KDIGO Clinical Practice Guideline for Acute Kidney Injury
Role of nac in the prevention of CI-AKI: Recommendations and Rationale

Role of nac in the prevention of CI-AKI

• 4.4.3: We suggest using oral NAC, together with i.v. isotonic crystalloids, in patients at increased risk of CI-AKI. (2D)

Rationale

NAC—in many, but not all, studies—has been shown to have a protective effect on CI-AKI when administered before the onset of renal insult; for a review, see McCullough.⁴⁹⁴ 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 be noted that the doses used in acetaminophen intoxication are still much higher than in the ‘‘high doses’’ used in CI-AKI prevention trials. In a recent review,⁴⁹⁵ doses of NAC 300 mg/ kg i.v. over 21 hours, 980 mg/kg i.v. over 48 hours, and 1330 mg/kg p.o. over 72 hours were mentioned to have been all comparably effective at preventing hepatotoxicity in most uncomplicated early-presenting acute acetaminophen overdoses. Although a variety of doses of NAC has been administered in the prevention of CI-AKI, the i.v. ‘‘high doses’’ used in one study⁴⁹⁶ are mostly 2 x 1200 mg NAC per day for 2–3 days, far below the doses used in acetaminophen intoxication. A meta-analysis⁴⁹⁷ of studies using high doses of NAC defined the latter as a daily dose greater than 1200 mg or a single periprocedural dose greater than 600 mg (periprocedural being described as immediately or within 4 hours of the planned contrast exposure). It should also be remembered that no FDA label is available for NAC as a preventive drug of AKI.

Suppl Tables 24 and 25 summarize the quite numerous RCTs where NAC has been compared to placebo on the impact of patient mortality, need for RRT, or prevention of CI-AKI. In most of the studies, i.v. fluids, either with isotonic saline or with isotonic bicarbonate, was used in both arms. Moreover, the impact of NAC on important ‘‘hard’’ patient outcomes, such as all-cause mortality, need for RRT, or doubling of SCr level has only rarely been studied. At present, there is no current evidence that either oral or i.v. NAC can alter mortality or need for RRT after contrast-media administration to patients at risk for CI-AKI. The only study showing a significant decrease in hospital mortality is the three-arm study of Marenzi et al.⁴⁹⁸ in patients undergoing primary angioplasty. Overall in-hospital mortality was higher in patients with CI-AKI, defined as a 25% increase in SCr, than in those without CI-AKI (26 % vs. 1 %; P < 0.001). Thirteen patients (11%) in the control group died, as did five (4%) in the standard-dose NAC and three (3%) in the highdose NAC group (P = 0.02). All other studies did not show a beneficial effect on mortality (Suppl Table 25). Overall, this evidence was deemed to be of moderate quality and the possible positive effect on mortality dubious.

The effect of NAC on the incidence of CI-AKI is quite variable. As is shown in the evidence profile (Suppl Table 24), the evidence that NAC reduces CI-AKI, as defined in the different trials, comes from studies with rather heterogeneous results; most of the studies were of either high or modest quality. In one study, a protective—even dose-dependent— effect was observed.⁴⁹⁸ In that study, the risk for CI-AKI was reduced by 54.5% in the standard-dose NAC group and by 75.8% in the high-dose NAC group. These findings are in sharp contrast to many other studies showing no effect and, in particular, with the large study of Webb et al.,⁴⁹⁹ which was terminated early after enrollment of 487 patients because of a determination of futility by the Data Safety Monitoring Committee. As mentioned earlier, combination studies of NAC with bicarbonate administration⁴⁸⁶ have found a moderate benefit for this combination, compared to the combination of NAC-saline.

As recently remarked by Fishbane,³⁶⁴ most of the studies published on NAC for the prevention of CI-AKI are quite small in size, and meta-analyses have been performed to increase the probability of explaining the full spectrum of utility for NAC. To date, seven out of the 11 meta-analyses that have been published on this subject found a net benefit for NAC in the prevention of CI-AKI.³⁶⁴ However, as pointed out before, marked heterogeneity in the studies, and publication bias must lead to the conclusion that ‘‘pooling of data to arrive at a summary estimate for treatment efficacy should generally be avoided in situations where the trials exhibit significant statistical and/or clinical heterogeneity’’. ^500,501 A recent prospective RCT⁵⁰² was performed in patients with decreased kidney function (CrCl ≤ 60 ml/min and/or SCr level of ≥ 1.1mg/dl [ ≥ 97.2 µmol/l]), comparing a high oral dose of NAC with high doses of vitamin C. All patients underwent a coronary angiography. The primary endpoint was the maximum increase of SCr level, and the secondary end-point was the incidence of CI-AKI, defined as a relative increase in baseline SCr level of ≥ 25% and/or anabsolute increase of ≥ 0.5mg/dl ( ≥ 44.2 µmol/l) within 48 hours after contrast-media administration. The maximum increase of SCr level was significantly lower in the NAC group than in the ascorbic acid group ( - 0.03 ± 0.18mg/dl [- 2.65 ± 15.9 µmol/l] vs. 0.04 ± 0.20 mg/dl [3.54 ± 17.7 µmol/l]), respectively (P = 0.026). The incidence of CI-AKI tended to be in favor of NAC rather than ascorbic acid, 1.2% vs. 4.4%, respectively, although this difference was not significant (P = 0.370). It was concluded that an oral high dose of NAC seemed to be more beneficial than ascorbic acid in preventing CI-AKI, particularly in diabetic patients with pre-existing CKD.

