Does human milk composition predict later risk of obesity? A systematic review.

BACKGROUND: Possible mechanisms behind the association of breastfeeding with a lower risk of later obesity are unknown but one possibility is the unique composition of human milk. Here, we systematically reviewed the evidence linking breast-milk macronutrient and hormonal composition with later obesity. METHODS: We searched 7 databases for studies that included infants predominantly breast-fed for the first 3 months and which analysed associations between a measure of breast-milk composition and later (> 6 months) measures of obesity or body composition. RESULTS: 47 publications were identified for full-text screening, of which 10 were eligible and only 3 found significant associations. Higher leptin concentration in breast milk at age 1 month was associated with lower infant BMI at 12, 18 and 24 months of age (1 study). Higher breast-milk adiponectin concentration at 6 weeks and 4 months were associated with adiposity at age 12 and 24 months (1 study). In 1 study, breast-milk carbohydrate content was positively associated, and fat content negatively associated, with adiposity at age 12 months. No significant associations were found between other hormones or macronutrients in human milk and later risk of obesity or body composition. CONCLUSIONS: The evidence linking breast-milk composition with later obesity was inconsistent and confined to single, individual studies. Our review highlights the methodological limitations of previous studies and the need for further research in this area.

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.

The Influence of Antithymocyte Globulin Dose on the Incidence of CMV Infection in High-risk Kidney Transplant Recipients Without Pharmacological Prophylaxis.

BACKGROUND: Optimizing antithymocyte globulin (ATG) dosage is critical, particularly for high-risk kidney transplant (KT) recipients without cytomegalovirus (CMV) prophylaxis. METHODS: We studied 630 KT recipients with expanded criteria donors or panel reactive antibody ≥50% at Hospital do Rim, Brazil (January 1, 2013 to May 21, 2015) to determine whether a single ATG dose was safe and effective in patients without CMV prophylaxis. Patients received ≥4 doses (1-1.5 mg/kg/per dose) until June 17, 2014, when the induction protocol changed to a single ATG dose (3 mg/kg). We used Cox regression to compare the risk of CMV infection and acute rejection (AR) among KT recipients by ATG dose. RESULTS: Adjusting for clinical and transplant factors, a single ATG dose was associated with a lower risk of CMV infection (adjusted hazard ratio [aHR]: 0.63; 95% confidence interval [CI], 0.42-0.93; P = 0.02) and a similar risk of AR (aHR: 1.16; 95% CI, 0.47-2.83; P = 0.8), compared to multiple doses. We found no differences in death-censored graft loss (5.0% versus 4.8%, aHR: 1.06; 95% CI, 0.51-2.23; P = 0.9) or mortality (4.7% versus 3.4%; aHR: 1.42; 95% CI, 0.62-3.24; P = 0.4) at 1-year post-KT by ATG dose. CONCLUSIONS: In our study of high-risk KT recipients without CMV prophylaxis, a single ATG dose decreased the risk of CMV infection without increasing the risk of AR or compromising graft or patient survival.

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.

Prospective randomized study comparing everolimus and mycophenolate sodium in de novo kidney transplant recipients from expanded criteria deceased donor.

The optimal immunosuppressive regimen for recipients of expanded criteria donor (ECD) kidneys has not been identified. In this single-center study, 171 recipients of ECD kidney transplants were randomized to receive antithymocyte globulin induction, and delayed introduction of reduced dose tacrolimus, prednisone and everolimus (r-ATG/EVR, n = 88), or mycophenolate (r-ATG/MPS, n = 83). No cytomegalovirus (CMV) pharmacological prophylaxis was used. The primary endpoint was the incidence of CMV infection/disease at 12 months. Secondary endpoints included treatment failure [first biopsy-proven acute rejection (BPAR), graft loss, or death] and safety. Patients treated with EVR showed a 89% risk reduction (13.6 vs. 71.6%; HR 0.11, 95% CI 0.06-0.220, P < 0.001) in the incidence of first CMV infection/disease. Incidences of BPAR (16% vs. 5%, P = 0.021), graft loss (11% vs. 1%, P = 0.008), death (10% vs. 1%, P = 0.013), and treatment discontinuation (40% vs. 28%, P = 0.12) were higher in the r-ATG/EVR, leading to premature study termination. Mean glomerular filtration rate was lower in r-ATG/EVR (31.8 ± 18.8 vs. 42.6 ± 14.9, P < 0.001). In recipients of ECD kidney transplants receiving no CMV pharmacological prophylaxis, the use of everolimus was associated with higher treatment failure compared with mycophenolate despite the significant reduction in the incidence of CMV infection/disease (ClinicalTrials.gov.NCT01895049).

