TYPE Review

PUBLISHED 09 January 2024

DOI 10.3389/fmed.2023.1180861

Prevention of contrast-associated
OPEN ACCESS acute kidney injury in an era of
increasingly complex
EDITED BY
Elham Ahmadian,
Tabriz University of Medical Sciences, Iran

REVIEWED BY
Yiwei Liu,
interventional procedures
Shanghai Children’s Medical Center, China
Takahide Kodama,
Toranomon Hospital, Japan
Cristina Somkereki 1,2, Renata Palfi 1 and Alina Scridon 2*
*CORRESPONDENCE
1
Cardiology Department, Emergency Institute for Cardiovascular Diseases and Transplantation Târgu
Alina Scridon Mureș, Târgu Mureș, Romania, 2 Physiology Department, University of Medicine, Pharmacy, Science
[email protected] and Technology “George Emil Palade” of Târgu Mureș, Târgu Mureș, Romania

RECEIVED 08 March 2023

ACCEPTED 27 December 2023
Radiological and interventional cardiology procedures are in continuous
PUBLISHED 09 January 2024
expansion, leading to an important increase in the incidence of contrast-
CITATION
Somkereki C, Palfi R and Scridon A (2024)
associated acute kidney injury (CA-AKI). Although numerous methods of CA-
Prevention of contrast-associated acute AKI prevention have been studied, at present, there is no consensus on the
kidney injury in an era of increasingly definition of this entity or on its prevention. In this paper, we aim to provide a
complex interventional procedures.
Front. Med. 10:1180861.
critical analysis of the existing data on the epidemiology, pathophysiology, and
doi: 10.3389/fmed.2023.1180861 clinical significance of CA-AKI. Existing and emergent approaches for CA-AKI
COPYRIGHT
prevention are also discussed, with a focus on parenteral fluid administration
© 2024 Somkereki, Palfi and Scridon. This is and on the most recent clinical and experimental data. We also emphasize a
an open-access article distributed under the number of questions that remain to be answered, and we identify hotspots for
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or future research.
reproduction in other forums is permitted,
provided the original author(s) and the
KEYWORDS
copyright owner(s) are credited and that the
original publication in this journal is cited, in contrast-associated acute kidney injury, percutaneous coronary intervention,
accordance with accepted academic periprocedural fluid administration, prevention, risk prediction
practice. No use, distribution or reproduction
is permitted which does not comply with
these terms.

1 Introduction
For decades, physicians have been concerned about the increasing use of contrast agents
and their risk of inducing acute kidney injury (1). Despite substantial research, there are still
many unknown aspects related to contrast-associated acute kidney injury (CA-AKI).
Consensus appears to exist among physicians that contrast-induced complications are not
clinically significant, and some authors question the very existence of this entity (2).
Meanwhile, numerous clinical studies support a deleterious effect of contrast agents on kidney
function, and animal studies clearly showed harmful effects (3–7).
The use of less nephrotoxic substances has reduced the incidence of CA-AKI (8). However,
at this point, there is no consensus on the exact incidence of CA-AKI in the era of modern
contrast agents, nor on the medium- and long-term impact of CA-AKI. Also, a wide array of
strategies with prophylactic and/or therapeutic potential have been evaluated, but there is no
consensus on the most effective strategy. Data regarding preventive measures such as fluid
administration, pharmacological strategies, use of different contrast agents, and renal
replacement therapies are conflicting. Isotonic saline administration seems to be, however, the
most effective way to prevent CA-AKI (9–11). In addition, although many factors have been
studied, with the exception of basal renal function, there is no consensus on the factors that
increase the risk of CA-AKI.

