The main findings of the present study (Fig. 1) were that (1) clinically overt CIN was rather rare, affecting 5.6% of the study population, (2) its occurrence was only affected by the baseline kidney function and the volume of contrast administered, and that (3) it was entirely regressive at the 1-month follow-up. Meanwhile, (4) subclinical kidney injury was considerably more common, affecting almost 18% of the study patients at the 48-hours follow-up, (5) was independently predicted only by the baseline kidney function, and (6) was persistent at the 1-month follow-up in more than 50% of the initially affected patients.
In the era of modern iodinated contrast media, clinically overt contrast-induced nephropathy is rather rare and entirely regressive after 1 month
With the progressive increase in the prevalence of atherosclerotic disease, the rate of angioplasty procedures is on a continuous rise worldwide.1 One of the most feared complications of such procedures is CIN. However, our data indicate that in the era of modern iodinated contrast agents, the incidence of CIN is rather low, affecting 5.6% of the study patients.
Several large-scale studies have even questioned the concept of CIN and the relationship between contrast media administration and acute kidney injury.9 Indeed, studies have shown similar rates of acute kidney injury in patients undergoing computed tomography scanning with and without intravenous administration of contrast media, and suggested that the risk of CIN may essentially be nonexistent in patients with normal baseline renal function.10 The relationship between contrast media administration and CIN appears to be, however, rather solid, when the contrast agent is administered intraarterially.11 Several hypotheses have been proposed to explain this discordance. Patients that undergo angiography procedures have more severe arterial disease than those who require intravenous administration of contrast media and are therefore at higher risk of acute kidney injury. Manipulation of the aorta could lead to dislodgement of cholesterol crystals, atherosclerotic plaque fragments, or thrombi, and to renal microembolization and could therefore promote kidney injury during intraarterial procedures.12 Moreover, intraarterial administration of contrast media, particularly in the abdominal aorta, above the level of the renal arteries, is associated with higher contrast concentrations in the renal vasculature.11 Together, these data suggest that the risk of CIN is therefore not directly linked to the route of contrast administration, but rather to the patients’ comorbid conditions, the characteristics of the procedure, and the volumes of contrast media administered.
Indeed, several risk factors have been associated with an increased risk of CIN. Among them, preexisting renal disease has been proposed as the most relevant risk factor for CIN. A linear relationship has been shown to exist between baseline serum creatinine and the risk of CIN, with an incidence of contrast-induced acute kidney injury of up to 62% in patients with preexisting chronic kidney disease and serum creatinine ≥ 2 mg/dL.13 Due to the major impact that diabetes mellitus exhibits on the renal and cardiovascular systems,14 this condition was also seen as a major non-modifiable risk factor for CIN.15 Several other parameters, such as advanced age,15 female gender,16 history of congestive heart failure,17 anemia,18 hyperuricemia,19 hypercholesterolemia,13 and the use of nephrotoxic drugs,20 have also been linked to an increased risk of CIN in various clinical studies, although their impact remains highly controversial.11 Multiple sources have also reported a dose-dependent relationship between the volume of contrast administered and the risk of CIN.21 In the present study, only basal renal function, as reflected by the baseline serum creatinine, and an increased volume of contrast administered were independently associated with an increased risk of CIN. For other parameters that were associated with CIN in univariate analysis (i.e., left ventricular ejection fraction, ongoing diuretic treatment, and anemia), the association was lost in the multiple logistic regression analysis.
In accordance with previous studies,22 clinically overt CIN was a transient, reversible event in the present study, and was associated with more prolonged hospital stay.