Incidence and risk factors associated with cytomegalovirus infection after the treatment of acute rejection during the first year in kidney transplant recipients receiving preemptive therapy.

INTRODUCTION: The complex interaction between cytomegalovirus (CMV) infection and acute rejection after kidney transplantation is well recognized. METHODS: This single center retrospective cohort analysis investigated the incidence and risk factors associated with CMV infection after treatment for acute rejection (tAR) in kidney transplant recipients receiving only CMV preemptive therapy. Of the 938 kidney transplants performed between 04/30/2014 and 04/30/2015 we identified 87 (9.3%) that were treated for acute rejection within the first year. RESULTS: Most patients (64%) received rATG induction therapy followed by tacrolimus in combination with azathioprine (67%) or mycophenolate (33%) and corticosteroids. The incidence of CMV infection/disease after tAR was 47%, of which 73% occurred within 30 days. Using multivariable logistic regression analysis, eGFR at 1 month (OR = 0.98; 95% CI, 0.97-0.99; P = 0.007) and timing of tAR (OR = 0.98; 95% CI, 0.96-0.99; P = 0.021) were independently associated with CMV infection/disease after tAR. CONCLUSION: In this cohort of kidney transplant recipients receiving tacrolimus-based immunosuppressive and preemptive CMV therapy, almost 50% developed CMV infection/disease after tARin the first year of transplantation. Early rejection and poor initial renal function were risk factors associated with CMV infection or disease.

Clinical features and outcomes of kidney transplant recipients with focal segmental glomerulosclerosis recurrence.

AIM: Focal segmental glomerulosclerosis recurs in up to 30% and up to 80% of adult and pediatric kidney transplant recipients, respectively. There is no standard of care treatment. The purpose of this study was to evaluate clinical characteristics, treatments and outcomes of patients with focal segmental glomerulosclerosis recurrence (FSGSr). METHODS: This was a retrospective single-center cohort study including FSGSr patients treated with plasmapheresis (PP) and combinations of high dose steroids, cyclosporine and rituximab. RESULTS: Among 61 patients included in this analysis the median time to diagnosis was 19 days. The incidence of first biopsy-confirmed FSGSr was 18% reaching 52.4% with follow-up biopsies. During PP treatment 54% of the patients developed infectious complications. PP was discontinued in 37% of patients due to treatment failure (no remission or graft loss) and in 26% due to an adverse event. All patients who discontinued PP due to adverse event did not show clinical response or lost the allograft. The incidence of acute rejection was 34.4%. The incidences of partial and complete remissions were 16.4% and 27.8%, respectively. Overall 6-years patient and graft survivals were 90.7% and 64.5%, respectively. CONCLUSION: This analysis confirms the low, variable and unpredictable rate of FSGSr remission, inconsistencies among available therapeutic options and its high rate of adverse events, and the negative impact on graft survival.

Early hospital readmission after kidney transplantation under a public health care system.

Early hospital readmission (EHR) is associated with increased mortality after kidney transplantation. This is influenced by population demographics and the comprehensiveness of the healthcare system. We investigated the incidence and risk factors associated with EHR and 1-year patient and graft survivals. METHODS: We included all recipients of kidney transplant between 2011 and 2012. We excluded recipients younger than 18 years, retransplants and who died or lost the graft during the index hospital admission. RESULTS: Among 1175 recipients, the incidence of EHR was 26.6%. The main reasons for EHR were infection (67%), surgical complications (14%), and metabolic disturbances (11%). Independent risk factors associated with EHR were recipient age (OR = 1.95, 95% CI 1.46-2.63, P < 0.001), CMV serology negative (OR = 2.2, 95% CI 1.31-3.65, P = 0.003), use of rabbit anti-thymocyte globulin (OR = 2.06, 95% CI 1.33-3.13, P < 0.001), treatment for acute rejection during index hospitalization (OR = 1.68, 95% CI 1.15-2.47, P = 0.008), and length of stay (OR = 1.72, 95% CI 1.18-2.5, P = 0.005). Patient (88.8% vs 97.6%, P < 0.001) and death-censored graft (97.4% vs 99.0%, P < 0.001) survivals were inferior comparing patients with and without EHR. Conclusion EHR was independently associated with mortality (OR 4.01, 95% CI 2.13-7.54, P < 0.001), but its incidence and causes are directly related to the local characteristics of the population and healthcare system.

