Contrast-induced nephropathy in invasive cardiology


Tilman N.U. Perrin, Eric Descombes, Stephane Cook


Contrast-induced nephropathy (CIN) is an acute renal injury due to the renal toxicity of iodinated contrast media. It is classically defined as a relative (≥25%) or absolute (≥0.5 mg/dl; 44 μmol/l) increase in serum creatinine from baseline value. CIN accounts for 10 to 15% of hospital-acquired acute renal failure and may rarely lead to irreversible renal function loss. Following percutaneous coronary intervention, reported incidence of CIN varies between 0 to more than 20%, depending on the prevalence of risk factors and used definition. Nowadays, the diagnosis of CIN relays on serum creatinine monitoring, although it is a late marker of acute kidney injury. Given the expanding number of percutaneous coronary interventions made in outpatient settings and the morbidity and mortality associated with CIN, early detection of CIN is of utmost clinical relevance. Several plasmatic and urinary biomarkers have been studied in that view, with plasmatic cystatine-C and urinary NGAL being the most promising. As no treatment specifically targets CIN once it develops, the main goal for clinicians remains prevention, with hydration status optimisation being the only proven strategy to date.

Here, we will review the recent evidence concerning CIN, its incidence, proposed early diagnostic biomarkers, as well as its treatment and prognostic implication.

Incidence, pathophysiology, diagnosis, prevention and prognosis


Contrast-induced nephropathy (CIN) is a decrease in glomerular filtration rate (GFR) following the injection of iodinated contrast media (CM). It is the third most common cause of in-hospital acute renal failure (12%) after decreased renal perfusion (42%) and post-operative acute renal failure (18%) [1]. Several routine diagnostic examinations are CM-based and may therefore be complicated by CIN. Reported incidence of CIN is 11% following outpatient computed tomography [2], 9% after peripheral angiography [3], and 4% after intravenous pyelography [4]. When the vast majority of CIN cases still develop after standard radiologic examinations, this complication may also be increasingly encountered after percutaneous coronary interventions (PCI) due to growing numbers of procedures, multiple comorbidities in patients undergoing PCI and larger amounts of CM used for complex coronary lesions.

Functionally, CIN is considered an intrinsic acute kidney injury (AKI), usually with conserved diuresis, but in severe cases acute tubular necrosis and even end-stage renal disease may develop. As acute renal failure is associated with disabling morbidity and mortality [5], prevention and early detection of CIN are of utmost clinical relevance [6, 7].


After intravascular CM injection, immediate renal toxicity may occur, and in most cases it remains fortunately free of significant clinical consequences. However, renal function can diminish and serum creatinine (SCr) may increase in the following days. In absence of an universally accepted definition [8], most authors define CIN as a relative (≥25%) or an absolute (≥0.5 mg/dl = 44 μmol/l) increase in SCr from baseline. In case of contrast-induced toxicity, SCr typically rises within the first 24–48 hours after exposition, peaks at 3–5 days and returns near to baseline within 1–3 weeks [9]. However, irreversible renal function losses occur in rare cases. Obviously, in addition to CM exposure, the diagnosis of CIN requires (1.) a temporal relationship between CM exposure and SCr elevation, and (2.) the exclusion of an alternative cause to the acute renal failure.

Epidemiology and prognosis

When considering the largest randomised controlled trials (n ≥250) addressing CIN following PCI during the last 5 years, protocol-defined CIN incidence ranges between <1% to >20%, with an increased incidence after emergency PCI [10–29].

