Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science

Abstract

Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.

Figure 1

(a) Number of publications reporting clinical use of acetylcysteine for CIN and (b) number of RCTs and patients recruited in published systematic reviews and meta‐analyses of studies assessing the effectiveness of NAC in CIN 1990–2020. There were no clinical or mechanistic studies of NAC published in the decade before Tepel’s publication in 2000. This paper was followed by a dramatic increase in the number of studies and systematic reviews, only beginning to fall after the publication of the negative ACT RCT in 2011. The largest meta‐analysis (search performed September 21, 2018) reported 74 RCTs and recruitment of 14,635 patients in 2017. In part (b), each dot/diamond represents a single published meta‐analysis including all known participants (excluding systematic reviews addressing subpopulations of trials). The most recent large RCT (PRESERVE; n = 4993) was not included in any of the meta‐analyses; the top right point (dark blue, n = 19,628) represents the sum of patients in the largest meta‐analysis plus this RCT. Key: Green diamond: number of studies in each systematic review (left y‐axis); Blue circles: number of participants in each systematic review (right y‐axis). CIN, contrast‐induced nephropathy; NAC, (N)‐acetylcysteine; RCT, randomized controlled trial.

Figure 2

CONSORT flow diagram. Number analyzed refers to the RBF primary outcome. *One participant had a myocardial infarction on his way to the hospital, one underwent emergency coronary angiography just before the study day, 5 participants had eGFR > 60 at recruitment and were withdrawn, whereas 5 withdrew consent before the study day. **In study 1, one participant developed high blood pressure during the first study arm and was withdrawn, whereas one withdrew consent after the first study day. In study 2, two participants withdrew consent before the first study started, one withdrew consent after the first study day, and one had eGFR > 60 at recruitment. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HV, healthy volunteer; NAC, (N)‐acetylcysteine; RBF, renal blood flow.

Figure 3

Pharmacokinetics of NAC. (a) IV NAC vs. placebo (only one set of placebo results is visible as all overlap), (b) oral NAC vs. placebo. Data are mean (±SD) plasma concentrations (μM). Study 1: healthy volunteers, without contrast (blue circles); study 2: patients with CKD3, without contrast (red diamonds); study 3: healthy volunteers, with contrast (purple squares); study 4: patients with CKD3, with contrast (green triangle). NAC concentrations in patients receiving placebo are shown with grey circles. Doses of NAC administered were i.v.: 200 mg/kg over 7 hours; oral: 1,200 mg b.i.d. for 2 days, starting the morning before the procedure. NAC, (N)‐acetylcysteine.

Figure 4

Systemic hemodynamics in (left column) healthy volunteers (HVs) and (right column) patients with CKD3, without (a, b, e, f) and with (c, d, g, h) contrast. a–d Mean (SD) heart rate (beats per min); (e–h): mean (SD) mean arterial pressure (MAP, mmHg). Participants received i.v. NAC (red triangles), oral NAC (blue squares), or double placebo (green circle). Black arrows indicate the timing of the contrast administration in the appropriate groups. CKD3, chronic kidney disease stage III; HR, heart rate; NAC, (N)‐acetylcysteine.

Figure 5

Renal blood flow (RBF) and glomerular filtration rate (GFR) in (left column) healthy volunteers (HVs) and (right column) patients with chronic kidney disease stage III (CKD3), without (a, b, e, f) and with (c, d, g, h) contrast. a–d Mean (SD, dotted lines) RBF (mL/min); e–h mean (SD, dotted lines) GFR (mL/min/1.73 m²). Participants received i.v. NAC (red triangles), oral NAC (blue squares), or double placebo (green circle). Black arrows indicate the timing of the contrast administration in the appropriate groups.

Figure 6

Blood and urinary renal biomarkers in patients with CKD3 receiving contrast. (a) mean (SD, dotted lines) serum creatinine concentration (μmol/L); (b): mean (SD, dotted lines) plasma cystatin‐C concentration (mg/L); (c) mean (SD, dotted lines) urinary KIM‐1/creatinine ratio; (d) mean (SD, dotted lines) urinary NGAL/creatinine ratio. Participants received i.v. NAC (red triangles), oral NAC (blue squares), or double placebo (green circle). CKD3, chronic kidney disease stage III; NAC, (N)‐acetylcysteine; NGAL, neutrophil gelatinase‐associated lipocalin.

Figure 7

Plasma antioxidant status in (left column) healthy volunteers (HVs) and (right column) patients with CKD3, without (a, b, e, f) and with (c, d, g, h) contrast. a–d Mean (SD, dotted lines) plasma (de‐acetylated) cystine concentration (mg/L); e–h: mean (SD, dotted lines) plasma oxygen radical absorbance capacity (ORAC, TEAC/μg inulin). Participants received i.v. NAC (red triangles), oral NAC (blue squares), or double placebo (green circle). CKD3, chronic kidney disease stage III; HV, healthy volunteer; NAC, (N)‐acetylcysteine; ORAC, oxygen radical absorbance capacity.