Contrast-induced nephropathy (CIN), a frequent complication following the administration of contrast media during radiographic procedures, poses a significant risk, especially for patients with pre-existing renal conditions. Effective preventative strategies are crucial to mitigate this risk. This article delves into various preventive measures for CIN, with a particular focus on the potential role of nebivolol, a third-generation beta-blocker, in kidney protection.
Understanding CIN Prevention
For patients identified as high-risk for CIN, meticulous monitoring of renal function is paramount. This involves assessing serum creatinine levels and calculating the estimated glomerular filtration rate (eGFR) both before and for five days following any procedure involving radiographic contrast agents [23].
Several strategies have been established to prevent CIN, and these can be broadly categorized as follows:
1. Adequate Hydration: The Cornerstone of Prevention
Volume supplementation stands as a fundamental, safe, and cost-effective approach to CIN prevention [130]. Hydration works by expanding intravascular volume, which in turn dampens the renin-angiotensin system. This reduction in renal vasoconstriction and hypoperfusion leads to increased diuresis. Consequently, the duration of contact between contrast material and renal tubules is limited, reducing its toxic impact on the tubular epithelium [131, 132]. Clinical evidence robustly supports hydration as a preventive measure in high-risk individuals [133].
It is crucial to dispel the outdated advice of restricting fluids before contrast administration. Conversely, patients should be encouraged to increase fluid intake, provided there are no contraindications. A suggested regimen includes oral intake of 500 mL of water or soft drinks before the procedure and 2,500 mL over the subsequent 24 hours. This fluid intake should aim to maintain a diuresis rate of at least 1 mL/min in a well-hydrated patient [134].
For high-risk patients, intravenous (IV) infusion of 0.9% saline at approximately 1 mL/kg per hour is recommended. This should commence 6–12 hours pre-procedure and continue for 12–24 hours post-procedure, provided diuresis is adequate and the cardiovascular status allows [23, 130]. Multiple studies have affirmed the effectiveness of hydration with normal saline (0.9% NaCl) or half-strength saline (0.45% NaCl) [134, 135]. However, isotonic (0.7%) solutions have demonstrated superior CIN reduction compared to half-isotonic solutions (2.0%) [130].
Alt Text: Intravenous hydration setup, a crucial element in contrast-induced nephropathy prevention, showing saline bags and IV tubing in a clinical environment.
Furthermore, sodium bicarbonate hydration has been suggested, and supported by meta-analyses and clinical studies, as potentially superior to sodium chloride hydration [136–142]. Recent meta-analysis indicates bicarbonate’s effectiveness primarily with low-osmolar contrast media (LOCM), not iso-osmolar contrast media (IOCM), and particularly in urgent coronary interventions [143]. In emergency coronary procedures, a 154 mEq/L sodium bicarbonate infusion has been used, with a bolus of 3 mL/kg/hour for one hour before contrast, followed by 1 mL/kg/hour for six hours during and after [137]. A clinical trial showed reduced CIN risk with bicarbonate infusion combined with oral acetazolamide, a carbonic anhydrase inhibitor, in patients undergoing coronary angiography or percutaneous coronary intervention [144, 145]. Sodium citrate has also been explored to alkalinize urine [146]. The rationale is that lower tubular fluid pH enhances reactive oxygen species (ROS) activity, damaging renal tubular cells. Sodium bicarbonate or acetazolamide-induced bicarbonate excretion reduces urine acidification, decreasing ROS production and increasing neutralization, thus protecting the kidneys from contrast agent injury [139, 140, 147, 148].
However, some studies have found no benefit of sodium bicarbonate over sodium chloride hydration in preventing CIN in patients with moderate to severe chronic kidney disease undergoing coronary angiography [149–152]. Paradoxically, some research suggests sodium bicarbonate might even increase CIN incidence due to prooxidant properties in the presence of ROS [153]. The European Renal Best Practice (ERBP) recommends volume expansion with either isotonic sodium chloride or sodium bicarbonate solutions over no volume expansion for high-risk CIN patients [154]. The ongoing PRESERVE trial (NCT01231555) is comparing isotonic sodium bicarbonate versus isotonic sodium chloride and oral N-acetylcysteine versus placebo for preventing adverse outcomes linked to CIN in high-risk patients undergoing angiography [155].
2. Discontinuation of Nephrotoxic Drugs
It is essential to discontinue potentially nephrotoxic drugs, such as aminoglycosides, vancomycin, amphotericin B, and nonsteroidal anti-inflammatory drugs (NSAIDs), prior to contrast media administration [48]. When aminoglycoside use is unavoidable, it should be limited to the shortest possible duration. ERBP suggests single-dose aminoglycoside regimens for infections in patients with stable, normal kidney function, with drug level monitoring [154]. For amphotericin B, saline loading is recommended for all patients receiving any formulation [154].
Metformin, a common oral antihyperglycemic for type 2 diabetes, is primarily eliminated by the kidneys. Contrast-induced renal failure can lead to metformin accumulation, causing lactic acidosis with high mortality (~50%). Therefore, metformin should be stopped at least 12 hours before contrast and resumed no sooner than 36 hours after, or until serum creatinine returns to baseline [3].
