Metabolic and Renal Effects of Mammalian Target of Rapamycin Inhibitors Treatment After Liver Transplantation: Real-Life Single-Center Experience.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors following liver transplantation (LT) are used to minimize calcineurin inhibitor (CNI)-related nephrotoxicity. Data about metabolic effects of mTOR inhibitors are still limited. AIM: This study aims to determine the renal and metabolic effects of different mTOR inhibitor-based protocols in real-life LT patients. METHODS: This is a retrospective cohort study of patients treated with mTOR inhibitors after LT. Demographics, treatment protocols, glomerular filtration rate (GFR), and metabolic parameters were collected over a period of 4 years. Initiation of blood pressure (BP), diabetes mellitus, and lipid medications was also noted. RESULTS: Fifty-two LT recipients received mTOR inhibitors. GFR improved significantly (by 1.96 mL/min/year), with greater improvement in patients with baseline renal dysfunction (+13.3 mL/min vs +4.5 mL/min at 3 years). Conversion to an mTOR inhibitor during the first post-transplant year resulted in a more durable improvement in GFR (for 4 years vs only 1 year for later conversion).No significant weight gain or new-onset diabetes mellitus was observed. However, there was some increase in total cholesterol (+7 mg/dL) and blood pressure (+2 mm Hg during the third year and +8 mm Hg in the fourth years), followed by initiation of lipid-lowering and BP medications in 25% and 13% of patients, respectively. CONCLUSIONS: Treatment with an mTOR inhibitor following LT resulted in improved kidney functions without significant negative metabolic effects such as weight gain or new-onset diabetes mellitus. This makes mTOR inhibitors a valuable immunosuppressive option in the face of the growing incidence of nonalcoholic steatohepatitis as a leading cause for LT.

PGE2 suppresses NK activity in vivo directly and through adrenal hormones: effects that cannot be reflected by ex vivo assessment of NK cytotoxicity.

Surgery can suppress in vivo levels of NK cell cytotoxicity (NKCC) through various mechanisms, including catecholamine-, glucocorticoid (CORT)-, and prostaglandin (PG)-mediated responses. However, PGs are synthesized locally following tissue damage, driving proinflammatory and CORT responses, while their systemic levels are often unaffected. Thus, we herein studied the role of adrenal factors in mediating in vivo effects of PGs on NKCC, using adrenalectomized and sham-operated F344 rats subjected to surgery or PGE(2) administration. In vivo and ex vivo approaches were employed, based on intravenous administration of the NK-sensitive MADB106 tumor line, and based on ex vivo assessment of YAC-1 and MADB106 target-line lysis. Additionally, in vitro studies assessed the kinetics of the impact of epinephrine, CORT, and PGE(2) on NKCC. The results indicated that suppression of NKCC by epinephrine and PGE(2) are short lasting, and cannot be evident when these compounds are removed from the in vitro assay milieu, or in the context of ex vivo assessment of NKCC. In contrast, the effects of CORT are long-lasting and are reflected in both conditions even after its removal. Marginating-pulmonary NKCC was less susceptible to suppression than circulating NKCC, when tested against the xenogeneic YAC-1 target line, but not against the syngeneic MADB106 line, which seems to involve different cytotoxicity mechanisms. Overall, these findings indicate that elevated systemic PG levels can directly suppress NKCC in vivo, but following laparotomy adrenal hormones mediate most of the effects of endogenously-released PGs. Additionally, the ex vivo approach seems limited in reflecting the short-lasting NK-suppressive effects of catecholamines and PGs.

Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. A randomized, double-blinded trial.

STUDY OBJECTIVE: to determine whether digoxin is effective in converting atrial fibrillation of recent onset to normal sinus rhythm. DESIGN: randomized, double-blinded, placebo-controlled trial with a maximum 18-hour treatment period. SETTING: emergency room and medical floors of a non-referral city hospital. PATIENTS: consecutive sample of 36 patients with atrial fibrillation of 7 days' duration or less, not on digitalis glycoside or anti-arrhythmic agents, with ventricular rate between 85 to 175 beats/min, without evidence of heart failure, acute myocardial infarction, unstable angina, preexcitation syndrome, thyrotoxicosis, hypokalemia, renal impairment, or severe metabolic disturbances. INTERVENTIONS: digoxin solution in capsules or identical placebo, given in doses of 0.6, 0.4, 0.2, and 0.2 mg, at 0, 4, 8, and 14 hours, respectively, or until conversion to sinus rhythm, whichever occurred first. Continuous electrocardiographic recording by Holter monitor. MEASUREMENTS AND MAIN RESULTS: nine of eighteen patients receiving digoxin and 8 of 18 receiving placebo had a return to sinus rhythm within 18 hours of study entry (95% confidence interval for the difference in proportions, -11% to 22%). Mean time to conversion was 5.1 hours in the digoxin group and 3.3 in the placebo group (95% Cl, -3.6 to 7.0 hours). CONCLUSIONS: spontaneous reversion to sinus rhythm is common in patients with atrial fibrillation of recent onset. Digitalization was not shown to affect the likelihood of reversion to sinus rhythm, and thus cannot be recommended for this purpose in patients with atrial fibrillation.