.46 ± 0.51 mg/dL; P = .005). C 2 monitoring revealed that a high percentage of patients were overexposed to CsA, mainly in the subgroup with most recent renal engraftments (12 to 24 months). The switch to C 2 monitoring was associated with a slower deterioration of graft function ( P = .02). Further, the mean values of C 2 over a 2-year follow-up were inversely correlated with sCr at the end of follow-up ( P = .0005). Finally, patients with mean threshold C 2 levels above 720 ng/mL, roughly corresponding to the median value of C 2, showed significantly lower levels of sCr at the end of follow-up ( P = .0004). In conclusion, C 2 monitoring of maintenance renal transplant patients allows one to identify a significant percentage of overexposed subjects, possibly limiting the rate of progression of chronic graft dysfunction. Target range values between 700 and 900 ng/mL appear to be associated with better long-term kidney graft function.

Donor hypertension increases graft immunogenicity and intensifies chronic changes in long-surviving renal allografts.

Marginal donor organs are used increasingly for transplantation. To define the influences of donor hypertension, we compared the behavior of kidney allografts from hypertensive and normotensive donors in an established rat model of chronic rejection. Donor hypertension was induced by partial occlusion of the right renal artery with a silver clip. After 10 weeks, the left kidney was removed and transplanted. Normotensive animals served as controls. All recipients were treated with a low dose of cyclosporine for 10 days (1.5 mg/kg). Blood pressure and proteinuria were determined weekly four times after transplantation. To examine the effects of donor hypertension on late events, grafts (n=6/time point) were examined morphologically and by quantitative reverse transcriptase-polymerase chain reaction analysis at serial intervals. Recipients of kidneys from hypertensive donors developed systemic hypertension in contrast with normotensive controls (P<0.05). Allografts from hypertensive animals showed accelerated deterioration in structure and function after transplantation. Proteinuria became significantly elevated as early as 6 weeks (P<0.05) compared with controls and increased progressively thereafter (P<0.005). Grafts from hypertensive donors, histologically normal at the time of engraftment, developed significant morphologic deterioration after 12 weeks (P<0.01). Changes in allografts from normotensive donors remained minor. mRNA of proinflammatory mediators in hypertensive donor grafts (P<0.01) was up-regulated before transplantation and increased progressively over time (P<0.01). Donor hypertension intensifies the chronic injury associated with allogeneic kidney transplantation in the rat model used. This condition also leads to induction of recipient hypertension and may be a more important risk factor for chronic graft dysfunction than previously appreciated.

Impact of Different Immunosuppressive Regimens on Antigen-Presenting Blood Cells in Kidney Transplant Patients

Background: Alloantigen-specific and unspecific immune processes contribute to chronic renal graft dysfunction. Despite ‘optimized immunosuppressive therapy’ (IS), the role of chronic cell activation still remains open. Methods: 69 kidney transplant recipients (NTX) were assessed for monocyte surface antigens CD14 (LPS receptor) and CD16 (Fc-γ-III receptor) by flow cytometry including the percentage amount of the proinflammatory CD14+CD16+ subset. 14 non-dialysis patients with chronic renal failure (CRF) and 24 healthy persons served as controls. Results: All 14 patients suffering from CRF revealed higher CRP serum levels compared to healthy controls (p = 0.01). NTX patients had a (not significant) tendency to higher CRP concentrations (p > 0.05). The mean expression of CD14 on monocytes (mCD14) was lower in patients with CRF and in NTX patients (p = 0.024 – p = 0.026). NTX patients revealed low expression of monocytic CD14 with no difference between the single IS therapy groups. The proinflammatory monocyte subpopulation positive for CD14 and CD16 was elevated both in uremic and NTX patients (p < 0.002), despite long-lasting IS therapy. Conclusions: Continuing IS therapy, even under ‘optimized’ drug-monitoring conditions, does not sufficiently prevent or suppress a microinflammatory (and potential fibrotic growth-promoting) status in NTX patients.

Effects of ileum transplantation and chronic rejection on absorption and synthesis of cholesterol in pigs.

