Immunosuppression in solid organ-transplant recipients and impact on nutrition support.

A key component to nutrition support is to consider immunosuppressive agents, the interaction with nutrients, and how the side effects of the medications influence nutrition support. The immunosuppression of the solid organ-transplant recipient involves the individualized titration of multiple therapeutic agents to prevent allorecognition and, thus, rejection of the transplanted organ. Induction immunosuppression includes the agents used at the time of transplant to prevent early rejection. Maintenance immunosuppression typically consists of oral medications taken for life. Regular therapeutic monitoring of immunosuppression is necessary to balance the risk of rejection with that of infections and malignancy. In the acute-care setting, multidisciplinary collaboration, including pharmacy and nutrition, is needed to optimize the route of administration, titration, and side effects of immunosuppression. Long-term nutrition management after transplant is also vital to prevent exacerbating adverse effects of immunosuppressive therapies, including diabetes mellitus, hypertension, dyslipidemia, obesity, and bone loss. This review summarizes common immunosuppressive agents currently utilized in solid organ-transplant recipients and factors that may influence decisions on nutrition support.

Immunosuppression in Uterus Transplantation: Experience From the Dallas Uterus Transplant Study.

BACKGROUND: Uterus transplantation is a temporary transplant allowing women with absolute uterine factor infertility to experience pregnancy and childbirth. The degree of immunosuppression (IS) required to prevent rejection while minimizing toxicity to the recipient and fetus remains an area of investigation. METHODS: In this article, we describe immunosuppressive therapy, rejection episodes, infections, and adverse events in 14 uterus transplant recipients. Induction consisted of antithymocyte globulin and methylprednisolone. Ten recipients (71%) received no steroids postoperatively, and 4 (29%) had steroids tapered off at 42 d. All received oral tacrolimus, either immediate release (n = 2, 14%) or extended release (n = 12, 86%). Mycophenolate was used in 4 cases (29%), de novo azathioprine in 9 (64%), and de novo everolimus in 1 (7%). RESULTS: Sixteen clinically silent, treatment-responsive rejection episodes occurred in 10 recipients. Five recipients (36%) experienced acute kidney injury. In 3 recipients, IS was discontinued due to renal dysfunction. Eleven infection episodes were noted in 7 recipients. No babies had congenital abnormalities. CONCLUSIONS: Our experience demonstrates that safe IS regimens can be used for uterus transplant recipients before and during pregnancy.

Pathophysiology of aortic aneurysm: insights from human genetics and mouse models.

Aneurysms are local dilations of an artery that predispose the vessel to sudden rupture. They are often asymptomatic and undiagnosed, resulting in a high mortality rate. The predisposition to develop thoracic aortic aneurysms is often genetically inherited and associated with syndromes affecting connective tissue homeostasis. This review discusses how elucidation of the genetic causes of syndromic forms of thoracic aortic aneurysm has helped identify pathways that contribute to disease progression, including those activated by TGF-ß, angiotensin II and Notch ligands. We also discuss how pharmacological manipulation of these signaling pathways has provided further insight into the mechanism of disease and identified compounds with therapeutic potential in these and related disorders.

A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCß) as a critical mediator of this pathway and demonstrate that the PKCß inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCß and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.

A Novel Microduplication in the Neurodevelopmental Gene SRGAP3 That Segregates with Psychotic Illness in the Family of a COS Proband.

Schizophrenia is a debilitating mental disorder affecting approximately 1% of the world's population. Childhood onset schizophrenia (COS), defined as onset before age 13, is a rare and severe form of the illness that may have more salient genetic influence. We identified a ~134 kb duplication spanning exons 2-4 of the Slit-Robo GTPase-activating protein 3 (SRGAP3) gene on chromosome 3p25.3 that tracks with psychotic illness in the family of a COS proband. Cloning and sequencing of the duplication junction confirmed that the duplication is tandem, and analysis of the resulting mRNA transcript suggests that the duplication would result in a frame shift mutation. This is the first family report of a SRGAP3 copy number variant (CNV) in schizophrenia. Considering that SRGAP3 is important in neural development, we conclude that this SRGAP3 duplication may be an important factor contributing to the psychotic phenotype in this family.