Sexual acquisition of HIV infection after solid organ transplantation: Late presentation and potentially fatal complications.

INTRODUCTION: While the growing knowledge on HIV among solid organ transplant recipients (SOT) is limited to either pretransplant infection or allograft transmission, there are only sparse reports describing HIV-infection after transplantation through sexual route, the primary mode of transmission in the general population. METHODS: From two different centers, we report nine new cases of HIV infection in SOT recipients attributed to sexual acquisition: eight cases of kidney-transplant recipients and one heart-transplant recipient. FINDINGS: There were nine cases of post-transplant HIV-infection detected among 14 526 transplants performed 1998 to 2015. In 6/9 cases, infection was contracted 5 years after SOT. All but one patient had stable allograft function under immunosuppressive therapy. The main trigger to diagnosis was late CMV disease and sexually transmitted diseases; five patients had CDC-stage 3 HIV infection. In 7/9 patients, virologic response and CD4 recovery were achieved within 3 months after starting antiretroviral therapy (ART). After an average of 3.6 years post diagnosis, 5/9 patients remained alive with well-controlled infection and functioning allograft. CONCLUSION: Sexual acquisition of HIV infection after SOT represents a difficult challenge, as it may occur in any kind of transplant and at any time. The course of infection resembles that of the general population, with life-threatening infectious complications, but good response to ART. Assessment of lifestyle and risk behavior is paramount, as indications may be not disclosed without direct questioning.

Renal transplantation in human immunodeficiency virus-infected recipients: a case-control study from the Brazilian experience.

BACKGROUND: Highly active antiretroviral therapy has turned human immunodeficiency virus (HIV)-infected patients with end-stage renal disease into suitable candidates for renal transplantation. We present the Brazilian experience with kidney transplantation in HIV-infected recipients observed in a multicenter study. METHODS: HIV-infected kidney transplant recipients and matched controls were evaluated for the incidence of delayed graft function (DGF), acute rejection (AR), infections, graft function, and survival of patients and renal grafts. RESULTS: Fifty-three HIV-infected recipients and 106 controls were enrolled. Baseline characteristics were similar, but a higher frequency of pre-transplant positivity for hepatitis C virus and cytomegalovirus infections was found in the HIV group. Immunosuppressive regimens did not differ, but a trend was observed toward lower use of anti-thymocyte globulin in the group of HIV-infected recipients (P = 0.079). The HIV-positive recipient group presented a higher incidence of treated AR (P = 0.036) and DGF (P = 0.044). Chronic Kidney Disease Epidemiology Collaboration estimated that glomerular filtration rate was similar at 6 months (P = 0.374) and at 12 months (P = 0.957). The median number of infections per patient was higher in the HIV-infected group (P = 0.018). The 1-year patient survival (P < 0.001) and graft survival (P = 0.004) were lower, but acceptable, in the group of HIV-infected patients. CONCLUSIONS: In the Brazilian experience, despite somewhat inferior outcomes, kidney transplantation is an adequate therapy for selected HIV-infected recipients.

Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses.

This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r-ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end-point was the incidence of first CMV infection/disease in the intention-to-treat population at 12 months. Patients treated with r-ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037-0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13-0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound-healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced-dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate (ClinicalTrials.gov NCT01354301).

Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.

Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

Safety profile comparing azathioprine and mycophenolate in kidney transplant recipients receiving tacrolimus and corticosteroids.

BACKGROUND: Debate is increasing on whether mycophenolic acid (MPA) provides survival benefits comparable to azathioprine (AZA) after renal transplantation. METHODS: This retrospective cohort study compared safety and efficacy of AZA (n = 662) vs. MPA (n = 267) in low-immunologic-risk kidney transplant recipients (KTR) receiving tacrolimus (TAC) and steroids between 1998 and 2007. Primary outcomes were treatment discontinuation and infection. Secondary endpoints included survival free from biopsy-proven acute rejection, graft loss, death, and renal function. RESULTS: The 5-year survival free of treatment discontinuation was higher in the MPA compared to the AZA group (74.1% vs. 60.3%, P < 0.001). MPA was discontinued exclusively because of adverse events (16.4%), while AZA was discontinued primarily for lack of efficacy (21.2%). In univariable analysis, MPA was associated with higher incidence of total (561.5 vs. 667.5 episodes/1000 person-year, P < 0.001), bacterial (167 vs. 158 episodes/1000 person-years, P = 0.001), and viral infections (83.2 vs. 100.4 episodes/1000 person-years, P = 0.001), but this association was not confirmed in multivariable analysis. Over 29% of viral infections in the AZA group occurred after conversion to MPA. A high incidence of tuberculosis was observed (2.9 episodes/1000 person-years) with a higher incidence (but not a statistically significant difference) in the AZA group. No significant differences were found in patient survival (90% vs. 89%, P = 0.78) or graft survival (81% vs. 77.7%, P = 0.08), but infection accounted for >50% of all deaths. CONCLUSION: The type of antimetabolite, AZA or MPA, was not independently associated with any safety or efficacy outcome 5 years after transplantation, suggesting that AZA is still a viable option for low-risk KTR receiving TAC and steroids.

Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year.

In this Phase 2b study, 331 low-to-moderate risk de novo kidney transplant patients (approximately 60% deceased donors) were randomized to a more intensive (MI) or less intensive (LI) regimen of tofacitinib (CP-690, 550), an oral Janus kinase inhibitor or cyclosporine (CsA). All patients received basiliximab induction, mycophenolic acid and corticosteroids. Primary endpoints were: incidence of biopsy-proven acute rejection (BPAR) with a serum creatinine increase of ≥0.3 mg/dL and ≥20% (clinical BPAR) at Month 6 and measured GFR at Month 12. Similar 6-month incidences of clinical BPAR (11%, 7% and 9%) were observed for MI, LI and CsA. Measured GFRs were higher (p < 0.01) at Month 12 for MI and LI versus CsA (65 mL/min, 65 mL/min vs. 54 mL/min). Fewer (p < 0.05) patients in MI or LI developed chronic allograft nephropathy at Month 12 compared with CsA (25%, 24% vs. 48%). Serious infections developed in 45%, 37% and 25% of patients in MI, LI and CsA, respectively. Anemia, neutropenia and posttransplant lymphoproliferative disorder occurred more frequently in MI and LI compared with CsA. Tofacitinib was equivalent to CsA in preventing acute rejection, was associated with improved renal function and less chronic allograft histological injury, but had side-effects at the doses evaluated.

Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients.

Everolimus allows calcineurin-inhibitor reduction without loss of efficacy and may improve renal-transplant outcomes. In a 24-month, open-label study, 833 de novo renal-transplant recipients were randomized to everolimus 1.5 or 3.0 mg/day (target troughs 3-8 and 6-12 ng/mL, respectively) with reduced-exposure CsA, or mycophenolic acid (MPA) 1.44 g/day plus standard-exposure CsA. Patients received basiliximab +/- corticosteroids. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up) and the main safety endpoint was renal function (estimated glomerular filtration rate [eGFR], by Modification of Diet in Renal Disease [MDRD]) at Month 12 (last-observation-carried-forward analyses). Month 12 efficacy failure rates were noninferior in the everolimus 1.5 mg (25.3%) and 3.0 mg (21.9%) versus MPA (24.2%) groups. Mean eGFR at Month 12 was noninferior in the everolimus groups versus the MPA group (54.6 and 51.3 vs 52.2 mL/min/1.73 m(2) in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively; 95% confidence intervals for everolimus 1.5 mg and 3.0 mg vs MPA: -1.7, 6.4 and -5.0, 3.2, respectively). The overall incidence of adverse events was comparable between groups. The use of everolimus with progressive reduction in CsA exposure, up to 60% at 1 year, resulted in similar efficacy and renal function compared with standard-exposure CsA plus MPA.

Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation.

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study.

This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

A Cost-Effectiveness Analysis of Organ Preservation Methods for Deceased Donor Kidneys at High Risk for Delayed Graft Function in Brazil.

