A Randomized Trial of Everolimus-based Quadruple Therapy vs Standard Triple Therapy Early After Lung Transplantation

Jens Gottlieb; Claus Neurohr; Joachim Müller-Quernheim; Hubert Wirtz; Bjoern Sill; Heinrike Wilkens; Vasiliki Bessa; Christoph Knosalla; Martina Porstner; Carmen Capusan; Martin Strüber


American Journal of Transplantation. 2019;19(6):1759-1769. 

In This Article

Abstract and Introduction


Calcineurin inhibitor (CNI) therapy after lung transplantation increases risk of kidney failure. Early everolimus-based quadruple low CNI immunosuppression may improve renal function without compromising efficacy or safety. A prospective, randomized, open-label, 12-month multicenter trial was conducted at 8 German sites. Patients 3–18 months after lung transplantation were randomized (1:1), stratified by baseline estimated glomerular filtration rate (eGFR). In the quadruple low CNI regimen, patients received everolimus (target trough level 3–5 ng/mL) with reduced CNI (tacrolimus 3–5 ng/mL or cyclosporine 25–75 ng/mL) and a cell cycle inhibitor plus prednisone. In the standard triple CNI regimen, patients received tacrolimus (target trough level >5 ng/mL) or cyclosporine (>100 ng/mL) and a cell cycle inhibitor plus prednisone. Of the 180 patients screened, 130 were randomized: 67 in the quadruple low CNI group and 63 in the standard triple CNI group. The primary endpoint (eGFR after 12 months) demonstrated superiority of the quadruple low CNI regimen: 64.5 mL/min vs 54.6 mL/min for the standard triple group (least squares mean, analysis of covariance; P < .001). Key efficacy parameters (biopsy-proven acute rejection, chronic lung allograft dysfunction, and death) and safety endpoints were similar between both groups. Quadruple low CNI immunosuppression early after lung transplantation was demonstrated to be efficacious and safe. Clinical trials registry: ClinicalTrials.gov NCT01404325.


The number of lung transplants has been rising steadily over the past decades.[1] Advances in donor management and preservation methods have expanded the donor pool and, increasingly, elderly patients with comorbidities are undergoing transplantation.[1,2] Long-term outcomes, however, remain inferior compared to other forms of solid organ transplantation. Fifty-six percent of lung transplant recipients survive more than 5 years,[1] with chronic lung allograft dysfunction (CLAD) and infections being the leading causes of death.[1]

Lung transplant recipients are at high risk of graft rejection, necessitating a more intensive immunosuppressive therapy relative to other solid organ transplants.[3] Maintenance therapy typically consists of a calcineurin inhibitor (CNI), a cell cycle inhibitor, and corticosteroids.[4] Chronic CNI therapy, however, is frequently associated with nephrotoxicity[5] and is an independent predictor for a decline in glomerular filtration rate (GFR) after lung transplantation.[6] This effect is dose dependent.[7,8] End-stage kidney disease including the need for renal transplantation affects almost 5% of the recipients within the first 5 years.[9] End-stage kidney disease adversely affects mortality. In large epidemiological studies, an estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2 was independently associated with higher rates of cardiovascular deaths, overall mortality, and hospitalizations.[10,11] These effects were more pronounced in patients with lower GFR.

Maintaining immunosuppressive efficacy and preserving long-term renal function has prompted interest in the use of mammalian target of rapamycin (mTOR) inhibitors to minimize CNI exposure. Additionally, consistent with evidence from renal[12,13] and heart[14] transplantation, the risk of cytomegalovirus (CMV) infections is reduced in lung transplant patients receiving an mTOR inhibitor–based immunosuppressive protocol.[15–17]

Everolimus in conjunction with reduced-exposure CNI therapy maintains immunosuppressive efficacy in de novo renal,[18] liver,[19] and heart[20] transplant patients. In lung transplantation, 2 randomized trials of everolimus with reduced CNI exposure, initiated early posttransplant, have shown a lower rate of acute rejection than standard CNI-based triple therapy in comparison to mycophenolic acid (MPA) formulations without affecting the incidence of CLAD.[15,21] In terms of renal function, de novo use of everolimus with moderately reduced CNI exposure does not appear to influence posttransplant renal deterioration after lung transplantation.[15,21] In contrast, a moderate improvement in renal function was observed in long-term thoracic transplant recipients, including lung transplanted patients, who were switched to add-on everolimus with low-dose CNI therapy late after transplantation.[22,23]

The aim of the current study was to demonstrate that everolimus with low CNI exposure in a quadruple immunosuppression regimen is superior to a standard triple CNI regimen in terms of renal function, as assessed by eGFR, in patients with impaired kidney function early after lung transplantation. The study included patients with mild-to-moderate impairment of kidney function and excluded those with severe impairment in whom an improvement in function was less likely.