Contrast-induced Acute Kidney Injury: A Contemporary Review

Clinically significant Contrast-Induced Acute Kidney Injury (CIAKI) is a severe complication of interventional contrast-based procedures of all kinds. It involves high morbidity, mortality, social and financial losses. Acute renal damage after coronary angiography or percutaneous coronary intervention may occur in 1-2% of cases in the general population or 50+% of cases with high CIAKI exposure. It is essential to detect high-risk patients with renal damage as a major and frequent CIAKI predisposing factor. There are novel biomarkers with rapid or nearly instant response to acute subclinical contrast-induced renal damage, which are highly valuable in CIAKI diagnosis and for this reason desire deeper clinical research. Despite a number of controversies, prophylactic and therapeutic measures are practically the same in a vast majority of guidelines. An intravenous 0.9% NaCl solution remains the only proven measure in CIAKI prophylaxis and treatment, while the use of other pharmacological approaches still needs more relevant prospective clinical research. The aim of this paper was to review contemporary evidencebased CIAKI data. *Corresponding author:


Introduction
Contrast-Induced Nephropathy (CIN), or Contrast-Induced Acute Kidney Injury (CIAKI), is acute damage to the renal parenchyma, caused by the intravascular administration of iodinated Contrast Media (CM) without other alternative reasons [1]. CIAKI was first described by clinicians in a 1950s case history, clinically proceeding as a lethal acute renal failure after intravenous pyelography in myeloma patients [2,3]. The incidence of CIAKI may be as low as 2% in patients without risk factors, but in those with risk factors, such as diabetes, the rate rises to 9%, and even as high as 90% in patients with diabetic nephropathy or preexisting chronic kidney disease [4,5]. Therefore, the number and the type of preexisting risk factors directly influence the incidence of renal insufficiency. Incidence rates are also procedure dependent, with reports in the literature ranging from 1.6-2.3% for diagnostic interventions to 14.5% overall in patients undergoing coronary intervention [4,5]. Renal damage after coronary angiography or percutaneous coronary intervention may develop in 1-2% of cases in the general population and almost 50% of patients with high CIAKI exposure [1,6]. A major CIAKI factor is existing nephropathy, especially in diabetic patients [5,7].
Every year, the growing number of patients receiving percutaneous cardiac care increases CM consumption and consequently CIAKI incidence. CIAKI entails an increased frequency and number of cardiovascular complications, extended admission, need for substitutive renal therapy, and fivefold increase in hospital mortality [8]. CIAKI's fully iatrogenic and predictable nature makes this disease available for a comprehensive study with focus on its pathophysiology, risk stratification, prophylaxis and treatment.
CIAKI meets one of the following criteria of acute kidney injury, regardless of etiology [9]: • Serum Creatinine (SC) increase by 26.5 mcmol/L within 48 h; • SC increase by 1.5+ times above its known or estimated level in previous 7 days; • Lower diuresis (oliguria <0.5 ml/kg/h) for 6 h (cannot be regarded as a reliable diagnostic criterion, since it rarely develops after CM administration for a variety of reasons).
The key factor in diagnosing and determining nephropathy severity is relative or absolute SC growth in the first 48-72 h after CM injection.
The downside of this definition is hyposensitivity to small oscillations of plasma creatinine, related to renal parenchyma damage, and the absent functional estimation of renal function condition [10][11][12].
The problem of using SC as a renal damage biomarker is that SC increase after CM injection characterizes a preexisting decrease in Glomerular Filtration Rate (GFR), not cellular damage. Creatinine increase is only observed 48-72 h after CM injection and has no clinical value during preexisting AKI [14]. However, a study by Ribichini et al. [15] has proved that SC increase by 5% 12 h after CM injection is an AKI marker with 75% sensitivity and 72% specificity. In addition, such SC growth dynamics may be used to estimate a 30day nephropathy prognosis [15].
Despite reliable correlation between changes in these markers' concentrations and AKI presence, their routine use is not yet included in current guidelines on CIAKI prophylaxis and treatment for lack of major multicenter studies [6,7,18,[41][42][43][44][45] and evidence of the relevant novel biomarker response in contrast-induced acute kidney injury.

