CsA Withdrawal Research Articles

Cyclosporine withdrawal in post‐renal transplant thrombotic microangiopathy

Thrombotic microangiopathy (TMA) is a well known complication of cyclosporine (CsA)-treated renal transplantation but optimum treatment strategies are not clearly defined. All patients transplanted between January 1996 and December 2001 at our center who had biopsy-proven TMA and in whom CsA was withdrawn were studied retrospectively. The TMA was found in nine of 688 patients (1.3%). All except one donor were living related. HLA matching was one haplotype in all except one where both haplotypes were different. There were five males and four females and the mean age was 24.9 +/- 9 yr. All of them developed TMA within 3 months of transplant. Five of nine had evidence of microangiopathic hemolysis on peripheral film. Serum creatinine at the time of diagnosis of TMA was 3.1 +/- 1.3 mg/dL. Cyclosporine was discontinued in all and mycophenolate mofetil was substituted for azathioprine. No episode of acute rejection occurred after CsA withdrawal. Graft function did not improve in four who eventually became dialysis-dependent after a mean duration of 12.6 +/- 8.3 months. Remaining patients showed stabilization or improvement in function and all had serum creatinine below 2 mg/dL after a mean follow up of 24 months. The CsA withdrawal in cases with TMA at a stage when significant functional deterioration has not taken place can salvage the graft.

Predictive Factors of Acute Rejection after Early Cyclosporine Withdrawal in Renal Transplant Recipients Who Receive Mycophenolate Mofetil

The aim of this randomized, open-labeled trial was to compare the incidence of acute rejection after an early (3 mo posttransplantation) withdrawal of cyclosporine (CsA) or mycophenolate mofetil (MMF) in renal transplantation. Among 218 eligible recipients, 108 nonsensitized, rejection-free patients who were under a triple drug regimen (CsA-MMF-prednisone) and had received a first kidney from a deceased donor were enrolled. At 3 mo after graft, they were gradually withdrawn from CsA (MMF group, n = 54) or MMF (CsA group, n = 54). A graft biopsy and a pharmacokinetic study of CsA and mycophenolic acid were systematically performed before the randomization. At 1 yr, graft and patient survival rates were 100% in each group. Renal function was improved in the MMF group compared with the CsA group (Cockcroft calculated clearance 64.7 +/- 18.7 versus 56.5 +/- 18.0 ml/min; P = 0.023). However, the probability of acute rejection was higher in the MMF group (18.5 versus 5.6%; P = 0.045). The 10 patients who developed acute rejection after CsA withdrawal had a significantly higher incidence of borderline changes on the randomization biopsy than the 44 rejection-free patients (five of 10 versus eight of 44; P = 0.034), and they displayed a lower area under the curve of mycophenolic acid (43 +/- 9 versus 58 +/- 22 mg/h per L; P = 0.045). Multivariate analysis confirmed that borderline changes and area under the curve of mycophenolic acid were significant risk factors of acute rejection after CsA discontinuation. It is concluded that a systematic graft biopsy and a pharmacokinetic study of mycophenolic acid are needed to reduce the risk for acute rejection after CsA withdrawal.

Clinical Experience with Everolimus (Certican) in Elderly Recipients: The ???Old-for-Old??? Concept

With an increasing number of elderly patients now waiting for a kidney transplant, and the percentage of kidney donors over 55 years also rising, harvesting older kidneys specifically for use in older recipients is a way of extending the donor pool for renal transplantation. Two case studies from an everolimus (Certican) Phase III trial (A2306) are presented. They illustrate clinical experience of achieving stable graft function in the "old-for-old" kidney transplant program at the Ramon y Cajal Hospital in Madrid, Spain. The first case study demonstrates that stable graft function can be achieved in an "old-for-old" kidney transplant patient, who receives everolimus in combination with reduced-exposure cyclosporine (CsA). To optimize graft function in the long-term, CsA C(2) blood levels should be <400 ng/ml. The second case study highlights how "old-for-old" renal transplant recipients can be at risk of calcineurin-inhibitor (CNI)-induced nephrotoxicity. Here, graft function did not improve following CsA dose reduction; thus, CsA was withdrawn 1 year posttransplant. Stable graft function that is acceptable for an "old-for-old" kidney transplant was then achieved with everolimus trough blood levels of 10-15 ng/ml and low-dose prednisone. In these cases, everolimus was used safely and effectively in the "old-for-old" kidney transplant setting. Its combination with reduced-exposure CsA, or its facilitation of CsA withdrawal, minimized the risk of nephrotoxicity in the older renal graft. These findings need to be confirmed in larger studies specific to this population.