An increase in SCr post-PCI is associated with poorer outcome regardless of initial renal function. In all-comers patients, even a mild increase in SCr (10–24% or 25–35 μmol/l) is linked to increased 30-day mortality (RR of 1.8 [CI 1.3–2.5]) [30] and, if patients suffering from acute myocardial infarction are excluded, a post-PCI SCr elevation is even associated with a higher 1-year mortality than periprocedural myonecrosis [31]. In a retrospective study of 5967 all-comer patients with normal renal functionundergoing PCI, Lindsay and colleagues reported that both the 1-year myocardial infarction rate (24.0% vs 11.6%, p <0.005) and the 1-year mortality rate (9.5% vs 2.7%, p <0.005) were significantly higher in those 208 patients (3.5%) developing significant CIN. This trend was even stronger in patients needing temporary dialysis (1.5% of CIN patients) and remained significant after adjustment for potentially confounding factors (age, diabetes, prior myocardial infarction).[32] Similarly, in 439 patients with chronic renal failure undergoing PCI, Gruberg and colleagues showed that 7% required transitory haemodialysis and 0.9% were discharged on chronic dialysis. Among the 161 (37%) patients developing CIN, there was a 2 to 3-fold increase in in-hospital (15% vs 5%, p = 0.001) and 1-year mortality (35–45% vs 19%, p = 0.001) in comparison to patients without CIN [33].

Finally, in an attempt to stratify the prognosis of patients who already developed CIN after PCI, Harjai and colleagues proposed a 3-level scoring system (grade 0 [SCr <25% and <44 μmol/l], grade 1 [SCr ≥25% and <44 μmol/l] and grade 2 [SCr ≥44 μmol/l]), and suggest that an increasing grade is correlated with a worse long-term outcome after PCI (6-month MACEs [12.4 vs 19.4 vs 28.6%, p = 0.003]; 6-month all-cause mortality [10.2 vs 10.4 vs 40.9%, p <0.0001]; n = 985) [34].

Physiopathology of renal iodine toxicity

CIN is a reduction in renal function consequent to the renal toxicity of intravascular iodine contrast. The physiopathology of CIN is multifactorial and is still incompletely understood. As shown in figure 1, at least five mechanisms could contribute to its pathogenesis:

Figure 1

Scheme of hypothesised pathways contributing to CIN pathogenesis.

1. Direct toxicity of CM to tubular epithelial cells: CM increase tubular osmolarity, as they are freely filtered and not resorbed. Tubular cells exposed to high osmotic load have been showed to suffer from impairment in intracellular transport and energy metabolism. They develop cytopathological changes called "osmotic nephrosis", ranging from tubular cell vacuolisation to necrosis [35].

2. CM-induced alteration in renal microvascular haemodynamics: Trials investigating modifications of blood flow in renal arteries exposed to CM have shown an initial increase in blood flow followed by a sustained reduction.[36] This might be the result of (a) a CM-induced increase in intratubular pressure leading to a decrease in renal blood flow, (b) a direct vasoconstrictor effect of CM on smooth muscle cells, (c) an increased tubuloglomerular feedback due to increased tubular osmolarity, and (d) CM-induced release of several endogenous vasoconstrictors such as adenosine and endothelin.[35] Blood flow reduction unfortunately affects particularly the outer medulla, which is particularly susceptible to ischaemia due to its high metabolic activity [36]. Ischaemia is obviously worsened by the impaired microvascular self-regulation found in diabetic and hypertensive patients.

3. Reperfusion and reactive oxygen species toxicity: Reactive oxygen species released by the subsequent reperfusion also contribute to renal damages. As the antioxidant reserve is decreased in elderly and the baseline oxidative stress is increased with CKD or diabetes, theses patients are especially vulnerable [36].

4. Toxicity due to inflammation: Similarly to other tissues, renal parenchymal damages may be worsened by CM-mediated complement cascade activation and inflammatory cytokine release [36].

5. Toxicity due to tubular obstruction: Precipitation of intratubular proteins induced by CM has been proposed to contribute to CIN. However, CM failed to precipitate Tamm-Horsfall protein in vitro and no evidence support this theory in clinical trials [35, 36]. Similarly, although some trials report massive precipitation of Bence-Jones protein in myeloma patients, the risk is decreased with new generation CM and hydration [35, 37, 38].

Therefore, the osmolarity as well as the viscosity and ionic properties of CM are involved in nephrotoxicity. It should finally be stressed that CIN remains an exclusion diagnosis with only spare histopathological findings. Therefore, a nontrivial proportion of "CIN"-labelled AKI might be of different aetiology, such as cholesterol or thromboembolic emboli, peri-interventional- hypotension, or interstitial nephritis.