Contrast media
As to CI nephropathy, radiopaque iodinated substances as the prime AKI cause, widely used in modern interventional radiology, cannot escape consideration. The first CM works were published in 1896 by E. Haschek and O. Lindenthal [46]. At that time, bismuth, plumbic and barium salts were used in stump vessel angiography but were unsafe for lifetime diagnostics. In the early 1920s, Osborne et al. [47] found that a syphilis patient's urine, after long-term treatment with iodinated drugs, acquires radiopaque properties. This observation led the researchers to the first successful pyelogram taken at Mayo Clinic in 1923. Intravascular iodinated CM were introduced into clinical practice by urologist Moses Swick [48] in 1928, thus initiating long-term experiments with structural CM modification so as to reduce their toxicity and increase efficiency.
In present-day interventional radiology, iodinated CM remains frontline therapy, despite the significant nephrotoxic effect, due to almost totally absent alternatives.  as ion composition, osmolality, and viscosity ( Table 2). Low-or isosmolar CM are recognized standards in interventional cardiology, which is confirmed by a number of studies, while ionic CM is used rarely nowadays due to frank nephrotoxicity [17,49,53].
A NEPHRIC study comparing use of isosmolar Iodixanol to low-osmolarIohexol in cohorts of high-risk nephropathy, diabetic patients with initial nephropathy showed ninefold lower CIAKI risk in the Iodixanol cohort [41]. A RECOVER study also showed a lower CIAKI incidence in the cohort administered with isosmolar Iodixanol versus low-osmolar Ioxaglate [54].
Although apparent benefit from using Iodixanol is not confirmed by the majority of clinical studies, the use of low-or isosmolar CM is most encouraged in clinical practice, especially in high-risk patients with strict contraindications against using high-osmolar CM.
CM injection amount is an independent CIAKI risk factor and even in small doses (30 ml) may trigger adverse effects in highrisk patients. Therefore, contrast-using procedures should be done on the "As Low As Possible" (ALAP) principle, using the precise CM amount to achieve satisfactory image quality. For example, diagnostic coronary angiography requires optimal CM amount at <30 ml, with minimum of 100 ml for Percutaneous Coronary Intervention (PCI) [8,55]. The Maximum Allowable Contrast Dose (MACD) is calculated by the formula "5 ml CM x body weight [kg]/initial plasma creatinine [mg/dL]" [56] and must not exceed allowable values.
Speaking about iodinated CM alternatives, first of all we should mention a gadolinium CM, usage of which did not show superiority to iodinated media in patients with moderate renal function impairment [57,58]. According to some researchers, gadolinium CM rises the incidence of nephrogenic systemic sclerosis (also known as nephrogenic fibrosing dermopathy) -serious invalidizing skin and internal organs sclerosis [59,60], however a series of multiple studies showed no evidence of that statement [61,62].
A promising yet controversial iodinated CM, alternative carbon dioxide is contraindicated in intra-arterial injection above the diaphragm (coronary and brachiocephalic arteries, thoracic aorta). CO 2 is currently used only in diagnostic endovascular procedures below the diaphragm (abdominal aorta, lower limb vessels) through an introduction system (CO 2 mmander) and portable tanks with carbon dioxide [63][64][65] (Table 2).

Risk factors
The patient's CIAKI risk during contrast X-ray must be measured before preoperative assessment and selecting the CM type.

2.
The presence of diabetes mellitus with diabetic nephropathy predisposes to developing adverse renal complications during CM injection, while diabetes mellitus with a normal renal function hardly affects CIAKI development [9,45,66]. Other major CIAKI risk factors are in the Table 3.

Risk Assessment
Given that patients with chronic kidney disease (CKD) and GFR<60 ml/min/1.73 m 2 are predisposed to a high CIN risk, all CM procedure candidates must have their GFR measured. Since CIAKI results from many factors, isolated GFR measurement does not reliably identify nephropathy risk, so risk assessment systems are developed based on the cumulative effect of many factors [67][68][69]. Clinical practice prefers several systems for measuring perceived CIAKI risk.
As calculated by Maioli et al. [44] risk stratification should factor in 7 basic parameters (Table 4) [70]. Availability of each parameter is assessed in points resulting in patient distribution into low, medium, high and very high-risk cohorts. CM injection in previous 72 h, low LVEF, difference between SC before the procedure and initial creatinine, higher initial creatinine, diabetes mellitus, 73+ age and lower GFR are factored in Table 4. (Table 5). In addition to patient distribution into low, medium, high and very high-risk cohorts, dialysis probability and death risk are also estimated. Points are awarded for hypotension, CKD, IABP, CHF, diabetes mellitus, 75+ age, anemia, and administered CM amount.

