Strategies for the management of adverse events associated with mTOR inhibitors

https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.12181

Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial.

Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

/pdf/everolimus-with-reduced-calcineurin-inhibitor-exposure-in-q7dqk781dh.pdf

Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation

https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.12280

Renal Function at Two Years in Liver Transplant Patients Receiving Everolimus: Results of a Randomized, Multicenter Study

BACKGROUND: Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain. METHODS: ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30-70 mL/min/1.73 m) were randomized to everolimus with CNI elimination (n=127) or CNI minimization (n=144), or continued CNI unchanged (controls, n=123) to assess the effect on measured GFR at month 24 after randomization. RESULTS: Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0±22.0 mL/min/1.73 m, 46.6±21.1 mL/min/1.73 m, and 46.0±20.4 mL/min/1.73 m in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m, 95% confidence interval [CI] -3.51 to 5.76, P=0.63) and CNI minimization (0.59 mL/min/1.73 m, 95% CI -3.88 to 5.07, P=0.79) versus controls at month 24 were nonsignificant that is, the primary endpoint was not met. No efficacy endpoint differed significantly between groups. Post hoc analyses showed that patients with baseline creatinine clearance (CrCl) more than 50 mL/min had a significantly greater increase in measured GFR after CNI elimination versus controls (difference 11.4 mL/min/1.73 m, 95% CI 2.1 to 20.8 mL/min/1.73 m, P=0.017). Adverse events resulted in discontinuation in 36 (28.3%) CNI elimination patients, 24 (16.7%) CNI minimization patients, and 5 (4.1%) controls (P<0.001 vs. CNI elimination; P=0.020 vs. CNI minimization). CONCLUSION: Conversion to everolimus with CNI elimination or minimization a mean of 5.6 years after kidney transplantation had no overall renal benefit and was associated with more frequent adverse events and discontinuations. Patients with CrCl more than 50 mL/min may benefit from a change in therapy more than 6 months after renal transplantation.

Conversion of Long-Term Kidney Transplant Recipients From Calcineurin Inhibitor Therapy to Everolimus : A Randomized, Multicenter, 24-Month Study

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-6143.2010.03129.x

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

E. Lackova1, D. Cibrik2, T. Johnston3, Y.S. Kim4, G. Civati5, R. Walker6, G. Zibari7, K. Mange8, C. Panis8, Z. Wang8, H. Tedesco-Silva9 1, Transplantation Center, NSP F.D. Roosevelta, Banská Bystrica/ SLOVAK REPUBLIC, 2, University of Michigan, Ann Arbor/MI/UNITED STATES OF AMERICA, 3, University of Kentucky Transplant Center, Lexington/UNITED STATES OF AMERICA, 4, Yonsei University College of Medicine, Seoul/KOREA, 5Divisione Nefrologia E Dialisi, Az. Osp. Niguarda Ca’ Granda, Milano/ITALY, 6, Royal Melbourne Hospital, Melbourne/AUSTRALIA, 7, Willis Knighton LSU Health Sciences Center, Shreveport,/UNITED STATES OF AMERICA, 8, Novartis Pharmaceuticals Corporation, East Hanover/UNITED STATES OF AMERICA, 9, Hospital do Rim e Hipertensao, Lagoa/ BRAZIL

60% reduction in cyclosporine exposure with everolimus over 12 months in de novo renal transplant recipients: results from a multicenter, randomized study: 1564

OBJECTIVES
The aim of our analysis was to evaluate the impact of the COVID-19 pandemic on the procurement program and kidney transplantation in Slovakia and to identify the risk factors for a severe course of COVID-19 disease, as well as the risk factors for COVID-19 fatalities, with the focus on the parameters preceding the infection. We compared morbidity and mortality from COVID-19 before and after the spread of the alpha variant of the virus and the same among transplant (KTRs) and haemodialysis patients in Slovakia.


METHODS
305 KTRs (68.8 % males) with confirmed SARS-CoV-2 positivity were included in the multicentric retrospective analysis. The patients were split into subgroups based on the time of falling ill and their clinical course.