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.

The Influence of Different Mouthpieces on Impulse Oscillometry Results.

BACKGROUND: Impulse oscillometry is a method of airway assessment and diagnosis that provides data on lung mechanics. In the literature, studies have used different types of mouthpieces or did not describe the model used for the tests. We sought to compare the 3 most commonly described mouthpieces in terms of test results, comfort, and subject preference. METHODS: Thirty-nine healthy volunteers were evaluated with spirometry and impulse oscillometry, assessing the resistance at 5 Hz and 20 Hz (R5 and R20, respectively), reactance at 5 Hz (X5), reactance area, and resonant frequency. A filter heat exchanger with a circular mouthpiece (B1), a filter heat exchanger with an oval mouthpiece (B2), and a filter heat exchanger with a circular mouthpiece coupled with a free-flow piece (B3) were compared using an acceptability and tolerance scale, and subjects noted their preference. RESULTS: Statistical analysis showed differences between all the mouthpieces and the predicted values for R5, R20, and X5. The mouthpiece comparison showed differences in R5 between a filter heat exchanger with an oval mouthpiece (B2) and a circular mouthpiece coupled with a free-flow piece (B3) (P = .007); resonant frequency between a filter heat exchanger with a circular mouthpiece (B1) and a filter heat exchanger with an oval mouthpiece (B2) (P = .004) and between a filter heat exchanger with a circular mouthpiece (B1) and a circular mouthpiece coupled with a free-flow piece (B3) (P = .003); and reactance area between a filter heat exchanger with a circular mouthpiece (B1) and a circular mouthpiece coupled with a free-flow piece (B3) (P = .01). In the subjective evaluation, acceptability and tolerance differences were found in the ease of carrying out the evaluation, and no difference was found with regard to the degree of discomfort. Ten subjects preferred a filter heat exchanger with a circular mouthpiece (B1), 15 preferred a filter heat exchanger with an oval mouthpiece (B2), and 14 preferred a circular mouthpiece coupled with a free-flow piece (B3). CONCLUSIONS: A circular mouthpiece coupled with a free-flow piece (B3) appeared to be the most suitable mouthpiece for the impulse oscillometry tests. It assured smaller impedance values for the respiratory system, and subjects expressed the most confidence in using this mouthpiece.

Cost-Effectiveness Analysis of Everolimus versus Mycophenolate in Kidney Transplant Recipients Receiving No Pharmacological Prophylaxis for Cytomegalovirus Infection: A Short-Term Pharmacoeconomic Evaluation (12 Months).

BACKGROUND: Modern immunosuppressive regimens, although associated with improved 1-year graft survival, are associated with adverse effects, including opportunistic infections, diabetes mellitus after transplantation, cardiovascular complications, and de novo malignancies. OBJECTIVES: To determine the short-term (12 months) cost-effectiveness of everolimus (EVR) versus mycophenolate sodium (MPS) in kidney transplant recipients receiving induction therapy, tacrolimus, prednisone, and no prophylaxis for cytomegalovirus infection. METHODS: A Markov state transition model was designed. Data from a single-center prospective trial were used along with data from the center's medical bills database. The target population comprised adults with low immunological risk submitted to first ABO-compatible transplantation with kidneys recovered from living or deceased donors. The time horizon was 12 months. The interventions included tacrolimus and prednisone plus a single 3-mg/kg dose of rabbit antithymocyte globulin (ATG) and EVR or basiliximab (BAS) and EVR or BAS and MPS. The clinical outcomes considered for this analysis were cytomegalovirus infection/disease, acute rejection, graft dysfunction, surgical complications, graft loss, and life-years gained. RESULTS: ATG/EVR was cost-saving compared with BAS/MPS on all evaluated outcomes; BAS/EVR outperformed BAS/MPS on most of the evaluated outcomes. Results were confirmed by sensitivity analysis. CONCLUSIONS: Compared with MPS, EVR is an alternative immunosuppressive agent that is able to provide resource-saving to the health care provider with effectiveness gains for the patient.