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The most up-to-date, though uncommon, system in clinical practice is the one by Tziakas et al. [18] (Table 6), using 5 variables, including the presence of previously detected CKD, permanent metformin introduction, previously done PCI, obliterating atherosclerosis of peripheral arteries and intraoperative injected CM amount. The score is distributed among 3 CIAKI exposure cohorts: low, medium and high-risk. (Table 6) Having assessed perceived CIAKI exposure, it is necessary to start preparing the patient for the procedure, based on the standardized prophylaxis and treatment protocol (Figure 2) [71].

Prophylaxis
CIAKI prophylaxis should begin with the cancellation of the patient's nephrotoxic drugs among non-steroidal anti-inflammatory, antifungal, antiviral, antitumoral, immunosuppressants and antibiotics, especially aminoglycosides, 24 h before the study. In diabetic patients, metformin introduction must be canceled 48 h before and limited 48 h after CM injection. ACE inhibitors and angiotensin receptor blockers, due to possible harm and inadequate data on their positive effects on renal hemodynamics and GFR, should be excluded from therapy 1 day before the study, although, under the KDIGO consensus, this allegation has not been fully proved [13,72].
To date, intravenous loading with a 0.9% NaCl solution is the only proved efficient CIAKI prophylactic measure [9,41,42,45,[73][74][75][76]. Despite the aforesaid superiority of using intravenous sodium bicarbonate, its role in nephropathy prophylaxis is comparable to 0.9% NaCl, based on the findings of some randomized studies [66,73,75,77]. Although one study did show the benefits of high sodium bicarbonate concentrations (833 mEq/L) [78], clinical guidelines for nephropathy prophylaxis have not supported this fact.
N-Acetyl Cysteine (NAC) was widely used in CIAKI prophylaxis in high-risk patients, based on some positive observations, in a dose of 600 mg twice a day, 2 days before the planned study [79]. Subsequent studies (~40 clinical trials and 13 meta-analyses) using both high Journal Home: https://www.boffinaccess.com/journals/renal-diseases-therapy/index.php

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oral NAC doses and intravenous drug injection showed contradictory results. NAC use causes no side effects (except for anaphylactoid reactions to high intravenous and oral doses) and is generally not contraindicated in CIAKI prophylaxis [42,45,80].
The most recent, major and well-designed PRESERVE (Prevention of Serious Adverse Events Following Angiography) study comparingintravenous 1.26% sodium bicarbonate, intravenous 0.9% sodium chloride and 5 days, oral acetylcysteine and oral placebo showed no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over placebofor the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of CIAKI [81].
Atrial natriuretic peptide, dopamine, fenoldopam as well as theophylline and ascorbic acid have not demonstrated positive effects in CIAKI prophylaxis, whereas forced diuresis with mannitol or furosemide is contraindicated due to its damaging action [42,45].
Using prostaglandin E1 and statins has shown clinical benefits, but insufficient observation still prevents their adoption. Targeted therapy with the infusion system Benefit™ for selective fenoldopam delivery and using the RenalGuard™ infusion system demonstrated a lower CIAKI incidence only in few minor clinical trials [82][83][84].
Patients already under hemodialysis do not require volume support before a contrast study, and dialysis after the procedure is necessary only with frank liquid overload. As to hemofiltration, benefits in high-risk cohorts were not confirmed, despite some authors' successful use in very high-risk patients with Stage 5 CKD before and after the radiographic contrast study [19,21,85,86].
Safe CM reinjection time is not exactly defined, but, according to the average renal function recovery time with CIAKI (3 weeks), this period is recommended for a repeated contrast study.
For high-risk patients, daily SC control for 5 days is indicated, and in case of oliguria, patient treatment is the same as with other

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AKI reasons including monitoring of acid-base, electrolyte and fluid balances. Severe cases may require temporary hemodialysis and permanent one in exceedingly rare cases [87,88].

Conclusion
Clinically significant CIAKI is a major complication of endovascular radiographic procedures, associated with high morbidity, mortality rates, and consequent socioeconomic losses. Despite few guideline differences, there are several strict positions in CIAKI prophylaxis and treatment. Early detection of high CIAKI exposure in patients is crucial for timely initiation of preventive measures and reducing likelihood of renal parenchyma damage and further nephropathy. In interventional cardiologist's and radiologist's practice, preference must be given to using only low-and isosmolar CM as less as possible. Based on the rapid or nearly instant reaction of some biomarkers to subclinical AKI, measuring their urine or plasma concentration is now a promising research trend, although their routine usage is not yet featured in current guidelines for CIAKI prophylaxis and treatment. Intravenous loading with a 0.9% sodium chloride solution is the only proven efficient CIAKI prophylactic measure, whereas other pharmacological support is either damaging or requires further research and more prospective studies.