We investigated the effects of ileum allotransplantation and chronic graft rejection on the synthesis and absorption of cholesterol. Twenty pigs underwent intestinal transection or ileum transplantation, in which the distal half of the jejunoileum was replaced with an ileal autograft or allograft. Conventional triple therapy with cyclosporine (10 mg/kg per day), azathioprine and methylprednisolone was tapered to cyclosporine (5 mg/kg per day) after 10 weeks. Serum lathosterol and campesterol, respective markers of cholesterol synthesis and absorption, were determined and related to graft histology. When compared to transected controls, auto- and allotransplantation of ileum similarly increased ( P<0.05) lathosterol and decreased ( P<0.01) campesterol for 12 weeks, despite normal graft histology. Chronic graft rejection progressed between 12 and 18 weeks, when a further increase in lathosterol (+104%) and decrease in campesterol (-67%) was observed. Obliteration of mesenterial arteries in chronically rejecting grafts was associated with high cholesterol synthesis ( R=0.975, P=0.0512). Auto- and allotransplantation of the ileum similarly modulate synthesis and absorption of cholesterol in pigs with non-rejecting grafts. Chronic rejection of the ileal graft appears to markedly increase cholesterol synthesis, which may primarily result from impaired ileal reabsorption of bile acids due to gradual obliteration of mesenterial arteries (chronic rejection). Serial measurements of cholesterol synthesis and bile acid absorption may prove to be a useful tool in the diagnosis of chronic rejection-associated small intestinal graft dysfunction.

Evidence for a protective role of trimetazidine during cold ischemia: targeting inflammation and nephron mass

Ischemia–reperfusion injury (IRI) is associated with an increased risk of acute rejection, delayed graft function, or chronic graft dysfunction. Mitochondria plays a central role in this process. Using an autotransplant pig kidney model, changes in renal function and morphology were determined after different periods of cold ischemia in kidneys preserved in the University of Wisconsin solution (UW), high-Na + version of UW (HEH) or Celsior (CEL) a newly developed high-Na + solution, with or without trimetazidine (TMZ). Kidney function was better preserved in HEH after 24 hr and particularly 48- and 72-hr cold storage than in CEL and UW. TMZ improved the preservation quality when added to the different solutions tested, particularly after 48- and 72-hr cold storage. Interstitial fibrosis and tubular atrophy were reduced in HEH with TMZ. CD4 + T-cell infiltration was also modulated by the preservation conditions. Peripheral-type benzodiazepine receptor (PBR) positive cells infiltration was also modulated by preservation conditions. TMZ was efficient to reduce IRI when added in the various preservation solutions. These results suggest that protection of the mitochondrial function should be a major target to limit IRI. In addition, this study outlines the role of CD4 + T cells and PBR expression in inflammatory responses after IRI.

Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen-Related

We have recently recognized humoral rejection (HR) in lung allograft recipients and its association with acute and chronic graft dysfunction. We have shown that C4d, a stable marker of classic complement activation, is deposited in lung allografts, correlating with clinical rejection and parenchymal injury. The antigenic target may be endothelium in the setting of recurrent acute rejection while varying components of the bronchial wall may be important in chronic graft dysfunction. We sought to establish whether there is a role for antibodies with histocompatibility antigen specificity in the lung humoral allograft phenomenon. Flow cytometric and ELISA assays to assess donor-specific antigens were conducted on sera from 25 lung transplant recipients who had experienced one or more episodes of clinical rejection; in addition, the serum samples were tested for evidence of antiendothelial cell antibody activity. Morphologically, each case had biopsies showing septal capillary injury with significant deposits of immunoreactants with microvascular localization and positive indirect immunofluorescent antiendothelial cell antibody assay. Panel-reactive antibody testing showed absence of MHC Class I/II alloantibodies; ELISA based crossmatch detecting donor-specific MHC Class I/II specific antibodies was negative. HR can occur in the absence of antibodies with HLA specificity; antigenic targets may be of endothelial cell origin.

