Dapagliflozin cardiovascular effects on end-stage kidney disease (DARE-ESKD-2) trial: rationale and design.

Purpose: Sodium glucose co-transporter 2 inhibitors (SGLT2i) remarkably reduced the incidence of hospitalization for heart failure and cardiovascular death of conservatively managed chronic kidney disease. We hypothesized that adding SGLT2i to standard treatment would yield cardiovascular benefits also in end-stage kidney disease (ESKD) individuals on dialysis. Methods: The DARE-ESKD-2 Trial (NCT05685394) is an ongoing, single-center, open-label, controlled trial aimed at assessing the cardiovascular effects of dapagliflozin in ESKD on dialysis. Eligible patients are adults on renal replacement therapy for more than 3 prior to enrollment. Exclusion criteria encompass pregnancy, liver failure, and current use of a SGLT2i. After signing an informed consent form, participants are randomized 1:1 to either dapagliflozin 10mg PO plus standard treatment or standard treatment alone for 6 months. Echocardiogram, anthropometry, blood sample collection, 6-min walk test, gait speed, and Kansas City Cardiomyopathy Questionnaire (KCCQ), are performed at baseline and at study termination. Participants are contacted monthly during treatment for outcomes disclosure. The primary endpoint of our study is the between-groups differences in posttreatment changes in plasma levels of N-terminal pro-B natriuretic peptide. Secondary endpoints include the differences between groups in the changes of echocardiography measurements, cardiopulmonary tests performance, body composition. The incidence of safety endpoints will also be diligently compared between study arms. Conclusion: The DARE-ESKD-2 trial will provide unprecedented data on the cardiovascular safety and efficacy of SGLT2i in ESKD individuals on dialysis. This study will pave the grounds for improving clinical outcomes of dialysis recipients.

Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3.

CONTEXT: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. OBJECTIVES: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. SETTING AND PARTICIPANTS: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. MAIN OUTCOME MEASURES: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. RESULTS: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3 mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. CONCLUSIONS: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.