Immunosuppressive Drug-Associated Adverse Event Profiles in De Novo Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses.

BACKGROUND: The safety of immunosuppressive regimens is influenced by the induction agent, maintenance drug combination, and prophylactic strategy for cytomegalovirus (CMV) infection. Herein, this safety analysis compares rabbit antithymocyte globulin (r-ATG) or basiliximab (BAS) combined with everolimus (EVR) versus BAS combined with mycophenolate sodium (MPS) in kidney transplant recipients receiving tacrolimus, prednisone, and preemptive CMV therapy. METHODS: In this single-center, prospective, randomized study, adverse events (AEs), serious AEs (SAEs), viral infections, laboratory abnormalities, dose reductions, and temporary or permanent discontinuation of the immunosuppressant were compared among patients receiving r-ATG/EVR (n = 85), BAS/EVR (n = 102), and BAS/MPS (n = 101). RESULTS: A total of 2741 AEs and 344 SAEs were observed. There were no differences in the proportion of patients with at least one AE (96% versus 98% versus 96%, respectively; P > 0.05). The proportion of patients with at least one SAE was highest in the BAS/MPS group (33% versus 48% versus 69%, respectively; P < 0.05). This difference was due primarily to a high incidence of CMV infection in the BAS/MPS group (4.7% versus 10.8% versus 37.6%, respectively). The incidence of mild/moderate abnormalities in creatinine, cholesterol, and triglyceride levels was higher in both EVR groups. The cumulative freedom from dose reduction or treatment discontinuation due to an AE was higher in both EVR groups than in the BAS/MPS group (89.2% versus 92.8% versus 76.3%, respectively, P = 0.003). There was no difference in the incidence of biopsy-confirmed acute rejection (9.4% versus 18.6 versus 15.8%, respectively; P = 0.403). CONCLUSIONS: This analysis suggests that r-ATG induction combined with EVR is associated with a comparable incidence of acute rejection, lower incidence of CMV infection, and fewer changes in initial immunosuppressive regimen due to AEs in kidney transplant recipients receiving tacrolimus, prednisone, and preemptive CMV therapy.

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.

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.

Tolerability of mycophenolate sodium in renal transplant recipients.

Background Kidney transplant recipients (KTR) receive fixed daily doses of mycophenolate sodium as part of the immunosuppressive regimen. Dose reductions occur primarily due to adverse events and may be associated with an increased risk of acute rejection and graft loss. Objectives To evaluate the tolerability of mycophenolate in kidney transplant recipients receiving tacrolimus and prednisone. Setting The study was performed at Hospital do Rim, Federal University of São Paulo in Brazil. Method This was a retrospective cohort study including 506 patients. Tolerability of mycophenolate sodium was classified into the following groups: Temporary reduction (TR), definitive reduction (DR), temporary interruption (TI), permanent discontinuation (PD) and without modification (WM). Main outcome measure The cause of mycophenolate dose change and its influence on rejection-free survival during the first 3 years after transplantation. Results The cumulative incidence of dose change was 51.2% (11%TR, 44%DR, 24%TI, and 21%PD). Gastrointestinal (45.3%), infection (31.9%) and hematological (14.9%) systems accounted for most of the dose changes. The adverse events with higher incidence were diarrhea, cytomegalovirus (CMV) infection and leukopenia. Changes in dose of mycophenole were associated with reduced acute rejection-free survival compared with patients WM group (71.4%TR, 58.9%DR, 56.7%TI, 53.7%PD vs. 74.2%WM, p = 0.020). Only patients with PD showed inferior patient (59.3% vs. 94.4%, p = 0.001) and death-censored graft (83.3% vs. 92.5%, p = 0.074) survivals compared to patients WM. Conclusion In this cohort, changes in the dose of mycophenolate were associated with increased risk of acute rejection and permanent discontinuation was associated with inferior patient and graft survival.

