Late acute cellular rejection after switch to everolimus monotherapy at 11 months following liver transplantation

Background Acute cellular rejection beyond the 6th month posttransplant is an uncommon complication after liver transplantation. The inadequate immunosuppression (IS) remains the main risk factor. We report a case of acute cellular rejection after a switch to everolimus monotherapy at 11 months following liver transplantation. Case presentation This was a 69-year-old man who underwent liver transplantation after hepatocellular carcinoma. The initial immunosuppression was a combination of three immunosuppressive drugs (corticosteroids + tacrolimus + mycophenolate mofetil). The corticosteroid therapy was stopped at the 4th month posttransplant. Serious side effects of the immunosuppressive drugs (agranulocytosis and renal dysfunction), which occurred 4 months after transplantation, required a reduction and then a discontinuation of tacrolimus and mycophenolate mofetil. Everolimus was introduced as a replacement. The patient was consulted at 11 months after liver transplantation, 1 month after stopping the two immunosuppressive drugs, for liver function test abnormalities such as cytolysis and anicteric cholestasis. A moderate late acute cellular rejection was confirmed by a liver biopsy. A satisfactory biological evolution was observed following corticosteroid boluses and optimization of basic immunosuppressive drugs. Conclusion Late acute cellular rejection remains an uncommon complication, observed mostly in the first year after liver transplantation. The main risk factor is usually the decrease of immunosuppression.

Sarcomere ACTC1 and MYO18A serum expression levels detect acute cellular rejection in cardiac transplant patients

Introduction and purpose The development of non-invasive approaches for the early diagnosis of cardiac allograft rejection is necessary. Given the central role of sarcomeric dysfunction in cardiomyocyte biology and sarcomere alterations, described in endomyocardial biopsies of transplant patients with rejection, we hypothesized that the serum expression levels of genes encoding sarcomeric proteins were altered in acute cellular rejection (ACR). Methods Forty consecutive serum samples from transplant recipients undergoing routine endomyocardial biopsies were included in an RNA sequencing analysis. Results We identified 61 sarcomeric genes, 19 of which were differentially expressed in patients with clinically relevant rejection (ACR grade ≥2R). A receiver operating characteristic curve was done to assess their accuracy for ACR detection, and found that 8 relevant actins, myosins, and other sarcomere-related genes showed great diagnostic capacity (AUC≥0.800); ACTC1 (AUC=1.000, p<0.0001) and MYO18A (AUC=1.000, p<0.0001) showed the best results. MYO18A had a good ability to detect mild rejection (AUC=0.789, p<0.05). We found a relationship between MYO18A and the left ventricular end-systolic (p<0.01) and end-diastolic (p<0.05) diameters. Conclusions ACTC1 and MYO18A also showed a significant correlation with the NT-proBNP levels (p<0.05). Because of their precision to detect ACR, we propose sarcomere ACTC1 and MYO18A serum expression levels as potential candidates for non-invasive ACR detection. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health Carlos IIIEuropean Regional Development Fund (ERDF)

Renal allograft rejection with thrombotic microangiopathy associated with a Kidd blood group system alloantibody

Introduction/Objective The Kidd blood group antigens are urea transporters found on the surface of red blood cells, renal tubular epithelial cells, and endothelial cells in the renal medulla and vasa recta. While controversial, some reports have described an association between Kidd antigen donor/recipient mismatches and kidney transplant rejection when recipients possess or form anti-Kidd alloantibodies. To date, none of these reports have described development of a thrombotic microangiopathy (TMA) in the renal graft associated with these antibodies. We describe a case of fulminant renal transplant rejection associated with TMA in a patient with anti-Jk(a) alloantibodies who received a deceased-donor kidney transplant (DDKT). Methods/Case Report A 64-year-old woman with end-stage renal disease secondary to AL amyloidosis caused by plasma cell neoplasm received a DDKT associated with delayed graft function. No pre- or post-transplant donor specific antibodies (DSA) were detected, the flow crossmatch testing was negative, and a pre-operative type and screen identified anti-Jk(a) alloantibodies. On post-transplant day 5, her creatinine remained elevated at 6 mg/dL (ref range: 0.4–1.3 mg/dL) with an acute drop in platelets and undetectable haptoglobin. Allograft biopsy showed a combination of TMA with some additional evidence of acute cellular rejection. Tacrolimus was stopped to rule out drug-induced TMA, and the workup showed negative Shiga toxin, normal ADAMTS13 activity, negative atypical HUS genetic testing, and negative antiphospholipid syndrome testing. Genotyping of the donor kidney was positive for the Jk(a) antigen. Eculizumab, IVIG, and a trial of 8 sessions of therapeutic plasma exchange (TPE) were administered. Her creatinine improved (1.93–2.05 mg/dL), indicating a significant antibody-mediated etiology to her delayed graft function. About one month later, her creatinine worsened, and she received another trial of TPE with IVIG and eculizumab. Despite a mild decrease in her creatinine, repeat biopsies showed acute cellular rejection, persistent TMA, and chronic allograft injury. No DSAs were ever detected. Her creatinine never recovered, and she is now dialysis-dependent. Results (if a Case Study enter NA) NA Conclusion We speculate that anti-Jk(a) antibodies interacting with a Jk(a)-positive donor kidney account for graft TMA. This case underscores the potential importance of matching Kidd antigens in kidney transplantation.

