Contemporary Modalities in the Prevention of Contrast-Induced Acute Kidney Injury the

Contrast-induced acute kidney injury (CI-AKI) is the third leading cause of acute kid ney injury deriving from the intravascular administration of contrast media in diagnostic and therapeutic procedures and leading to longer in-hospital stay and increased short and long-term mortality. Its pathophysiology, although not well-established, revolves around medullary hypoxia paired with the direct toxicity of the substance to the kidney. Critically ill patients, as well as those with pre-existing renal disease and cardiovascular comorbidities, are more susceptible to CI-AKI. Despite the continuous research on the field of CI-AKI prevention, clinical practice is based mostly on periprocedural hydration. In this review, all the investigated methods of prevention are being presented, with the potency of RenalGuard and contrast-removal systems being stressed as the method of choice for CI-AKI prevention in high-risk individuals.


Introduction
Contrast media (CM), intravascularly administered in radiodiagnostics to enhance vascular visibility, have as complication the occurrence of acute kidney injury, beginning soon after their administration. This clinical entity is known as contrast-induced acute kidney injury (CI-AKI) and is the third leading cause of acute kidney injury, after defect of renal perfusion and nephrotoxic drugs administration [1]. CI-AKI is associated with elevation of serum creatinine after exclusion of alternative causes of renal impairment, within 48-72 hours after the injection of the CM, which usually returns to baseline values over 1-3 weeks. The first 24 hours postexposure are crucial to the development of CI-AKI, since in 80% of cases serum creatinine started rising within 24 hours post-exposure and nearly all patients who progressed to serious renal dysfunction had an increase in serum creatinine within this period of time. CI-AKI is related to serious adverse events, as chronic kidney disease (CKD), myocardial infarction, stroke and death while patients who developed CI-AKI had higher mortality at one month [2,3]. The reported one-year mortality rate varies according to the degree of renal impairment prior to the radiocontrast procedure, ranging from 8-23%, and can be as high as 55% in those who develop CI-AKI that requires dialysis [4,5]. In this review, we present the various methods used in CI-AKI prevention while also elaborating on the novel approaches that are currently being investigated.

CI-AKI Risk Stratification
Mehran et al. developed a simple risk score for the prediction of CI-AKI and the need for dialysis after PCI by investigating 8357 patients [12]. A weighted integer score is attributed to each risk factor and the sum gives rise to the CI-AKI risk score, a predictor of the risk of CI-AKI occurrence and necessity for dialysis (Table 1).
Lately, there has been novel predictors for CI-AKI risk especially in patients undergoing PCI after ST-elevation MI such as the Athens CI-AKI Score or the PRECISE-DAPT [13,14]. However, since renal function is a major determinant of CI-AKI incidence, estimation of GFR is usually the most practical method of risk stratification [15] in the elderly, diabetic or hypertensive patient population as well as patients with pre-existing renal disease (   Recently, the breakthrough AMACING trial brought more controversy to the table, as no intervention was non-inferior to IV infusion of 0.9% saline according to current guidelines for CI-AKI prevention, while also being more cost-effective, in patients with eGFR between 30-59 ml/min/1,73m2 referred for elective procedures requiring CM. Importantly, no subgroup differences were noted according to eGFR, diabetes mellitus status or the type of the procedure. Concerning adverse events, 5.5% of patients receiving IV hydration faced hydration-related complications AKI [42]. A balanced hydration therapy consisting of temporary forced diuresis with furosemide and replacement of urine output by saline infusion, matched minute-to-minute to urine volume, using the specialized RenalGuard System has also been described (Table 2). Dorval et al. in a study of 23 patients at high risk for CI-AKI development who underwent a radiocontrast procedure, used RenalGuard balanced hydration and noticed CI-AKI incidence lower than predicted (9,5% versus 14,5% to 55%) [43]. Moreover, in patients undergoing transcatheter aortic valve implantation hydration with RenalGuard was highly protective against CI-AKI (RenalGuard: 1/22 vs. Control: 10/26) [44]. Recently, Briguori et al.
highlighted the superiority of RenalGuard system with a urine rate of over 300ml/hour compared to a LVEDP-guided hydration regimen, as demonstrated by a statistically significant decrease in CI-AKI incidence as well as reduced 1-month major adverse events (death, dialysis-dependent renal failure, pulmonary edema or sustained kidney injury) in patients undergoing coronary and peripheral vessel procedures [45]. Patients on RenalGuard exhibited a higher hypokalemia rate, however. The encouraging results of RenalGuard in such study population will be further evaluated in another RCT of 326 patients at increased risk for CI-AKI (NCT01456013).  [55]. However, based on the most recent data from PRESERVE trial, NAC doesn't affect CI-AKI incidence, the need for dialysis, or death when compared to oral placebo in patients at risk for renal adverse events undergoing angiography [48]. Given all the above date, the use of NAC is not recommended.  have anti-oxidative and anti-inflammatory action and they can be renoprotective. They decrease free radical formation through the increase of heme oxygenase-1 protein production, which is an antioxidant protein interfering with NADPH oxidase activity [56].
Studies concerning the effectiveness of statins in CI-AKI prevention had controversial results (Table 3)  (Alprostadil: 6.56% vs. Control: 16.74%) [64]. In spite of these promising results, they are currently not recommended in CI-AKI prophylaxis and further investigation with larger multicentre RCTs is mandatory.

Contrast Removal Strategies
Hemodialysis-Hemofiltration: CM can be removed from the blood by intermittent hemodialysis immediately after radiographic contrast studies. A session of hemodialysis can remove 60%-90% of the administered CM. Peritoneal dialysis is also effective in removing the CM but lasts longer than hemodialysis [65]. Several high-risk population, with no events of CI-AKI and a slower 1-year progression of kidney disease being noted [73]. Hemofiltration may, therefore, decrease the risk of CI-AKI, but it is costly, often requires intensive care unit admission and carries its own risks.
Therefore, additional studies are needed to support the benefit and cost-effectiveness of hemofiltration.
Contrast Removal-Reduction Systems: During coronary angiography, the removal of the majority of injected CM from the coronary sinuses before it enters the systemic circulation represents an innovative approach. A catheter is inserted into the coronary sinus through the right femoral vein and blood is transferred into an extracorporeal contrast-absorbing column.
Even though it has been effective in reducing CI-AKI incidence, a high technique failure rate (57%) has limited its clinical use [72,74].
More recently, a novel contrast reduction system (DyeVert™) was employed for the prevention of CI-AKI, based on limiting excess CM administration and aortic reflux. Its impact was evaluated in 96 patients undergoing coronary angiography, with results showing less CM exposure without affecting image quality [75].
This CM volume reduction translated in a lower incidence of CI-AKI in a study of 451 patients undergoing coronary procedures for acute coronary syndromes (DyeVert™: 8% vs. Control: 19%) [76].
Importantly, in a UK-based cost-utility analysis, the use of DyeVert™ was accompanied with a significant cost savings as well as improve quality of life effectiveness [77].