Editorial Comment: Reduction in Calcineurin Inhibitor Exposure and Maintenance of Effective Immunosuppression: Clinical Experience with Everolimus (Certican)

Editorial Comment: Reduction in Calcineurin Inhibitor Exposure and Maintenance of Effective Immunosuppression: Clinical Experience with Everolimus (Certican)

Kaposi's Sarcoma in Renal Transplant Patients: Predisposing Factors and Prognosis

Among 772 kidney transplant recipients in two centers 25 patients developed Kaposi's sarcoma (KS) (3.2%). The twenty-two of 25 recipients with regular follow-up records were compared for predisposing factors with another group of 22 renal transplant recipients. All patients received cyclosporine (CsA), azathioprine, or mycophenolate mofetil and steroids; patients who received cadaver donor organs additionally received antilymphocyte globulin for induction. KS was diagnosed at a mean of 25.8 months after transplantation. The male to female ratio; mean age; mean follow-up period; hepatitis B, hepatitis C, cytomegalovirus status; and other infection rates were similar in the two groups. Some HLA-DR antigens were detected only in patients with KS. All patients had mucocutaneous involvement, which was multiple in 54.5%. Visceral involvement, and lymph node involvement, or both was detected in seven patients. First-line treatment was to stop CsA and reduce the doses of the other drugs. Three patients underwent additional surgical excision. Fourteen (63.6%) patients experienced complete remissions, including six who required additional chemotherapy or radiotherapy after incomplete or lack of responses to first-line treatment. Two patients died with functioning grafts due to generalized KS. Seven patients returned to hemodialysis at a mean of 36 months after the diagnosis of KS. No significant predisposing factor was observed other than the prevalence of specific HLA-DR antigens. Chemotherapy or radiotherapy should be initiated for patients with multiple, diffuse, and rapidly progressive lesions or organ dysfunction in addition to withdrawal of CsA and tapering of other drugs. Generalized KS displays the poorest prognosis.

Serum TGF-β1 Correlates With Chronic Histopathological Lesions in Protocol Biopsies of Kidney Allograft Recipients

Introduction Transforming growth factor-β (TGF-β) is a well-known profibrotic factor playing a role in chronic kidney allograft nephropathy. Cyclosporine (CsA)-sparing immunosuppressive regimens may improve long-term graft function. Our aim was to study the influence of immunosuppressive treatment with versus without calcineurin inhibitors on serum TGF-β levels and histological changes in protocol biopsies of kidney allograft recipients. Patients and Methods In this prospective, randomized study of 42 low-rejection risk patients we randomized two groups: group A: mycophenolate mofetil (MMF), prednisone, daclizumab, and reduced CsA dose for 7 months (5 mg per kg per day) followed by complete withdrawal ( n = 21); and group B: normal CsA dose (10 mg per kg per day adjusted according to C 2 levels), MMF, prednisone, and no daclizumab ( n = 21). Methods In both groups we performed histological assessments (Banff 97) and measured serum TFG-β levels before as well as, at 3 and 12 months after transplantation. Results We found a relationship between immunosuppressive regimen and the TGF-β concentration over 1 year of observation. Before transplant the TGF-β1 levels did not differ between the groups ( P = .29); at 3 months they were 33 ± 9 vs 49 ± 15 pg per mL, respectively, in groups A and B ( P = .08), and at 12 months they were 39.5 ± 4 versus 55.5 ± 11 pg per mL, respectively, in groups A and B ( P = .03). Protocol biopsies at 12 months in group B showed chronic tubular lesions more pronounced than in group A. TGF-β1 concentrations were significantly higher among group B than A. We conclude that TGF-β1 concentration may predict the development of kidney graft fibrosis; early CsA withdrawal may achieve a reduction in chronic tubular and interstitial injury of cadaveric kidney allografts.