Risk factors and risk assessment

Risk factors for CIN can be divided into patient-related or intrinsic risk factors, and procedure-related orextrinsic risk factors. Most prevalentintrinsic risk factors are pre-existence of renal failure, concomitant hypotension, presence of congestive heart failure, older age, anaemia, diabetes mellitus, and concomitant use of nephrotoxic drugs [6, 39, 40]. On the other hand, extrinsic risk factors comprise the total amount and type of CM used, its route of administration (arterial versus venous) and the time period between two (or iterative) CM expositions [41, 42].

To help clinicians to minimise or stratify the risk of CIN, several score have been proposed. Mehran et al. compiled a "simple risk score" illustrated in table 1 to predict CIN occurrence after PCI, with weighted coefficients for independent predictors of CIN. Risk 1 category (≤5 points) is associated with a 7.5% risk of CIN and 0.04% risk of dialysis; risk 2 category (6 to 10 points) with risks of 14% and 0.12%; risk 3 category (11 to 16 points) with risks of 26.1% and 1.09%; and risk 4 category (≥16 points) with risks of 57.3% and 12.6% respectively [40]. As it is known that CM volume is an important factor for renal toxicity, other authors tried to determine a volume to risk correlation, particularly in high-risk patients. In patients with CKD, Brown and colleagues proposed the calculation of a "maximal allowable contrast dose" (MACD; contrast volume limit [ml = 5 × body weight {kg}]/[88.4 × SCr {μmol/l}]). Their results showed that patients receiving contrast volumes exceeding the MACD were more likely to develop CIN or to need dialysis (propensity-matched OR if exceeding the MACD 1.75 [95%CI 1.49–2.07, p <0.001] and 3.13 [1.73–5.65, p <0.001] respectively) [43]. In patients with ST-elevation myocardial infarction, Nymann et al. proved that an adjustment of contrast amount to the eGFR allows a reduction of the incidence of CIN [44].

Table 1: Independent risk factors for Contrast-Induced Nephropathy (CIN) and calculation of Mehran simple risk-score.
CIN risk factors Mehran simple risk-score definition [40] Integer score
Decreased renal perfusion Systolic blood pressure <80 mm Hg for at least 1 h requiring inotropic support with medications or intra-aortic balloon pump within 24 h of the procedure 5
Intra-aortic balloon pump within 24 h of the procedure 5
Congestive heart failure class III or IV by New York Heart association classification and/or pulmonary oedema 5
Older age Age >75 years 4
Anaemia Baseline haematocrit value <39% for men and <36% for women 3
Diabetes Present or not 3
Contrast media volume Absolute amount 1 for each 100 ml
Impaired baseline renal function Baseline serum creatinine >1.5 mg/dl    or Baseline eGFR <60 ml/min 4 2 for 40–60 ml/min 4 for 20–40 ml/min 6 for <20 ml/min

Early diagnosis

CIN induces the same clinical and laboratory abnormalities than other causes of acute renal failure. Most patients developing CIN are asymptomatic, but in severe cases they become oliguric or anuric. Metabolic acidosis and hyperkalaemia are the most frequent laboratory findings, with potential fatal consequences. Microscopic urine examination may show renal tubular cell casts and/or debrits as well as urate and/or oxalate crystals. However, these findings are not specific for CIN [45]. A persistent nephrogram on radiograph or CT-scan has been studied for detection of CIN [46], but its clinical relevance has not been validated. Therefore, the diagnosis of acute kidney injury (AKI) relies on the monitoring of functional markers and/or biomarkers in serum and urine. To improve patient management, an ideal marker should be accurate and proportional to renal injury, and have an early kinetic after renal damage. Moreover it should help to differentiate acute structural damage (AKI) from functional impairment (prerenal azotaemia) or chronic kidney disease (CKD). This is even more important as intrinsic acute renal failure is grieved with an increased risk of in-hospital mortality and/or need for dialysis [47].

