Serum KL-6 and eGFR Predict Everolimus-Induced Lung Injury in Heart Transplant Recipients: A Retrospective Observational Study

Background Everolimus (EVR) is widely used in heart transplant recipients because it enables a dose reduction of calcineurin inhibitors and suppresses cytomegalovirus infection and cardiac allograft vasculopathy. However, EVR has been associated with drug-induced lung injury (LI). Although EVR-induced LI has been reported in patients with malignancies and recipients of solid organ transplants other than heart transplant, its incidence and risk factors in heart transplant recipients remain unclear. This study aimed to determine the incidence of EVR-associated LI and identify risk factors using serum Krebs von den Lungen-6 (KL-6) as a biomarker. Methods This retrospective observational study included patients who received a heart transplant at the University of Tokyo Hospital from June 2006 to April 2021. The patients were categorized into two groups: those who received EVR after heart transplantation (EVR group) and those who did not (non-EVR group). Baseline and peak serum KL-6 levels were compared between groups, and KL-6 elevation was defined as a peak level ≥ 500 U/mL. Multivariable logistic regression analysis was performed in the EVR group to identify independent risk factors. Receiver operating characteristic (ROC) analysis determined optimal cutoff values, and a composite risk score was constructed. Event free survival was evaluated using the Kaplan–Meier method. Results Seventy-three heart transplant recipients were included (58 and 15 for EVR and non-EVR groups, respectively). Peak serum KL-6 levels were significantly higher in the EVR group than in the non-EVR group (320 [235–509] vs. 157 [127–263] U/mL, p  = 0.002). KL-6 elevation occurred in 27.6% and 6.7% of patients in the EVR and the non-EVR group, respectively. Within the EVR group, higher baseline KL-6 levels and lower eGFR were independently associated with KL-6 elevation. ROC analysis identified cutoff values of baseline KL-6 > 268 U/mL and eGFR < 60 mL/min/1.73 m². Patients with higher composite risk scores experienced earlier KL-6 elevation. Conclusions EVR administration was associated with increased serum KL-6 levels in heart transplant recipients. Elevated baseline KL-6 levels and impaired renal function before EVR initiation were independent predictors of EVR-associated LI. Assessment of these parameters may help earlier detection and management of EVR-induced LI.