Switching from Cyclosporine to Tacrolimus in Patients with Chronic Transplant Dysfunction or Cyclosporine-Induced Adverse Events

Progressive renal-function decline caused by chronic allograft nephropathy is the main cause of long-term failure after kidney transplantation. Moreover, chronic cyclosporine (CsA)-induced nephrotoxicity is an important nonimmunologic factor contributing to graft dysfunction and loss, and adverse events may require CsA withdrawal. Tacrolimus (Tac) replaced CsA-based immunosuppression in 133 transplant patients (114 kidney, 15 kidney-pancreas, 4 pancreas after kidney) with progressive loss of renal function (71% of patients) or CsA intolerance (29% of patients) not responding to CsA dose-lowering. The primary end-points of this prospective study focusing on renal function were the safety and efficacy of Tac immunosuppression. Tac was generally well tolerated but definitively withdrawn for 23 (17%) patients (21 graft failures, 1 case of diabetes, and 1 case of clinical intolerance). Differential creatinemia (creatinemia-nadir creatinemia after transplantation) decreased significantly from 85.4+/-9.8 to 39.0+/-7.5 mumol/L (P<0.001; mean+/-SEM) after 1 year and 3.6+/-18.1 mumol/L (P<0.01) after 4 years. For patients with CsA intolerance, switch to Tac improved intolerance symptoms in all cases. Blood urea, creatinine clearance, blood total cholesterol, and triglycerides improved significantly, and the percentage of hypertensive patients remained stable with no de novo hypertension. During follow-up, one patient experienced an acute rejection episode (not histologically proven), and four died. Twenty-one (16%) transplants failed, significantly more frequently in patients with advanced renal impairment before Tac (P<0.0001). Switching from CsA to Tac can be an alternative strategy in kidney-transplant patients suffering from chronic allograft dysfunction or CsA toxicity. The persistently improved renal function over several months of evaluation suggests that in these patients, Tac might be less nephrotoxic than CsA and could prolong transplant function despite CsA failure.

Cardiovascular risk profile in patients treated with sirolimus after renal transplantation

Renal transplant patients are inherently predisposed to cardiovascular disease (CVD) as a result of prolonged exposure to multiple cardiovascular risk factors. Approximately one half of all late graft losses are due to death with a functioning graft, and CVD is the most frequent cause of death with a functioning graft among these patients. Immunosuppressive therapies associated with a reduced burden of risk for CVD would therefore greatly decrease post-transplantation morbidity and mortality. The nephrotoxic effects observed with the use of calcineurin inhibitors (CNIs), such as cyclosporine (CsA), run counter to the goal of renal transplant therapy. Sirolimus, a more recent immunosuppressive agent with a unique mechanism of action, offers an alternative to CsA. Recent data from a 4-year study investigating early CsA withdrawal from a sirolimus-CsA-steroid (SRL-CsA-ST) combination demonstrated significantly better renal function, lower blood pressure, and improved graft survival after CsA withdrawal. During that trial, the increase in serum lipids induced by sirolimus was generally manageable with lipid-lowering therapy. Further investigation is warranted to evaluate the value of CNI-free therapy compared with CNI-based regimens in reducing cardiovascular risk factors and improving patient and graft survival.

Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation

We report the 48-month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL-CsA-ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL-CsA-ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL-ST, n = 215). SRL-ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL-ST. Differences in the incidences of biopsy-proven acute rejection after randomization (6.5% vs. 10.2%, SRL-CsA-ST versus SRL-ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL-CsA-ST-treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL-ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL-CsA-ST regimen rapidly improves renal function and ultimately results in better graft survival.

Immunotherapy and Chemotherapy Can Result in Long-Term Survival for Patients with Recurrent or Progressive Non-Hodgkin's Lymphoma after Reduced-Intensity Allogeneic Stem Cell Transplantation.