In daily practice, changes in SCr are used to estimate acute modifications in renal function and SCr monitoring remains the cornerstone for diagnosis of CIN. Unfortunately creatinine is a late and insensitive indicator of acute changes in renal function as there is a 24–48 hours delay between renal insult and SCr changes [48].

Because of this pitfall and since an early diagnosis may decrease morbidity and improve patient survival [49], accurate biomarkers are eagerly awaited for the early detection of tubular dysfunction/lesion. In invasive cardiology, early detection of CIN could allow a pre-discharge selection of outpatients needing hospitalisation for closer renal, metabolic and volaemic control. Recently, several promising biomarkers of tubular insult have been under investigation and the following plasmatic or urinary ones are of special interest. Table 2 summarises some of their characteristics relevant for the diagnosis of CIN.

Table 2: Relevant characteristics of biomarkers for the diagnosis of CIN after PCI.
Biomarker Molecular weight (kDa) Site of lesion Significant increase in CIN-patients AUC for CIN-prediction (cut-off)
pNGAL 25 Distal and collector tubules 2 hours [111] 0.92 (≥100 ng/ml at 2 hours) [112]
pCysC 13 Glomeruli and proximal tubule 8 hours [111] 0.92 (≥10% increase at 24 hours) [62]
uNGAL 25 Distal and collector tubule 2 hours [111] 0.92 (≥100 ng/ml at 2 hours) [112]
uIL-18 18 Distal tubule 8 hours [111] 0.75 (≥25% increase at 24 hours) [66]
uL-FABP 14 Proximal tubule 24 hours [111] NA
uβNAG 130 Proximal tubule 24 hours [73] NA
βNAG = n-acetyl-β-glucosaminidase; CysC = cystatin C; IL-18 = interleukin 18; L-FABP = liver fatty acid-binding protein; NGAL = neutrophil gelatinase-associated lipocalin; p = plasma; u = urinary; NA = not available.

Potential plasmatic biomarkers

Plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL or Lipocalin-2 [LCN2]).

NGAL is of particular interest in this setting and has been considered as the "renal troponin" [50]. NGAL is a small protein of the lipocalin superfamily that was first isolated in 1993 from the supernatant of activated human neutrophils [7, 51]. It is also expressed and secreted by immune cells, hepatocytes and renal tubular cells in various pathologic states. Beside its bacteriostatic effects by transmembranous iron shuttling, NGAL acts as a growth and differentiation factor in multiple cell types, including renal epithelia, where it limits apoptosis and contributes to maintain the tubular structure [52]. NGAL is massively and rapidly upregulated in kidneys following an ischemic or nephrotoxic injury, and is thought to participate in limiting parenchymal damage [52, 53]. It is primarily synthesised in the ascending loop of Henle and in collecting ducts but has also nephroprotective effects in the proximal tubule [52]. NGAL – as marker of AKI – is increasingly studied since its serum and urinary levels increase well before the increase of SCr [54] and have a better sensitivity than SCr alone for acute kidney injury detection [48]. More specifically, plasma and urine NGAL levels are also known to be powerful independent predictors of CIN, in-hospital outcomes, and risk for dialysis or death [7, 48, 55]. However, despite being considered as a promising biomarker for early diagnosis of acute tubular necrosis by several authors [56], plasma NGAL (pNGAL) is less specific than its urinary counterpart. In fact, pNGAL is already increased in patients with CKD [53] or systemic illnesses [52], and increases 6-times less than urinary NGAL in case of renal injury [52].

Plasma cystatine C (CysC)

CysC is produced at a constant rate by all nucleated cells. Under normal circumstances, it is freely filtered by the glomeruli and totally reabsorbed in the proximal tubule. In the absence of tubular dysfunction, its serum level reflects glomerular filtration and can be used as a functional marker for acute and chronic changes in GFR [57]. In intensive care settings, plasma cystatine C (pCysC) was able to detect AKI earlier and was more sensitive than SCr in detecting minor glomerular filtration rate reductions [58, 59]. This early increase of pCysC following a renal insult is also reported in trials addressing renal CM toxicity [60, 61]. In CKD patients, a >10% increase in pCysC 24 hours after PCI predicts CIN (as defined by a >0.3 mg/dL increase in SCr) with a sensitivity of 100% and a specificity of 86% (n = 410) [62]. Unfortunately, pCysC levels may also be influenced by several non-renal factors including corticosteroids administration, thyroid dysfunction, systemic inflammation, neoplasia, age and eventually muscular mass [57].

