Table 6.
The effects of non-statin on the prevention of contrast-induced nephropathy: reports from clinical studies
| Study type | Models | Intervention (drug/dose/route/duration) | Major findings | Interpretations | References | |
|---|---|---|---|---|---|---|
| Renal function | Oxidative stress/inflammatory markers | |||||
| Randomized, double-blind, placebo-controlled trial | Patients with Cr ≥ 1.2 mg/dL undergoing clinically driven, nonemergent CAG or PCI treated with nonionic, low- or iso-osmolar contrast | Ascorbic acid/3 g/po/2 h prior to procedure + 2 g/po/night and morning after procedure (n = 118) vs. Placebo (n = 113) |
↓ CIN ↓ Cr ↓ CrCl changes ↔ BUN |
– | Ascorbic acid prevented CIN after coronary imaging procedures in patients with pre-existing renal dysfunction | [110] |
| Prospective randomized-controlled trial | Patients with Cr > 1.2 mg/dL or CrCl < 50 mL/min underwent elective CT treated with iopromide | NAC/600 mg/po/bid/1 day prior to and after CT (n = 41) vs. Placebo (n = 42) |
↓ CIN ↓ Cr changes at 48 h after CT |
– | Short-term pretreatment with NAC prevented CIN | [82] |
| Prospective randomized-controlled trial | Patients with Cr > 1.2 mg/dL or CrCl < 70 mL/min underwent elective CAG ± PCI treated with iopromide |
NAC/600 mg/po/bid/1 day prior to and after CAG (n = 92) No NAC (n = 91) |
↔ CIN ↔ Cr changes at 48 h after CAG ↓ Cr changes at 48 h after CAG by using small volume of CM |
– | Short-term NAC prevented CIN in patients with CKD and using small volume of CM | [83] |
| Randomized, double-blind, placebo-controlled trial | Patients with Cr ≥ 1.4 mg/dL or CrCl < 50 mL/min underwent elective CAG treated with ioxilan | NAC/600 mg/po/bid/1 dose prior to and 3 doses after CAG (n = 25) vs. Placebo (n = 29) |
↓ CIN ↓ Cr at 48 h after CAG ↓ Cr changes |
– | Short-term NAC reduced risk of CIN in patients with CKD | [84] |
| Prospective randomized, double-blind study | Patients with Cr > 106 µmol/L underwent elective CAG treated with non-ionic, low osmolar iodine | NAC/1,000 mg/po/bid/24 h prior to and 24 h after CAG (n = 24) vs. Placebo (n = 25) | ↓ CrCl changes at 24 and 96 h after CAG |
↑ urinary NO ↔ urinary F2-isoprostanes |
Short-term NAC prevented CIN in patients with CKD undergoing CAG via increasing NO production | [85] |
| Prospective, randomized, double-blind, placebo-controlled trial | Patients with Cr > 1.2 mg/dL or CrCl < 60 mL/min underwent elective CAG ± PCI treated with iopamidol | NAC/600 mg/po/bid/1 day prior to and after procedure (n = 102) vs. Placebo (n = 98) |
↓ CIN ↓ Cr at 48 h after procedure ↑ CrCl |
– | Short-term NAC prevented CIN in patients with moderate CKD after CAG | [86] |
| Prospective randomized trial | Patients with Cr ≥ 1.5 mg/dL underwent CAG treated with iopromide or ioxilan | NAC/600 mg/po/bid/after randomization, 4 h later and every 12 h after CAG total 5 doses (n = 21) vs. Placebo (n = 22) |
↓ CIN ↓ Cr changes at 48 and 72 h after CAG |
– | Short-term NAC reduced CIN in patients with mild to moderate renal impairment undergoing CAG | [87] |
| Prospective randomized trial | Patients with Cr > 1.8 mg/dL (males), > 1.6 mg/dL (females), or CrCl < 50 mL/min underwent CAG ± PCI | NAC/1000 mg/po/bid/1 h prior to and 4 h after procedure (n = 36) vs. Placebo (n = 44) |
↔ CIN ↓ Cr changes at 48 h |
– | Short-term high-dose NAC prevented the rise of Cr 48 h after CAG/PCI and might prevent CIN | [88] |