Reduced-intensity allogeneic stem cell transplantation (RIST) has been demonstrated to clinically benefit patients (pts) with relapsed, chemotherapy-sensitive non-Hodgkin's lymphoma (NHL). The most significant challenge after RIST is treatment of recurrent or progressive disease, and the subsequent outcomes of NHL pts, who either have progressed or relapsed after RIST, have not been previously reported. To address this question we performed a retrospective analysis on 35 pts who had undergone RIST from HLA-matched siblings for refractory/relapsed NHL (excluding CLL/SLL). Outcomes were analyzed from Day +100 on, as all pts had achieved complete donor chimerism by this time point and this was a scheduled time of disease assessment as per protocol. All pts had received the identical reduced-intensity conditioning regimen consisting of fludarabine and cyclophosphamide and had received cyclosporine (CSA)-based GVHD prophylaxis. For pts with recurrent or progressive NHL, we employed a sequential approach of CSA withdrawal, followed by rituximab (ritux), followed by donor lymphocyte infusion (DLI), and then followed by chemotherapy +/− DLI; specific treatment was dependent upon the presence or absence of GVHD and CD20 expression. At Day +100 post-RIST 23/35 pts were in a complete remission (CR) of which 4 (DLC = 2, FCC = 1, MCL = 1) were subsequently observed to relapse. The disease status at Day +100 among the remaining 12 pts (DLC = 10, FCC = 1, PTCL =1) not in CR at Day +100 post-RIST was partial remission (PR) = 2, stable disease (SD) = 1, and progressive disease (PD) = 9, as compared to pre-RIST evaluation. Among the 4 pts who relapsed after an initial CR post-RIST, 3 had CSA withdrawn, 1 received ritux, 3 received DLI, and 2 received chemotherapy + ritux. There subsequently were 3 CR and 1 PR. CR were maintained 12, 24+, and 26+ months after intervention. Three of these 4 pts are alive, and the 12 month probability of survival beyond Day +100 post-RIST was 75%. Among the 12 pts who were not in CR at Day +100 post-RIST, all 12 subsequently had CSA withdrawn, 7 received ritux, 5 received chemotherapy, and 3 received DLI. For the 2 pts in PR at Day +100 both achieved a CR by 6 months post-RIST. The one SD patient achieved a PR and died +11 months post-RIST. Among the 9 pts with PD at Day +100, 2 achieved CR, which have been maintained for 22+ and 4+ months, respectively. The 12 month probability of survival beyond Day +100 post-RIST for the 12 pts not in CR at Day +100 was 44%. The 12 month probability of survival beyond Day +100 post-RIST for all 16 pts was 52%. These data demonstrate that relapse after achievement of CR post-RIST is low, and that the majority of these patients can achieve sustained survival with post-transplant therapies. For NHL pts who do not initially achieve a CR at Day +100 post-RIST, subsequent outcome appears to correlate with disease status at Day +100; however, sustained, complete remissions could be achieved for a minority of patients with progressive disease post-RIST. These data indicate that further immunotherapy and additional chemotherapy can result in significant long-term survival for NHL pts with recurrent or progressive disease post-RIST.

The Application of Sequential and Quantitative Analysis of Donor Chimerism in Adoptive Immunotherapy Following Allogeneic Stem Cell Transplantation.

