Endothelial cells LEENE on noncoding RNAs in diabetic vasculopathy.

Long noncoding RNAs (lncRNAs) have emerged as key mediators of regulated gene expression in diverse biologic contexts, including cardiovascular disease. In this issue of the JCI, Tang, Luo, and colleagues explored the contributions of lncRNAs in diabetic vasculopathy. The authors identified the lncRNA LEENE as a key mediator of angiogenesis and ischemic response. In a model of diabetic peripheral arterial disease, loss of LEENE led to impaired vascular perfusion, while its overexpression rescued the ischemic defect. The authors used unbiased chromatin affinity assays to decipher LEENE's interactome and mode of action. These findings offer insights as to why patients with diabetes are uniquely susceptible to developing peripheral vascular disease and fill important gaps in our understanding of mechanisms that connect metabolic dysregulation with impaired angiogenesis.

Pharmacotherapy in familial hypercholesterolemia - Current state and emerging paradigms.

Familial hypercholesterolemia is a highly prevalent but underdiagnosed disease marked by increased risk of cardiovascular morbidity and mortality. Aggressive reduction of LDL-cholesterol is a hallmark of cardiovascular risk mitigation in familial hypercholesterolemia. More recently, we have witnessed an expanded repertoire of pharmacologic agents that directly target LDL-cholesterol and/or reduce heart disease burden. In this state-of-the-art review, we explore the development, clinical efficacy and limitations of existing and potential future therapeutics in familial hypercholesterolemia.

Emergent prelabor cesarean delivery in solid organ transplant recipients: associated risk factors and outcomes.

BACKGROUND: Pregnancies after solid organ transplant are at a higher risk of antepartum admission and pregnancy complications including cesarean delivery. Emergent prelabor cesarean delivery is associated with increased maternal and neonatal morbidity in other high-risk populations, but its incidence and impact in transplant recipients is not well-understood. OBJECTIVE: This study aimed to characterize the risk factors and outcomes of emergency prelabor cesarean delivery in kidney and liver transplant recipients. STUDY DESIGN: This was a retrospective cohort study of all kidney and liver transplant recipients at >20 weeks gestation enrolled in the Transplant Pregnancy Registry International between 1976 and 2019. Participants admitted antepartum who required emergency prelabor cesarean delivery were compared with those admitted antepartum who underwent nonemergent birth. The primary outcomes were severe maternal morbidity and neonatal composite morbidity. Multivariable logistic regression was conducted for neonatal composite morbidity. RESULTS: Of 1979 births, 181 pregnancies (188 neonates) with antepartum admission were included. 51 pregnancies (53 neonates, 28%) were delivered by emergent prelabor cesarean delivery compared with 130 pregnancies (135 neonates, 72%) admitted antepartum who subsequently did not require emergent delivery. The most common indication for emergent delivery was nonreassuring fetal heart tracing (44 pregnancies /51 emergent deliveries = 86%). Pregnant people who underwent emergent prelabor cesarean delivery were less likely to deliver at a transplant center (37.3% vs 41.5%; P=.04) and had increased rates of chronic hypertension (33.3% vs 16.2%; P=.02). There was no significant difference in severe maternal morbidity (3.9% vs 4.6%; P=.84), though there was an increase in surgical site infection in the emergent prelabor cesarean delivery cohort (3.9% vs 0%; P=.02). Among those with emergent prelabor cesarean delivery, there was a significant increase in neonatal composite morbidity (43.4% vs 19.3%; P<.001) with earlier gestational age at delivery (33.4 vs 34.7 weeks; P=.02), lower birthweight (1899 g vs 2321 g; P<.001), lower birthweight percentile (30.3% vs 40.6%; P=.03), increased neonatal intensive care unit admission (52.8% vs 35.6%; P=.03), and increased neonatal mortality (11.3% vs 1.5%; P=.002). After adjusting for year of conception, race, hypertensive disorders, and fetal malformations, there was a persistent increased risk of neonatal morbidity (adjusted odds ratio, 3.01; 95% confidence interval, 1.50-6.08; P=.002) associated with emergent prelabor cesarean delivery after transplant. CONCLUSION: Almost one-third of kidney and liver transplant recipients admitted antepartum had an emergency prelabor cesarean delivery, and 63% of this cohort delivered outside of a transplant center. Pregnancies after transplantation should involve multidisciplinary transplant-obstetrics collaboration to ensure optimal antepartum disease management, especially for preexisting hypertension, to prevent and mitigate obstetrical and neonatal morbidity in the setting of emergent cesarean delivery.

Pregnancy care in solid organ transplant recipients.

Recipients of solid organ transplants who become pregnant represent an obstetrically high-risk population. Preconception planning and effective contraception tailored to the individual patient are critical in this group. Planned pregnancies improve both maternal and neonatal outcomes and provide a window of opportunity to mitigate risk and improve lifelong health. Optimal management of these pregnancies is not well defined. Common pregnancy complications after transplantation include hypertension, preterm birth, infection, and metabolic disease. Multidisciplinary preconception and prepartum management, and counseling decrease complications and benefit the maternal-neonatal dyad.

Mode of Obstetric Delivery in Kidney and Liver Transplant Recipients and Associated Maternal, Neonatal, and Graft Morbidity During 5 Decades of Clinical Practice.