3. N-acetylcysteine (NAC)
Experimental evidence indicates that iodinated contrast media can induce hypoxia and ROS formation in the kidney, potentially contributing to CIN. NAC, an antioxidant, may act as a free-radical scavenger, a reactive sulfhydryl compound, and enhance nitric oxide (NO) vasodilation [23, 45, 156]. Pretreatment with NAC has shown to reduce contrast-medium-induced cytotoxicity in kidney cells exposed to various contrast agents [157]. NAC has also demonstrated the ability to improve ischemic renal failure in animal models [158].
Alt Text: N-acetylcysteine (NAC) capsules, highlighting their antioxidant role in potentially mitigating contrast-induced nephropathy.
However, the protective effect of NAC against CIN in high-risk patients remains debated. Some studies report a protective effect [159–161], while others have not found it to be beneficial [153, 162–168]. NAC may offer additional benefits to the heart and vessels beyond kidney protection [169]. Despite the conflicting results, NAC is often suggested for high-risk patients at an oral dose of 600 mg twice daily on the day before and the day of the procedure [23]. Intravenous doses of 150 mg/kg over 30 minutes before the procedure or 50 mg/kg over 4 hours have been suggested for patients unable to take oral medication [160].
4. Antioxidant Vitamins C and E
While in vitro studies have shown ascorbic acid (vitamin C) does not reduce contrast-medium-induced cytotoxicity in kidney cells [157], clinical results are mixed. Some studies suggest a protective effect of ascorbic acid (3g orally 2 hours before, 2g the night and morning after) in patients undergoing coronary procedures [170, 171], while others deny its prophylactic benefit in patients with renal dysfunction exposed to contrast dye [172]. High-dose NAC may be more effective than ascorbic acid in preventing CIN, especially in diabetic patients with renal insufficiency undergoing coronary angiography [173].
Vitamin E (α– or γ-tocopherol), known for its antioxidant and anti-inflammatory properties, has shown promise. Prophylactic oral administration of either 350 mg/day of α-tocopherol or 300 mg/day of γ-tocopherol (5 days before and 2 days after coronary procedures), combined with 0.9% saline, has been effective in protecting against CIN in chronic kidney disease patients undergoing elective coronary procedures with iopromide (low-osmolar, nonionic contrast medium). CIN incidence was significantly lower in the vitamin E groups compared to placebo [174].
5. Statins
Hypercholesterolemia has been implicated as a CIN risk factor due to compromised NO synthesis and increased ROS generation [175]. Recent studies indicate statins’ beneficial role in preventing CIN in patients undergoing percutaneous coronary intervention [176–178]. Rosuvastatin (10 mg/day for five days) significantly reduced contrast-associated acute kidney injury (CIAKI) risk in diabetic patients with chronic kidney disease undergoing angiography [179]. Simvastatin has shown dose-dependent nephroprotective effects in rats [180]. Chronic pravastatin treatment before contrast exposure has been important for CIN prevention in patients with renal insufficiency undergoing coronary procedures [181], with pravastatin showing a lower CIN incidence compared to simvastatin [182]. Short-term atorvastatin and chronic statin therapy may protect renal function after elective coronary angiography [183].
Statins’ nephroprotective effect against contrast media may be attributed to their antioxidant, anti-inflammatory, antithrombotic, and vasodilator properties, improving renal microcirculation, rather than solely lipid metabolism [184, 180]. Meta-analyses support short-term high-dose statin pretreatment for reducing serum creatinine and CIN rates in patients undergoing contrast media procedures [186]. High-dose atorvastatin pretreatment has prevented CIN and shortened hospital stays in acute coronary syndrome patients undergoing percutaneous coronary intervention [187].
6. Nebivolol: A Promising Agent
Nebivolol, a third-generation beta-blocker, possesses vasodilator and antioxidant properties [188, 189]. It is hypothesized to protect against CIN through these actions, particularly its NO-mediated vasodilation and ROS reduction. Animal studies in rats have demonstrated nebivolol’s protective role against CIN [190, showing reduced medullary congestion, protein casts, and tubular necrosis, decreased oxidative stress, reduced microproteinuria, and increased kidney nitrite levels after contrast media exposure [190].
Alt Text: Nebivolol tablets, showcasing a medication that may offer protection against contrast-induced nephropathy through its antioxidant and vasodilator actions.
Clinical studies in humans have also indicated nebivolol’s benefits. Oral nebivolol (5 mg per day for one week) reduced CIN incidence in patients with renal dysfunction undergoing coronary angiography [191]. Pretreatment with nebivolol (5 mg every 24 hours for 4 days) appeared protective against contrast media nephrotoxicity in patients undergoing coronary angiography and ventriculography [192]. These findings suggest nebivolol as a potential pharmacological approach to mitigate CIN risk, particularly in vulnerable populations. Further research is warranted to fully elucidate its optimal usage and effectiveness compared to other preventive strategies.