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In this paper, we aim to provide a critical analysis of the existing number of patients to be exposed to contrast media, the population
data on the epidemiology, pathophysiology, and clinical significance exposed to these procedures is also older and sicker, and the volume
of CA-AKI. Existing and emergent approaches for CA-AKI prevention of contrast media administered is also higher in these patients
are also discussed, with a focus on parenteral hydration and on the (26–31).
most recent clinical and experimental data in this field. The incidence of CA-AKI also seems to be influenced by several
other major factors, including the type, volume, and route (arterial vs.
venous) of contrast media administered. While there is agreement that
2 Epidemiology of contrast-associated intra-arterial contrast agent administration can cause acute kidney
acute kidney injury in the era of injury and that the incidence of CA-AKI is significantly higher after
modern iodinated contrast media intra-arterial than after intravenous contrast administration,
retrospective studies suggest that intravenous contrast material
In a recent study including more than 7,000 patients, CA-AKI administration for CT examinations may associate a similar risk of
occurred in 6.5% of patients receiving intra-arterial administration of CA-AKI to non-contrast CT (32, 33). Meanwhile, according to a
contrast media (12). In other studies, intra-arterial contrast systematic review and meta-analysis published in 2016, CA-AKI risk
administration led to CA-AKI in more than 13% of patients, whereas did not differ among types of low-osmolar contrast media and there
the risk of CA-AKI following intravenous contrast administration was also no difference between the route of administration of the
appeared to be negligeable (13). Development of CA-AKI after cardiac contrast media (34).
and radiologic procedures is associated with a significant increase in
morbidity, mortality, and costs, and with prolonged hospitalization
(14). At present, CA-AKI is defined as an impairment of renal function 3 Brief overview of the
after parenteral administration of contrast media in the absence of pathophysiology of
other identifiable causes, characterized by an increase in serum contrast-associated acute kidney
creatinine (SCr) of at least 0.5 mg/dL (≥44 μmol/L) or ≥ 25% above injury
baseline within the first 48 h after contrast administration (14). This is
also the definition most frequently used in clinical trials. The European The exact mechanisms of CA-AKI remain to date unknown.
Society of Urogenital Radiology defines CA-AKI based on an increase Several causes have been described and there are two major theories
in SCr by ≥0.5 mg/dL or ≥ 25% within the first 3 days after intravascular regarding the mechanism of CA-AKI: direct cytotoxic effects of
administration of contrast medium, without an alternative etiology (15). contrast media and renal vasoconstriction resulting in medullary
The incidence of CA-AKI is increasing mainly due to the increase hypoxemia (Figure 1) (21). Contrast agents have been shown to
in the number of interventional procedures. In the United States only, exhibit direct toxic effects on renal tubular cells, caused by oxygen free
over one million cardiac catheterization procedures are performed radicals release, altered mitochondrial function, and apoptosis, all
annually (16). The continuous development of interventional culminating in renal ischemia (35, 36). Contrast agents exert their
cardiology has also led to increasingly complex procedures that toxic effects mainly on renal tubular epithelial cells, causing
require administration of considerably larger amounts of contrast vacuolization and osmotic nephrosis, and on endothelial cells.
material (17). According to the study by Jennings et al., the crude rate Although the exact mechanisms responsible for contrast media-
of angiography and percutaneous coronary interventions (PCI) induced cytotoxicity remain elusive, these agents have been shown to
performed in Ireland increased by 47.8 and 35.9%, respectively, from stimulate cellular pathways involved in apoptosis by activating
2004 to 2011, with rates of 6,689 and 1,825 per million individuals in caspase-3, caspase-9, and the bcl2 pathway (37). In addition,
2011 (17). Among those cases, the reported incidence of CA-AKI administration of contrast media has been linked to redistribution of
ranged from 0 to >50% (18–21). Similar increases in the number and cell membrane proteins and disruption of intercellular junctions,
complexity of interventional cardiology procedures were also seen in DNA damage, mitochondrial dysfunction, and a significant reduction
more recent studies performed in Spain and Switzerland (22, 23). in cell proliferation, leading to alterations in cell polarity, loss of
A recent review and meta-analysis pointed out a higher incidence cytoskeletal integrity, displacement of membrane proteins and cellular
of CA-AKI after intra-arterial than after intravenous contrast medium adhesion molecules, and necrosis of tubular epithelial cells (38–42).
administration, but the overall incidence of CA-AKI seemed to The toxicity of contrast media on the tubular and endothelial cells
be decreasing over time, together with the need for dialysis. The is further accentuated by oxidative stress and hypoxia (43, 44).
incidence of CA-AKI was 9% and that of kidney failure requiring Increased adenosine and endothelin release in response to contrast
dialysis was 0.5% after intra-arterial administration of contrast medium agent administration leads to renal vasoconstriction, whereas reduced
(24). According to Chalikias et al. (25), the incidence of CA-AKI after nitric oxide and prostaglandin synthesis decreases the vasodilation of
PCI ranges from 2 to 20%, depending on baseline kidney function. the renal vascular bed (36). Together, these mechanisms are
In addition to the increasing number of angiographies and responsible for ischemia in the deeper portion of the outer medulla,
computed tomography (CT) examinations, causing an increasingly an area with increased oxygen demand. Many of the deleterious effects
of contrast agents on the kidneys are mediated by increased
production of oxygen free radicals and oxidative stress. Medullary
Abbreviations: CA-AKI, contrast-associated acute kidney injury; CT, computed hypoxia and adenosine catabolism increase the production of oxygen
tomography; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; free radicals, which not only scavenge nitric oxide, but also increase
NGAL, neutrophil gelatinase-associated lipocalin; PCI, percutaneous coronary the synthesis of vasoconstricting substances such as endothelin,
interventions; SCr, serum creatinine. adenosine, angiotensin II, and thromboxane A2. Constriction of

