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Sirolimus is approved for prophylaxis of organ rejection following renal transplantation. Rates of treatment-emergent adverse events (TEAEs) leading to sirolimus discontinuation differ geographically.Rates of TEAEs, serious AEs (SAEs), and discontinuations were evaluated in 3 clinical trials of conversion from calcineurin inhibitors to sirolimus. Posttransplantation, patients were treated over 4 years (study 1), over 1 year (study 2), and over 2 years (study 3). TEAEs, SAEs, and discontinuation rates were compared between Latin America (LATAM) vs North America (NA) and Europe/rest of world (EU/ROW). Data from studies 2 and 3, with similar times to conversion, were pooled.Study 1 comprised 551 patients (LATAM, n=189); studies 2/3 comprised 395 (LATAM, n=111). LATAM patients were significantly younger than NA or EU/ROW patients in study 1 and studies 2/3 (P .0001), with a lower proportion of white patients and higher proportion of patients of other races in LATAM vs NA (P .0001) and EU/ROW (P = .02) groups. Almost all patients reported TEAEs. Discontinuation because of medical events was significantly lower (P .05) in LATAM vs NA or EU/ROW. Hypercholesterolemia and hypertriglyceridemia were more common, and anemia and peripheral edema less common in LATAM; diarrhea and proteinuria did not differ by region. Types of AEs leading to discontinuation did not differ by region.LATAM renal transplant recipients converted to sirolimus were more likely to remain on therapy than patients in other regions.

While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long-term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection-associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long-term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15 years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI-based regimens to sirolimus. Sirolimus-containing regimens are associated with preservation of good renal function, with promising characteristics for improving long-term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low-dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI-free combination with mycophenolate mofetil (following CNI-to-sirolimus conversion at 3-6 months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.

Bristol- Myers Squibb Roche Pfizer Novartis Astellas Genzyme Genentech Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. the coprimary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). the mean measured glomerular filtration rate was 4-7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. the incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients. Univ Paris 11, IFRNT, Bicetre Hosp, Paris, France Hosp Rim & Hipertensao Unifesp, São Paulo, Brazil Emory Univ, Transplant Ctr, Atlanta, GA 30322 USA Univ Calif San Francisco, Kidney Transplant Serv, San Francisco, CA 94143 USA Complexo Hosp Santa Casa, Hosp Dom Vicente Scherer, Porto Alegre, RS, Brazil Univ Barcelona, Renal Transplantat Unit, Hosp Clin & Prov, Barcelona, Spain Inst Nefrol, Buenos Aires, DF, Argentina Tulane Sch Med, New Orleans, LA USA Bristol Myers Squibb Co, Princeton, NJ USA Univ Hosp Bellvitge, Barcelona, Spain Hosp Rim & Hipertensao Unifesp, São Paulo, Brazil Web of Science

Background. The efficacy and safety of converting maintenance renal transplant recipients from calcineurin inhibitors (CNIs) to sirolimus (SRL) was evaluated. Methods. Eight hundred thirty renal allograft recipients, 6 to 120 months posttransplant and receiving cyclosporine or tacrolimus, were randomly assigned to continue CNI (n=275) or convert from CNI to SRL (n=555). Primary endpoints were calculated Nankivell glomerular filtration rate (GFR; stratified at baseline: 20-40 vs. >40 mL/min) and the cumulative rates of biopsy-confirmed acute rejection (BCAR), graft loss, or death at 12 months. Enrollment in the 20 to 40 mL/min stratum was halted prematurely because of a higher incidence of safety endpoints in the SRL conversion arm. Results. Intent-to-treat analyses at 12 and 24 months showed no significant treatment difference in GFR in the baseline GFR more than 40 mL/min stratum. On-therapy analysis of this cohort showed significantly higher GFR at 12 and 24 months after SRL conversion. Rates of BCAR, graft survival, and patient survival were similar between groups. Median urinary protein-to-creatinine ratios (UPr/Cr) were similar at baseline but increased significantly after SRL conversion. Malignancy rates were significantly lower at 12 and 24 months after SRL conversion. Post hoc analyses identified a subgroup with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11, whose risk-benefit profile was more favorable after conversion than that for the overall SRL conversion cohort. Conclusions. At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation. Superior renal function was observed among patients who remained on SRL through 12 to 24 months, particularly in the subgroup of patients with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11.

