Contrast-induced nephropathy (CIN) is an increasingly common cause of iatrogenic acute kidney injury (AKI) associated with increased health-care resource utilization by extending the hospital stay, increasing the short- and long-term mortality, and accelerated progression of underlying chronic kidney disease (CKD).1,2 It is an important reversible and transient cause of hospital-acquired renal failure, the incidence of which varies between 0% and 24% depending on patient’s risk factors, the amount and type of agent administered, and the types of radiological procedures performed.3 In simple terms, CIN is defined as impairment of renal function (measured as either a 25% increase in serum creatinine from baseline or a 0.5 mg/dL increase in absolute serum creatinine value) within 48–72 h of administration of contrast material.4,5 CIN is potentially preventable; high-risk patients can often be identified ahead of time, and most procedures requiring contrast material are performed on a nonemergent basis with ample time to institute prophylactic measures. Recent studies have confirmed that the use of low or iso-osmolar agents, with lowest effective dose possible, and the administration of preprocedure intravenous (i.v.) isotonic crystalloid solution mitigated the risk of CIN in high-risk patients. The proposed pathophysiologic mechanisms of CIN are complex including intrarenal vasoconstriction with resultant medullary hypoxia, generation of reactive oxygen species, and direct renal tubular toxicity. This article will review the recent evidence concerning the incidence CIN, its pathogenesis, and risk factors that increase the likelihood of developing CIN.6,7,8 In addition, this report provides vital information on prevention and management of CIN.
The pathophysiology of CIN is complex and poorly understood. Multiple mechanisms act in concert to induce CIN. Intrarenal vasoconstriction, generation of reactive oxygen species, and direct tubular damage are the predominant factors that lead to CIN.6,7 However, relative contribution of each mechanism alone is not known.6,7
Several groups have documented immediate vasoconstriction and reduction in renal blood flow occurring after administration of contrast medium.6,7,8,9,10,11,12 Multiple studies in animal models have shown that intra-arterial infusion of ionic contrast medium caused transient initial increase in blood flow followed by an intense and prolonged constriction of renal vasculature.6,7 Although the mechanism for this vasoconstriction is not completely known, these investigators demonstrated the importance of calcium influx in the vasoconstrictive phase following contrast exposure.8 Recent information has demonstrated that the flow to the outer medulla is reduced by 40% following contrast material administration and is associated with a 60% reduction in oxygen delivery. These changes result in ischemic injury, which contributes to the histo- pathologic findings seen in CIN models.9,10
Multiple agents are implicated in producing renal vasoconstriction. For instance, there is significant evidence for the role of endothelin in the pathogenesis of CIN. A seminal study demonstrated a significant elevation in plasma endothelin level within 5 min of contrast material administration.11 Importantly, the study revealed that no significant change in plasma endothelin levels was detected until the volume of the contrast material exceeded 150 mL. Adenosine has also been found to induce local renal vasoconstriction.11 In addition to the presence of vasoconstrictors, there is concomitant impairment of vasodilatation in patients with CIN.10 Nitric oxide (NO) is a potent vasodilator produced from L-arginine in the presence of the enzyme NO synthase. High-osmolar contrast agents reduce NO production, and this reduction was proportional to osmolality of the solution.10,12 However, concerns regarding NO inhibition following contrast administration and its negative impact on renal function have been raised by Sancak et al.13,14
A compromised medullary blood supply brought on by contrast administration creates a mismatch between the metabolic demands of thick ascending limbs of the loop of Henle and its own blood supply resulting in the production of superoxide (a potent reactive oxygen species) leading to oxidative tubular damage.15 Preexisting chronic renal failure, increased age, and diabetes decrease the ability to accommodate oxidative stress and lead to increased risk of CIN.15
Contrast administration induces osmotic diuresis in euvolemic patients with normal kidney function.16 Exposure of renal tissue to high osmotic radiocontrast agents results in characteristic histopathologic changes called “osmotic nephrosis.”16 The most frequent histopathologic features of “osmotic nephrosis” include intense focal or diffuse proximal tubular vacuolization as well as full-blown tubular necrosis. Iodinated contrast media reduce the viability of cultured renal cells and induce apoptosis.16 Other toxic effects include cellular energy failure, disturbance of cellular calcium, and alterations in tubular cell polarity.16 Investigators have demonstrated contrast material retention within renal cortex as well as medulla and its association with CIN.16,17,18,19 A recent study revealed that renal cortical contrast retention at 24 h, as determined by computerized tomography scan, had a better predictive value for the development of CIN than did the 24-h serum creatinine level. This was seen more intensely in patients with preexisting renal damage as well as older individuals.15
Taken together, renal vasoconstriction coupled with impaired vasodilatation is important mechanism that can result in CIN. In this context, ischemic damage to the kidney can be seen with the administration of contrast material. Contrast agents can be retained by the kidney and are capable of causing tubular toxicity and generating reactive oxygen species that can further augment renal injury.18,20
For optimal management, it is critically important for providers to be able to stratify patients according to their risk for CIN. Preexisting CKD with concomitant diabetes mellitus poses the highest risk for CIN. Other factors that increase the risk for CIN include advanced age, cardiovascular disease, preprocedure hemodynamic instability, and concomitant use of certain drugs. Table 1 summarizes some common risk factors.20,21,22,23,24,25,26,27,28,29,30 A quick review of the risk factors could be very helpful in evaluating patients who would be at risk for the development of CIN.