Potential urinary biomarkers

Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL or Lipocalin-2 [LCN2])

Urinary NGAL (uNGAL) is increased in case of AKI and remains low in patients with prerenal azotaemia or normal renal function [49, 63]. To note, less than 0.2% of tagged NGAL injected in the circulation appears in urine during the first hour [64]. uNGAL is of interest for the early diagnosis of CIN, as it increases already 2 hours after tubular injury [54]. Haase M. et al. analysed data from 191 patients in 3 studies and found that when uNGAL is measured within 6 hours after CM exposition, the sensitivity is 0.78, the specificity is 0.96, and the area under the receiver operating characteristic (ROC) curve is 0.89 for the diagnosis of CIN (cut-off for uNGAL: 100 ng/ml) [56].

Urinary interleukin-18 (IL-18, interferon-gamma-inducing factor)

In 2004, Parikh and colleagues demonstrated that patients with acute tubular necrosis had significantly greater median urinary IL-18 (uIL-18) concentrations than those with other renal conditions (normal renal function, pre-renal azotaemia, urinary tract infection, and chronic renal insufficiency). Therefore, they proposed it as a specific biomarker of proximal acute tubular necrosis [65]. More recently, the same group showed in patients undergoing cardiac surgery that increased uIL-18 levels were associated with AKI, longer hospital stay and higher risk for dialysis or death (cut-off: 60 pg/ml) [55]. On the other hand, 24 hours after PCI, uIL-18 levels are significantly increased in patients developing CIN compared to controls, reducing the diagnostic delay by 24 hours [66].

Urinary liver-type fatty acid-binding protein (L-FABP)

L-FABP is a cytoplasmic protein that facilitates the long-chain fatty acid transport from the plasma membrane to beta-oxidation sites and reduces the oxidative stress by binding of fatty acid oxidation products [67]. Its urinary levels are significantly elevated in patients with AKI [67, 68]. This biomarker is of particular interest as a sensitive and predictive early biomarker of AKI, but it might have a low specificity due to interferences with different systemic processes regularly found in critically-ill patients [67]. Interestingly, according to the study by Nakamura and colleagues (n = 66), even pre-PCI urinary L-FABP levels predict CIN [69].

Urinary kidney injury molecule-1 (KIM-1)

KIM-1 is a transmembranous protein normally not detectable in urine, but expressed at very high levels in proximal tubular epithelial cells soon after an ischemic or toxic injury [70]. Han and colleagues report that urinary KIM-1 is able to rapidly detect AKI [70], with higher levels for "pure" ischaemic insult than for other types of acute renal failure [71]. Since the pathogenesis of CIN is multifactorial, the use of this biomarker seems limited in this particular context [71, 72].

Urinary N-Acetyl-β-glucosaminidase (β-NAG)

β-NAG is a lysosomal enzyme found mainly in proximal tubular cells that is a sensitive marker of proximal tubular injury from various aetiologies [70]. Compared with SCr, urinary β-NAG peaks earlier [73]. However, its discrimative power seems insufficient to allow clinical use for AKI diagnosis [63].

Prevention and therapy of CIN

Patients developing CIN should receive similar supportive care as every patient with acute renal failure: monitoring as well as correction of serum electrolytes abnormalities and metabolic acidosis, and tight control of fluid balance. Therefore, as no treatment specifically targets CIN, the main goal for clinicians remains prevention and support. Table 3 summarises the main preventive guidelines. First of all, some general considerations should be kept in mind: the indicationfor contrast-based procedures should always be pondered carefully and outweighed against the potential risk of CIN. Then, whenever possible, concomitant nephrotoxic drugs such as non-steroidal anti-inflammatory drug, nephrotoxic antibiotics or chemotherapeutic agents and/or iterative expositionto CM should be avoided.