The influence of clinical, environmental, and socioeconomic factors on five-year patient survival after kidney transplantation.

INTRODUCTION: The risk of death after kidney transplant is associated with the age of the recipient, presence of comorbidities, socioeconomic status, local environmental characteristics and access to health care. OBJECTIVE: To investigate the causes and risk factors associated with death during the first 5 years after kidney transplantation. METHODS: This was a single-center, retrospective, matched case-control study. RESULTS: Using a consecutive cohort of 1,873 kidney transplant recipients from January 1st 2007 to December 31st 2009, there were 162 deaths (case group), corresponding to 5-year patient survival of 91.4%. Of these deaths, 25% occurred during the first 3 months after transplant. The most prevalent cause of death was infectious (53%) followed by cardiovascular (24%). Risk factors associated with death were history of diabetes, dialysis type and time, unemployment, delayed graft function, number of visits to center, number of hospitalizations, and duration of hospital stay. After multivariate analysis, only time on dialysis, number of visits to center, and days in hospital were still associated with death. Patients who died had a non-significant higher number of treated acute rejection episodes (38% vs. 29%, p = 0.078), higher mean number of adverse events per patient (5.1 ± 3.8 vs. 3.8 ± 2.9, p = 0.194), and lower mean eGFR at 3 months (50.8 ± 25.1 vs. 56.7 ± 20.7, p = 0.137) and 48 months (45.9 ± 23.8 vs. 58.5 ± 20.2, p = 0.368). CONCLUSION: This analysis confirmed that in this population, infection is the leading cause of mortality over the first 5 years after kidney transplantation. Several demographic and socioeconomic risk factors were associated with death, most of which are not readily modifiable.

The influence of clinical, environmental, and socioeconomic factors on five-year patient survival after kidney transplantation / A influência de fatores clínicos, ambientais e socioeconômicos na sobrevida de cinco anos após o transplante renal

ABSTRACT Introduction: The risk of death after kidney transplant is associated with the age of the recipient, presence of comorbidities, socioeconomic status, local environmental characteristics and access to health care. Objective: To investigate the causes and risk factors associated with death during the first 5 years after kidney transplantation. Methods: This was a single-center, retrospective, matched case-control study. Results: Using a consecutive cohort of 1,873 kidney transplant recipients from January 1st 2007 to December 31st 2009, there were 162 deaths (case group), corresponding to 5-year patient survival of 91.4%. Of these deaths, 25% occurred during the first 3 months after transplant. The most prevalent cause of death was infectious (53%) followed by cardiovascular (24%). Risk factors associated with death were history of diabetes, dialysis type and time, unemployment, delayed graft function, number of visits to center, number of hospitalizations, and duration of hospital stay. After multivariate analysis, only time on dialysis, number of visits to center, and days in hospital were still associated with death. Patients who died had a non-significant higher number of treated acute rejection episodes (38% vs. 29%, p = 0.078), higher mean number of adverse events per patient (5.1 ± 3.8 vs. 3.8 ± 2.9, p = 0.194), and lower mean eGFR at 3 months (50.8 ± 25.1 vs. 56.7 ± 20.7, p = 0.137) and 48 months (45.9 ± 23.8 vs. 58.5 ± 20.2, p = 0.368). Conclusion: This analysis confirmed that in this population, infection is the leading cause of mortality over the first 5 years after kidney transplantation. Several demographic and socioeconomic risk factors were associated with death, most of which are not readily modifiable.

