The Effect of Everolimus Versus Mycophenolate Upon Proteinuria Following Kidney Transplant and Relationship to Graft Outcomes

Abstract

Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3 months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time-dependent model to correlate the risk of proteinuria to EVR trough levels up to 24 months posttransplant. eGFR and graft loss was compared by proteinuria status at 3 months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5 mg/day), higher exposure EVR (3.0 mg/day) and MPA-treated patients had proteinuria ≥ 300 mg/g Cr at 3 months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p = 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels >8 ng/mL were significantly associated with proteinuria compared to 3-8 ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3 months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24 months, regardless of treatment arm. We identify a dose-dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2 years was not evident.

Evaluation and Management of Proteinuria After Kidney Transplantation

“…A recent study by Wiseman et al 45 suggests a dose dependent effect of everolimus on proteinuria. In this randomized trial 277 patients received 1.5 mg/day of everolimus, 279 received 3 mg/day of everolimus, and 277 received mycophenolic acid (MPA).…”

Donor-Specific Anti-Human Leukocyte Antigens Antibodies, Acute Rejection, Renal Function, and Histology in Kidney Transplant Recipients Receiving Tacrolimus and Everolimus

“…Evidence from several studies has demonstrated that risk factors associated with the development of proteinuria include higher EVR concentrations [19]. Moreover, proteinuria is more common in patients who were converted from CNI to mTOR-based immunosuppressive regimen [20,21,22].…”

Critical analysis of graft loss and death in kidney transplant recipients treated with mTOR inhibitors

“…Although specific causes of death and graft loss have not been studied systematically, adverse events typically associated with the use of imTORs such as proteinuria, [22][23][24] diabetes mellitus after transplantation [25][26][27] and dyslipidemia 27 may be involved in these findings. These complications, however, are associated with the relatively high blood concentrations of iCN and imTOR initially used.…”