Objective In order to investigate the value of sequential and quantitative analysis of chimerism to predict relapse or graft rejection after allogeneic stem cell transplantation, to determine the optional time point of adoptive immunotherapy and to estimate the efficacy of adoptive immunotherapy.Methods 70 patients who received HLA compatible allo-HSCT were evaluated. Peripheral blood and bone marrow were collected before and after transplantation in different period. Serial and quantitative analysis of donor chimerism (DC) both prior to and following adoptive immunotherapy were performed by multiplex PCR amplification of STR markers (STR-PCR) and capillary electrophoresis with fluorescence detection.Results 13 of 70 patients relapsed at median time of 6months post transplant (4/13 patients developed hematologic relapse and 9/13 patients appeared cytogenetic or molecular relapse respectively). 2 of 70 patients experienced graft rejection. Before the time of relapse or graft rejection, STR-PCR indicated the decreasing DC in all 15 patients, at levels ranging from 24.8%~86.2%. The declining value of donor chimerism (DC< 90%) was detected in four patients 26 days before relapse or graft rejection diagnosed clinically. Adoptive immunotherapy was used to treat 15 patients(9 CML, 5 AML, 1 MDS). A response to immunotherapy was achieved in 6 patients(6 CML) following withdrawal of CsA and in a further 4 patients(2 CML, 1 M2, 1 MDS) after additional donor lymphocyte infusion(DLI). In these patients, the value of DC increased with convertion to a predominant donor profile (>90%) or converted to stable full donor chimerism(FDC)(6 patients) or stable mixed chimerism(MC)(4 patients) shortly after immunotherapy. All these 10 patients who responsed to immunotherapy developed acute or chronic GVHD. While in the patients without response, the level of DC decreased persistently or declined after transient increasing. Three patients without response received second DLI but remain failed to therapy.Conclution The results demonstrate that the decreasing value of DC can identify the patients who have high risk of relapse or graft failure and can be used to guide adoptive immunotherapy implementation at early stage. The sequential and quantitative monitoring of DC has been shown to be a valuable tool to determine the optional time point of immunotherapy and to early evaluate the efficacy of treatment. Furthermore, it can present a rational basis for treatment intensification in patients who did not respond to first-line DLI treatment

Campath-1H-Based Reduced-Intensity Conditioning Followed by Allogeneic Blood Stem-Cell Transplantation and Preemptive CD8-Depleted Donor Lymphocyte Infusions.

Recent reports have demonstrated the feasibility of using the anti-CD52 antibody Campath-1H for in vivo T-cell depletion (TCD) in the context of a fludarabine/melphalan-based reduced-intensity conditioning regimen (Kottaridis et al. Blood 2000, 96:2419). Major disadvantage of this protocol is the severe immunosuppression which results in an increased rate of opportunistic infections and disease relapses. Donor lymphocyte infusions (DLI) are frequently used to overcome this limitation. The application of DLI, however, is associated with a profound risk of GvHD. Depletion of CD8+ lymphocytes from either the allotransplant or from DLI has proven feasible to reduce the incidence of GvHD (Nimer et al. Transplantation 1994, 57:82; Giralt et al. Blood 1995, 86:4337).We set up a phase-I allotransplantation study which combines the Campath-1H (100mg)/fludarabine (150mg/m2)/melphalan (140mg/m2) preparative regimen with the preemptive administration of CD8-depleted DLI in patients with hematological malignancies not eligible for myeloablative conditioning. After early withdrawal of CsA immunosuppression, CD8-depleted DLI are scheduled in a dose-escalating regimen starting on day +60 after HLA-identical sibling transplantation and on day +120 after unrelated donor transplantation, respectively. For CD8-depletion of donor leukaphereses a new CliniMACS-based protocol using clinical grade CD8 Microbeads is used. Our data show that this procedure is efficient in reducing the content of CD8+ T-cells by at least 2.5 to 3.5 logs, while CD4+ cells remain largely unchanged.In this ongoing study, 8 patients (4 myeloma, 2 CMPD, 1 ALL, 1 NHL) were included and received peripheral blood stem cells (PBSC) from HLA-identical sibling (1), HLA-matched (5) or DRB1-mismatched unrelated donors (2), according to high-resolution HLA typing. Chimerism analyses on total bone marrow-derived cells as well as on purified CD4, CD8, CD19, CD14 and CD15-positive peripheral blood cells showed durable complete donor chimerism in all but one patient (see below). After successful withdrawal of CsA, 2 patients already received CD8-depleted DLI without any acute toxicity. In the first patient (UPN 3), who was transplanted from an HLA-identical sibling, DLI were given on days 60 and 120 (1 and 5 x 106 CD4+ T cells, respectively). The second patient (UPN 4), who was transplanted from a matched unrelated donor, received the first dose of 1 x106 CD8-depleted DLI on day 120. DLI were regularly followed by a more than 2-fold increase of CD4+ cells during the first two weeks after application, while CD8+ cells remained unchanged. After the second DLI, patient UPN 3 developed a grade 2 GvHD of the skin (d+22 after DLI). Both patients were at high risk for CMV reactivation (donor: CMV negative, host: CMV positive) and repeatedly received preemptive treatment. Immediately prior to the second DLI, the CD8+ cell count in patient UPN 3 increased during an ongoing CMV reactivation. Line-specific chimerism analysis revealed that more than 50% of these CD8+ cells were of host origin. As expected, transfer of CD8-depleted DLI from CMV-negative donors was unable to entirely prevent CMV reactivation in seropositive patients. Nevertheless, our preliminary data suggest that the preemptive transfer of CD8-depleted DLI is able to accelerate immune reconstitution after reduced intensity TCD allogeneic PBSCT without rapid increase of CD8+ donor cells.