RESULTS
The procurement program and kidney transplants in Slovakia dropped in the observed period by 28.6 % (p<0.0001) and by 33.5 % (p<0.0001) respectively. Age over 59 years (p=0.0088) and diabetes mellitus (p=0.0106) were identified as independent risk factors for severe course of the disease. Risk factors for death were the age over 59 years (p=0.0003) and graft dysfunction with CKD-EPI<0.5 mL/s (p=0.0029). The prevalence of the alpha variant in Slovakia was associated with a severe course in KTRs treated with corticoids (p=0.0273) and in graft dysfunction with CKD-EPI<0.5 mL/s (p=0.0076); the risk of death was higher in KTRs over 59 years (p=0.0173) and again with CKD-EPI<0.5 mL/s (p=0.0393). KTRs had a 3.7 times lower risk of infection compared to the haemodialysis patients (p<0.0001), with mortality of 9.8 % vs 30 % (p<0.0001).


CONCLUSION
The procurement and transplant program is sustainable even during a pandemic, provided that measures are set up quickly. Morbidity and mortality from COVID-19 in KTRs was comparable to the situation in EU countries. Patients in the haemodialysis program had a worse prognosis (Tab. 5, Fig. 1, Ref. 21) Keywords: COVID-19, kidney transplantation, dialysis, immunosuppression, obesity, diabetes mellitus.

How COVID-19 crisis influenced kidney transplant recipients in Slovakia.

Introduction: Stable long term kidney function and safety of the donor nephrectomy are essential prerequisites for the living kidney donation. In our retrospective multicenter analysis we evaluated the impact of selected risk factors (age, BMI, arterial hypertension) on the severity of change in glomerular filtration rate (GFR) after kidney donation. Materials and Methods: In the period of years 2015 to 2019 there were 35 open and 46 hand assisted retroperitoneoscopic (HARS) donor nephrectomies performed in 4 transplant centers. 78 donors were eligible for analysis. Mean follow up of the donors was 3 ± 1,4 years. GFR was calculated according to CKD-EPI formula before donation (eGFR_baseline), at the time of maximal decrease (eGFR_min) and at the end of follow up (eGFR_end). ΔGFR refers to the change of eGFR in a donor and is expressed as a difference between eGFR_baseline and eGFR_min (ΔGFR_max) or eGFR_end (ΔGFR_end) respectively. We used unpaired t test, Fisher test and linear regression for statistical analysis. Results and Discussion: We found strong correlation between ΔGFR_end and eGFR_baseline, (r=0.5111, p< 0.0001). Age, BMI and eGFR_min did not correlate with ΔGFR_end. Hypertensive donors did not have significantly higher ΔGFR_end than normotensive donors (-26.9 vs. -24.6ml/min, p=0.49). 32 donors (41%) had eGFR_baseline between 60-90ml/min/1,73m2. In comparison with the subgroup of donors whose eGFR_baseline was more than 90 ml/min/1,73m2, these donors were older (52.2±8.8 vs 46.1±8.6 years, p=0.0034) and their ΔGFR_max and ΔGFR_end were lower (-28.2 ± 12.7 ml/min vs -43 ± 9.6ml/min, p<0.0001 for ΔGFR_max and -16.3 ± 13 ml/min vs -32.1 ± 10.4 ml/min, p<0.0001 for ΔGFR_end). No donor reached eGFR less than 30 ml/min/1,73m2 at the end of follow up. Conclusion: Our results demonstrate favourable mid term renal outcomes even in living kidney donors with slightly reduced predonation eGFR. 

E. Lackova

Papers

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

60% reduction in cyclosporine exposure with everolimus over 12 months in de novo renal transplant recipients: results from a multicenter, randomized study: 1564

How COVID-19 crisis influenced kidney transplant recipients in Slovakia.

P8.088: Mid Term Evolution of the Glomerular Filtration Rate in Living Kidney Donors