RESUMO Introdução: O risco de óbito após transplante renal está associado à idade do receptor, presença de comorbidades, condição socioeconômica, às características ambientais locais e ao acesso a serviços de atenção à saúde. Objetivo: Investigar as causas e fatores de risco associados ao óbito nos primeiros cinco anos após o transplante renal. Métodos: Este é um estudo unicêntrico retrospectivo com pareamento dos grupos caso e controle. Resultados: Em uma coorte consecutiva de 1.873 receptores de transplante renal atendidos de 1/1/2007 a 31/12/2009 foram registrados 162 óbitos (grupo caso), correspondendo a uma taxa de sobrevida após cinco anos de 91,4%. Dos óbitos registrados, 25% ocorreram nos primeiros três meses após o transplante. A causa de óbito mais prevalente foi infecção (53%), seguida de doença cardiovascular (24%). Os fatores de risco associados a mortalidade foram histórico de diabetes, tipo e tempo em diálise, desemprego, função tardia do enxerto, número de consultas, número de hospitalizações e tempo de internação hospitalar. Após análise multivariada, apenas o tempo em diálise, o número de consultas e dias de internação permaneceram associados a mortalidade. Os pacientes que foram a óbito tiveram um número não significativamente maior de tratamentos de episódios de rejeição aguda (38% vs. 29%; p = 0,078), maior número médio de eventos adversos por paciente (5,1 ± 3,8 vs. 3,8 ± 2,9; p = 0,194) e TFGe média mais baixa aos três meses (50,8 ± 25,1 vs. 56,7 ± 20,7; p = 0,137) e 48 meses (45,9 ± 23,8 vs. 58,5 ± 20,2; p = 0,368). Conclusão: A presente análise confirmou que nessa população, a infecção foi a principal causa de mortalidade nos primeiros cinco anos após transplante renal. Vários fatores de risco demográficos e socioeconômicos foram associados a mortalidade, a maioria não prontamente modificável.

Heightened expression of HLA-DQB1 and HLA-DQB2 in pre-implantation biopsies predicts poor late kidney graft function.

BACKGROUND: Accurate pre-transplant prediction of late graft function remains an unmet need in kidney transplantation. The aim of this study was to evaluate HLA genes expression levels in pre-implantation biopsies (PIB) of deceased donor kidneys as markers for long-term graft outcome. METHODS: HLA genes expression analysis was initially performed using microarray data of 53 PIB, previously generated by our laboratory. The validation analysis was performed by real-time PCR in 116 PIB from an independent cohort. RESULTS: The microarray data showed association between high expression levels of HLA class II genes, especially HLA-DQB1 and -DQB2, in kidneys from young (18 to 49-year-old) donors and poor (eGFR < 45 mL/min/1.73 m2) 1- and 5-year graft function. A subsequent study in an independent cohort, in which only HLA-DQB2 expression was evaluated, validated the association between increased HLA-DQB2 expression in PIB of kidneys from young donors and poor 1-year graft function: expression levels ≥0.0025 relative units conferred an odds ratio of 22.5, with positive and negative predictive values of 71.4% and 90.0%, respectively. CONCLUSION: Heightened expression of HLA-DQB1 and -DQB2 in PIB are promising tools for pre-transplant risk assessment of poor late graft function in transplants with kidneys from 18 to 49-year-old donors.

Limitations of the interpretation and extrapolation of clinical trial data in kidney transplant recipients.

OBJECTIVE: The risks and benefits of the participation of kidney transplant recipients in randomized clinical trials (RCTs) investigating new immunosuppressive therapies are unknown. DESIGN AND SETTING: We included patients from 12 prospective phase II/III RCTs randomized to the experimental (G1, n=319) or standard-of-care internal control group (G2, n=118). We constructed two additional external control groups with (G3, n=319) or without (G4, n=319) matching inclusion/exclusion criteria based on transplant date. The primary outcome analysis was the composite clinical efficacy failure, defined as biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up 12 months after kidney transplantation. RESULTS: Survival free of composite clinical efficacy failure was higher among participants in RCT, without difference between experimental or standard-of-care therapy (80∙3 vs 78∙0 vs 69∙9 vs 66∙1%, P<.001), respectively. Patient (98.1 vs 99.2 vs 96.9 vs 91.8 P<.001) and graft (94.0 vs 98.3 vs 90.9 vs 82.4) survivals were also higher in G1 compared to G4, but no differences in survival free of BPAR were observed (85.3 vs 78.8 vs 82.8 vs 81.2 P>.05), respectively. CONCLUSION: These findings suggested that new treatments investigated in kidney transplant recipients are not associated with detectable harm compared to standard of care.