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FIGURE 1
Pathophysiology of contrast-associated acute kidney injury. Two main mechanisms contribute to the pathogenesis of contrast-associated acute
kidney injury: direct cytotoxic effects on tubular and endothelial cells and intrarenal vasoconstriction, favored by an imbalance between
vasoconstricting and vasodilating mediators. The medullary hypoxia resulting from renal vasoconstriction further alters the structure and function of
renal tubular cells. The increased production of free oxygen species and the consequent increase in oxidative stress aggravate renal vasoconstriction
and exert toxic effects on renal tubular cells. In parallel, renal ischemia and local cytotoxic effects aggravate oxidative stress, creating a vicious cycle.
The coexistence and mutual stimulation of these mechanisms eventually result in contrast-associated acute kidney injury.

glomerular and peritubular capillaries and of vasa recta further leads impairment, and older age) the incidence is estimated to be >20% and
to alterations in renal perfusion and blood flow autoregulation, and to up to 30% (50). In 2008, Mehran et al. (14) proposed a risk score for
distal ischemia (45, 46). At its turn, ischemia then increases the prediction of CA-AKI after PCI. In this score, points are given for the
formation of oxygen free radicals, thus leading to a vicious circle in presence of hypotension, use of intra-aortic balloon pump, symptoms
which ischemia promotes oxidative stress and oxidative stress of congestive heart failure, age, anemia, DM, volume of contrast media
aggravates the preexisting ischemia. Experiments performed on administered, and the estimated glomerular filtration rate (eGFR).
isolated mouse kidney vessels showed that decreased nitric oxide According to the Mehran risk score, a score < 6 points indicates a risk
availability and increased superoxide production induced by contrast for CA-AKI of 7.5%, a risk score between 6 points and 10 points
media resulted in more pronounced vasoconstriction in the afferent indicates a risk for CA-AKI of 14%, a risk score between 11 points and
than in the efferent arterioles, providing a pathophysiological 16 points indicates a risk for CA-AKI of 26%, and a risk score > 16
explanation for the reduction in glomerular filtration following points indicates a risk for CA-AKI of 57% following intra-arterial
administration of contrast media (47). In addition, increased oxidants administration of contrast media (14).
levels alter mitochondrial and nuclear DNA, lead to damage in Many risk factors have been reported to increase the risk of
membrane lipids and cellular proteins, and activate c-Jun N-terminal, CA-AKI, but few of them have been identified as independent
ERK, and p38-MAPK kinases, promote apoptosis and necrosis via predictors of CA-AKI. Barett et al. analyzed a series of clinical trials
activation of caspase-3 and caspase-9 (48, 49). using multivariate analysis and identified baseline renal disease, heart
failure, DM, and the dose of contrast media administered as predictors
of increased risk of CA-AKI, with pre-existing renal disease being the
4 Clinical significance of most significant predictor of CA-AKI (51).
contrast-associated acute kidney Data regarding the role of DM as a risk factor for CA-AKI remain
injury controversial. In Mehran’s risk score, DM is included as an
independent predictor of CA-AKI. However, few articles have
4.1 Predictors of contrast-associated acute evaluated risk score models among patients with DM undergoing
kidney injury PCI. Hyperglycemia is associated with an increase in oxygen-derived
free radicals, which will lead to vasoconstriction, one of the most
While in the general population the incidence of CA-AKI has important mechanisms involved in the pathophysiology of CA-AKI
been estimated to be <2%, in patients at high risk (patients with (52–54). Yao and co-workers proposed a simple clinical identification
diabetes mellitus [DM], congestive heart failure, chronic renal tool for predicting contrast-induced nephropathy in patients with DM