Randomized Trial of Machine Perfusion Versus Cold Storage in Recipients of Deceased Donor Kidney Transplants With High Incidence of Delayed Graft Function.

BACKGROUND: This study compared the use of static cold storage versus continuous hypothermic machine perfusion in a cohort of kidney transplant recipients at high risk for delayed graft function (DGF). METHODS: In this national, multicenter, and controlled trial, 80 pairs of kidneys recovered from brain-dead deceased donors were randomized to cold storage or machine perfusion, transplanted, and followed up for 12 months. The primary endpoint was the incidence of DGF. Secondary endpoints included the duration of DGF, hospital stay, primary nonfunction, estimated glomerular filtration rate, acute rejection, and allograft and patient survivals. RESULTS: Mean cold ischemia time was high but not different between the 2 groups (25.6 ± 6.6 hours vs 25.05 ± 6.3 hours, 0.937). The incidence of DGF was lower in the machine perfusion compared with cold storage group (61% vs. 45%, P = 0.031). Machine perfusion was independently associated with a reduced risk of DGF (odds ratio, 0.49; 95% confidence interval, 0.26-0.95). Mean estimated glomerular filtration rate tended to be higher at day 28 (40.6 ± 19.9 mL/min per 1.73 m2 vs 49.0 ± 26.9 mL/min per 1.73 m2; P = 0.262) and 1 year (48.3 ± 19.8 mL/min per 1.73 m2 vs 54.4 ± 28.6 mL/min per 1.73 m2; P = 0.201) in the machine perfusion group. No differences in the incidence of acute rejection, primary nonfunction (0% vs 2.5%), graft loss (7.5% vs 10%), or death (8.8% vs 6.3%) were observed. CONCLUSIONS: In this cohort of recipients of deceased donor kidneys with high mean cold ischemia time and high incidence of DGF, the use of continuous machine perfusion was associated with a reduced risk of DGF compared with the traditional cold storage preservation method.

mTOR inhibitors in pancreas transplant: adverse effects and drug-drug interactions.

INTRODUCTION: Patient and pancreas allograft survival improved following reductions in surgical complications, tighter donor selection and optimization in immunosuppressive protocols. However, long-term survival of pancreas allografts is adversely affected by rejection and immunosuppressive regimen toxicity. Areas covered: This article reviews the existing literature and knowledge of mammalian target of rapamycin inhibitors (mTORi). Some clinically relevant drug-drug interactions are highlighted. We summarize the nephrotoxic and diabetogenic mechanisms of mTORi after pancreas transplant, the alternatives to minimize these effects, and report on other adverse events. Expert opinion: Calcineurin inhibitor (CNI)-based regimens remain the mainstay treatment after pancreas-kidney transplant. However, long-term use of CNIs may be associated with nephrotoxicity. Switching from CNIs to mTORi (sirolimus/SRL and everolimus/EVR) may preserve kidney function, mainly EVR conversion. However, mTORi promote an imbalance of mTOR signaling during long-term follow-up and may ultimately contribute to proteinuria and hyperglycemia. These drugs disrupt autophagy, inhibit cell proliferation, and downregulate VEGF. Therefore, it is important to comprehend and interpret the experimental data. It is equally important to critically analyze clinical studies. Of importance, minimization of side effects, based on safe approaches, can prolong kidney allograft survival. Additional randomized-controlled studies are required to assess the impact of mTORi on pancreas allograft survival.

