KDIGO Clinical Practice Guideline for Acute Kidney Injury
N-ACETYLCYSTEINE (NAC): Recommendations and Rationale

N-ACETYLCYSTEINE (NAC)

• 3.9.2: We suggest not using NAC to prevent AKI in critically ill patients with hypotension. (2D)

Rationale

NAC has been most frequently applied in the prevention of CI-AKI, and this topic is discussed in more detail in Chapter 4.4.

NAC is a modified form of L-cysteine, an amino acid that is a precursor to reduced glutathione that can regenerate glutathione stores. It is known to be a potent antioxidant that scavenges oxygen-free radicals in the body. It also has vasodilatory properties derived from enhanced nitric oxide availability.³⁵⁹ NAC has been shown to attenuate ischemic and nephrotoxic ARF in a number of animal studies,^360–363 and the pharmacological characteristics of NAC that could play a role in the prevention of AKI have recently been summarized.³⁶⁴ NAC undergoes extensive first-pass metabolization in the gastric mucosa and liver. This results in a very low oral bioavailability, with substantial intrapatient variability (3–20%), as well as inconsistency between available oral products. The plasma half-life of acetylcysteine after i.v. injection is approximately 6–40 minutes, and there is extensive binding to plasma and tissue proteins through the sulfhydryl group. Virtually no acetylcysteine can be detected in the systemic circulation after i.v. or oral administration, suggesting that any potential therapeutic benefit must be due to secondary effects such as the induction of glutathione synthesis, rather than due to direct effects. As these secondary effects are not directly measurable, the determination of the optimal dosage schedule has been necessarily empirical.³⁶⁵

A particularly important problem with NAC is whether it can alter SCr independent of a change in GFR. NAC has been reported to decrease SCr levels in subjects with normal kidney function. This reduction in SCr was not accompanied by a change in serum cystatin C levels. This suggests an effect independent of a change in GFR, such as an increase in tubular secretion of creatinine or a decrease in creatinine production.³⁶⁶ By contrast, in vitro analysis on the effect of NAC on SCr³⁶⁷ showed no analytical interference with the measurement of SCr by any of the commonly used analytical methods. Haase et al.,³⁶⁸ studied 30 patients with normal kidney function who received i.v. NAC for 24 hours in association with cardiac surgery. No change in the ratio of SCr to cystatin C, compared to baseline values, was observed at the end of the 24-hour infusion or 48 hours after the cessation of the infusion. In addition, there was no effect on urinary creatinine excretion during the infusion. However, in clinical practice, NAC is generally recommended for patients with CKD, with an eGFR < 60 ml/min per 1.73 m². Mainra et al.,³⁶⁹ observed no change in SCr or cystatin C at 4, 24, or 48 hours after administration of a single 600-mg dose of NAC to 30 patients with CKD Stage 3. Finally, Rehman et al.,³⁷⁰ tested the potentially confounding effect of NAC in a CKD population (Stages 3–5) following doses of NAC currently recommended for prophylaxis of AKI. There was no effect of NAC on either SCr or cystatin C levels.

It is thus safe to conclude that NAC, in doses currently recommended for prophylaxis of AKI, has—by itself—no effect on SCr or cystatin C levels. In addition, NAC is inexpensive and appears to be safe, although it may have some detrimental effects on myocardial and coagulation function.^371–373 The ‘‘safety’’ of NAC should further be amended, particularly when high i.v. doses are used, as in some of the RCTs in CI-AKI. When prospectively studied in acetaminophen poisoning, i.v. NAC produced anaphylactoid reactions in up to 48% of participants.³⁷⁴ Although most of these reactions were mild, at least one death has been reported in a patient with asthma.³⁷⁵ It should also be noted that the doses of acetaminophen used are still much higher than in the ‘‘high doses’’ used, particularly in AKI trials. Besides the prevention of CI-AKI, NAC has also been tested in the setting of cardiothoracic surgery and liver transplantation, and in hypotensive critically ill patients.