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undergoing PCI. The score includes four predictive factors and SCr and body weight (5 x kg/SCr) or by multiplying 4 times the eGFR
demonstrated good discrimination and predictive ability for CA-AKI (calculated using the Cockroft-Gault or the Modification in Diet in
and clinical outcomes after PCI (52). The study population was Renal Disease equations) (57). According to recent data, use of
divided into groups according to the risk score: low (5.9% risk of systems specifically designed to reduce the volume of contrast media
CA-AKI), moderate (32.9% risk of CA-AKI), and high (60% risk of administered could further reduce risk of CA-AKI (59).
CA-AKI) risk score (52). Oxidative stress and inflammation have also
been incriminated in CA-AKI occurrence in patients with acute
ST-segment elevation myocardial infarction (36). Malnutrition and 4.3 Clinical impact of contrast-associated
baseline inflammatory status have also been recently proposed as risk acute kidney injury
factors for CA-AKI in patients undergoing PCI (55, 56).
4.3.1 Short term implications of
contrast-associated acute kidney injury
4.2 Impact of contrast media on the risk of Contrast-associated acute kidney injury is associated with
contrast-associated acute kidney injury prolonged hospitalization and increased hospital-related costs, higher
morbidity, and increased short-term mortality (60–66), although
At present, contrast media are commonly divided into high- emergent hemodialysis is rarely needed following administration of
osmolar (osmolality in the range of 1,000 to 2,000 mOsm/kg), iodinated contrast media (67). There are consistent data regarding the
low-osmolar (osmolality in the range of 500 to 1,000 mOsm/kg), and prolongation of hospitalization in patients with CA-AKI, proving that
iso-osmolar (osmolality in the range of 290 to 300 mOsm/kg) contrast the higher the creatinine values, the higher the number of days of
media. The introduction of low- and iso-osmolar contrast media has hospitalization, which will increase at its turn the socio-economic
determined a reduction in the incidence of CA-AKI following intra- burden for the medical systems (68). According to Rihal et al., patients
arterial contrast administration, particularly in high-risk patients (57). who developed CA-AKI after coronary angiography and PCI also had
In 1989, Schwab and co-workers published the results of a markedly higher incidence of in-hospital mortality than those who
randomized controlled trial comparing a high-osmolar (diatrizoate) did not develop CA-AKI (22% vs. 1.4%; p < 0.0001) (68). Another
with a low-osmolar (iopamidol) contrast agent in 443 patients retrospective trial demonstrated that even a small (0.25 mg/dL to
undergoing cardiac catheterization. They were unable to demonstrate 0.5 mg/dL) increase in SCr was associated with an increase of
a difference in the incidence of nephrotoxicity between the two groups in-hospital mortality (69). Meanwhile, in a secondary analysis of the
(8, 58). Two years later, Taliercio and co-workers demonstrated, PRESERVE cohort, underlying chronic kidney disease was associated
however, that the use of low-osmolar contrast medium (iopamidol) with cardiovascular events by day 90 following angiography, but this
was less nephrotoxic than that of high-osmolar contrast medium was not the case for CA-AKI, most of which was stage 1 (70).
(diatrizoate) in high-risk patients undergoing cardiac angiography.
These findings were strengthened by the prospective randomized trial 4.3.2 Long-term implication of
by Rudnick et al., which demonstrated that in patients with DM alone contrast-associated acute kidney injury
or combined with preexisting renal insufficiency undergoing cardiac In addition to short-term complications, CA-AKI is also
angiography, the risk of CA-AKI was significantly lower when low- associated with long-term mortality. Altered hemodynamics is
and iso-osmolar contrast media were used (20). In the Nephrotoxicity associated with increased risk of CA-AKI and higher mortality rates.
in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar However, according to Sun et al., in a group of 696 patients with acute
Non-Ionic Contrast Media (NEPHRIC) study by Aspelin et al. the myocardial infarction and left ventricular ejection fraction >40%,
incidence of CA-AKI was much lower when iodixanol was used rather CA-AKI was an independent predictor of long-term mortality,
than a low-osmolar non-ionic medium in patients with DM and in regardless of hemodynamic abnormalities (71).
patients with preexisting renal insufficiency undergoing angiography
(8). In patients undergoing invasive cardiac procedures, isoosmolal
and low-osmolality agents have shown a significant reduction in the 5 Prophylactic strategies for
risk of CA-AKI compared with high-osmolality agents (57). In that contrast-associated acute kidney
study, iodixanol (an iso-osmolar agent) was shown to have the lowest injury
risk for CA-AKI in patients at high risk (patients with chronic kidney
disease and diabetes) (57). Iodixanol was shown to be superior to 5.1 Periprocedural fluid administration
low-osmolality agents in this subset of patients and in those with renal
dialysis and is thus recommended by The National Kidney Foundation Many randomized clinical trials have studied different
Kidney Disease Outcome Quality Initiative Guidelines (57). pharmacological agents to prevent CA-AKI. However, according to an
The risk of CA-AKI also increases as contrast volume increases. update published in the e-journal of the European Society of
Thus, the recommended contrast doses in patients with chronic Cardiology Council for Cardiology Practice, intravenous fluid volume
kidney disease are <30 mL for diagnostic catheterization and < 100 mL loading with isotonic saline (normal saline 0.9%) is considered the
if a PCI is planned (57). According to the European Society of single most important measure to prevent the occurrence of CA-AKI
Cardiology, there are three simple ways of calculating maximum (57). Volume resuscitation with isotonic saline is particularly
contrast volume to reduce the risk of CA-AKI. For example, < 100 mL important in hypovolemic patients. Questions remain, however,
should be used if significant chronic kidney disease is present and PCI regarding the most adequate fluid and the optimal route of fluid
is planned, or the volume of contrast should be adjusted according to administration – oral or intravenous (72). Trivedi and co-workers