Use of C4d as a Diagnostic Adjunct in Lung Allograft Biopsies

Purpose: Humoral allograft rejection is a defined mechanism for cardiac and renal graft dysfunction; C4d deposition, a stable component of complement activation, inversely correlates with graft survival. With the recent recognition of humoral rejection in lung grafts, we examined C4d's role as a prognostic adjunct in lung allografts. Material and Methods: Twenty‐three lung recipients underwent biopsies for deterioration in clinical status or routine surveillance. Clinically unwell patients possessed acute rejection or bronchiolitis obliterans syndrome (BOS). Biopsies attributable to infection were excluded from the study. In addition to routine light microscopy, an attempt was made to correlate the clinical status and morphologic findings with the pattern of C4d deposition and also to compare these clinical and morphologic parameters with the other assessed immunoreactants. Panel reactive antibody testing was also carried out at various points in their post transplantation course whereby in 6 of the cases the samples were procured at exactly the same time as the tissue samples. Results: The patients were segregated into two groups: those patients with recurrent acute rejection and those with BOS. In those patients with symptomatic acute rejection, all biopsies showed light microscopic and immunofluorescent evidence of humoral allograft rejection. The level of C4d was positively correlated with the degree of parenchymal injury, the hallmark being one of septal capillary necrosis. In addition, high and intermediate levels of C4d correlated with a clinical diagnosis of acute rejection. C4d was the strongest predictor of parenchymal injury and of the clinical status (p < .0001) compared to other the immunoreactants C1q, C5b‐9 and immunoglobulin. There was no specific correlation between C4d deposition and the presence of acute cellular rejection. In those patients fulfilling clinical criteria of BOS, deposits of C4d as well as other immunoreactants were found in the bronchial wall as opposed to the rarity of this finding in bon‐BOS patients. However the only statistically significant predictor of BOS was bronchial wall deposition of C1q. In no case were panel reactive antibodies at significant levels discovered post transplantation. Conclusions: In the context of acute rejection, C4d deposition correlates with clinical evidence of rejection and the degree of humoral rejection assessed pathologically; there is no association with the presence of histocompatibility related antibodies. It is a more specific predictor of allograft status compared to other immunoreactants. C4d deposition within the bronchial wall is a feature of BOS and hence may be used as a marker of chronic graft dysfunction. The antigenic target resulting in C4d deposition may not be histocompatibility related.

Biopsy eosinophilia as a predictor of renal graft dysfunction

AIM The aim of this research was to assess the impact of eosinophilia in renal biopsy specimens obtained during an acute rejection (AR) episode on the severity and reversibility of rejection and on long-term graft function. Material Among 165 renal graft recipients who underwent transplantation (Tx) in 2001 and 2002 whose biopsy specimens revealed AR, 49 with tissue eosinophilia were compared with control group of 48 without this feature. The average biopsy time was 60.6 and 95.8 days, respectively. Biopsies during delayed graft function were performed in 46.9% of patients with eosinophilia and 29% in the control group. The immunosuppressive regimen was based on tacrolimus or cyclosporine. Results Tissue eosinophilia was observed in 49 of 165 patients (29.6%): 5 patients had eosinophilia <10/mm 2, 31 patients 10–100/mm 2, 13 patients >100mm 2 (3 patients >300/mm 2). Severity of AR according to Banff score was statistically lower in the control group ( P < .002). Patients with tissue eosinophilia who initially received steroid-free treatment presented with significantly higher ( P = .02) biopsy/patients index (2.3 vs 1.81) than the total eosinophilic group. Serum creatinine values at 6 and 12 months after transplantation (Tx) were higher among eosinophilic when compared with the control group (2.41 vs 1.82 mg/dL, P < .002; 2.10 vs 1.98 mg/dL, P = .006, respectively). Chronic rejection within the first year occured in 25% of patients with tissue eosinophilia, and 8.3% of patients in the control group. One-year graft survival rate among patients with tissue eosinophilia was lower compared with the control group (89.8% and 93.7%, respectively). Conclusions Biopsy eosinophilia is a negative predictor that indicates a more severe course of AR and a worse response to treatment with the threat of chronic graft dysfunction.

Efficacy and safety of doxazosin GITS in hypertensive renal transplant patients: comparison of 8 and 4 mg

Background Hypertension (HT), a prevalent complication in renal transplant patient (RT), must be accurately treated because cardiovascular disease is the leading cause of death and of chronic graft dysfunction. Sympathetic activity may contribute to HT in RT, yielding the rationale to suspect that doxazosin, an α 1-adrenergic receptor inhibitor, may lower blood pressure (BP). The aim of this study was to evaluate the efficacy and safety of doxazosin GITS (4 and 8 mg) in RT. Methods Twenty-three hypertensive RT received doxazosin 4 mg once daily for 4 weeks (W 4) followed by a 4-week washout (W 0) and 17/23 treated with doxazosin 8 mg for 4 more weeks (W 8) due to persistent HT. All patients underwent 24-hour ambulatory blood pressure monitoring (ABPM) after W 0, W 4, and W 8. Laboratory tests were performed, adverse events recorded, and prostatic symptomatology examined. Statistical analysis included Saphiro-Wilks, Student t, ANOVA, Wilcoxon, or Friedman tests. Results The systolic, diastolic, and mean BP were significantly lowered at W 4 in awake ( P < .001) and 24 hour period ( P < .005) but not sleep recordings. Doxazosin 8 mg had no significant additional effect to lower BP at any period. Normotension was reached in 13% and 21.7% of patients at W 4 and W 8, respectively. Palpitations were the only reported adverse event after treatment (incidence similar to placebo). There was no significant change in the laboratory values. Conclusions Doxazosin (−4 mg) effectively decreased BP in awake and 24-hour periods without a significant improvement during sleep. A double dose of the drug added little benefit. Optimal BP was reached by an insufficient number of patients. Doxazosin proved to have a good tolerance and safe profile. This results suggest that doxazosin should be considered a good add-on treatment to other antihypertensive drugs in RT.

