N-acetylcysteine For Chronic Kidney Disease:A Systematic Review And Meta-analysis

Objective. To evaluate the safety and benefits of N-acetylcysteine (NAC) for chronic kidney disease (CKD), in order to provide the evidence for clinical decision making and further research.Methods. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, Clinical Trials Registry Platform and CBM database (all up to April 13,2015), as well as the reference sections of retrieved articles. Two reviewers independently identified the trials according to the inclusion and exclusion criteria to screen the literature, extract data, evaluate the quality of the included trials, and analyzed the data using the Cochrane Collaboration’s Review Manager 5.3 software. The major outcome included glomerular filtration rate (GFR), serum creatinine (Scr), cardiovascular deaths and so on. For continuous data, we used mean difference (MD) or standardized mean difference (SMD), each effect size was represented with 95% confidence intervals (CI). For dichotomous data, we used risk ratio (RR) and 95% confidence intervals.Results. The search retrieved 1199 titles, of which 16 articles (11 RCTs) were included, involving 569 CKD patients. Two of the 11 trials were of a randomized crossover design. We extracted the final results. Other 9 trials used randomized parallel design. The outcomes of 11 trials were quite different. All the studies did not report all-cause mortality, withdrawn events due to side effects and serious adverse events. The summary results of the studies showed that NAC group can not delay the decline of eGFR in CKD patients as compared with placebo group, the MD for endpoint value was 1.27ml/min (-7.51,10.05), and the MD for change from baseline value was -1.86ml/min (-3.58,-0.15). NAC can decrease serum creatinine as compared with placebo, the MD for endpoint was -0.04mg/dL (-0.07,-0.01), the MD for change from baseline was -0.04mg/dL (-0.05,-0.02). On the long-term treatment effect, NAC can reduce 2 years risk of cardiovascular events in CKD patients [RR=0.60(0.38,0.95), (NNT=5.29)], but had no effect on mortality. In addition, NAC decreased the levels of homocysteine (Hcy) and inflammatory mediators (procalcitonin, TNF-a, hs-CRP, IL-6, IL-1) more than patients in the placebo group. Simultaneously, according to the dosage, administration route and treatment course of NAC, we carried out the subgroup analysis. The administration route subgroup results showed that comparing with placebo, oral administration of NAC can not delay the decline of eGFR. the MDs for endpoint and change from baseline value were 1.27ml/min (-7.51,10.05) and -1.86ml/min (-3.58,-0.15). respectively. But oral administration of NAC can decrease serum creatinine, inflammatory mediators (procalcitonin, TNF-a, hs-CRP, IL-6.1L-1) levels in CKD patients as compared with placebo. During dialysis course (4 hours), intravenous administration of 5g NAC can significantly reduce blood homocysteine [MD=-8.58(-13.31,-3.85)]. Treatment course subgroup showed that NAC reduced more Scr in more than 1 month group than within 1 month group. As for safety outcomes, oral administration of NAC was well tolerated, adverse events had no statistics significant difference between the NAC and placebo group, common adverse events were gastrointestinal discomfort, adding dosage and extending the treatment course of NAC did not increase the adverse reactions. The adverse reactions appeared to be more in the intravenous administration of NAC group than in placebo group, the RR was 2.79 (1.09,7.12) (NNH=9.85), the common adverse reactions were hypotension, itching, and extending the treatment course did not increase the incidence of adverse reactions.Conclusions. NAC has no additional benefit in delaying the decline of eGFR in CKD patients, it can decrease serum creatinine level, but decrease at small range, and the clinical significance is limited. NAC reduce more Scr in more than 1 month group than within 1 month group. NAC is safety, oral NAC is well tolerated as compared with intravenous administration, either orally or intravenously, extending the treatment course, the adverse events did not increase. Due to the inclusion of trials quality and quantity limitations, these conclusions still need more high quality (large sample, adequate allocation concealment, triple-blinded, longer follow-up time) randomized controlled trials to be further validated.