Finally, a randomized, single-blind, controlled trial was recently published to assess NAC effects on CI-AKI and reperfusion injury in ST-segment elevation myocardial infarction (MI) patients undergoing primary angioplasty with moderate contrast-media volumes (between 120–230 ml of an iso-osmolar contrast medium).⁴⁹⁶ The patients undergoing primary angioplasty were randomized to either highdose NAC (two times 1200 mg/d for 48 hours; or placebo plus fluids). CI-AKI occurred in 14% of the NAC group and in 20% of the placebo group (P = 0.28). The myocardial salvage index was also not different between both treatment groups. Activated oxygen protein products and oxidized lowdensity lipoprotein as markers for oxidative stress were reduced by as much as 20% in the NAC group, whereas no change was evident in the placebo group.

Thus, despite high-dose i.v. NAC reducing oxidative stress, it does not provide an additional clinical benefit, compared to placebo, with respect to CI-AKI and myocardial reperfusion injury in nonselected patients undergoing angioplasty. A recent meta-analysis of all prospective trials of individuals randomized to either orally or i.v. administered high doses of NAC, defined as a daily dose greater than 1200 mg or a single periprocedural dose (within 4 hours of contrast-media exposure) > 600 mg, was published by Trivedi et al.⁴⁹⁷ The overall effect size, assuming a common OR, was 0.46 (95% CI 0.33–0.63) for the occurrence of CI-AKI with the use of highdose NAC. The results of the more conservative randomeffects approach were similar (OR 0.52; 95% CI 0.34–0.78).

Another recently published meta-analysis of RCTs included published trials and conference abstracts (Figure 16).⁵⁰³ The primary and secondary outcomes of interest were CI-AKI, and renal failure requiring dialysis, respectively. Ten RCTs met the inclusion criteria. Nine studies compared combination treatment (bicarbonate and NAC) to NAC and normal saline; one study compared combination therapy to NAC alone; one study compared combination therapy to NAC with normal saline, and a separate arm with NAC and ascorbic acid. Collectively, combination treatment of NAC with i.v. sodium bicarbonate reduced CI-AKI by 35% compared to the other above-mentioned combinations (RR 0.65; 95% CI 0.40–1.05). However, the combination of NAC plus sodium bicarbonate did not significantly reduce renal failure requiring dialysis (RR 0.47; 95% CI 0.16–1.41). It was concluded that combination prophylaxis with NAC and sodium bicarbonate substantially reduced the occurrence of CI-AKI overall, but not dialysis-dependent renal failure. This paper suggests that combination prophylaxis should be incorporated for all high-risk patients (emergent cases or patients with pre-existing CKD). Most of the studies administered NAC orally; some studies used the i.v. route or even a combination of oral and i.v. There was also a substantial variation in doses and timing of NAC administration.

One additional study was recently published and was thus not included in the meta-analysis discussed above. Koc et al.,⁵⁰⁴ investigated the efficacy of prophylactic i.v. NAC and fluids for the prevention of CI-AKI in patients with mild to moderate renal dysfunction (SCr ≥ 1.1 mg/dl [ ≥ 97.2 µmol/l] or a CrCl ≤ 60 ml/min) who were undergoing coronary angiography. A group of patients was assigned to i.v. NAC (bolus of 600 mg twice daily before and on the day of the procedure) plus high-dose normal saline, a second group to only high-dose saline, and a third (control) group received standard saline. Patients in the NAC plus high-dose saline group received an i.v. bolus of 600 mg of NAC twice daily before and on the day of the coronary procedure (total 2.4 g) plus i.v. 0.9% saline 1 ml/kg/h before, on, and after the day of the coronary procedure. Patients in the high-dose arm received the same amount of isotonic saline, while patients in the control group received an i.v. dose of 0.9% saline 1 ml/kg/h for 12 hours before and 12 hours after the coronary procedure. The rate of CI-AKI in the NAC plus high-dose saline group was lower than in the high-dose saline group without NAC. No significant differences in the primary and secondary end-points were found between the high-dose saline and control groups.

In conclusion, based on the evidence tables and even taking the last recent study into account, the overall benefit of NAC is not consistent or overwhelming. On the other hand, oral NAC has a low risk of adverse events and usually a low cost.