Subclinical kidney injury is rather common after administration of iodinated contrast agents and persists in more than half of patients at 1-month follow-up
Clinically overt renal dysfunction related to contrast administration therefore appears to be entirely regressive in one month. However, mechanistically, it seems unlikely that contrast-induced renal injury could be fully devoid of any long-term impact. The pathophysiology of CIN remains incompletely elucidated at this point. The most accepted theory involves contrast-induced vasoconstriction, leading to renal hypoxia,23 increased production of oxygen-free radicals, and subsequently to renal injury.24 Other factors, including a rise in blood viscosity, changes induced by the contrast media on the renal blood supply,25 ischemia-reperfusion injury, release of angiotensin II, dopamine, and vasopressin, and a direct cytotoxic effect of contrast agents on the renal tubular cells have also been shown to contribute to the deleterious effects exhibited by contrast media on the kidneys.15 These mechanisms strongly suggest that contrast agents may not be entirely innocuous over the long term and that, similar to other clinical settings,26,27 measurement of biomarkers more sensitive than serum creatinine may be required to detect subtle renal changes in this setting. The diagnosis of CIN relies at present on measurement of serum creatinine. This approach has, however, several limitations, including the delayed and non-linear response to renal impairment of serum creatinine and its sensitivity to numerous non-renal factors, such as age, gender, diet, medication, muscle mass, hydration status, and volume of intravascular fluid.28 Moreover, creatinine is a marker of glomerular filtration, and not a marker of tubular damage, which is the injury typical for CIN. Meanwhile, NGAL has been proposed as one of the most promising biomarkers of renal structural injury.29 Unlike serum creatinine, NGAL is specifically produced by the distal nephron and rapidly released into the bloodstream, which makes NGAL a much more sensitive marker of kidney injury.30 Studies have also pointed NGAL as an earlier marker of kidney injury than serum creatinine in various clinical settings, including in patients with normal renal function, with septic shock, or post-cardiac surgery,4,31,32 causing NGAL to be seen as a ‘kidney troponin’.33 Based on these data, the Acute Dialysis Quality Initiative proposed a combination of kidney functional (i.e., serum creatinine) and structural (e.g., NGAL) damage markers to stratify the risk of acute kidney damage.30
In line with these data, in the present study, repeated NGAL evaluation demonstrated that acute renal injury was much more common than reflected by serum creatinine, affecting almost 18% of the study patients. Moreover, our data indicate that unlike CIN, which was regressive at the 1-month follow-up, subclinical kidney injury was still present after 1 month in more than half of patients in whom the kidneys were initially affected by the contrast media. In addition, similarly to what was seen for clinically overt CIN, the occurrence of subclinical kidney injury was also independently associated in the present study with the basal renal function, as reflected by the baseline serum creatinine. Moreover, the risk of developing subclinical kidney injury following contrast administration was related to a lower degree of baseline kidney dysfunction than the risk of clinically overt CIN.
Clinical implications
In line with previous studies, our data indicate that the occurrence of clinically overt CIN is favored not only by non-modifiable (baseline kidney function), but also by modifiable factors – the volume of contrast administered. Technological innovations and technical adjustments, such as lowering the X-ray voltage or using the latest generation imaging platforms could thus be of use for CIN prevention by reducing the amount of contrast media that is being administered.34 However, such approaches may not be efficient for reducing the risk of contrast-induced subclinical kidney injury. Unlike CIN, contrast-induced subclinical kidney injury was not affected by contrast volume in the present study, but only by a non-modifiable factor – the baseline kidney function. Oral and intravenous hydration, and pharmacologic strategies such as methylxanthines, statins, ascorbic acid, N-acetyl cysteine, or dihydropyridine calcium channel blockers have all been proposed as potentially efficient interventions for the prevention of CIN.15 None of the patients included in the present study was receiving methylxanthines, ascorbic acid, or N-acetyl cysteine, and almost all patients (i.e., 98.8%) were undergoing statin therapy. Thus, the potential impact of such strategies on the risk of CIN could not be evaluated in the present study. Dihydropyridine calcium channel blockers did not appear to affect, however, the risk of CIN or of subclinical kidney injury in the present study.
Strengths and limitations
The effects of contrast media at the renal level were assessed in a prospective study, using both functional (i.e., serum creatinine) and structural (i.e., NGAL) renal damage markers, providing a comprehensive view on contrast-induced kidney injury. In addition, to the best of our knowledge, this is the first study to evaluate the long-term effects of contrast media on subclinical kidney injury, as reflected by the levels of NGAL. These analyses demonstrated that subclinical kidney injury was still present after 1 month in more than half of patients in whom the kidneys were initially affected by the contrast media, suggesting that these patients may be at increased risk for further, potentially clinically significant renal impairment, particularly if exposed to nephrotoxic agents or repeated administration of contrast media. Studies with longer-term follow-up of renal function, including after repeated administration of contrast agents, will have to clarify this issue. The long-term impact of the renal changes identified in the present study on ‘hard’ clinical endpoints (e.g., dialysis, death) also remains to be clarified. The prospective nature of the present study allowed us to evaluate the renal impact of a large series of parameters associated with contrast-induced kidney injury in previous studies. Yet, only baseline kidney function and the volume of contrast administered were identified as independent predictors of CIN, whereas subclinical contrast-induced kidney injury was only independently predicted by the baseline serum creatinine. The relatively low number of patients included in the present study may have affected our ability to detect other potential predictors of contrast-induced acute kidney injury. However, with the exception of baseline kidney function, which has been related to CIN in the vast majority of previous studies, the role of the other tested factors is highly controversial in the literature.11 Although NGAL is clearly a valuable biomarker of contrast-induced subclinical kidney injury, one should be aware that NGAL is not specific for this condition and that low levels of NGAL can also originate from other sources, such as neutrophils, cardiomyocytes, prostatic cells, or respiratory and gastrointestinal epithelia.4 Finally, the impact of contrast media on the kidneys was evaluated in the present study using serum creatinine and NGAL. Evaluation of additional parameters, such as urinary NGAL, molecule-1, or cystatin C would also have been of interest to fully elucidate the renal effects of contrast media.