Heart transplantation and antibody-mediated rejection: role of myocardial strain as an early marker of cardiac dysfunction in patients with anti-HLA antibody

Background Antibody-mediated rejection of the transplanted heart is still currently diagnosed by endomyocardial biopsy whereas clinical elements, anti-Human Leukocite Antigens (HLA) antibody and graft dysfunction represents supplementary components. Purpose The aim of the study was to identify though a non-invasive imaging technique, such as advanced transthoracic echocardiography, early signs of altered cardiac function in patients with anti-HLA antibodies and no histological signs of antibody-mediated rejection. Methods The study population included 117 heart transplanted patients, in whom both acute and chronic rejection was excluded. They were divided into two groups “HLA+`' (45 patients) and “HLA−” (72 patients), based on the presence and the absence of circulating anti-HLA antibodies, respectively. The echocardiographic exam was performed within one week from the biopsy, including Speckle Tracking analysis. Results Deceleration Time of E wave was the strongest traditional echocardiographic parameter which correlated with circulating anti-HLA antibodies (165±39,5 vs 196,5±25; p<0.001). Regarding strain analysis, both left ventricular global longitudinal strain (−16,1±3,4 vs −19,8±2,0; p<0.001) and right ventricular strain (−17,2±0,7 vs −20,6±0,5; p=0.0002) differed significantly between the two subgroups (Figure 1). On the other hand, neither peak atrial longitudinal strain nor peak atrial contraction strain showed a significant correlation with anti-HLA antibodies. Conclusion The presence of circulating anti-HLA antibodies seems to be correlated with a mild cardiac dysfunction, even in the absence of antibody-mediated rejection. This subtle dysfunction is not completely detectable by standard echocardiographic parameters, whereas strain analysis has showed promising results since it revealed more clearly an impaired function of both ventricles in heart transplanted HLA+ patients, with potentially important clinical repercussion. FUNDunding Acknowledgement Type of funding sources: None. Figure 1

New Perspectives on Desensitization in the Current Era - An Overview

Blood group and tissue incompatibilities remain significant barriers to achieving transplantation. Although no patient should be labeled “un-transplantable” due to blood group or tissue incompatibility, all candidates should be provided with individualized and realistic counseling regarding their anticipated wait times for deceased donor or kidney paired donation matching, with early referral to expert centers for desensitization when needed. Vital is the careful selection of patients whose health status is such that desensitizing treatment is less likely to cause serious harm and whose anti-HLA antibody status is such that treatment is likely to accomplish the goal of increasing organ offers with an acceptable final crossmatch. Exciting new developments have re-energized the interest and scope of desensitization in the times ahead.

Donor-Specific Antibody is Associated with Increased Expression of Rejection Transcripts in Renal Transplant Biopsies Classified As No Rejection

Background: Donor-specific HLA antibody (DSA) is present in many kidney transplant patients whose biopsies are classified as no-rejection (NR). We explored whether in some NR kidneys DSA has subtle effects that are not currently being recognized. Methods: We used microarrays to examine the relationship between standard-of-care DSA and rejection-related transcript increases in 1679 kidney transplant indication biopsies in the INTERCOMEX study (ClinicalTrials.gov NCT01299168), focusing on biopsies classified as NR by automatically assigned archetypal clustering. DSA testing results were available for 835 NR biopsies and were positive in 271 (32%). Results: DSA-positivity in NR biopsies was associated with mildly increased expression of ABMR-related transcripts, particularly IFNG-inducible and NK cell transcripts. We developed a machine learning DSA probability (DSAProb) classifier based on transcript expression in biopsies from DSA-positive vs. DSA-negative patients, assigning scores using 10-fold cross-validation. This DSAProb classifier was very similar to a previously described "ABMR probability" classifier trained on histologic ABMR in transcript associations and prediction of molecular or histologic ABMR. Plotting the biopsies using Uniform Manifold Approximation and Projection revealed a gradient of increasing molecular ABMR-like transcript expression in NR biopsies, associated with increased DSA (P<2E-16). In biopsies with no molecular or histologic rejection, increased DSAProb or ABMR probability scores were associated with increased risk of kidney failure over three years. Conclusions: Many biopsies currently considered to have no molecular or histologic rejection have mild increases in expression of ABMR-related transcripts, associated with increasing frequency of DSA. Thus mild molecular ABMR-related pathology is more common than previously realized.