Serum KL-6 and eGFR predict everolimus-associated KL-6 elevation in heart transplant recipients: a retrospective observational study

Abstract Background Everolimus (EVR), which is widely used in heart transplant recipients, has been associated with drug-induced lung injury. Although EVR-associated lung injury has been reported in patients with malignancies and recipients of other solid organ transplants, its incidence and risk factors in heart transplant recipients remain unclear. Krebs von den Lungen-6 (KL-6) is a serum biomarker widely used in the assessment of interstitial lung diseases and may reflect pulmonary involvement, including drug-induced lung injury. This study aimed to determine the incidence and risk factors for KL-6 elevation after EVR administration in heart transplant recipients. 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). Multivariable logistic regression analysis was performed in the EVR group to identify independent risk factors for KL-6 elevation (defined as a peak level ≥ 500 U/mL). Receiver operating characteristic (ROC) analysis was used to determine optimal cutoff values, and a composite risk score was constructed. Event-free survival was evaluated using the Kaplan–Meier method. Results Seventy-three patients were included (58 in the EVR group and 15 in the non-EVR group). 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 non-EVR groups, 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 m 2 . Higher composite risk scores were associated with a greater incidence of KL-6 elevation, and patients with both risk factors experienced earlier KL-6 elevation. Conclusions EVR administration was associated with KL-6 elevation in heart transplant recipients. Elevated baseline KL-6 levels and impaired renal function before EVR initiation were independent predictors of KL-6 elevation. Assessment of these parameters may help earlier detection of EVR-associated KL-6 elevation.