Table 3: Prevention of CIN (based on references [39, 113, 114]).
Clinicians should:
1. Be aware that CIN is a potentially serious complication.
2. Ponder the risk and benefit of any CM-based exam.
3. Optimise hydration status with oral and intravenous fluids.
4. Stop concomitant nephrotoxic medications (diuretics, NSAIDs, chemotherapy).
5. Use only new generation CM.
6. Use the lowest amount of CM.
7. Monitor SCr at 24–72 hours after CM-exposition, at least in high-risk patients.
8. Try keeping 1 week interval between 2 CM-based exams.

Contrast media (CM)

The type and amount of contrast mediumimpact on the risk of CIN. Briefly, all iodine CM consist in ≥1 benzene ring linked to three iodine atoms. Three generations have been described according to the osmolality. The first-generation contrast agents (iothalamate, diatrizoate, metrizoate) are composed of iodinated ionic monomers and are considered "ionic high osmolar" (about 2000 mOsm/l), as an ionizing carboxyl group dissociates in solution. The second-generation contrast agents (iohexol, ioversol, iopromide, iomeprol, iopamidol), called "low-osmolar", are nonionic monomers with intermediate osmolality. Finally, the last generation of contrast agents (iodixanol) are dimers of two benzene rings and are virtually "iso-osmolar" in comparison to plasma (290 mOsm/l) [8, 74]. It is considered that osmolality per se contributes to the reported difference in CIN incidence, with lessened osmotic load and tubular work for last-generation CM [75, 76]. In a meta-analysis Barrett et al. concluded that the incidence of CIN is significantly reduced by use of "low-osmolar" compared to "ionic high-osmolar" CM only among patients with pre-existing CKD [77]. In addition, From et al. report that "iso-osmolar" agents shows a significant benefit when compared to iohexol but not in comparison to other "low-osmolar" CM [78]. However, "high-osmolar ionic" CM have progressively been replaced by "low or iso-osmolar" agents in current routine practice.

As discussed previously, the volume of the CM used also contributes to the risk of renal toxicity. Therefore, in high-risk patients and even more in patients with pre-existing renal failure or diabetes, the CM volume should be limited as much as possible and, in example, levography done only if echocardiographic measurement is not possible.


Hydration is the best-proven way to prevent CIN [13, 79]. Isotonic normal saline (NaCl 0.9%) is routinely used. The use of sodium bicarbonate (NaBic 1.4% or NaHCO3 154 to 166 mEq/l) is also of interest since it reduces the production of free radicals by decreasing tubular acidity and scavenges the oxidant pernitrite [80]. Individual results from trials comparing normal saline (NaCl 0.9%) to sodium bicarbonate (154 mEq/l in dextrose 5%) gave contradictory results [12, 13, 17, 19, 21, 22], but a recent meta-analysis by Kunadian et al. favours the use of sodium bicarbonate [80].

Hydration is usually performed using a peripheral line, with a classical infusion rate of 1 ml/kg/h during 12 hours before and after PCI. To note, the pre-PCI hydration can be replaced by a rapid one-hour perfusion (3 ml/kg) in emergency situations. Using a combination of oral volume supplementation and intravenous isotonic or half-isotonic infusion at a rate of 1 ml/kg/h between 8 a.m. the day of procedure and 8 a.m. the following morning, Mueller and colleagues reported a CIN-incidence (≥0.5 mg/dl increase in SCr within 48 hours of procedure) as low as 1.4% after PCI in a Swiss cohort of 425 consecutive patients (mean baseline eGFR: 89 ml/min). Even in the subgroup of patients with eGFR ≤60 ml/min (n = 43), the incidence of CIN remained low (4.7%), with no patient requiring dialysis [81].

