Non-invasive assessment of rejection in pediatric transplant patients: Serologic and echocardiographic prediction of biopsy-proven myocardial rejection

Background: Cardiac allograft rejection is a multifocal immune process that is currently assessed using biopsy-guided histologic classification systems (International Society for Heart and Lung Transplantation). Cardiac troponin T and I are established serologic markers of global myocyte damage, The use of load-independent measures of contractility have also been shown to accurately assess the presence of ventricular dysfunction. Little is known about their utility in accurately predicting rejection in the pediatric age group. We undertook the present study to compare rejection grade with echocardiographic and serologic estimates of transplant rejection-related myocardial damage. Methods: We compared histologic rejection grades (0 to 4) with patient characteristics, echocardiographic measurements, catheterization measurements, and biochemical markers for 86 evaluations in 37 transplant recipients at Children's Hospital. Results: In univariate analyses, biopsy scores correlated (p < 0.05) inversely with left ventricular systolic function (shortening fraction) and contractility (stress velocity index, SVI), and directly with mitral E-wave amplitude. In multivariate analyses, lower contractility and higher mitral E-wave amplitude remained significantly (p less than or equal to 0.01) associated with rejection (SVI, p = 0.002, odds ratio = 0.393; E wave, p = 0.0002, odds ratio = 228). Most rejection episodes were associated with elevation of biochemical markers of myocardial injury. Although troponin I was weakly associated with differences between rejection grades (p = 0.034), troponin T, creatine kinase-MB fraction, and C-reactive protein did not differ with biopsy-rejection scores. Serum markers had a poor predictive capacity for biopsy-detected rejection. Conclusion: Progressively depressed left ventricular contractility and diastolic function are found with worsening pediatric heart transplant rejection-biopsy score; however, sensitive and specific serum markers do not correspond to the degree of active myocardial injury. The use of echocardiographic measures of contractility is associated with a specificity of 91.8% but low sensitivity of 66.7%. Overall we found poor concordance between serum markers and grade of rejection. It is unclear whether myocardial injury as assessed by serum markers, echocardiography, or histologic scoring is more important for assessment of acute rejection or long-term outcome, but it does not appear that serum and tissue markers of rejection can be used interchangeably.