Impact of chronic allograft nephropathy and subsequent modifications of immunosuppressive therapy on late graft outcomes in renal transplantation.

Chronic allograft nephropathy (CAN) is the leading cause of organ failure in renal transplant recipients. We retrospectively evaluated the impact of varying immunosuppression in CAN patients on long-term graft survival. We retrospectively analysed 158 cyclosporin (CsA)-treated renal transplant recipients with biopsy-proven CAN with follow-up of >1 year. Immunosuppression remained unchanged in 75 (NOVAR) and was modified in 83 patients (VAR). In 36.1% of VAR patients, it was increased; in 63.8%, the addition of other immunosuppressants was associated with a 20% reduction in or withdrawal of CsA. A regression model, for creatinine clearance (CrCl) slope analysis after therapy variation, and Cox's analysis were applied. In VAR patients, two-phase regression did not show a correlation between the inflection point in the CrCl slope and treatment variation. Changing immunosuppression gave a borderline advantage in long-term graft survival compared with NOVAR (P = 0.088). In univariate analysis, severe histological lesions, proteinuria >0.5 g/day and CrCl <25 ml/min at biopsy correlated with poor graft outcome (P = 0.0009). In multivariate analysis, only proteinuria and low CrCl remained significative. Stratifying histological lesions in relation to therapy variation showed that severe lesions significantly decreased survival in both VAR and NOVAR groups; however, the highly negative impact of severe lesions in NOVAR patients on graft survival [relative risk (RR) 3.602] was reduced in VAR patients (RR 1.951), with a 10 year graft survival since biopsy of 0.16 vs 0.34 (P = 0.0001). In transplant patients with CAN, variation of immunosuppression can reduce the negative impact of severe chronic lesions.

CALCINEURIN INHIBITOR WITHDRAWAL IN RENAL TRANSPLANT RECIPIENTS: IMPROVEMENT IN RENAL FUNCTION AND REDUCTION OF CARDIOVASCULAR RISK

P239 Aims: Immunosuppressive regimens with cyclosporine (CSA) reduced the occurrence of acute rejection episodes in renal transplants, with better graft survival. However, side effects such as nephrotoxicity, systemic hypertension and metabolic disorders have a negative impact on patient survival, increasing the cardiovascular mortality. Regimens with lower CSA doses has been proposed to reduce cardiovascular risk. The aim of the present study was to analyze the safety and efficacy of slow CSA withdrawal in renal transplant patients with chronic allograft nephropathy (CAN). Methods: renal transplant patients followed >12 months, with impaired renal function (serum creatinine >1.5mg%) and/or hyperlipidemia and hyperuricemia were included in the present protocol. Immunossupressive regimen included full dose of mofetil mycophenolate (MMF, 2 to 3 grams/day) and at least 5 mg/day of prednisone. CSA dose was reduced in a step by step basis (0.5mg/kg/day every month), with complete withdrawal after 6 months of study. Clinical and laboratory data were analyzed at each time point. Results: 63 renal transplant patients (56 male, 7 female), mean age 41 ± 9 years old, recipients from cadaveric (n=39) or living related (n=24), followed for 66 ± 30 months post transplant (12 to 122 months) were included in this study. Sixty one patients completed the CSA withdrawn and no acute rejection episodes were observed during the study period (mean follow up of 8 months after withdrawal). Two patients were drop out because of GI intolerance to MMF. A significant reduction in both serum creatinine (2.05 ± 0.7mg/dl CSA treatment vs. 1.69 ± 0.7 mg/dl CSA free p<0.05), and in systemic blood pressure (104 ± 8 mmHg CSA vs. 97.5 ± 7 mmHg CSA free, p<0.05) occurred with CSA withdrawal. Increase in glomerular filtration rate occurred after CSA withdrawal (Cockrofi Gault clearance 64.5 ± 10.1 ml/min with CSA vs. 74.4 ± 9.4 ml/min, CSA free, p<0.05). A improvement in metabolic profile was also observed after CSA withdrawal, with reduction in both total cholesterol levels (233 ± 52 mg/dl vs. 196 ± 57 mg/dl, p<0.05) and serum uric acid levels (8.2 ± 1.7 mg/dl vs. 7.5 ± 1.6 mg/dl, p<0.05). The number and dose of anti-hypertension drugs, allopurinol and statins was also observed after CSA withdrawal.. Conclusions: in renal transplant patients with CAN and metabolic disorders, CSA withdrawal in presence of full dose MMF was safe, leading to a better blood pressure control and glomerular filtration recovery. The slowly reduction in CSA dosage avoided acute rejection episodes in this series. A longer follow up is needed in order to evaluate the effect of CSA free regimen in the occurrence of cardiovascular events.