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evaluated 53 patients undergoing cardiac catheterization. The patients to their results, fluid administration alone was the least effective
were randomized into two groups: one group, consisting of 27 preventive strategy for CA-AKI, and in patients with DM none of the
patients, received intravenous normal saline for 24-h (1 mL/kg/h) strategies used to prevent CA-AKI was effective. Compared to saline
beginning 12 h prior to catheterization, and the other group, consisting administration alone, six other strategies were more effective in
of 26 patients, was allowed unrestricted oral fluids. Ten out of the 53 reducing the incidence of CA-AKI in that study: statins,
subjects developed acute renal insufficiency. The incidence of acute N-acetylcysteine, xanthines, sodium bicarbonate, ischemic
renal insufficiency was significantly lower in the group with saline preconditioning, and the combination of N-acetylcysteine plus
administration (1 out of 27) as compared to the group allowed sodium bicarbonate (78).
unrestricted oral fluids (9 out of 26; p = 0.005 between the two groups; The duration of peri-procedural fluid administration also remains
relative risk: 0.11; 95% confidence interval 0.015 to 0.790) (73). a matter of debate. Previously, patients undergoing coronary
A randomized comparison of two fluid regimens (isotonic [0.9%] angiography were admitted for overnight intravenous fluid
vs. hypotonic [0.45%] saline) performed in 1,620 patients undergoing administration, and a 12-h isotonic saline administration protocol was
coronary angioplasty was published by Mueller and co-workers, applied before and after the procedure. Accumulating data indicate,
demonstrating that isotonic saline administration was superior to however, similar results for CA-AKI prevention with 1-h prior and 6-h
hypotonic hydration in the prevention of contrast media-associated post-procedural fluid administration (79, 80). The Optimal timing of
nephropathy. In the group with isotonic saline administration, 5 of hydration to erase contrast-associated nephropathy (OTHER CAN)
685 patients developed CA-AKI (0.7%; 95% confidence interval study also failed to show a significant difference in CA-AKI incidence
0.1–1.4%) vs. 14 of 698 patients in the hypotonic hydration group (2%; in patients with moderate renal impairment when comparing
95% confidence interval 1.0–3.1%; p = 0.04 between groups) (74). In overnight i.v. to bolus fluid administration (p = 0.13) (81).
the POSEIDON trial, left ventricular end-diastolic pressure-guided Administration of 250 mL of sodium bicarbonate before contrast
volume expansion with isotonic saline was more efficient than the administration was also compared with 2,000 mL normal saline
standard (1.5 mL/kg/h) saline administration protocol in preventing administration pre- and post-coronary intervention and was found to
CA-AKI in patients undergoing cardiac catheterization (75). Forced be non-inferior (82). In a more recent study, simplified hydration with
diuresis with dopamine, furosemide, or mannitol have shown no normal saline from 1 h before to 4 h after coronary angiography at a
benefit in the prevention of CA-AKI, and their use has even been rate of 3 mL/kg/h was non-inferior to standard hydration with normal
described to be harmful in different studies (76). saline 12 h before and 12 h after coronary angiography at a rate of
Current guidelines recommend prophylactic isotonic saline 1 mL/kg/h in preventing CA-AKI (83).
administration pre- and post-arterial administration of iodinated
contrast media for prevention of CA-AKI in high-risk patients, based