Influence of CYP3A4 and CYP3A5 polymorphisms on tacrolimus and sirolimus exposure in stable kidney transplant recipients.

BACKGROUND: Polymorphisms in genes encoding for drug-metabolizing enzymes and drug transporters are among multiple factors that modulate the pharmacokinetic variability of tacrolimus (TAC) and sirolimus (SRL). This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) on TAC and SRL dose-adjusted concentrations (C0/D) in stable kidney transplant recipients. METHODS: This is an exploratory and prospective study, which includes 46 stable kidney transplant recipients. These patients were monitored from the 3rd to the 24th month after transplantation. The SRL group consisted of 25 patients receiving TAC, prednisone (PRED), and mycophenolate sodium (MPS), which were converted from TAC to SRL at 3rd month after transplantation. The TAC group consisted of 21 patients who underwent treatment with TAC, PRED, and MPS. Both groups were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T), CYP2C8 rs10509681 (c.1196A>G) and ABCB1 rs1045642 (c.3435C>T), rs1128503 (c.1236C>T), and rs2032582 (c.2677G>T/A) polymorphisms. RESULTS: In the TAC group, CYP3A4 rs2242480 A allele carriers were associated with lower TAC C0/D. For CYP3A5 rs15524 SNP, C0/D was higher among patients carrying TT genotype when compared with CT and CC genotype carriers in the SRL and, more consistently, in the TAC groups. For ABCB1 rs1045642 SNP, TT genotype was associated with reduced SRL C0/D, but only at month 15. CONCLUSIONS: CYP3A4 rs2242480 and CYP3A5 rs15524 SNPs resulted in significant changes in SRL and TAC C0/D at different times after transplantation.

Association of the PPP3CA c.249G>A variant with clinical outcomes of tacrolimus-based therapy in kidney transplant recipients.

BACKGROUND: The effects of genetic variants related to the pharmacodynamic mechanisms of immunosuppressive drugs on their therapeutic efficacy and safety have been poorly explored. This study was performed to investigate the influence of the PPP3CA c.249G>A variant on the clinical outcomes of kidney transplant recipients. PATIENTS AND METHODS: A total of 148 Brazilian patients received tacrolimus (TAC)-based immunosuppressive therapy for 90 days post-kidney transplantation. The PPP3CA rs3730251 (c.249G>A) polymorphism was determined by real-time polymerase chain reaction. Single-nucleotide polymorphism (SNP) data for CYP3A5 rs776746 (CYP3A5*3C; g.6986A>G) were used to eliminate the confounding effects of this variant. RESULTS: The PPP3CA c.249G>A SNP did not influence early TAC exposure, renal function, or other laboratory parameters, including levels of urea, creatinine, glucose, and lipids, and blood counts. This variant also did not account for the cumulative incidence of biopsy-confirmed acute rejection or delayed graft function. Regarding adverse events, PPP3CA c.249A allele carriers initially had a 3.05-fold increased probability of treatment-induced blood and lymphatic system disorders compared with c.249GG genotype individuals (95% confidence interval: 1.10-8.48, p=0.032). However, this result was not maintained after adjusting for body weight and CYP3A5*3C SNP status (p=0.086). CONCLUSION: The PPP3CA c.249G>A variant does not influence the clinical outcomes of Brazilian patients in the early phase of TAC-based immunosuppressive regimen.

Influence of ABCC2, CYP2C8, and CYP2J2 Polymorphisms on Tacrolimus and Mycophenolate Sodium-Based Treatment in Brazilian Kidney Transplant Recipients.

