Anmol Sharma

© 2015 Elsevier Inc. β-adrenergic signaling pathways mediate key aspects of cardiac function. Its dysregulation is associated with a range of cardiac diseases, including dilated cardiomyopathy. Previously, we established an iPSC model of familial DCM from patients with a mutation in TNNT2, a sarcomeric protein. Here, we found that the β-adrenergic agonist isoproterenol induced mature β-adrenergic signaling in iPSC-derived cardiomyocytes but that this pathway was blunted in DCM iPSC-CMs. Although expression levels of several β-adrenergic signaling components were unaltered between control and DCM iPSC-CMs, we found that phosphodiesterases 2A and PDE3A were upregulated in DCM iPSC-CMs and that PDE2A was also upregulated in DCM patient tissue. We further discovered increased nuclear localization of mutant TNNT2 and epigenetic modifications of PDE genes in both DCM iPSC-CMs and patient tissue. Notably, pharmacologic inhibition of PDE2A and PDE3A restored cAMP levels and ameliorated the impaired β-adrenergic signaling of DCM iPSC-CMs, suggesting therapeutic potential. In this paper, Wu etal. profiled the β-adrenergic signaling properties in human iPSC-CMs and demonstrated novel epigenetic mechanisms that underlie the compromised β-adrenergic signaling in DCM, a common cause of heart failure and cardiac transplantation. These results enhance our understanding of DCM pathogenesis and may uncover new therapeutic targets.

Amit Sharma, Rajesh Ramanathan, Marc Posner, Robert A Fisher Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA: Pediatric kidney transplantation is the preferred treatment for children with end-stage renal disease. The most common indications for transplantation in children are renal developmental anomalies, obstructive uropathy, and focal segmental glomerulosclerosis. Living donor kidney transplants are often performed pre-emptively and offer excellent graft function. Policy changes in deceased-donor kidney allocation have increased the proportion of such transplants in pediatric recipients. Adequate pretransplant workup along with evaluation of urologic abnormalities is imperative in achieving good outcomes. Overall, patient and graft outcomes after kidney transplantation have improved, with five-year deceased donor and living donor graft survivals of 78.8% and 84.3%, respectively. Improvements in induction and maintenance immunosuppression have contributed to the gradual improvement in outcomes. Unique challenges in pediatric recipients include increased graft thrombosis, adverse growth, and abnormal development relating to immunosuppression, increased rejection due to nonadherence, increased susceptibility to opportunistic infections, and post-transplant malignancy. This review focuses on the current practices and outcomes in pediatric kidney transplantation in North America. We discuss the indications for transplantation, the evaluation process, some key surgical and immunologic considerations, and the common risk factors for graft dysfunction. Keywords: pediatric kidney transplantation, end-stage renal disease, dialysis, organ donors, immunosuppression.