Maintenance immunosuppression with cyclosporine (CsA) is associated with nephrotoxicity, hyperlipidemia, and hypertension. This long-term study (core study + 4 yr of follow-up) investigated the long-term efficacy and safety of CsA withdrawal from a mycophenolate mofetil (MMF)-based regimen. Seventy-seven patients were maintained on CsA, MMF, and steroids (CsA-MMF group), and 74 were given a CsA-free regimen of MMF and steroids (MMF group). Serum creatinine and creatinine clearance were measured at 6-month intervals. Patient and graft survival, acute rejection episodes, malignancies, BP, and lipid profile were also recorded. At 5 yr, patient and graft survival was 93 and 88%, respectively, for the MMF group and 95 and 92%, respectively, for the CsA-MMF group. During follow-up, seven MMF patients experienced acute rejection episodes compared with one CsA-MMF patient (P = 0.0283). Nine grafts were lost to chronic rejection in the MMF group versus three in the CsA-MMF group. No demographic or immunologic characteristics were associated with acute or chronic rejection in the MMF group, but the doses of both MMF and steroids decreased significantly between 1 and 5 yr. The MMF group showed a trend toward improved creatinine clearance (67.4 versus 61.7 ml/min; P = 0.0500). Withdrawal of CsA from an MMF-containing immunosuppressive regimen resulted in an increased risk for acute rejection episodes and graft loss as a result of rejection throughout the 5-yr study period. The creatinine clearance-confirmed improvement in renal function observed at year 1 was maintained at 5 yr BP and cholesterol levels were well controlled in both groups.

Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein-Barr virus (EBV(-)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m(2) . Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time.

One of the main goals in the current care of kidney transplant recipients is to extend long-term graft survival. Efficacious immunosuppressive agents devoid of nephrotoxicity are needed. In human clinical transplantation, sirolimus combined with other immunosuppressive drugs has proven to be a powerful immunosuppressant capable of preventing acute graft rejection, as well as of improving renal function, renal histology, and graft survival when compared with immunosuppressive regimens that include calcineurin inhibitors. The valuable experience gained through many clinical studies allows clinicians to plan sirolimus use. We present a review of the clinical experience and literature review on the use of sirolimus in the first 12 months posttransplantation.

To analyze risk factors for Pneumocystis carinii pneumonia (PCP) in kidney transplant recipients.In a case-control study, 17 PCP cases diagnosed between July 1994 and July 2000 were matched with two controls each (previous and subsequent kidney transplant recipients who did not develop PCP during the same follow-up period). Demographics, organ origin, human leukocyte antigen (HLA) mismatches, use of poly- or monoclonal anti-CD3 antibodies (Po/MoAb) for induction or rejection treatment, rejection episodes, cumulative steroid dose for rejection treatment, immunosuppressive regimens, and other infections were analyzed.No significant differences were seen in gender (male 10 vs. 15), mean age (39.7 vs. 35.4 years), organ origin (cadaver donor 13 vs. 19), HLA mismatches, or Po/MoAb use in induction treatment. Significant differences were observed in PCP cases for rejection history (P=0.02), and median and total number of rejection episodes (P=0.0018). The relative risks for PCP for 1, 2, andor =3 rejection treatments vs. no such treatment were 1, 1.05, and 6.30, respectively (P=0.021). The relative risk for PCP for steroid-resistant rejection was 4.34 (95% confidence interval [CI], 1.04-18.89) (P=0.019), and that for the use of Po/MoAb for rejection treatment was 7.23 (95% CI, 1.28-49.34) (P=0.006). The relative risk for PCP for 0, 1, andor =2 previous or concomitant cytomegalovirus (CMV) infection vs. no such infections were 1.0, 2.32, and 13.0, respectively (P=0.012). The relative risks for PCP for tuberculosis (TB) was 18 (95% CI, 1.76-852.03), that for bacterial pneumonia was 14.22 (95% CI, 2.16-150.23), and that for hepatitis C virus infection was 5.25 (95% CI, 1.03-28.91). Immunosuppressive regimens with tacrolimus, mycophenolate mofetil (MMF), steroids (P=0.06), and MMF as a single variable (P=0.05) were more frequently used in cases. Primary trimethoprim-sulfamethoxazole prophylaxis failure was observed in 12 patients in association with heavy immunosuppression and concomitant infections.The risk of PCP in kidney transplant recipients is related to the number and type of rejection treatments. It is also related to the occurrence of CMV infection, and to other immunomodulating infections such as TB and hepatitis C, and might also be increased with the use of newer and more potent immunosuppressive agents. Primary prophylaxis failure may occur in association with some of these risk factors.