To maintain an optimal hydration status and a high urinary output (≥300 ml/h), while minimising the risk of pulmonary edema, Briguori et al. proposed the use of the RenalGuard System, which matches urinary output with intravenous hydration and furosemide administration. The nephro-protective effect of this system may be due to an increased urine output diluting the tubular CM, and to the blockade of the Na-K-2Cl co-transporter, decreasing the oxygen consumption of tubular cells. Briguori et al. showed that the use of the RenalGuard System with normal saline hydration in high-risk patients (eGFR ≤30 ml/min and/or Mehran risk score ≥11 points) significantly decreases the incidence of CIN (2.7%), when compared to usual hydration with sodium bicarbonate (13%; p = 0.001) [82]. Although the hydration solution was different in both groups, the nephron-protective effect of the RenalGuard system was already shown with use of normal saline in both control and RenalGuard groups by Bartorelli et al. [83]. Finally it is worth noting that patients treated with the RenalGuard System had no increased risk of periprocedural pulmonary edema or electrolyte imbalance [82]. However, , even if RenalGard gated hydration seems to be a promising tool for prevention of CIN, one should not forget the difficulty of its use in emergency settings and the risk of urinary tract infection brought by ureteral catheterisation.

Nephroprotective drugs

N-acetylcysteine (NAC)

The prophylactic use of NAC is under debate. Being a precursor for glutathione synthesis, NAC has the potential to diminish oxidative stress by directly scavenging superoxide radicals and increasing intracellular glutathione. In addition, NAC improves renal haemodynamics by combining and stabilising bioavailable nitric oxide [10, 84, 85]. However, since the first positive study addressing NAC for the prophylaxis of CIN in 2000 [86], several trials have given discordant results [10, 27, 87, 88]. The recently published Randomised Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT) addressing 2308 patients with at least 1 risk factor for CIN undergoing coronary or peripheral angiography fails to show a beneficial effect of high-dose NAC on CIN-incidence (12.7%) or other composite outcomes. Even subgroups analysis, for example in patients with pre-existing kidney disease or diabetes, does not show a significant benefit of NAC [10].


Beside their hypolipaemic role, statins improve endothelial function and decrease oxidative stress and inflammation [89]. In a review by Zhang and colleagues, chronic statin treatment (≥1 week) reduces the risk of CIN (p <0.05), whereas a short-term high-dose therapy does not [89]. These results have to be interpreted cautiously due to heterogeneity in statin regimens (drug used, doses and duration of therapy) and in procedural characteristics [90–92].

Vasoactive drugs

As contrast administration elicits an afferent arteriolar vasoconstriction that decreases renal blood flow and glomerular filtration rate, several vasoactive treatments have been studied in small collectives with some encouraging results.

Prostaglandin E1

Prostaglandin E1 (PGE1) is a well-known vasodilator that improves renal blood flow. A 20 ng/kg/min PGE1 infusion has a significant protective effect on post-PCI SCr elevation [93, 94], but higher infusion rates are not associated with increased benefits, probably due to the associated decrease in systemic blood pressure [93].


"Low-dose" or "renal-dose" dopamine (0.5–2.5 μg/kg/min) has also been proposed for CIN prevention as it (1.) increases renal plasma flow and glomerular filtration rate via a dilatory effect on renal vasculature, (2.) improves tubular function and (3.) increases cardiac output [95]. However, neither Gare et al. nor Abizaid et al. show any significant beneficial effect of dopamine for CIN-incidence reduction in CKD patients [95, 96].

Fenoldopam mesylate

Fenoldopam mesylate is a specific dopamine-1 receptor agonist that selectively increases both the renal cortical and outer medullary blood flow while decreasing systemic vascular resistance. Unfortunately it also fails to reduce CIN-incidence in CKD patients [97, 98]. To note, some dedicated catheters, such as the Benephit system, have been designed in order to deliver per-procedural protective treatments directly into the kidney arteries. In a retrospective serie of 285 patients, Weisz et al. reported a 71% decreases in CIN incidence with local fenoldopam therapy (0.05–0.8 µg/kg/min) [99].


Adenosine is a vasoactive mediator which levels increase secondary to oxygen consumption or decreased intracellular ATP and contributes to afferent arteriolar vasoconstriction in kidneys following CM-exposure. The clinical benefit of the competitive adenosine antagonist theophylline is debated. Erley and colleagues reported that theophylline administration prevents a post-PCI fall in GFR measured by inuline clearance during the 4 post-procedural hours [100]. However other groups found no significant protective effect of theophylline on renal function [88, 96, 100, 101].