Mycophenolatemofetil for immunosuppression after liver transplantation: a follow-up study of 191 patients.

Mycophenolatemofetil (MMF) combined with calcineurin inhibitors (CNIs) as immunosuppression after orthotopic liver transplantation (OLT) is still under discussion. We retrospectively investigated the immunosuppressive potency of MMF for treatment of steroid-resistant acute rejection (AR) or chronic rejection (CR), chronic graft dysfunction, and CNI-induced toxicity in patients after OLT. Between 1988 and 2001 we performed 1386 OLTs in 1258 patients. Since 1995, 191 patients have received MMF after OLT for steroid-resistant AR or CR, chronic graft dysfunction (115 patients), and CNI-induced toxicity (76 patients). The mean follow-up time was 56 months. Of 47 patients with steroid-resistant AR, 12 had been treated with OKT3, without resolving the rejection. Overall, bilirubin and transaminases decreased significantly within 2 weeks after the addition of MMF, and liver function normalized in 38 patients. Five of eight patients with CR demonstrated stable liver function after a follow-up of 55+/-8 months; 52 of 60 patients with chronic graft dysfunction improved within 3 months; and 46 of 59 patients with CNI-induced nephrotoxicity improved after MMF treatment and a reduction of CNIs (with a significant decrease in serum creatinine within 2 weeks and an increase of creatinine clearance within 3 months). Clinical symptoms improved in 10 of 12 patients with neurotoxicity and four of five patients with hepatotoxicity. Side effects of MMF, such as gastrointestinal disorders or bone marrow toxicity, occurred in 60 patients (31.4%). The incidence of infections did not increase. Patient survival was 93%, and graft survival was 88.2%. MMF is a potent and safe immunosuppressive agent in OLT recipients for rescue therapy in AR, CR, or chronic graft dysfunction and helps to reduce the serious toxic side effects of CNIs.

Treatment by Mycophenolate Mofetil of Advanced Graft Vascular Disease in Non‐Human Primate Recipients of Orthotopic Aortic Allografts

Failure to control chronic graft dysfunction [e.g. graft vascular disease (GVD)] is the primary cause of immunologic graft failure. This is the first study of mycophenolate mofetil (MMF) for the treatment of GVD in non-human primate recipients of aortic allografts. Abdominal aortic allografts were exchanged between mixed leukocyte reaction (MLR) -mismatched, blood-group-compatible cynomolgus monkeys. Six control recipients were untreated. Individualized treatment with frequent dose adjustments of MMF insured that treatment was close to the maximum tolerated dose (mean 99.2 mg/kg/day). Immune-mediated injury proceeded unhindered until day 45, after which MMF treatment began. Changes in intimal volume (IV) were quantified by intravascular ultrasound (IVUS) and compared to histology on day 105. Serial IVUS measurements of IV (mm(3)) in controls showed progressive GVD. In four out of six animals, MMF was well tolerated, thus enabling optimum treatment; in all these animals, IV was significantly less than in the control animals (p = 0.02). In the two remaining animals, high doses were not tolerated; at day 105, there was no significant difference in IV between them and the controls. We found a significant correlation between the mean MMF tolerated dose and the inhibition of progression of IV (r = -0.88, p = 0.015). When high MMF doses were tolerated, MMF slowed progression of GVD.

Ischemia and reperfusion injury

Organ allografts, particularly from less than optimal donors, may not be biologically inert at the time of transplantation but may trigger or amplify subsequent host responses against the foreign tissues. These potentially activated organs may provoke a continuum between the inflammatory changes evoked in the recipient by initial nonspecific, antigen-independent insults and the later onset of antigen-dependent, immunologic alloresponsiveness. Older donors, hypertension and other donor factors, the peripheral events surrounding brain death, the use of non-heart-beating donors, and ischemia-reperfusion injury may all contribute to initial graft injuries. These in turn may provoke the eventual onset of progressive chronic graft dysfunction. The effects of these insults, with special reference to cardiac transplants, are reviewed.