The clinical benefit of machine perfusion (MP) was recently assessed in a 1-year Brazilian multicenter prospective randomized trial, that showed that the use of MP was associated with a reduced incidence of delayed graft function (DGF) compared to static cold storage (SCS) in kidney transplant recipients (45% vs 61%). The objective of the present analysis is to consider the cost-effectiveness of MP relative to SCS based on clinical data from this Brazilian cohort. A decision tree model was constructed to simulate a population of 1000 kidney transplant recipients based on data derived from this Brazilian multicenter clinical trial. The model accounts for different health state utilities to estimate the cost-effectiveness of deceased donor kidney transplantation in Brazil comparing 2 kidney preservation methods: MP and SCS. The model accounts for 3 possible graft outcomes at 1 year post-transplantation: success (an immediate functioning kidney), failure (primary nonfunction requiring a return to dialysis), or DGF 1 year post-transplant. MP provided 612 total quality-adjusted life years (QALYs) (0.61 QALYs per patient) as compared to SCS (553 total QALYs, 0.55 QALYs per patient). MP was cost effective relative to SCS (US$22,117/QALY, R$70,606/QALY). The use of MP also resulted in more functioning grafts than SCS (821 vs 787), leading to a cost per functioning graft of US$38,033 (R$121,417). In conclusion, this analysis indicates that, despite the initial added cost associated with MP, the use of MP results in more functioning grafts (821 vs 787) and higher patient quality of life relative to SCS in Brazil.

Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients.

Chronic allograft nephropathy is among the major causes of graft loss even in low-risk kidney transplant recipients and correlates with acute nephrotoxic events during the first year post-transplant. Therefore, calcineurin inhibitor-free regimens may improve patient and graft survival among recipients of living-related kidney transplants. To confirm this hypothesis, we evaluated the efficacy and safety of two calcineurin inhibitor-free regimens in 92 low-risk recipients of one-haplotype living-related kidney transplants. Immunosuppression consisted of tacrolimus, azathioprine and prednisone (group I, GI, N = 38), 2 doses of daclizumab, mycophenolate mofetil (MMF), and prednisone (GII, N = 33) and 2 doses of daclizumab, MMF, sirolimus and prednisone (GIII, N = 21). At 12 months, treatment failure (biopsy-confirmed acute rejection, graft loss or death) was higher in GII compared to GIII and GI (54.5 vs 24.0 vs 13.1%, P < 0.01, respectively). In patients of black ethnicity the incidence of acute rejection was 25 vs 83.3 vs 20% (P = 0.055), respectively. Patient and graft survival was comparable. There were no differences in mean creatinine or calculated creatinine clearance at 12 months. Overall incidence of post-transplant diabetes mellitus (3.3%) and cytomegalovirus disease (4.3%) was similar in all groups. Further development of effective calcineurin inhibitor-free regimens should exclude patients of black ethnicity and may need full-induction therapy, perhaps with depleting agents, and concentration-controlled use of sirolimus and MMF.

Worse renal transplant outcomes observed among Afro-Brazilian patients on prospective registry data of 2461 renal transplants at least 1 year follow-up.

We present prospective registry data of 2461 (live donor = 1753 and deceased donor = 08) renal transplants performed between 1999 and 2003. All subjects were followed for more than 1 year after transplantation and most were treated with a calcineurin inhibitor and azathioprine. Afro-Brazilian, white, and mixed patients constituted 11% (272), 67.1% (1651), and 14.9% (367) of the population respectively. Mean dialysis time was 42.3 +/- 32.9 months and delayed graft function, occurred in more than 60%. Three-year patient survival rates were 96.3%, 92.8%, and 86.7% for living-related, living-unrelated, and deceased donors, respectively. Corresponding 3-year graft survival rates were 87.3%, 82.1%, and 71.3% and functional graft survival rates were 90.2%, 88.8%, and 81.5%. The poorer transplant outcome observed among Afro-Brazilian patients has been mainly attributed to differences in absorption of cyclosporine, tacrolimus, and mycophenolate mofetil.

Thymoglobulin and rate of infectious complications after transplantation.

UNLABELLED: Thymoglobulin is used as an induction agent in kidney transplantation, but the optimal dose is not well established. However, its use may be associated with increased infectious complications after transplantation. METHODS: This retrospective study of 61 high-risk renal recipients of transplants from deceased donors performed between June 2001 and April 2004 included patients treated with thymoglobulin. Patients were divided into two groups according to the total thymoglobulin dose (G1, n = 30, <7 mg/kg; G2, n = 31, >7 mg/kg) and followed for at least 1 year. RESULTS: Mean recipient age was 43 +/- 14 years; 41% were males; 63% non-Whites. Mean cold ischemia time was 26.3 +/- 7 hours. Mean PRA was 23% (0-100%). Second transplantation was performed in 18 (29.5%) patients. Mean donor age was 42.1 +/- 16 years, and 59% had a cerebral vascular accident as the cause of death. Patient- and death-censored graft survival at 12 months were 86% and 88%, respectively. There were 149 infectious episodes among 47 (78%) patients. The incidence of infection was 1.7 +/- 0.24 infections per patient per year in G1 (lower dose) vs 3.12 +/- 0.23 in G2 (P < .001). Bacterial (0.66 +/- 1.0 vs 1.48 +/- 1.26 infections per patient per year, P = .009) and viral infections (0.9 +/- 0.71 vs 1.41 +/- 0.71; P = .006) were more frequent in the higher dose group. CONCLUSION: This study suggested that a greater number of infectious episodes were present when the total dose of thymoglobulin was higher than 7 mg/kg.

