Decreased incidence of acute rejection without increased incidence of cytomegalovirus (CMV) infection in kidney transplant recipients receiving rabbit anti-thymocyte globulin without CMV prophylaxis - a cohort single-center study.

Induction therapy with rabbit anti-thymocyte globulin (rATG) in low-risk kidney transplant recipients (KTR) remains controversial, given the associated increased risk of cytomegalovirus (CMV) infection. This natural experiment compared 12-month clinical outcomes in low-risk KTR without CMV prophylaxis (January/3/13-September/16/15) receiving no induction or a single 3 mg/kg dose of rATG. We used logistic regression to characterize delayed graft function (DGF), negative binomial to characterize length of hospital stay (LOS), and Cox regression to characterize acute rejection (AR), CMV infection, graft loss, death, and hospital readmissions. Recipients receiving 3 mg/kg rATG had an 81% lower risk of AR (aHR 0.14 0.190.25 , P < 0.001) but no increased rate of hospital readmissions because of infections (0.68 0.911.21 , P = 0.5). There was no association between 3 mg/kg rATG and CMV infection/disease (aHR 0.86 1.101.40 , P = 0.5), even when the analysis was stratified according to recipient CMV serostatus positive (aHR 0.94 1.251.65 , P = 0.1) and negative (aHR 0.28 0.571.16 , P = 0.1). There was no association between 3 mg/kg rATG and mortality (aHR 0.51 1.253.08 , P = 0.6), and graft loss (aHR 0.34 0.731.55 , P = 0.4). Among low-risk KTR receiving no CMV pharmacological prophylaxis, 3 mg/kg rATG induction was associated with a significant reduction in the incidence of AR without an increased risk of CMV infection, regardless of recipient pretransplant CMV serostatus.

Use of mTOR inhibitor as prophylaxis for cytomegalovirus disease after kidney transplantation: A natural experiment.

OBJECTIVES: To describe the incidence of cytomegalovirus (CMV) infection/disease in kidney transplant recipients receiving an mTOR-inhibitor-containing immunosuppressive regimen without prophylactic CMV treatment. METHODS: This single-center retrospective cohort analysis included all de novo kidney transplant recipients (09/15/2015-07/31/2017) receiving 3 mg/kg single dose of rabbit antithymocyte globulin induction, tacrolimus, everolimus, and prednisone. Preemptive therapy was initiated only in patients deemed at higher risk for CMV infection: (a) D+/R- CMV patients; (b) after treatment for acute rejection (ARt); and (c) after everolimus discontinuation (EVRd). RESULTS: Of 230 patients, there were no episodes of CMV disease among 217 (94%) without criteria to initiate preemptive therapy. Of 77 (33.5%) patients initiating preemptive therapy, 13 were D+/R-, 30 were ARt, and 34 were EVRd. The overall incidence of first CMV infection/disease was 6% (46.1% in D+/R-, 13.3% ARt [all patients had also discontinued everolimus], and 11.8% after early [<90 days] EVRd). The incidence of biopsy-proven acute rejection was 5.6%, and median glomerular filtration rate at month 12 was 47 mL/min/1.73m2 . One-year patient and death-censored graft survivals were 97.4% and 98.1%. CONCLUSION: This study suggests that everolimus-containing immunosuppressive regimen reduces the need for preventive strategies for CMV infection in the majority of kidney transplant recipients, reducing antiviral drug-associated toxicities and healthcare-related expenditures.

Pharmacokinetics and Long-Term Safety and Tolerability of Everolimus in Renal Transplant Recipients Converted From Cyclosporine.

