A Systematic Review of the Effect of N-Acetylcysteine on Serum Creatinine and Cystatin C Measurements.

Introduction: N-acetylcysteine (NAC) is an antioxidant that can regenerate glutathione and is primarily used for acetaminophen overdose. NAC has been tested and used for preventing iatrogenic acute kidney injury or slowing the progression of chronic kidney disease, with mixed results. There are conflicting reports that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, we conducted a systematic review of the literature to determine whether there is an effect of NAC on kidney function as measured with serum creatinine and cystatin C.

Methods: A literature search was conducted to identify all study types reporting a change in serum creatinine after NAC administration. The primary outcome was change in serum creatinine after NAC administration. The secondary outcome was a change in cystatin C after NAC administration. Subgroup analyses were conducted to assess effect of creatinine assay (Jaffe vs. non-Jaffe and intravenous vs. oral).

Results: Six studies with a total of 199 participants were eligible for the systematic review and meta-analysis. There was a small but significant decrease in serum creatinine after NAC administration overall (weighted mean difference [WMD], -2.80 μmol/L [95% confidence interval {CI} -5.6 to 0.0];  = 0.05). This was greater with non-Jaffe methods (WMD, -3.24 μmol/L [95% CI -6.29 to -0.28];  = 0.04) than Jaffe (WMD, -0.51 μmol/L [95% CI -7.56 to 6.53];  = 0.89) and in particular with intravenous (WMD, -31.10 μmol/L [95% CI -58.37 to -3.83];  = 0.03) compared with oral NAC (WMD, -2.5 μmol/L [95% CI -5.32 to 0.32];  = 0.08). There was no change in cystatin C after NAC administration.

Discussion: NAC causes a decrease in serum creatinine but not in cystatin C, suggesting analytic interference rather than an effect on kidney function. Supporting this, the effect was greater with non-Jaffe methods of creatinine estimation. Future studies of NAC should use the Jaffe method of creatinine estimation when kidney outcomes are being reported. Even in clinical settings, the use of an enzymatic assay when high doses of intravenous NAC are being used may result in underdiagnosis or delayed diagnosis of acute kidney injury.