Efficacy of Prolonged- and Immediate-release Tacrolimus in Kidney Transplantation: A Pooled Analysis of Two Large, Randomized, Controlled Trials.

BACKGROUND: Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). METHODS: Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). RESULTS: Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5-15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). CONCLUSIONS: Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.govNCT00189839; NCT00717470.

Relationship of cyclosporin and sirolimus blood concentrations regarding the incidence and severity of hyperlipidemia after kidney transplantation.

The influence of drug concentrations on the development of persistent posttransplant hyperlipidemia was investigated in 82 patients who received cyclosporin A (CsA) and prednisone plus sirolimus (SRL) (52) or azathioprine (AZA) (30) during the first year after transplantation. Blood levels of CsA and SRL, daily doses of AZA and prednisone, and cholesterol, triglyceride, and glucose concentrations were determined during each visit (pretransplant and 30, 60, 90, 120, 180, and 360 days posttransplant). Persistent hyperlipidemia was defined as one-year average steady-state cholesterol (CavCHOL) or triglyceride (CavTG) concentrations above 240 and 200 mg/dL, respectively. Mean cholesterol and triglyceride concentrations increased after transplantation (P < 0.01) and were higher in patients receiving SRL compared to AZA (P < 0.001). Patients receiving SRL showed a significantly higher number of cholesterol (> 229 or > 274 mg/dL) and triglyceride (> 198 or > 282 mg/dL) determinations in the upper interquartile ranges. CsA and SRL interquartile ranges correlated with cholesterol concentrations (P = 0.001) whereas only SRL interquartile ranges correlated with triglyceride concentrations (P < 0.0001). Only pretransplant cholesterol concentration > 205 mg/dL was independently associated with development of persistent hypercholesterolemia (CavCHOL > 240 mg/dL, relative risk (RR) = 20, CI 3.8-104.6, P = 0.0004) whereas pretransplant triglyceride concentration > 150 mg/dL (RR = 7.2, CI 1.6-32.4, P = 0.01) or > 211 mg/dL (RR = 19.8, CI 3.6-107.9, P = 0.0006) and use of SRL (RR = 3, CI 1.0-8.8, P = 0.0049) were independently associated with development of persistent hypertriglyceridemia (CavTG > 200 mg/dL). Persistent hypercholesterolemia was more frequent among patients with higher pretransplant cholesterol concentrations and was dependent on both CsA and SRL concentrations. Persistent hypertriglyceridemia was more frequent among patients with higher pretransplant triglyceride concentrations and was dependent on SRL concentrations.

Impact of initial exposure to calcineurin inhibitors on kidney graft function of patients at high risk to develop delayed graft function.

We conducted a retrospective analysis of the influence of full doses of calcineurin inhibitors [8-10 mg kg-1 day-1 cyclosporine (N = 80), or 0.2-0.3 mg kg-1 day-1 tacrolimus (N = 68)] administered from day 1 after transplantation on the transplant outcomes of a high-risk population. Induction therapy was used in 13% of the patients. Patients also received azathioprine (2 mg kg(-1) day(-1), N = 58) or mycophenolate mofetil (2 g/day, N = 90), and prednisone (0.5 mg kg(-1) day(-1), N = 148). Mean time on dialysis was 79 +/- 41 months, 12% of the cases were re-transplants, and 21% had panel reactive antibodies > 10%. In 43% of donors the cause of death was cerebrovascular disease and 27% showed creatinine above 1.5 mg/dL. The incidence of slow graft function (SGF) and delayed graft function (DGF) was 15 and 60%, respectively. Mean time to last dialysis and to nadir creatinine were 18 +/- 15 and 34 +/- 20 days, respectively. Mean creatinine at 1 year after transplantation was 1.48 +/- 0.50 mg/dL (DGF 1.68 +/- 0.65 vs SGF 1.67 +/- 0.66 vs immediate graft function (IGF) 1.41 +/- 0.40 mg/dL, P = 0.089). The incidence of biopsy-confirmed acute rejection was 22% (DGF 31%, SGF 10%, IGF 8%). One-year patient and graft survival was 92.6 and 78.4%, respectively. The incidence of cytomegalovirus disease, post-transplant diabetes mellitus and malignancies was 28, 8.1, and 0%, respectively. Compared to previous studies, the use of initial full doses of calcineurin inhibitors without antibody induction in patients with SGF or DGF had no negative impact on patient and graft survival.