| Prospective randomized-controlled trial | Patients with Cr > 2.0 mg/dL and < 6.0 mg/dL or CrCl < 40 mL/min and > 8 mL/min underwent CAG treated with iopamiro | NAC/400 mg/po/bid/1 day prior to and after CAG (n = 60) vs. Placebo (n = 61) |
↓ Cr ↓ Cr changes at 48 h |
– | Short-term NAC protected CIN in patients with CKD undergoing CAG | [89] |
| Prospective randomized-controlled trial | Patients with eGFR 30–60 mL/min/1.73 m2 underwent CAG treated with ioversol |
NAC/600 mg/po/bid/1 day prior to and after CAG (n = 73) vs NAC/600 mg/po/bid/1 day prior to and after CAG + theophylline/200 mg/po/bid/1 day prior to and after CAG (n = 72) vs No NAC (n = 72) |
↓ CIN (NAC + theophylline) ↓ Cr at 48 h after CM (NAC + theophylline) |
– | Short-term NAC along with theophylline prevented CIN in patients with eGFR 30–60 mL/min/1.73 m2 | [90] |
| Double-blind, placebo-controlled, randomized study | Age 18–80 years with Cr 1.4–5.0 mg/dL and CrCl < 70 mL/min/1.73 m2 scheduled for elective CAG treated with iopamidol | NAC/600 mg/po/bid/2 day prior to and 2 day after angiography (n = 13) vs. Placebo (n = 11) |
↑ CrCl ↓ α-GST |
↔ urinary 15-isoprostane F2t | Short-term NAC treatment was associated with suppression of oxidative stress-mediated proximal tubular injury | [91] |
| Prospective randomized-controlled trial | Patients with Cr > 1.36 mg/dL or CrCl < 50 mL/min underwent CAG or PCI treated with iodixanol |
NAC/150 mg/kg/IV/30 min prior to CM + NAC/50 mg/kg/IV/4 h after CM (n = 41) vs No NAC (n = 39) |
↓ CIN ↓ Cr at 48 and 96 h after CM |
– | Short-term IV NAC prevented CIN | [107] |
| Single center, Prospective, single-blind, placebo-controlled, randomized controlled trial | STEMI undergoing primary PCI treated with iopromide | NAC/1200 mg/day/IV/bid/bolus prior to and up to 48 h after PCI (n = 126) vs. Placebo (n = 125) |
↔ CIN ↔ Cr ↔ CrCl |
↓ activated oxygen protein products at day 1–2 ↓ oxidized LDL at day 1–3 |
High-dose IV NAC reduced oxidative stress after reperfusion of MI but not provided additional clinical benefit to nephropathy | [108] |
| Randomized, placebo-controlled, double blind trial | Age > 18 years with Cr ≥ 1.2 mg/dL or CrCl < 50 mL/min underwent CAG treated with iomeperole |
NAC/600 mg/po/bid/1 day prior to and after CAG (n = 19) vs Zinc/60 mg/po/1 day prior to CAG (n = 18) vs. Placebo (n = 17) |
↔ CIN ↔ Cr ↓ cystatin C |
– | Short-term NAC and zinc did not prevent CIN but NAC had renoprotective effect by reducing cystatin C | [92] |
| Double-blind, placebo and comparator-drug-controlled, randomized trial | eGFR 15–44.9 mL/min/1.73 m2 or 45–59.9 mL/min/1.73 m2 in DM underwent CAG or noncoronary angiography | NAC/1200 mg/po/bid/1 h prior to, 1 h, and 4 day after angiography (n = 2495) vs. Placebo (n = 2498) |
↔ CIN ↔ Cr at 90–104 day after angiography |
– | Oral NAC did not prevent CIN | [93] |
| Pragmatic randomized-controlled trial | Patients with at least 1 risk factor for CIN (age > 70 years, Cr > 1.5 mg/dL, DM, CHF, LVEF < 0.45, hypotension) underwent coronary or peripheral arterial diagnostic intravascular angiography or percutaneous intervention | NAC/600 mg/po/bid/1 day prior to and after procedure (n = 1172) vs. Placebo (n = 1136) |
↔ CIN ↔ Cr |
– | Short-term NAC did not reduce the risk of CIN | [94] |
| Randomized prospective study | Patients with Cr ≥ 1.6 mg/dL or CrCl ≤ 60 mL/min underwent PCI treated with low-osmolality nonionic CM |