7. Experimental Agents: HSA-Trx and Sodium Butyrate
Human serum albumin-thioredoxin (HSA-Trx) is an experimental agent with a longer half-life than thioredoxin-1 (Trx), a natural ROS scavenger. In vivo and in vitro studies have shown HSA-Trx’s ROS scavenging activity, preventing CIN and renal tubular apoptosis in rat models [193].
Sodium butyrate, another experimental agent, has demonstrated anti-inflammatory activities in rats, reducing inflammation and oxidative damage in CIN models by decreasing nuclear factor kappa B (NF-κB) activation [194].
8. High-Dose Steroids
High-dose steroids (oral prednisone, 1 mg/kg) concurrently given with IV saline may be beneficial for renal tubule protection during endovascular procedures involving arterial iodinated contrast media [195]. Steroids may favorably impact inflammation and renal tubular cell apoptosis and necrosis, as seen in renal ischemia-reperfusion models where dexamethasone showed protective effects [196].
9. Choice of Contrast Medium
Low-osmolar contrast media (LOCM) are less nephrotoxic than high-osmolar contrast media (HOCM), and iso-osmolar contrast media (IOCM) may be even less so [23]. While studies in patients with normal renal function haven’t shown significant nephrotoxicity differences between HOCM and LOCM, patients with chronic kidney disease have a higher CIN incidence with HOCM compared to LOCM [113, 197].
Table 2. Iodinated contrast media commonly used in clinical practice.
| Name | Type | Iodine content (mg/mL) | mOsm/kg | Osmolality type |
|---|---|---|---|---|
| Ionic | ||||
| Diatrizoate (Hypaque 50) | Monomer | 300 | 1,550 | HOCM |
| Metrizoate Isopaque (Conray 370) | Monomer | 370 | 2,100 | HOCM |
| Ioxaglate (Hexabrix) | Dimer | 320 | 580 | LOCM |
| Nonionic | ||||
| Iopamidol (Isovue-370) | Monomer | 370 | 796 | LOCM |
| Iohexol (Omnipaque 350) | Monomer | 350 | 884 | LOCM |
| Iodixanol (Visipaque 320) | Dimer | 320 | 290 | IOCM |
Nonionic dimers are considered ideal as they provide the most iodine with minimal osmolality impact. While IOCM was initially thought superior, recent analyses suggest similar safety profiles between IOCM and LOCM, with potential differences among LOCM molecules themselves [199, 200]. Clinical trials comparing iopamidol (LOCM) and iodixanol (IOCM) in chronic kidney disease patients undergoing cardiac procedures showed no statistically significant difference in CIN rates [125].
10. Minimizing Contrast Dosage
Faster imaging technologies allow for reduced intravascular contrast volumes. Cigarroa’s formula suggests a contrast limit of 5 mL per kilogram body weight/serum creatinine (mg/dL), with a 300 mL maximum for diagnostic coronary arteriography [202]. Laskey’s formula uses a contrast volume to calculated creatinine clearance ratio, with a cut-off point of 3.7 for percutaneous coronary intervention [203, 204], recently revised to 2.0 [201, 205]. Other authors suggest a ratio of grams of iodine to creatinine clearance, with 1.42 or 1.0 as target ratios to prevent CIN [201]. However, these formulas require further validation due to patient heterogeneity and varying risk factors.
11. Avoidance of Diuretics
Furosemide or mannitol with saline infusion, intended to reduce renal hypoxia by decreasing transport activity, have not shown benefit and may even be harmful [135, 206, 207]. Diuretics should generally be avoided in high-risk patients susceptible to volume depletion before contrast exposure [74].
12. Other Agents with Limited or Controversial Evidence
Atrial natriuretic peptide (ANP) [207, 209], calcium channel blockers [135, 210–214], adenosine antagonists (theophylline, aminophylline) [215–221], dopamine agonists (fenoldopam, fenoldopam mesylate) [163, 207, 221, 222–225], and endothelin receptor blockers [226] have shown limited or controversial results in CIN prevention and are not routinely recommended. Prostaglandin E1 [227] has shown some positive results. Haemodialysis or haemofiltration for contrast removal has not been shown to reduce acute renal failure incidence [228–231] and is not recommended for routine CIN prevention [154].
13. Consider Alternative Imaging: MRI with Gadolinium
For patients at increased CI-AKI risk, alternative imaging methods should be considered [94]. MRI with gadolinium-based contrast agents is an option. Gadolinium agents are not iodinated and were initially thought to pose no nephropathy risk [232]. However, gadolinium agents have been linked to acute renal failure and nephrogenic systemic fibrosis, especially in pre-existing renal failure patients [233, 234]. Therefore, careful consideration is necessary even with MRI contrast agents in high-risk individuals.
Conclusion
Preventing contrast-induced nephropathy requires a multifaceted approach, primarily centered around adequate hydration and risk factor management. While established strategies like saline hydration and nephrotoxic drug discontinuation are crucial, emerging agents like nebivolol and statins show promising potential in further reducing CIN risk. The choice of contrast media and minimizing contrast dosage are also important considerations. Ongoing research continues to refine our understanding and expand the arsenal of preventive measures against CIN, aiming to improve patient safety during essential radiographic procedures.
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