Exposure-efficacy relationships of a fingolimod-everolimus regimen in kidney transplant patients at risk for delayed graft function.

OBJECTIVE: We explored relationships between blood levels of fingolimod (FTY720) and everolimus versus treated biopsy-proven acute rejection (BPAR) in an open-label trial in de novo kidney transplant recipients. METHODS: Patients (n = 52) who fulfilled predefined criteria placing them at increased risk of delayed graft function received fingolimod 2.5 mg/d, everolimus 2 mg twice daily with trough blood levels (C0) adjusted to 4 to 8 ng/mL, and corticosteroids. Everolimus and fingolimod C0 were collected over 1 year; efficacy readout was at 3 months. RESULTS: Fingolimod C0 accumulated over the first 3 months with a time-averaged level (C0avg) of 5.7 +/- 3.5 ng/mL. At steady state in months 3 to 12, C0 was 7.0 +/- 4.4 ng/mL. Overall, 30 patients (58%) were free from BPAR to month 3. Patients were divided into four groups based on whether their fingolimod C0avg and everolimus C0avg were above or below the population medians. Freedom from BPAR was 53% and 57% for low fingolimod combined with low and high everolimus, whereas the percentages were improved to 83% and 85% for high fingolimod combined with low and high everolimus. CONCLUSIONS: This pilot study with an everolimus-fingolimod regimen demonstrated trends in freedom from rejection that were drug concentration-related and that underscored, in particular, a strong contribution to efficacy from fingolimod.

Conversion from azathioprine to mycophenolate mofetil followed by calcineurin inhibitor minimization or elimination in patients with chronic allograft dysfunction.

UNLABELLED: The purpose of this study was to evaluate the effects of the conversion from azathioprine (AZA) to mycophenolate mofetil (MMF) followed by calcineurin inhibitor (CNI) elimination or minimization in patients with progressive chronic allograft dysfunction (CAD). METHODS: Between November 6, 1999 and February 12, 2003, 169 patients receiving CNI/AZA/prednisone (153 CsA; 14 tacrolimus) were included in this study. Demographics, immunosuppression, graft function, hematology, and biochemistry were obtained before (-6, -3, and -1 month) and 1, 3, 6, 9 and 12 months after and at last follow-up visit after conversion. RESULTS: Mean age was 34 +/- 12 years, 66% males, 51% Caucasian, and 72% living allograft recipients. Mean follow-up times before and after conversion were 32.4 and 19.4 months; 10 patients completed 3 years of follow-up. CNI elimination was performed in 39% and minimization in 61% of patients. Overall there was significantly improved graft function at 1 year after conversion (2.6 +/- 1.0 vs 2.1 +/- 0.6 mg/dL, P = .038). The slopes of the regression lines of 1/Cr vs time were significantly improved from preconversion to after conversion (-0.026 vs +0.007 mg(-1)/dL per day(-1), P = .001). There was a significant decrease in mean systolic (141 +/- 21 vs 135 +/- 22 mm Hg, P = .015) and diastolic (89 +/- 15 vs 84 +/- 14 mm Hg, P = .005) blood pressure values at 1 year. There were four episodes of acute rejection (Banff IA) treated with steroids. Three years after conversion, patient and graft survivals were 95% and 79%, respectively. One patient developed posttransplant lymphoproliferative disease. CONCLUSION: Among patients with CAD, conversion from AZA to MMF followed by CNI minimization or elimination was a safe and effective strategy to preserve or improve graft function.

Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients.

FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 +/- 0.05 (0.25 mg), 0.73 +/- 0.12 (0.5 mg), 3.26 +/- 0.51 (1 mg), and 7.15 +/- 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r(2) = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 +/- 5.3% and ED50 = 0.48 +/- 0.08 mg, r(2) = 0.94) or concentration (Emax = 78.3 +/- 2.9% and EC50 = 0.59 +/- 0.09 ng/ml, r(2) = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.