Importance: Rates of cesarean delivery (CD) are increased among transplant recipients. There is a need to define the indications for CD and associated outcomes among transplant recipients to determine the safest mode of obstetric delivery. Objective: To evaluate the association of mode of obstetrical delivery with maternal and neonatal morbidity among pregnant women who have received a kidney or liver transplant. Design, Setting, and Participants: This registry-based retrospective cohort study used data from the Transplant Pregnancy Registry International, which has recruited participants since 1991 from 289 diverse academic and community settings, mainly in North America. Eligible participants were recipients of a kidney or liver transplant who were aged 18 years or older at the time of a live birth at or later than 20 weeks' gestational age and who delivered between 1968 and 2019. The data were analyzed from April 30, 2020, to April 16, 2021. Exposures: Scheduled CD, a trial of labor resulting in CD (TOL-CD), or a TOL resulting in vaginal delivery (TOL-VD). Main Outcomes and Measures: The primary outcomes were severe maternal morbidity and neonatal composite morbidity. Multivariate regression was conducted to calculate odds ratios (ORs) or ß values and 95% CIs with adjustment for differences in maternal comorbidities and gestational age at delivery. Nonmedical indications for CD are those not associated with decreased morbidity or mortality in the obstetric literature. Results: This study included 1865 women, of whom 1435 were kidney transplant recipients and 430 were liver transplant recipients. The age range of the participants was 18 to 48 years; the median body mass index among the participants was in the normal range, and the median transplant-to-conception interval was more than 2 years. Compared with a scheduled CD, a TOL was not associated with increased severe maternal morbidity among kidney transplant recipients (TOL-CD: adjusted odds ratio [aOR], 1.80 [95% CI, 0.77-4.22]; TOL-VD: aOR, 1.22 [95% CI, 0.57-2.62]) (for liver transplant recipients, the numbers were too small for multivariate modeling). In the adjusted model, a TOL was associated with a decrease in neonatal composite morbidity among kidney transplant recipients who underwent TOL-CD (aOR, 0.52; 95% CI, 0.32-0.82) and TOL-VD (aOR, 0.36; 95% CI, 0.24-0.53) and liver transplant recipients who underwent TOL-VD (aOR, 0.41; 95% CI, 0.19-0.87) but not for TOL-CD (aOR, 0.58; 95% CI, 0.21-1.61). The main factors associated with CD after labor were placental abruption (aOR, 12.96; 95% CI, 2.85-59.07) and pregestational diabetes (aOR 5.44; 95% CI, 2.54-11.68). The rate of CD was 51.6% (741 of 1435) among kidney transplant recipients and 41.4% (178 of 430) among liver transplant recipients. In total, 229 of 459 kidney transplant recipients (49.9%) and 50 of 105 liver transplant recipients (47.6%) had scheduled CDs performed for either a nonmedical indication or a repeated indication, although women with these indications are candidates for a TOL. Conclusions and Relevance: In this cohort study, TOL vs a scheduled CD was associated with improved neonatal outcomes among kidney and transplant recipients and not with increased severe maternal morbidity among kidney transplant recipients. These findings may be used to facilitate multidisciplinary decisions regarding the mode of obstetrical delivery.

Differentiating Acute Rejection From Preeclampsia After Kidney Transplantation.

OBJECTIVE: To evaluate the clinical and laboratory characteristics in pregnancy that differentiate preeclampsia from acute renal allograft rejection and to investigate the maternal, neonatal, and graft sequelae of these diagnoses. METHODS: We conducted a retrospective case-controlled registry study of data abstracted from Transplant Pregnancy Registry International deliveries between 1968 and 2019. All adult kidney transplant recipients with singleton pregnancies of at least 20 weeks of gestation were included. Acute rejection was biopsy proven and preeclampsia was diagnosed based on contemporary criteria. Variables were compared using χ2, Fisher exact, and Wilcoxon rank sum tests as appropriate. Multivariable linear regression was used to analyze preterm birth. Kaplan-Meier curves with log-rank test and Cox proportional hazards model were used to compare graft loss over time. RESULTS: There were 26 pregnant women with biopsy-confirmed acute rejection who were matched by the year they conceived to 78 pregnant women with preeclampsia. Recipients with acute rejection had elevated peripartum serum creatinine levels (73% vs 14%, P<.001), with median intrapartum creatinine of 3.90 compared with 1.15 mg/dL (P<.001). Conversely, only patients with preeclampsia had a significant increase in proteinuria from baseline. Although there were no significant differences in maternal outcomes, graft loss within 2 years postpartum (42% vs 10%) and long-term graft loss (73% vs 35%) were significantly increased in recipients who experienced acute rejection (P<.001 for both). The frequency of delivery before 32 weeks of gestation was 53% with acute rejection and 20% with preeclampsia. After controlling for hypertension and immunosuppressant use, acute rejection was associated with higher frequency of delivery at less than 32 weeks of gestation (adjusted odds ratio 4.04, 95% CI 1.10-15.2). CONCLUSION: In pregnancy, acute rejection is associated with higher creatinine levels, and preeclampsia is associated with increased proteinuria. Acute rejection in pregnancy carries a risk of prematurity and graft loss beyond that of preeclampsia for kidney transplant recipients. FUNDING SOURCE: The Transplant Pregnancy Registry International is supported in part by an educational grant from Veloxis Pharmaceuticals.