Prevalência de síndrome metabólica em pacientes com esquizofrenia refratária / Metabolic syndrome prevalence in patients with refractory schizophrenia / Prevalencia de síndrome metabólico en pacientes con esquizofrenia refractaria

RESUMO Objetivo: Estimar prevalência de síndrome metabólica (SM) e seus fatores associados em pacientes com es quizofrenia refratária em uso do antipsicótico clozapina. Método: Trata-se de um estudo descritivo e trans versal, realizado na Região Ampliada Oeste do Estado de Minas Gerais (MG), em 2015, com uma amostra de 72 pacientes. Foram coletados dados sociodemográficos, clínicos, antropométricos e bioquímicos. Realizou-se análise descritiva, univariada e multivariada. Resultados: Observou-se prevalência de SM em 47,2% da amos tra, com predomínio entre as mulheres (58,8%). Pacientes com SM apresentaram percentuais mais elevados de alterações, principalmente em relação à glicemia e triglicérides. O uso de quatro ou mais medicamentos e a presença de sobrepeso e obesidade estiveram associados à SM. Além disso, pacientes com a síndrome apresen taram um histórico de menos internações psiquiátricas, comparados àqueles que não a possui. Conclusão: A prevalência de SM encontrada nos pacientes com esquizofrenia refratária foi elevada e alarmante. A presença de sobrepeso e obesidade e o uso de 4 ou mais medicamentos podem estar associados com o desenvolvimento de SM neste grupo. Essa taxa pode representar um importante indicador de risco cardiovascular, sendo sugerida a construção de estratégias de prevenção primária das alterações metabólicas, bem como se indica que o paciente seja acompanhado periodicamente, principalmente em relação aos componentes da SM.

ABSTRACT Objective: To estimate the prevalence of the metabolic syndrome (MS) and its associated factors in patients with refractory schizophrenia using the antipsychotic clozapine. Method: This is a descriptive cross-sectional study conducted in the extended western region of Minas Gerais (MG), Brazil, in 2015, using a sample of 72 patients. We collected sociodemographic, clinical, anthropometric and biochemical data and conducted descriptive univariate and multivariate analysis. Results: We verified the prevalence of MS in 47.2% of the sample, with a greater predominance among women (58.8%). Patients with MS showed higher change values, especially in relation to blood glucose and triglycerides. The use of four or more medications and the presence of overweight and obesity were associated with MS. In addition, patients with the syndrome had fewer cases of psychiatric hospitalizations than those who did not have it. Conclusion: High and alarming levels of MS prevalence were found in patients with refractory schizophrenia. The presence of overweight and obesity and the use of 4 or more medications may be associated with the development of the MS in this group. These levels could represent an important indicator of cardiovascular risk, which raises the need to develop strategies for primary prevention of metabolic alterations, and highlights the importance of a periodical monitoring of the patient, especially regarding the components of the MS.

RESUMEN Objetivo: Estimar la prevalencia del síndrome metabólico (SM) y sus factores asociados en pacientes con es quizofrenia refractaria que utilizan clozapina como antipsicótico. Material y método: Se trata de un estudio descriptivo y transversal realizado en la región ampliada del oeste de Minas Gerais (MG) en 2015, con una muestra de 72 pacientes. Se recogieron datos sociodemográficos, clínicos, antropométricos y bioquímicos. Se realizó análisis descriptivo, univariado y multivariado. Resultados: Se observó prevalencia de SM en el 47,2% de la muestra, con una prevalencia entre las mujeres (58,8%). Los pacientes con SM tenían mayores porcenta jes de alteración, especialmente en la glucosa en sangre y triglicéridos. El uso de cuatro o más medicamentos y la presencia de sobrepeso y obesidad se asociaron con SM. Además, los pacientes con el síndrome tenían un historico de hospitalizaciones psiquiátricas menor que los que no lo tienen. Conclusión: La prevalencia del SM encontrado en pacientes con esquizofrenia refractaria fue alto y alarmante. La presencia de sobrepeso y obesidad, y el uso de 4 o más fármacos puede estar asociado con el desarrollo de la SM en este grupo. Esta tasa puede representar un importante indicador de riesgo cardiovascular, y sugiere la construcción de estrategias de prevención primaria de los cambios metabólicos, así como que el paciente debe controlarse periódicamente, especialmente en relación con los componentes del SM.

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.

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.