Effect of rapamycin on cytokine profile in kidney transplant recipients treated with triple drug therapy

The aim of this study was to explore differences in the cytokine profile among de novo kidney transplant recipients treated with either Rapamycin (Rapa) + cyclosporine (CsA) + prednisone (P) or CsA + azathioprine (Aza) + P. Patients and methods Among the 13 adult kidney transplant recipients studied, seven received Rapa + CsA + P while the remaining six received CsA + Aza + P with their living donors serving as controls ( n = 13). Spontaneous production of IL-2, IFNγ, IL-10, and TGF-β were measured by ELISA in supernatants from 24-hour cultured unstimulated peripheral blood mononuclear cell (PBMC) at time zero (the day before the transplant), and at 3 and 6 months posttransplant. Cytokines were also measured 1 month after CsA withdrawal in the Rapa + CsA + P group. Results From time zero to the end of the study, IL-2, IFNγ, and IL-10 were present at low or undetectable levels in all three groups. TGF-β tended to increase in supernatants from patients under Rapa + CsA + P at 6 months posttransplant and at 1 month after CsA withdrawal without correlation to Rapa blood levels. TGF-β remained stable throughout the study period for patients included in the CsA + Aza + P group. There was no difference in this cytokine level between these study groups at any given time. Conclusions This study showed no differences in the spontaneous cytokine profiles evaluated in patients treated with both therapeutic schemes.

Maximizing the clinical outcome with mTOR inhibitors in the renal transplant recipient: defining the role of calcineurin inhibitors

Abstract The synergistic action of mTOR inhibitors and calcineurin inhibitors (CNIs) provide a rationale for combination therapy, with the potential for CNI-dose reduction and corresponding clinical benefits. CNI therapy is necessary in the early post-transplant phase to deliver sufficient immunosuppressive potency, but use of standard-dose cyclosporine (CsA) with either sirolimus or everolimus has been associated with inferior renal function. Withdrawal of CsA from an mTOR-based regimen reduces renal toxicity, but this may be achieved at the price of increased late rejection and sirolimus-related adverse events. Use of a concentration-controlled mTOR inhibitor with low-exposure CsA seems to be effective in preventing rejection with good renal function. Currently, routine withdrawal of CNIs from an mTOR-inhibitor based regimen, or substitution of an mTOR inhibitor for a CNI, is not justified except in patients who experience toxicity (particularly nephrotoxicity) and who do not respond to CNI dose optimization.

