Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats

Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.Univ Fed Sao Paulo, Disciplina Nefrol, Dept Med, Sao Paulo, SP, BrazilUniv Cruzeiro Sul, Programa Interdisciplinar Ciencias Saude, Inst Ciencias Atividade Fis & Esporte, Sao Paulo, SP, BrazilUniv Sao Paulo, LEMA, Escola Enfermagem, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Enfermagem Clin & Cirurg, Escola Paulista Enfermagem, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Disciplina Nefrol, Dept Med, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Enfermagem Clin & Cirurg, Escola Paulista Enfermagem, Sao Paulo, SP, BrazilWeb of Scienc

Systematic Review and Meta-Analysis: An Empirical Approach to Defining Treatment Response and Remission in Pediatric Obsessive-Compulsive Disorder

©. This manuscript version is made available under the CC-BY-NC 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the, Submitted, version of a Published Work that appeared in final form in Journal of the American Academy of Child and Adolescent Psychiatry. To access the final edited and published work see: https://doi.org/10.1016/j.jaac.2021.05.027Objective: A lack of universal definitions for response and remission in pediatric obsessive- compulsive disorder (OCD) has hampered the comparability of results across trials. To address this problem, we conducted an individual participant data diagnostic test accuracy meta-analysis to evaluate the discriminative ability of the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) in determining response and remission. We also aimed to generate empirically derived cutoffs on the CY-BOCS for these outcomes. Method: A systematic review of PubMed, PsycINFO, Embase and CENTRAL identified 5,401 references, 42 randomized controlled clinical trials (RCTs) were considered eligible and 21 provided data for inclusion (N 1,234). A score ≤ 2 in the Clinical Global Impressions Improvement and Severity scales were chosen to define response and remission, respectively. A two-stage random-effects meta-analysis model was established. The area under the curve (AUC) and the Youden Index were computed to indicate the discriminative ability of the CY-BOCS and to guide for the optimal cutoff, respectively. Results: The CY-BOCS had sufficient discriminative ability to determine response (AUC 0.89) and remission (AUC 0.92). The optimal cutoff for response was a ≥ 35% reduction from baseline to posttreatment (sensitivity [95% CI] 83.9 [83.7, 84.1]; specificity [95% CI] 81.7 [81.5, 81.9]). The optimal cutoff for remission was a posttreatment raw score ≤ 12 (sensitivity [95% CI] 82.0 [81.8, 82.2]; specificity [95% CI] 84.6 [84.4, 84.8]). Conclusion: Meta-analysis identified empirically optimal cutoffs on the CY-BOCS to determine response and remission in pediatric OCD RCTs. Systematic adoption of standardized operational definitions for response and remission will improve comparability across trials for pediatric OCD