Short-term immunosuppressive treatment of the donor ameliorates consequences of ischemia/ reperfusion injury and long-term graft function in renal allografts from older donors.

Grafts from so-called "marginal donors" are increasingly used for organ transplantation. The combination of reduced organ quality and additional inflammatory damages may be particularly detrimental in these grafts. In a previous study, we showed the beneficial effects on long-term graft outcome of "suboptimal" grafts by the induction of heme oxygenase-1. Here we tested the impact of short-term donor treatment with established immunosuppressants. Twelve-month-old Fischer 344 donor rats either were treated with prednisolone, mycophenolate mofetil, RAD, or FK506 24 hr and 1 hr before organ harvesting or remained untreated. Renal allografts were perfused with University of Wisconsin solution and kept at 4 degrees C for an ischemic period of 2 hr. Morphologic, immunohistologic, and real time reverse transcriptase-polymerase chain reaction analyses for relevant markers were performed at serial intervals and at the end of the observation period (6 months). All animals survived the observation period, although the ischemic time resulted in accelerated chronic graft dysfunction. Grafts from donors treated with prednisolone or FK506 demonstrated significantly improved graft function and structure by 6 months. Mononuclear infiltrates were significantly reduced by the end of the observation period, whereas intragraft mRNA levels of tumor necrosis factor-alpha and interleukin-10 were significantly altered during the early period after transplantation. Minor improvements in graft function and histologic alterations of suboptimal grafts were observed after pretreatment with mycophenolate mofetil and RAD. Donor treatment with approved immunosuppressants, in particular prednisolone or FK506, represents a novel therapeutic strategy of clinical relevance, most importantly when using grafts from marginal donors.

Tissue injury and repair in allografts: novel perspectives

Recent research achievements might considerably alter scientific concepts of pathways involved in tissue injury and repair. Accumulating evidence for an important role of alloantibodies in acute and chronic allograft rejection led to a renewed interest in humoral kidney transplant rejection. Studies reassessing the mechanisms of antibody- and complement-mediated injury now shed new light on the pathogenic mechanisms underlying acute or chronic graft dysfunction and injury. A closer look at humoral effector mechanisms revealed that endothelial cell activation and injury may play a key role in humoral rejection, and further uncovered an important interplay between humoral and cellular alloimmunity. Regeneration of cells after injury has been thought to rely on activation of local progenitor cells. Recent investigation indicates that regeneration of grafted solid organs is not exclusively based on self-renewal of tissues but obviously also involves repopulation of the graft by recipient cells, creating chimerism in the vasculature and other compartments. Besides reparative compensation of cell loss, chimerism of endothelial cells might also alter immunologic properties of the graft, thus favoring adaptation and graft survival. On the other hand, however, myofibroblasts mediating deleterious arterial intimal proliferation may also be of recipient origin. A possible source of graft-repopulating recipient cells are bone marrow-derived adult stem cells with the amazing capacity of differentiating into cell types of all three germ cell layers. Reliable diagnosis of humoral mechanisms in allograft rejection and identification of involved effector mechanisms should provide the basis for development and targeted application of specific anti-humoral treatment. Recently emerged new concepts of mechanisms underlying tissue regeneration might pave the way for entirely new therapeutic approaches in human disease.

Risk factors for chronic graft dysfunction in 918 renal transplants

(40% vs 25%), graft perfusion with Euro-Collins solution (37% vs 19%), DGF (40% vs 25%), and AR (44% vs 16%) (Table 1). The immunosuppressive regimen of azathioprine (Aza) prednisone (Pred) was associated with the highest (37%) incidence of CD and mycophenolate mofetil (MMF) CyA Pred with the lowest (13%) risk. In this series of renal transplants, CD emerged as the second cause of graft failure, with a rate of 30.6%, after death with a functioning graft (DWFG) with a 40.6% rate. We found a clear influence of AR on CD as a cause of graft loss: with 0, 1, or 1 AR episodes the graft loss due to CD was 22%, 43.5%, and 59%, respectively. The 1-year SCr significantly correlated with later development of CD (40% of CD with SCr 1.2 mg/dL vs 12% of CD with SCr 1.2 mg/dL). Graft survival rates at 1, 3, 5, 10, and 15 years were 98%, 86%, 68%, 36%, and 23% in the CD group, respectively, and 99%, 95%, 92%, 84%, and 74% in the group without CD, respectively. These differences in graft survival were statistically significant (P .000) (Fig 1). Patient survival rates at 1, 3, 5, 10, and 15 years were 99%, 96%, 90%, 70%, and 57% in the CD group, respectively, and 99%, 96%, 92%, 85%, and 75% in the group without CD, respectively. These differences in graft survival were also statistically significant (P .0016).