on expert consensus. The recommended protocol is 1 mL/kg/h 12 h 5.2 Pharmacological agents for prevention
before and continued for 24 h after the procedure or 0.5 mL/kg/h if the of contrast-associated acute kidney injury
left ventricular ejection fraction is less than or equal to 35% and in
heart failure patients with New York Heart Association class >2 Studies on the benefit of natriuretic peptides, aminophylline,
according to the ESC/EACTS Guidelines on Myocardial theophylline, statins, and ascorbic acid on CA-AKI prevention have
Revascularization published in 2018 (53). yielded mixed results (Table 1). Many other pharmacological agents
The A Maastricht Contrast-Induced Nephropathy Guideline have also been studied in order to reduce the risk of CA-AKI. Until
(AMACING) trial demonstrated that no isotonic saline administration now, there are inconsistent data about angiotensin converting enzyme
was non-inferior to prophylactic saline administration among patients inhibitors / angiotensin II receptor blockers, calcium channel blockers,
with chronic kidney disease (eGFR 45–59 mL/min/1.73m2) and theophylline, ascorbic acid, and statins (84–88). Dopamine,
diabetes or at least two other risk factors (anemia, cardiovascular fenoldopam, and atrial natriuretic peptide have shown no benefit, and
disease, ongoing nonsteroidal anti-inflammatory drugs or diuretics forced diuresis with mannitol or furosemide is not indicated and may
usage, age > 75 years), or multiple myeloma or lymphoplasmocytic even be dangerous (88). Prostaglandin E1, also known as alprostadil,
lymphoma with small chain proteinuria receiving intravascular (intra- has been proposed as an effective preventative measure for CA-AKI. A
arterial or intravenous) contrast. A total of 660 patients were enrolled meta-analysis including 19 randomized controlled trials has recently
in that study, with a follow-up period of 35 days; 43% of patients were been published, showing that alprostadil might be associated with a
older than 75 years, 41% were females, 32% were diabetic, and all reduction in the incidence of CA-AKI. Of the 19 trials, 13 reported the
patients received the same low-osmolar contrast medium (iopromide). use of prostaglandin E1 to prevent CA-AKI in patients undergoing
In patients with prophylactic isotonic saline administration, the interventions for coronary heart disease. Even though the results of
incidence of symptomatic heart failure episodes was significantly this meta-analysis showed that the use of prostaglandin E1 might
higher than in the group with no saline administration. There was no be associated with a significant reduction in CA-AKI, the results
difference between the two groups in the incidence of renal failure and require further verification (89).
all-cause mortality. However, due to its inclusion and exclusion N-acetylcysteine has been widely used for the prevention of
criteria, the findings can only be applied to hemodynamically stable CA-AKI in high-risk patients, mainly because of its favorable side
outpatients, with eGFR >30 mL/min/1.73m2, who received a relatively effect profile, low costs, and positive results from some randomized
small amount of contrast media (< 100 mL) (77). clinical studies. Data are available at present from over 40 clinical trials
In 2017, Giacoppo and co-workers published the results of a meta- using N-acetylcysteine for prevention of CA-AKI in high-risk patients,
analysis that evaluated data from 124 trials and 28,240 patients and even though the studies with negative results outnumber those
investigating different strategies used to prevent CA-AKI. According with positive results with a 2:1 ratio, the benefit in the positive studies