NAC/600 mg/po/bid/1 day prior to and after procedure (n = 45) vs Fenoldopam/0.1 µg/kg/min/IV/4 h prior to and 4 h after procedure (n = 38) vs No NAC or fenoldopam (n = 40) |
↔ CIN ↔ Cr changes at 24 and 48 h after procedure |
– | Short-term NAC or fenoldopam did not prevent CIN in patients with CKD | [95] |
| Prospective, double-blind, placebo-controlled, randomized clinical trial | Age > 18 years with DM and Cr ≥ 1.5 mg/dL for men and ≥ 1.4 mg/dL for women underwent elective CAG treated with iohexol or iodixanol or diatrizoate meglumine | NAC/600 mg/po/bid/24 h prior to and after procedure (n = 45) vs. Placebo (n = 45) |
↔ CIN ↔ Cr changes at 48 after CAG ↔ BUN changes at 48 after CAG ↔ CrCl changes at 48 after CAG |
– | Short-term NAC did not prevent CIN in patients with DM and CKD | [96] |
| Prospective randomized-controlled trial | Patients with Cr > 1.2 mg/dL or CrCl < 50 mL underwent elective CAG treated with iodixanol |
NAC/600 mg/po/bid/1 day prior to and after CAG (n = 73) No NAC (n = 106) |
↔ CIN ↔ Cr changes at 48 h after CAG |
– | Short-term NAC did not prevent CIN in patients with CKD | [97] |
| Randomized-controlled trial | Patients with Cr > 1.7 mg/dL underwent CAG treated with iohexol | NAC/1200 mg/po/1 h prior to and 3 h after CAG (n = 38) vs. Placebo (n = 41) |
↔ CIN ↔ Cr changes at 48 h after CAG |
– | Short-term NAC did not prevent CIN after CAG | [98] |
| Prospective, randomized clinical study | Age ≥ 18 years with CrCl < 55 ml/min underwent elective coronary ± peripheral angiography treated with iodixanol | NAC/600 mg/po/bid/1 day prior to and after procedure (n = 99) vs. Placebo (n = 101) | ↔ CIN | – | Short-term NAC did not prevent CIN | [99] |
| Prospective, open-label, randomized, controlled trial | Patients with Cr 1.69–4.52 mg/dL underwent elective CAG or PCI treated with iopromide | NAC/400 mg/po/tid/1 day prior to and after procedure (n = 46) vs No NAC (n = 45) |
↔ CIN ↔ Cr changes at 48 h after procedure ↔ eGFR changes at 48 h after procedure |
– | Short-term NAC did not prevent CIN in patients with moderate to severe renal insufficiency undergoing CAG or PCI | [100] |
| Multicenter, randomized, double-blind, placebo-controlled clinical trial | Diabetic patients with Cr ≥ 106.08 µmol/L or CrCl < 50 mL/min underwent elective CAG or PCI treated with ioxaglate | NAC/600 mg/po/bid/1 day prior to and after procedure (n = 77) vs. Placebo (n = 79) |
↔ CIN ↔ Cr changes at 48 h after procedure ↔ CrCl changes at 48 h after procedure |
– | Short-term NAC did not prevent CIN in patients undergoing cardiac catheterization | [101] |
| Prospective, randomized, double-blind placebo-controlled trial | Patients with Cr ≥ 1.5 mg/dL or CrCl < 50 mL/min underwent CAG treated with iopamidol | NAC/600 mg/po/tid/24 h prior to and after procedure (n = 41) vs. Placebo (n = 39) | ↔ CIN | – | Short-term NAC did not prevent CIN in CKD patients undergoing CAG | [102] |
| Prospective, randomized, double-blind, placebo-controlled trial | Age ≥ 19 years with Cr > 1.2 mg/dL and CrCl < 50 mL/min underwent elective CAG ± PCI treated with iopamidol | NAC/1,500 mg/po/1 day prior to and every 12 h after procedure for 4 doses (n = 49) vs. Placebo (n = 47) |
↔ CIN ↔ Cr ↔ BUN |
– | Short-term NAC did not prevent CIN in patients with CKD undergoing elective CAG | [103] |
| Prospective, randomized, single-blinded, single-center clinical trial | Age > 18 years with eGFR > 30 mL/min/1.73 m2 underwent elective CAG or PCI treated with iopromide |