Human lung tissue resident memory T cells are re-programmed but not eradicated with systemic glucocorticoids after acute cellular rejection

Acute cellular rejection is common after lung transplantation and is associated with an increased risk of early chronic rejection. We present combined single cell RNA and T cell receptor sequencing on recipient derived T cells obtained from the bronchoalveolar lavage of three lung transplant recipients with acute cellular rejection and compare them with T cells obtained from the same three patients after clinical treatment of rejection with high-dose, systemic glucocorticoids. At the time of acute cellular rejection, we find an oligoclonal expansion of cytotoxic CD8+ T cells, that all persist as tissue resident memory T cells following successful treatment. Persisting CD8+ allograft-resident T cells have reduced gene expression for cytotoxic mediators following therapy with glucocorticoids. This clonal expansion is discordant with circulating T cell clonal expansion at the time of rejection, suggesting in-situ expansion. These findings pose a potential biological mechanism linking acute cellular rejection to chronic allograft damage.

Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation

Background: Acute cellular rejection is a major determinant of mortality and re-transplantation after heart transplantation. We sought to evaluate prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for risk of acute cellular rejection after heart transplantation. Methods: The current study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiologic assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure × hyperemic mean transit time. The primary endpoint was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared using multivariable Cox proportional hazard regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of c-index, net reclassification index (NRI), and integrated discrimination index (IDI). Results: Mean age of recipients was 51.2±13.1 years (81.2% male), and cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 vs. 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-unit increase: adjusted HR 1.18, 95% CI 1.04-1.34, P=0.011) and the optimal cut-off value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% vs. 3.8%, adjusted HR 15.3, 95% CI 3.6-65.7, P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 vs. 0.74, P<0.001; NRI 1.05, P<0.001, IDI 0.20, P<0.001). Conclusions: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02798731

Short- and long-term outcomes after heart transplantation in cardiac sarcoidosis and giant-cell myocarditis: a systematic review and meta-analysis

Heart transplantation (HTx) is a valid therapeutic option for end-stage heart failure secondary to cardiac sarcoidosis (CS) or giant-cell myocarditis (GCM). However, post-HTx outcomes in patients with inflammatory cardiomyopathy (ICM) have been poorly investigated. We searched PubMed, Scopus, Science Citation Index, EMBASE, and Google Scholar, screened the gray literature, and contacted experts in the field. We included studies comparing post-HTx survival, acute cellular rejection, and disease recurrence in patients with and without ICM. Data were synthesized by a random‐effects meta‐analysis. We screened 11,933 articles, of which 14 were considered eligible. In a pooled analysis, post-HTx survival was higher in CS than non-CS patients after 1 year (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.60–1.17; I2 = 0%) and 5 years (RR 0.72, 95% CI 0.52–0.91; I2 = 0%), but statistically significant only after 5 years. During the first-year post-HTx, the risk of acute cellular rejection was similar for patients with and without CS, but after 5 years, it was lower in those with CS (RR 0.38, 95% CI 0.03–0.72; I2 = 0%). No difference in post-HTx survival was observed between patients with and without GCM after 1 year (RR 1.16, 95% CI 0.05–2.28; I2 = 0%) or 5 years (RR 0.98, 95% CI 0.42–1.54; I2 = 0%). During post-HTx follow-up, recurrence of CS and GCM occurred in 5% and 8% of patients, respectively. Post-HTx outcomes in patients with CS and GCM are comparable with cardiac recipients with other heart failure etiologies. Patients with ICM should not be disqualified from HTx. Graphic abstract