BACKGROUND: Conversion from cyclosporine (CsA) to everolimus (EVR) in kidney transplant recipients receiving mycophenolate sodium (MPS) and corticosteroids has been used to reduce CsA associated toxicities. Nevertheless, exposures produced by the initial EVR dose, the steady state pharmacokinetic and long-term safety and tolerability have not been explored in detail. METHODS: Twenty-four stable kidney transplant recipients receiving CSA, MPS, and corticosteroids were converted from CSA to EVR. The initial EVR dose was 3 mg BID. Weekly monitoring of EVR blood concentrations was followed by a full 12 hour pharmacokinetic profile 28 days after conversion. Therapeutic drug monitoring, safety, and tolerability were analyzed during 5 years of follow-up. RESULTS: The study population was relatively young (mean of 42 years) with a predominance of males (62%) and White (67%) recipients of kidneys from living (54%) or deceased (46%) donors. Mean time of the conversion was 61 months after transplantation. In the first 7 patients, the initial EVR dose of 3 mg BID resulted in mean EVR trough blood concentration of 14.7 ± 3.7 ng/mL at day 7. The initial EVR dose was then reduced to 2 mg BID for the following 17 patients. Four weeks after conversion, mean EVR dose was 1.7 ± 0.5 mg BID (7 patients were receiving 1 mg BID and 17 were receiving 2 mg BID) resulting in mean EVR trough blood concentration of 4.0 ± 1.4 ng/mL. Whereas mean maximum concentration (13.4 ± 2.8 versus 22.9 ± 7.4 ng/mL, P = 0.003) and mean apparent clearance (232 ± 79 versus 366 ± 173 mL/min, P = 0.016) were higher, mean area under the curve (78.2 ± 22.1 versus 102.5 ± 38.5 ng.h/mL, P = 0.067) and mean C0 (3.7 ± 1.3 versus 4.1 ± 1.5 ng/mL, P = 0.852) were no different comparing patients receiving 1 mg and 2 mg EVR BID. Mean inter-subject variability of area under the curve, trough concentration, and maximum concentration was 38%, 36%, and 38%. EVR treatment was discontinued in 29% of patients due to proteinuria (N = 2), pneumonia (N = 2), dyslipidemia (N = 2), and anemia (N = 1) and MPS dose was reduced in 58% of patients. CONCLUSIONS: The initial 3 mg BID dose produced high EVR trough blood concentrations. The 2 mg BID dose appears to be the appropriate initial dose to provide therapeutic concentrations but still requires initial intensive therapeutic monitoring to achieve and maintain blood concentrations within the therapeutic target concentration. The combination of EVR and full dose MPS has limited long-term tolerability and safety.

Long-Term Follow-Up of De Novo Use of mTOR and Calcineurin Inhibitors After Kidney Transplantation.

BACKGROUND: Long-term efficacy and safety of de novo use of the mammalian target of rapamycin inhibitors (mTORi) have been evaluated primarily using registry data. METHODS: This was a pooled retrospective analysis of data obtained from 10 prospective randomized trials in de novo kidney transplant recipients (n = 581) receiving calcineurin inhibitors (CNIs) combined with sirolimus (n = 329), everolimus (n = 128), or antimetabolites (n = 124). RESULTS: There were no differences in patient (84.5 versus 80.9 versus 89.7%, P = 0.996), graft (65.4 versus 59.5 versus 73.1%, P = 0.868), and biopsy-confirmed acute rejection-free (78.1 versus 77.3 versus 79.0%, P = 0.976) survivals, respectively. The incidence of cytomegalovirus infection was lower (6 versus 3 versus 11%, P = 0.024) but treatment discontinuation was higher among patients receiving mTORi (66.0 versus 47.7 versus 31.5%, P < 0.001), respectively. At 5 years, median estimated glomerular filtration rate (49.6 versus 43.9 versus 53.2 mL/min, P = 0.006) was lower and the proportion of patients with proteinuria (53 versus 40 versus 23%, P < 0.001) was higher among patients receiving mTORi, respectively. CONCLUSIONS: The efficacy of de novo use of mTORi is comparable with that of antimetabolites in kidney transplant recipients receiving calcineurin inhibitor. Apart from the lower cytomegalovirus infection rate, the safety profile is unfavorable, showing higher treatment discontinuation rates and higher incidence of proteinuria.

Flavonoids from Plinia cauliflora (Mart.) Kausel (Myrtaceae) with antifungal activity.

Plinia cauliflora is a plant species with edible fruits but its chemical composition is not totally known yet although former studies showed its potential as antifungal agent. This work aimed the chemical analysis of the leaves, the activity against fungi species and evaluated cytotoxicity. Extract was obtained with 70% ethanol. An ethyl acetate fraction was obtained and glycosylated quercetin and myricetin were isolated. Samples were tested against Candida species, dermatophytes and entomopathogenic fungi. Cytotoxicity was evaluated against fibroblast cells. Extract showed good activity against C. albicans (minimum inhibitory concentration at 156 µg/mL), C. parapsilosis (78 µg/mL), C. krusei (19 µg/mL), Trichophyton rubrum (78 µg/mL) and Microsporum canis (156 µg/mL). Isolated compounds were more active against C. krusei and T. rubrum. The extract, which was the more active sample, demonstrated low cytotoxic effect and encourage more studies against rising non-albicans species and dermatophyte T. rubrum.