NAC/600 mg/po/bid/24 h prior to and after procedure (n = 157) vs NaHCO3/1.5 mL/kg/h/IV/6 h prior to and 6 h after procedure (n = 159) vs. NAC/600 mg/po/bid/24 h prior to and after procedure + NaHCO3/1.5 mL/kg/h/IV/6 h prior to and 6 h after procedure (n = 150) vs No NAC or NaHCO3 (n = 161) |
↔ CIN | – | NAC and NaHCO3 did not reduce incidence of CIN | [104] |
| Single-center prospective controlled trial | Patients with Cr > 1.2 mg/dL underwent CAG or PCI treated with ioxaglate |
NAC/600 mg/po/bid/1 day prior to and after procedure (n = 88) vs NaHCO3/1 mL/kg/h/IV/6 h prior to and 6 h after procedure (n = 88) vs No NAC or NaHCO3 (n = 88) |
↓ CIN (NaHCO3 > NAC > No NAC or NaHCO3) ↓ CrCl (NaHCO3 > NAC = No NAC or NaHCO3) |
– | NaHCO3 protected CIN better than NAC and standard treatment | [105] |
| Prospective randomized trial | Patients with CrCl > 30 mL/min/1.73 m2 underwent CAG ± PCI treated with iopromide | NAC/1200 mg/IV/12 h prior to and after procedure (n = 53) vs. Placebo (n = 51) |
↔ CIN ↔ CrCl |
– | Short-term IV NAC did not prevent CIN in patients with normal, mild and moderate CKD undergoing coronary procedure | [109] |
| Single center, prospective, randomized study | CAD with Cr ≥ 1.5 mg/dL ± CrCl < 60 mL/min) who underwent elective CAG treated with iomeprol |
NAC/704 mg/po/bid/1 day prior to and up to 2 day after CAG (n = 7) vs GSH/100 mg/min/IV/30 min prior to CAG (n = 7) vs Control group (n = 7) |
↔ CIN |
↑ LOOHs at 2 h after CAG (control > NAC > GSH) ↓ serum GSH at 2 h after CAG (NAC > control > GSH) |
GSH protected kidney against CM-induced oxidative stress more effectively than oral administration of NAC before CAG | [106] |
| Randomized trial | Age > 18 years underwent elective or emergent CAG |
NaHCO3 (166 mEq/L)/3 mL/kg/h/IV/1 h prior to CAG + 1 mL/kg/h/IV/6 h after CAG (n = 50) vs NaHCO3 (166 mEq/L)/3 ml/kg/h/IV/6 h prior to CAG + 1 mL/kg/h/IV/6 h after CAG (n = 50) |
↑ Cr and ↓ eGFR 48 h post-intervention (short regimen) ↔ Cr and↔ eGFR 48 h post-intervention (long regimen) ↓ serum K |
– | Long-term regimen of bicarbonate supplementation was more effective strategy to prevent CIN than short regimen | [111] |
| Cross-sectional case–control study | CAD with at least 1 risk factor for CIN (DM, advanced age, reduced GFR, anemia) undergoing CAG |
Nebivolol/po/at least 1 mo (n = 45) vs No nebivolol (n = 114) |
↔ CIN ↔ Cr, eGFR, NGAL in both groups before and after CAG ↑ Cr and NGAL and ↓ eGFR in both groups compared to levels before CAG |
– | Nebivolol did not prevent CIN in patients undergoing CAG | [113] |
| Pilot study | Patients with Cr > 2 mg/dL undergoing CAG treated with iomeprol | MESNA/800 mg/IV/30 min prior to and up to 4 h after iomeprol (n = 12) |
↓ CIN ↓ Cr at 48 h |
– | MESNA prevented CIN in patients with renal impairment | [112] |
α-GST, α-glutathione S-transferase; BUN, blood urea nitrogen; CAD, coronary artery disease; CAG, coronary angiography; CHF, congestive heart failure; CIN, contrast-induced nephropathy; CKD, chronic kidney disease; CM, contrast media; Cr, creatinine; CrCl, creatinine clearance; CT, computed tomography; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; GSH, glutathione; IV, intravenously; LDL, low-density lipoprotein; LOOHs, lipid hydroperoxides; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NAC, N-acetylcysteine; NGAL, neutrophil gelatinase-associated lipocalin; NO, nitric oxide; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction