N-acetylcysteine is effective for prevention but not for treatment of folic acid-induced acute kidney injury in mice

Objectives: There is controversy regarding the benefits of N-acetylcysteine in acute kidney injury. This study was to compare three commonly used regimens and explore which regimen is best for the protection of acute kidney injury. Design: Prospective experimental study. Setting: University research laboratory. Interventions: Acute kidney injury was induced with folic acid intraperitoneal injection in mice. Mice in pretreatment were treated with a subcutaneous injection of N-acetylcysteine before the folic acid injection. Mice in posttreatment were treated with N-acetylcysteine after folic acid. Mice in pre- + posttreatment were treated with N-acetylcysteine before folic acid and after folic acid. Placebo mice received vehicle only using the pre- + posttreatment protocol. Fourteen healthy animals were given N-acetylcysteine to evaluate for toxicity and the other 24 mice subjected to folic acid were killed for kidney histology and analysis for oxidative injury. The same studies were also carried out in milder acute kidney injury (lower folic acid) model. Measurements and Main Results: Plasma concentrations of creatinine, cystatin C, and reduced glutathione were measured. Survival time was assessed up to 7 days. The survival rates in N-acetylcysteine pretreatment mice were significantly better (73.33% vs. 46.67%, p < .04) and acute kidney injury was significantly less compared with placebo. However, mice with posttreatment exhibited significantly worse survival and more severe acute kidney injury. Histologic findings were consistent with functional parameters. Glutathione levels decreased less in N-acetylcysteine pretreatment but also increased beginning on day 2 compared with placebo (11.5 vs. 8.1 mu g/mL, p < .05). Glutathione levels did not increase in N-acetylcysteine posttreatment. However, three different N-acetylcysteine interventions neither significantly improved nor worsened renal function in the milder acute kidney injury model. Conclusion: N-acetylcysteine pretreatment was effective in reducing the incidence and severity of acute kidney injury as well as in increasing survival. However, N-acetylcysteine posttreatment worsened folic acid toxicity. Only pretreatment was effective in increasing glutathione. These data may help explain the variation from clinical studies of N-acetylcysteine use. (Crit Care Med 2011; 39: 2487-2494)