Is chronic calcineurin inhibitor toxicity responsible for long-term deterioration of renal function in transplant recipients?

Dose reduction or discontinuation of calcineurin inhibitors (CIs) in renal allograft recipients results in a measurable improvement in renal function, as assessed by a decrease in serum creatinine or improvement in glomerular filtration rate. In general, this effect has been presumed to result from a discontinuation of the acute vasoconstrictive action of CIs on the afferent arteriole. Does it reflect the resolution of chronic CI toxicity? Does chronic CI toxicity explain part of the syndrome of chronic allograft nephropathy (CAN)? We have observed evidence of a continued improvement in renal function or a lack of further deterioration after CI dose reduction or discontinuation in patients with CAN. This improvement in renal function remains evident for up to several years after the intervention and is observed even when the period of acute vasoconstriction (6 months after intervention; the period when the greatest rate of change occurs) is taken into account. These findings suggest a detrimental effect of CIs on renal function that may be, at least in part, reversible and independent of vasoconstriction. In this review, we examine the data concerning the relationship between CI and chronic graft dysfunction.

INOS and peroxynitrite formation during acute rejection after human heart transplantation

endomyocardial biopsy (EMB) beyond 2 years post-transplant remains uncertain. We performed a retrospective analysis reflecting our singleinstitution experience with 4041 biopsies (188 patients) from 1986-2001. Late ISHLT grade 3A rejection ocurring beyond 2 years posttransplant was detected in 24% of cardiac transplant recipients (33 of 139 patients) up to 10 years post-transplant. Late rejection could not be attributed to subtherapeutic levels of immunosuppression or other established parameters. Late rejection was only marginally correlated with the incidence of moderate rejection within the first 2 posttransplant years (p 0.09). Unlike the incidence of moderate rejection in the first post-transplant year showing a steady decline toward more recent years (2.1430.13), the incidence of late rejection appeared not to be influenced by transplant era (mean 0.11 0.056) over a 10 year observation period (1989-1999). Spontaneous resolution of moderate rejection beyond 2 years post-transplant occurred in all 17 patients in whom specific anti-rejection therapy had been electively withheld. Mortality beyond 2 years post-transplant was slightly lower (p 0.033) in the late rejecting group (n 33) than in the control group (n 106), no difference was found in the prevalence of transplant vasculopathy diagnosed by coronary angiography. EMB continues to detect episodes of moderate rejection even very late after heart transplantation without a close correlation with the rejection frequency in the early posttransplant period. Late rejection may represent a distinct biological entity as evidenced by its spontaneous resolution, lack of an era effect as is found for early rejection and no negative impact on survival. The future role of late EMB will depend on its predictive value for diagnosis and risk stratification of chronic graft dysfunction.

Modulation of peripheral-type benzodiazepine receptor levels in a reperfusion injury pig kidney-graft model.

Ischemia-reperfusion injury is associated with an increased risk of acute rejection, delayed graft function, or chronic graft dysfunction. Mitochondria play a central role in this process. Using an autotransplantation pig kidney model, both early (40 min and 7 days) and late (2-16 weeks) changes in renal function and morphology were determined after different periods of cold ischemia in University of Wisconsin or Euro-Collins solutions. We have also investigated the expression of the peripheral-type benzodiazepine receptor (PBR), which is also critical in maintaining outer mitochondrial membrane stability. Function of the kidneys was better preserved after 1 hr and 24 hr than after 48 hr and 72 hr in Euro-Collins and University of Wisconsin solutions. Medulla injury was reduced in 1 hr-preserved and 24 hr-preserved groups. PBR was found to be present in epithelial cells of the deep cortical and outer medulla in both normal human and well-preserved pig kidneys. PBR expression was modulated by ischemia-reperfusion injury and the concurrent tubular injury and repair processes. This study indicates that PBR expression correlates with the quality of kidney preservation and might serve as an index of kidney and mitochondria viability. Moreover, these data suggest that PBR might be involved in membrane biogenesis during reperfusion. In addition, considering the identical localization of PBR in human and pig kidneys, these findings could have a direct application in human clinical settings of kidney pathology.