Calcium channel inhibitors

It has been shown that calcium channel inhibitors antagonise pre-glomerular vasoconstriction in dogs [102] and prevent increases in intracellular calcium concentrations in anoxic animal cell culture [103]. However, their short-term use for CIN prevention yielded various results: only one trial showed benefit of initiating a calcium inhibitor treatment shortly before PCI [104], while the others did not [105, 106].

Angiotensin-converting enzyme inhibitors

Angiotensin-converting enzyme inhibitors (ACEIs) play an important role in treating heart disease and some of its risk factors. Angiotensine-II acts on renal micovascular haemodynamic homeostasis by inducing efferent arteriolar vasoconstriction. As ACEI are known for decreasing GFR, several groups have addressed their role in CIN. In a recent review, Patel and colleagues found conflicting results of the short- and long-term ACEI use on CIN-incidence, even in high-risk patients [107]. On the other hand, pre-procedural withholding of long-term (≥1 month) ACEI or ARB therapy in patients with stage III-IV CKD undergoing elective PCA has shown no beneficial effect on SCr levels measured one day after contrast medium exposure [24].


In view of these elements, several unresolved questions remain concerning the management of CIN. First of all, CIN is usually an asymptomatic complication, which diagnosis relies on SCr increase following CM exposition, but without clear-cut diagnostic criteria. Second, the physiopathology of CIN is multifactorial and still incompletely understood, making it hard to improve diagnostic and therapeutic tools. Third, the comparison of CIN-incidence between trials is matter of caution, as CIN definitions and prevalence of risk factors are often quite different among the studies. However, once the contributing variables are taken into account, it appears that in the era of modern contrast media, CIN remains, fortunately, reversible in most cases. Even in patients with risk factors such as CKD or diabetes, the risk of dialysis-dependent end-stage renal disease due to CIN remains low (<1%). It is important to note that although gadolinium has been proposed as CM for angiography in high-risk patients for CIN, its use is grieved with the risk of development of nephrogenic systemic fibrosis (NSF) in CKD patients, especially those with eGFR ≤30 ml/min or dialysis-dependent [108]. In CKD patients, the incidence of NSF could even exceed the risk of CIN, as some series show the incidence to be as high as 5% [109, 110]. As there is no available treatment to stop the chronic progressive course of the disease resulting in variable organ damage (skin, joints, lungs, kidneys…) and leading to death, the European Society of Urogenital Radiology does not recommend the use of gadolinium to avoid the nephrotoxicity associated with iodinated CM [108].

As no treatment specifically targets CIN once it develops, the main goal for clinicians remains prevention. They can use several scores to carefully estimate the risk of CIN before referring a patient for elective PCI, particularly for high-risk patients and/or procedures. Once decision for CM-injection is made, clinicians have only 2 proven ways to reduce the incidence of CIN: (1.) optimal hydration – with some data favouring the use of sodium bicarbonate over normal saline – and (2.) the use of lowest amount of CM. To date, N-acetylcysteine, as well as all other drugs, failed to confirm any beneficial preventive effect in large-scale randomised studies.

In current practice, the standard method for renal function monitoring remains SCr, although it is late and insensitive. As the number of PCI made on outpatient basis grows, there is an urgent need for tools allowing an early and accurate detection of CIN. In this regard urinary NGAL and plasma cystatin C seem to be the most promising. Permitting closer renal function monitoring after CM exposure, these early biomarkers will also help developing new preventive and/or therapeutic methods for the management of CIN. However, in view of the very rare long-term consequences of CIN after PCI, and as long as no specific treatment targets CIN, we recommend the use of theses costly biomarkers only for selected patients.


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Funding / potential competing interests: This work was funded by the "Schweizerische Herzstiftung" (Bern, Switzerland) and the "Fondation Lausannoise pour la Recherche en Hypertension" (Lausanne, Switzerland).