KAPOSI’S SARCOMA IN RENAL TRANSPLANT PATIENTS: PREDISPOSING FACTORS AND PROGNOSIS

Among 772 kidney transplant recipients in two centers 25 patients developed Kaposi's sarcoma (KS) (3.2%). The twenty-two of 25 recipients with regular follow-up records were compared for predisposing factors with another group of 22 renal transplant recipients. All patients received cyclosporine (CsA), azathioprine, or mycophenolate mofetil and steroids; patients who received cadaver donor organs additionally received antilymphocyte globulin for induction. KS was diagnosed at a mean of 25.8 months after transplantation. The male to female ratio; mean age; mean follow-up period; hepatitis B, hepatitis C, cytomegalovirus status; and other infection rates were similar in the two groups. Some HLA-DR antigens were detected only in patients with KS. All patients had mucocutaneous involvement, which was multiple in 54.5%. Visceral involvement, and lymph node involvement, or both was detected in seven patients. First-line treatment was to stop CsA and reduce the doses of the other drugs. Three patients underwent additional surgical excision. Fourteen (63.6%) patients experienced complete remissions, including six who required additional chemotherapy or radiotherapy after incomplete or lack of responses to first-line treatment. Two patients died with functioning grafts due to generalized KS. Seven patients returned to hemodialysis at a mean of 36 months after the diagnosis of KS. No significant predisposing factor was observed other than the prevalence of specific HLA-DR antigens. Chemotherapy or radiotherapy should be initiated for patients with multiple, diffuse, and rapidly progressive lesions or organ dysfunction in addition to withdrawal of CsA and tapering of other drugs. Generalized KS displays the poorest prognosis.

Maximizing the clinical outcome with mTOR inhibitors in the renal transplant recipient: defining the role of calcineurin inhibitors.

The synergistic action of mTOR inhibitors and calcineurin inhibitors (CNIs) provide a rationale for combination therapy, with the potential for CNI-dose reduction and corresponding clinical benefits. CNI therapy is necessary in the early post-transplant phase to deliver sufficient immunosuppressive potency, but use of standard-dose cyclosporine (CsA) with either sirolimus or everolimus has been associated with inferior renal function. Withdrawal of CsA from an mTOR-based regimen reduces renal toxicity, but this may be achieved at the price of increased late rejection and sirolimus-related adverse events. Use of a concentration-controlled mTOR inhibitor with low-exposure CsA seems to be effective in preventing rejection with good renal function. Currently, routine withdrawal of CNIs from an mTOR-inhibitor based regimen, or substitution of an mTOR inhibitor for a CNI, is not justified except in patients who experience toxicity (particularly nephrotoxicity) and who do not respond to CNI dose optimization.

Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies.

We examined the rates of malignancy at 2 yr after transplantation in renal allograft patients receiving sirolimus (SRL) in continuous combination with cyclosporine (CsA), SRL as base therapy or SRL maintenance therapy after early withdrawal of CsA. A total of 1295 patients were enrolled in two double-blind studies comparing SRL with azathioprine (AZA) or placebo administered in continuous regimens with CsA. In two other trials (n = 161), SRL given as base therapy was compared with CsA. In the fifth trial, patients were randomly assigned at 3 months to either remain on CsA + SRL therapy (n = 215) or to have CsA eliminated with SRL being continued in concentration-controlled doses (n = 215). At 2 yr after transplantation, patients receiving SRL in continuous combination with CsA had a significantly lower incidence of skin cancer compared with patients receiving placebo. Patients receiving SRL as base therapy had no malignancies compared with a 5% incidence in those receiving CsA. The incidence of malignancy was significantly lower in patients receiving concentration-controlled SRL with elimination of CsA compared with those who remained on CsA + SRL. Based on the currently available data, patients receiving SRL-based therapy without CsA or SRL maintenance therapy after early CsA withdrawal have lower rates of malignancy in the first 2 yr after renal transplantation. SRL immunotherapy may be beneficial in protecting renal transplant patients from skin cancer even when given in combination with CsA.

Sirolimus-Based Therapy Following Early Cyclosporine Withdrawal Provides Significantly Improved Renal Histology and Function at 3 Years

Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen improved renal function and blood pressure. We report the protocol-mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL-CsA-ST were randomized at 3 months after transplantation to remain on SRL-CsA-ST, or to have CsA withdrawn (SRL-ST group). Protocol-mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL-ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL-ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL-ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA-withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL-CsA-ST regimen resulted in improved renal histology and function.