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TABLE 1 Impact of pharmacologic strategies on the occurrence of contrast-associated acute kidney injury.

Beneficial May be beneficial Inconsistent data No benefit May be harmful

Isotonic saline Prostaglandin E1 Nicorandil Dopamine Mannitol
Trimetazidine Alprostadil Fenoldopam Furosemide
Alpha-tocopherol Atrial natriuretic peptide
Angiotensin converting enzyme inhibitor / angiotensin II
receptor blockers
Calcium channel blockers
Theophylline
Ascorbic acid
Statins
N-acetylcysteine

was significant. The reason for these contradictory results is not yet preventing CA-AKI, especially in patients receiving high volumes of
known but might be related to the use of different types and volumes intra-arterial low-osmolality contrast agents (92). According to the
of contrast agents, different invasive procedures, and different dosages, American Society of Nephrology, until a well-powered definitive study
timings, and routes of N-acetylcysteine administration, or simply to will be performed, the use of acetylcysteine is probably reasonable
the fact that N-acetylcysteine is not effective in this setting. The first because the drug is safe, well tolerated by patients, and inexpensive.
article about the use of N-acetylcysteine to prevent CA-AKI was The dose recommended is the dose used by Tepel (i.e., 600 mg twice
published by Tepel and co-workers back in 2000. The study included daily, on the day before and the day of exposure to contrast) (93). An
83 patients undergoing CT with a low-osmolality contrast agent update about CA-AKI from the e-journal of the European Society of
(iopromide). Patients were randomly assigned in two groups: a study Cardiology Council for Cardiology Practice states that the use of
group, consisting of 41 patients, who received acetylcysteine (600 mg acetylcysteine is not contraindicated but does not advocate for its use
twice daily) and saline solution (0.45%) intravenously before and after either (57).
contrast administration, and a control group, consisting of 42 patients, A meta-analysis of 124 trials about preventive strategies for CA-AKI
who received placebo and saline. While in the study group only 1 (2%) in patients undergoing percutaneous coronary procedures which
out of the 41 patients developed CA-AKI, in the control group 9 (21%) included N-acetylcysteine, statins, saline, natriuretic peptides,
out of the 42 patients developed CA-AKI (p = 0.01 between groups) peripheral ischemic preconditioning, ascorbic acid, dopaminergic
(90). In contrast to those results, another randomized controlled trial agents, N-acetylcysteine + sodium bicarbonate, and sodium bicarbonate
of N-acetylcysteine to prevent CA-AKI in patients undergoing cardiac alone, was published in May 2017. From all the evaluated measures,
angiography published by Durham and co-workers was unable to statin administration was associated with marked and consistent
prove an additional benefit of acetylcysteine along with fluid reduction in CA-AKI compared with saline, while the other nine
administration. Seventy-nine patients were enrolled in that study, and preventive strategies failed to demonstrate any reduction in the
there was no significant difference between groups at baseline in any incidence of CA-AKI (78). Nicorandil, alprostadil, and alpha-tocopherol
measured parameter. There was no difference between groups in the were also associated with a significant reduction of CA-AKI according
mean duration of angiography, mean volume of contrast, or mean to some authors, while others failed to demonstrate the same beneficial
total intravenous saline administered, and there was also no significant effects (94–96). Association of trimetazidine 35 mg twice daily with
difference between groups in the incidence of CA-AKI. Contrast- saline administration 12 h before and after coronary angiography was
associated acute kidney injury occurred in 9 out of 41 patients (22%) also shown to reduce the incidence of CA-AKI in some studies (97).
in the control group and in 10 out of 38 patients (26.3%) in the group
receiving acetylcysteine, with a non-significant statistical difference
between the two groups (91). The main differences between Tepel’s 5.3 Avoiding potentially nephrotoxic agents
and Durham’s trials were the dosage and timing of acetylcysteine
administration, the route of administration being the same in both The American College of Radiology Guideline recommended
studies. While in Tepel’s trial the patients received acetylcysteine until 2013 temporary discontinuation of metformin in patients
600 mg orally on the day of administration of the contrast agent and undergoing procedures with intravenous administration of contrast
on the day before, on top of intravenous saline administration (90), in media. The American College of Radiology Guideline from 2016
Durham’s study the patients received N-acetylcysteine 1,200 mg orally separates these patients into two groups: the group with eGFR
1 hour prior to and 3 hours following cardiac catheterization (91). ≥30 mL/min/1.73m2, in which there is no need to discontinue
Since the elimination half-time of acetylcysteine is 2.1 h and oral metformin either prior to or following the administration of contrast
administration leads to peak serum levels in approximately 1 hour, the media, and the group with eGFR <30 mL/min/1.73m2, in which
administration in Durham’s trial appears to be more rational from the metformin should be temporarily discontinued at the time of or prior
standpoint of acetylcysteine pharmacokinetics (91). In 2004, Briguori to the procedure, withheld for 48 h subsequent to the procedure, and
and co-workers emphasized for the first time the potential importance reinstituted only after renal function has been re-evaluated and found
of acetylcysteine dosage. Their study indicated that double dose (i.e., to be normal (98).
1,200 mg, orally, twice daily) of N-acetylcysteine seems to be more According to a meta-analysis performed by Wang et al., (99) the
effective than the standard dose (i.e., 600 mg, orally, twice daily) in use of renin-angiotensin-aldosterone system blockers, including