STUDY OBJECTIVE: To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. DESIGN: Pharmacogenetic analysis of patients enrolled in a previously published study. PATIENTS: One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation. MEASUREMENTS AND MAIN RESULTS: ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05). CONCLUSION: The ABCC2 c.3972C >T polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.-76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.

Influence of ABCC2, CYP2C8, and CYP2J2 polymorphisms on tacrolimus and mycophenolate sodium-based treatment in brazilian kidney transplant recipients

STUDY OBJECTIVE: To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. DESIGN: Pharmacogenetic analysis of patients enrolled in a previously published study. PATIENTS: One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation.MEASUREMENTS AND MAIN RESULTS:ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05)...

Association of the PPP3CA c.249G>A variant with clinical outcomes of tacrolimus-based therapy in kidney transplant recipients

BACKGROUND:The effects of genetic variants related to the pharmacodynamic mechanisms of immunosuppressive drugs on their therapeutic efficacy and safety have been poorly explored. This study was performed to investigate the influence of the PPP3CA c.249G>A variant on the clinical outcomes of kidney transplant recipients.PATIENTS AND METHODS:A total of 148 Brazilian patients received tacrolimus (TAC)-based immunosuppressive therapy for 90 days post-kidney transplantation. The PPP3CA rs3730251 (c.249G>A) polymorphism was determined by real-time polymerase chain reaction. Single-nucleotide polymorphism (SNP) data for CYP3A5 rs776746 (CYP3A5*3C; g.6986A>G) were used to eliminate the confounding effects of this variant.

Prospective Randomized Trial Investigating the Influence of Pharmaceutical Care on the Intra-Individual Variability of Tacrolimus Concentrations Early After Kidney Transplant.

BACKGROUND: This study evaluated the influence of pharmaceutical care (PhC) in the intra-individual variability of dose-corrected whole blood tacrolimus (TAC) trough concentrations, adherence to immunosuppressive therapy and clinical outcomes. METHODS: We randomized 128 kidney transplant recipients to receive PhC consisted of predefined instructions provided by a pharmacist (PhC group, n = 64) or standard nurse staff instructions (control group, n = 64) from day 3 to day 90 after kidney transplantation. The study was powered to detect at least 50% reduction in the coefficient of variation (%CV), calculated from 6 dose-corrected whole blood TAC trough concentrations, in the PhC group. Patient adherence was evaluated using Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS) questionnaire. RESULTS: There was no difference in the %CV comparing PhC and control group (31.4% ± 12.3% versus 32.5% ± 16.1%, P = 0.673). There were no differences in the proportion of patients showing TAC concentrations within predefined target concentrations in each study visit. There was no difference in the proportion of nonadherent patients at day 28 (17% versus 26%, P = 0.135) and day 90 (27% versus 25%, P = 0.457) based on BAASIS questionnaire answers, respectively. There were no differences in clinical outcomes. CONCLUSIONS: Universal PhC in addition to standard nurse staff instruction was not associated with reduced intra-individual variability of dose-corrected whole blood TAC trough concentrations or improved adherence.

Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients.

BACKGROUND: Polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment. OBJECTIVE: The aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes. MATERIAL AND METHODS: Brazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms. RESULTS: Frequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05). CONCLUSION: The results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation.

Plasma proteomics for the assessment of acute renal transplant rejection.

