Estefani Y. Hernández-Cruz , Omar E. Aparicio-Trejo , Fadi A. Hammami , Daniel Bar-Shalom , Martin Tepel , Jose Pedraza-Chaverri , Alexandra Scholze
{"title":"N-acetylcysteine in Kidney Disease: Molecular Mechanisms, Pharmacokinetics, and Clinical Effectiveness","authors":"Estefani Y. Hernández-Cruz , Omar E. Aparicio-Trejo , Fadi A. Hammami , Daniel Bar-Shalom , Martin Tepel , Jose Pedraza-Chaverri , Alexandra Scholze","doi":"10.1016/j.ekir.2024.07.020","DOIUrl":null,"url":null,"abstract":"<div><div>N-acetylcysteine (NAC) has shown beneficial effects in both acute kidney disease and chronic kidney disease (CKD) in preclinical and clinical studies. Different dosage and administration forms of NAC have specific pharmacokinetic properties that determine the temporal pattern of plasma concentrations of NAC and its active metabolites. Especially in acute situations with short-term NAC administration, appropriate NAC and glutathione (GSH) plasma concentrations should be timely ensured. For oral dosage forms, bioavailability needs to be established for the respective NAC formulation. Kidney function influences NAC pharmacokinetics, including a reduction of NAC clearance in advanced CKD. In addition, mechanisms of action underlying beneficial NAC effects depend on kidney function as well as comorbidities, both involving GSH deficiency, alterations in nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent signaling, oxidative stress, mitochondrial dysfunction, and disturbed mitochondrial bioenergetics. This also applies to nonrenal NAC mechanisms. The timing of preventive NAC administration in relation to potential injury is important. NAC administration seems most effective either preceding, or preceding and paralleling conditions that induce tissue damage. Furthermore, studies suggest that very high concentrations of NAC should be avoided because they could exert reductive stress. Delayed administration of NAC might interfere with endogenous repair mechanisms. In conclusion, studies on NAC treatment regimens need to account for both NAC pharmacokinetics and NAC molecular effects. Kidney function of the patient population and pathomechanisms of the kidney disease should guide rational NAC trial design. A targeted trial approach and biomarker-guided protocols could pave the way for the use of NAC in precision medicine.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"9 10","pages":"Pages 2883-2903"},"PeriodicalIF":5.7000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney International Reports","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2468024924018503","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
N-acetylcysteine (NAC) has shown beneficial effects in both acute kidney disease and chronic kidney disease (CKD) in preclinical and clinical studies. Different dosage and administration forms of NAC have specific pharmacokinetic properties that determine the temporal pattern of plasma concentrations of NAC and its active metabolites. Especially in acute situations with short-term NAC administration, appropriate NAC and glutathione (GSH) plasma concentrations should be timely ensured. For oral dosage forms, bioavailability needs to be established for the respective NAC formulation. Kidney function influences NAC pharmacokinetics, including a reduction of NAC clearance in advanced CKD. In addition, mechanisms of action underlying beneficial NAC effects depend on kidney function as well as comorbidities, both involving GSH deficiency, alterations in nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent signaling, oxidative stress, mitochondrial dysfunction, and disturbed mitochondrial bioenergetics. This also applies to nonrenal NAC mechanisms. The timing of preventive NAC administration in relation to potential injury is important. NAC administration seems most effective either preceding, or preceding and paralleling conditions that induce tissue damage. Furthermore, studies suggest that very high concentrations of NAC should be avoided because they could exert reductive stress. Delayed administration of NAC might interfere with endogenous repair mechanisms. In conclusion, studies on NAC treatment regimens need to account for both NAC pharmacokinetics and NAC molecular effects. Kidney function of the patient population and pathomechanisms of the kidney disease should guide rational NAC trial design. A targeted trial approach and biomarker-guided protocols could pave the way for the use of NAC in precision medicine.
期刊介绍:
Kidney International Reports, an official journal of the International Society of Nephrology, is a peer-reviewed, open access journal devoted to the publication of leading research and developments related to kidney disease. With the primary aim of contributing to improved care of patients with kidney disease, the journal will publish original clinical and select translational articles and educational content related to the pathogenesis, evaluation and management of acute and chronic kidney disease, end stage renal disease (including transplantation), acid-base, fluid and electrolyte disturbances and hypertension. Of particular interest are submissions related to clinical trials, epidemiology, systematic reviews (including meta-analyses) and outcomes research. The journal will also provide a platform for wider dissemination of national and regional guidelines as well as consensus meeting reports.