Frontiers in Medicine 06 frontiersin.org

Somkereki et al. 10.3389/fmed.2023.1180861

angiotensin-converting enzyme inhibitors and angiotensin II receptor angioplasty procedures. Moreover, our data indicated that unlike
blockers, could be associated with an increased risk of developing CA-AKI, which was regressive at the 1-month follow-up, subclinical
CA-AKI. However, larger clinical trials, with more strict inclusion kidney injury was still present after 1 month in more than half of
criteria, are needed in order to clarify this hypothesis. Other patients in whom the kidneys were initially affected by the contrast
pharmacological agents, such as certain antibiotics, anticonvulsant, media (104).
antineoplastic, nonsteroidal anti-inflammatory, hypouricemic, and
immunosuppressive agents can also cause acute tubular necrosis,
leading to nephrotoxicity and renal impairment, and should thus 7 Conclusion
be avoided in these patients (100).
Contrast-associated acute kidney injury is relatively frequent after
intra-arterial administration of contrast agents and has a clinical
6 Gaps in knowledge and future impact in the short, medium, and long term. Despite the numerous
research studies carried out, there is still no consensus regarding the predictors
and the most effective prophylactic measures for CA-AKI. Overall,
Despite the accumulating data regarding CA-AKI, there are still data from prospective clinical trials indicate that most prophylactic
many unknown aspects related to this condition, particularly in measures provide negligible impact on CA-AKI. The only exceptions
patients with vascular disease, in whom chronic ischemia and are periprocedural isotonic saline administration and usage of a small
inflammation (101) could further contribute to alterations in kidney volume of contrast media, which have proven their effectiveness in
function. Future studies will have to provide new information CA-AKI prophylaxis in several large clinical trials. Further studies will
regarding the optimal methods of prevention and treatment of this have to confirm or deny the protective role of other agents, such as
condition following intra-arterial administration of contrast media, N-acetylcysteine, nicorandil, alprostadil, statins, ascorbic acid,
which is more and more often encountered in clinical practice. Studies trimetazidine, and others. For intravenous administration of iodinated
will also have to clarify the long-term impact of CA-AKI on kidney contrast media, reviewing patients’ medications, optimizing cardiac
function, to avoid further complications (102). Prophylactic strategies output, and reducing the doses of contrast agent are efficient means to
are insufficiently effective, and this is largely due to the fact that the prevent post-procedural increase in plasma creatinine.
pathophysiology of CA-AKI is not yet sufficiently understood. Further
studies will thus have to elucidate CA-AKI pathophysiology and to
identify the optimal prophylactic strategies. Author contributions
The definition of CA-AKI is currently based only on SCr values,
but there is no unanimously accepted definition for CA-AKI, and SCr CS and RP drafted the manuscript. AS supervised the work. All
might be too coarse to identify subtle, but potentially relevant changes authors contributed to the article and approved the submitted version.
in renal function following administration of contrast media. Finer
markers, such as neutrophil gelatinase-associated lipocalin (NGAL),
cystatin-C, interleukin-18, or beta-2 microglobulin may be needed to Conflict of interest
allow earlier and more accurate detection of CA-AKI (103).
Although CA-AKI is considered largely regressive, this conclusion The authors declare that the research was conducted in the
is based only on creatinine monitoring, which is, as mentioned above, absence of any commercial or financial relationships that could
a very rough marker. The pathophysiology of CA-AKI, which involves be construed as a potential conflict of interest.
tubular necrosis, suggests that it is very unlikely that contrast agents
will have absolutely no impact on the kidney in the long term, at least
in certain high-risk patients. Studies using more sensitive markers will Publisher’s note
have to evaluate this aspect. If a degree of renal damage, even
subclinical, persists, this could be relevant if the patient is subsequently All claims expressed in this article are solely those of the authors
exposed to nephrotoxic agents or repeated administration of contrast and do not necessarily represent those of their affiliated organizations,
media. Indeed, in a recent study, we showed, using repeated NGAL or those of the publisher, the editors and the reviewers. Any product
evaluation, that acute renal injury was much more common than that may be evaluated in this article, or claim that may be made by its
reflected by SCr, affecting almost 18% of patients undergoing manufacturer, is not guaranteed or endorsed by the publisher.

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