Immunosuppressive agents are key in ensuring long-term graft survival in renal transplant recipients. Clinicians seek to achieve a balance between a low rate of acute rejections and avoidance of toxicities related to immunosuppression. The mammalian target of rapamycin (mTOR) inhibitors bind to the immunophilin FKBP12, blocking the activity of mTOR, a serine threonine protein kinase involved in the proliferation and clonal expansion of antigen-activated T cells, the primary mechanism underlying acute transplant rejection.
Calcineurin inhibitors (CNIs) are known to be associated with nephrotoxicity; kidney transplant recipients receiving mTOR inhibitors can benefit from reduced exposure to CNIs, with no loss of immunosuppressive efficacy. Results of the CRAD001A2309 study demonstrated that treatment with the mTOR inhibitor everolimus (EVR), particularly at a trough concentration of 3 to 8 ng/mL, allowed for reduced exposure to the CNI cyclosporine (CsA), while maintaining renal function and a reduced risk of treated biopsy-proven acute rejection (tBPAR).
According to the 2013 Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients annual report, the most frequently used CNI-based do novo regimen for all solid organ transplantation was tacrolimus (Tac), not CsA. Tac and EVR in combination have been shown to be safe and well-tolerated in earlier studies. When the agents were given simultaneously, there were no pharmacokinetic interactions in an open-label exploratory study. In the CRAD001AUS09 open-lable, randomized study also found no pharmacokinetic interactions between concentration-controlled EVR and low- or standard-dose Tac (LTac or sTac) in a population of de novo renal transplant patients.
Researchers led by Fuad S. Shihab, MD, recently conducted a study designed to correlate the efficacy and safety events with EVR and Tac concentrations. The study examined the incidence of post-transplantation tBPAR, graft loss, and other adverse events associated with EVR and Tac exposure at 12 months post-transplant in the phase 3b, multicenter, randomized, open-label noninferiority CRAD001AUS92 study. The researchers also examined post-transplantation renal function in the study population. Results were reported in the American Journal of Transplantation [2017;17(9):2363-2371].
There were 309 patients in the full analysis set who were randomized to EVR + LTac; three of those patients did not receive study medication and were excluded from the safety set (n=306). Mean age was 50 years and 67% were male. Of the 309 in the full analysis set, 94.8% (n=292) completed the 12-month study period. There were 105 patients (34.0%) who discontinued the study medication, due primarily to adverse events.
At the end of the 12-month study period, 19.1% (n=59/309) of the patients in the EVR + LTac group experienced tBPAR. Patients with EVR trough concentration of <3 ng/mL had the highest rates of tBPAR, compared with those with EVR trough concentration of ≥3 ng/mL (64.7% vs 14.0%, respectively). The lowest rates of tBPAR were associated with EVR 6 to <8 ng/mL. Four patients had Tac <2 mg/mL; of those, two cases of tBPAR were reported (50.0% vs 19.3% at ≥2 ng/mL).
At 12 months post-transplantation, graft loss had occurred in four of 309 patients (1.3%). Patients in the group with the lowest EVR and Tac concentrations had the highest rate of graft loss: EVR<3 ng/mL (n=2/19), 10.5% vs 0.4% at ≥3 ng/mL and Tac <2 ng/mL (n=2/2), 100.0% vs 0.3% at ≥2 ng/mL. All four cases of graft loss occurred within the first month after transplantation and none were due to rejection (one case each of infarcted kidney, renal artery stenosis, renal vein thrombosis, and acute tubular necrosis).
At 12 months post-transplantation, low estimated glomerular filtration rate (eGFR) was reported in 8.8% of participants (n=27/306); decreased eGFR was reported in 18.0% (n=55) of patients in the EVR + LTac group. Analysis of eGFR rates in patients without graft rejection revealed that those with lower EVR levels had lower eGFR values (P=.001 for low eGFR and P=.003 for decreased eGFR).
Adverse events were seen most often in patients with EVR levels <3ng/mL. Of the 306 patients included in the safety set, 22.2% (n=68) discontinued study medication due to an adverse event. The most common reason for discontinuation was BK viral infection (2.3%; n=7).
Study limitations cited by the authors included the small number of patients in some categories; because EVR levels were targeted to be maintained between 3 and 8 ng/mL, there were fewer patients in the highest and lowest trough concentration groups. Further, the need to adjust EVR and Tac trough levels throughout the study required an unblinded study design, introducing the potential for bias in adverse event reporting.
“In summary,” the researchers said, “the US92 study provides evidence that a regimen combining EVR 3 to 8 ng/mL and a low dose of Tac allows for good efficacy, excellent renal function, and a favorable safety profile at 12 months post-transplantation. Underexposing patients to EVR may lead to an increased rate of rejection and an increased incidence of adverse events. Renal dysfunction was higher with increased Tac trough concentrations and with decreased EVR trough concentrations. Collectively, these findings further support the importance of maintaining an EVR trough concentration of 3 to 8 ng/mL when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients.”
Immunosuppressive agents are key in maintaining long-term graft survival in renal transplant recipients, and achieving the correct balance between a low rate of acute rejections and avoidance of toxicities related to immunosuppression is a challenge in kidney transplantation.
Researchers analyzed data from the CRAD001AUS92 study to correlate efficacy and safety events with everolimus (EVR) and tacrolimus (Tac) concentrations; they examined the incidence of post-transplantation acute rejection, graft loss, and other adverse events associated with EVR and Tac exposure.
Balanced efficacy and safety at 12 months post-transplant was achieved with an EVR trough concentration of 3 to 8 ng/mL combined with low Tac in renal transplant recipients.