Renal transplant is the best treatment for patients with chronical kidney disease however acute graft rejection is the major impediment to success in renal transplantation leading to loss of the organ the first year after transplantation. The aim of this study was to identify plasma proteins that may be early biomarkers of acute rejection of renal allograft, developing a diagnostic model that avoids the loss of the transplanted organ. Shotgun proteomics (LC-MS/MS) method was used to analyze a set of thirty-one plasma samples, including 06 from patients with acute graft rejection after transplantation (rejection group/Rej-group) and twenty-five from renal transplant patients with stable renal graft function (control group/Ct-group). As results nineteen proteins were upregulated in the rejection group compared to the control group, and two proteins were downregulated; and three were present exclusively in the rejection group. After analysis, we selected four proteins that were related to the acute phase response and that were strongly associated with each other: they are alpha-1 antitrypsin (A1AT), alpha-2 antiplasmin (A2AP), serum amyloid A (SAA) and apolipoprotein CIII (APOC3). We think that simultaneous monitoring of SAA and APOC3 can provide insights into a broad profile of signaling proteins and is highly valuable for the early detection of a possible acute renal graft rejection. STATEMENT OF SIGNIFICANCE OF THE STUDY: In this study we did plasma shotgun patients with and without acute rejection of renal allograft. In a clinical setting an acute rejection is typically suspected upon an increase in plasma creatinine and renal biopsy. But these methods are late and unspecific; sometimes the rejection process is already advanced when there is an increase in serum creatinine. Therefore, it is necessary to find proteins that can predict the allograft rejection process. In our study were able to identify changes in the concentration of plasma protein belonging to a network of protein interaction processes the acute phase response. We believe, therefore, that development of a routine diagnosis of these proteins can detect early acute rejection of renal allograft process, thus preventing its loss.

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.

Post-transplant soluble CD30 levels are associated with early subclinical rejection in kidney transplantation.

Several studies have shown association of high pre- or post-transplant levels of soluble CD30 (sCD30) with acute rejection and poor late kidney transplant outcome. Our goal was to investigate whether sCD30 levels at month-3 post-transplant are associated with subclinical rejection, presence of CD30(+) cells within the graft, and expression of immune response genes in peripheral blood mononuclear cells. The study comprised 118 adult first kidney graft recipients, transplanted at a single center, receiving tacrolimus in low concentration. All were submitted to a protocol biopsy at month-3. Subclinical rejection was identified in 10 biopsies and sCD30 levels ≥ 61.88 ng/mL (P = 0.004), younger recipient age (P = 0.030) and non-Caucasian ethnicity (P = 0.011) were independently associated with this outcome. Rare CD30(+) cells were present in only two biopsies. There was a correlation between sCD30 levels and CD30 gene expression in peripheral blood mononuclear cells (r = 0.385, P = 0.043). These results show that high sCD30 levels are independent predictors of graft dysfunction and may contribute to patient selection protocols by indicating those who could benefit from a more thorough evaluation.

Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.

OBJECTIVE: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. DESIGN: Systematic review and meta-analysis of individual patient data. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. ELIGIBILITY: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. RESULTS: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. CONCLUSIONS: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

Association of high post-transplant soluble CD30 serum levels with chronic allograft nephropathy.

The purpose of this study was to evaluate the association of post-transplant soluble CD30 (sCD30) levels, isolated or in combination with of anti-HLA class II antibodies and of serum creatinine levels, with kidney graft loss due to chronic allograft nephropathy (CAN), and type of lesions in graft biopsies for cause. The study comprised 511 first kidney graft recipients, transplanted at a single center, with a graft functioning for at least 2.8 years. A single blood sample was collected from each patient. sCD30 levels were determined by ELISA, and HLA antibodies by Luminex assay. The minimum follow-up after testing was 9.3 years. High sCD30 levels, set at sCD30 ≥ 34.15 ng/mL, the presence of HLA class II antibodies, and serum creatinine ≥ 1.9 mg/dL were independently associated with CAN-graft loss (P values <0.0001, 0.05, <0.0001, respectively), and the combined hazard ratio for CAN-graft loss was 20.2. Analyses of 166 biopsies for cause showed that high sCD30 levels and creatinine were independently associated with interstitial lesions. Post-transplant sCD30 serum levels, especially in conjunction with information regarding HLA class II antibodies and serum creatinine levels, provide valuable information regarding graft outcome and could be useful for the management of kidney transplant recipients.