Preexisting impairment of renal function
Preexisting CKD is of paramount importance and places patients at a high risk for the development of CIN. In a series of 1144 patients, Davidson et al19 investigated patients undergoing cardiac catheterization and documented a low risk of CIN (increment of creatinine levels of at least 0.5 mg/dL) in patients with normal renal function compared to those with preexisting CKD (creatinine level exceeding 1.2 mg/dL). These investigators found that the risk for CIN increased significantly (20%) when serum creatinine exceeded 2.0 mg/dL.
Diabetes mellitus with preexisting chronic kidney disease
Diabetics with CKD are reported to have a four-fold increase in the risk for development of CIN when compared with patients without diabetic nephropathy.20 Diabetes mellitus with associated renal insufficiency has been identified as an independent risk factor for contrast nephropathy, with as many as 56% of those who develop the condition progressing to irreversible renal failure. Diabetics with advanced CKD (serum creatinine >3.5 mg/dL) are at a particularly higher risk for the development of CIN.20,21
In many studies, higher prevalence of CIN was observed in patients with increased age, possibly reflecting the decline in renal function with age. Advanced age is associated with increased vascular stiffness with declined endothelial function resulting in reduced vasodilator responses as well as a reduced capacity for vascular repair with pluripotent stem cells.
All these factors together increase the risk of CIN in the elderly patient and reduce the potential for prompt recovery.22
Reduction of effective intravascular volume
Reduction of effective intravascular volume (due to congestive heart failure, liver cirrhosis, or abnormal fluid losses), prolonged hypotension (especially when induced by intensive antihypertensive treatment combined with angiotensin-converting enzyme (ACE) inhibitors, and diuretics, most notably furosemide), and dehydration have been reported as contributing to prerenal reduction in renal perfusion, thus enhancing the ischemic insult of contrast media.22,23,24,25
Contrast volume and timing of contrast administration
High doses and repeated injections of contrast material administered within 72 h augment the risk of AKI due to contrast material. The first-generation contrast agents are rarely used today and are ionic and hyperosmolar compared with plasma and impart a higher risk of nephrotoxicity.27 In contrast, low osmolar (iohexol, ioversol, and iopamidol) or iso-osmolar (iodixanol) agents are associated with a much lower risk of causing CIN. Iodixanol is a nonionic dimeric iso-osmolar contrast medium and offers an even lower risk of nephrotoxicity than lowosmolar contrast agents.26,28
Concomitant use of medications
Diuretics lead to volume depletion and cause intrarenal vasoconstriction. In this context, they increase the risk of contrast nephropathy. There are other agents that can cause direct nephrotoxicity. These include cyclosporine A, aminoglycosides, amphotericin, and cisplatin. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the local vasodilatory effects of prostaglandins and increase the risk of CIN.29,30 Likewise, ACE inhibitors and angiotensin receptor blockers (ARB) can potentially increase the likelihood of contrast nephropathy. In a large study (n = 5299), patients taking an ACE inhibitor/ARB were more likely to have contrast-induced AKI (odds ratio: 1.43, 95% confidence interval: 1.06–1.94).31 Thus, it is prudent to review the list of medications before contrast administration. If possible, nephrotoxic drugs should be withheld at the time of contrast administration.
Management of Contrast Nephropathy
To date, there is no definitive treatment of AKI following radiocontrast administration. However, prevention still remains the corner stone of this entity and as such demands a careful analysis of the risk factors and implementation of preventive strategies noted below.
Maintenance of volume status
Avoidance of intravascular volume depletion is the single most important strategy to reduce the risk of contrast-induced renal injury. In this context, maintenance of adequate hydration is of paramount importance. Often patients are receiving NSAIDs. Such agents should be stopped 24–48 h before the procedure. Recommended regimens for volume replacement for hospitalized patients undergoing contrast administration include normal saline administered at 1 mL/kg/h for 6–12 h preprocedure, intraprocedure, and continued for 6–12 h postprocedure.32,33 In patients with compensated congestive heart failure, fluids should be administered based on physician discretion and with frequent lung examination. Normal saline produces better volume expansion and has been shown to have superiority over hypotonic solutions such as 0.45% saline.34,35,36 While diuretics are not recommended, a recent study demonstrated that loop diuretics may decrease the incidence of CIN.37
Conflicting data continue to surround the use of sodium bicarbonate versus normal saline. Thus far, the largest randomized clinical study failed to show any benefit of sodium bicarbonate over normal saline.38,39 As such, normal saline is the best available solution to reduce the risk of contrast nephropathy.
The sulfhydryl group of N-acetylcysteine is an excellent antioxidant and scavenger of free oxygen radicals. However, it has failed to show conclusive evidence of protecting against the development of CIN.40,41 Because of its low cost, lack of adverse effects, and potential beneficial effect, this agent is frequently a part of the protective strategies of multiple medical centers against contrast nephropathy. Nevertheless, based on the lack of conclusive evidence, we do not recommend this agent.40,41
Prophylactic hemofiltration and hemodialysis
Clinicians often ask for dialysis therapy soon after the administration of contrast material. However, there is no conclusive evidence that prophylactic dialysis prevents renal injury due to contrast administration.42 At present, we do not recommend prophylactic dialysis therapy. Dialysis itself is not devoid of complications and requires an invasive procedure of a large bore catheter insertion.
Oral hydration and other measures
Due to the ease of administration and essentially no cost, oral hydration is an attractive and viable option compared to i.v. fluid replacement. A recent meta-analysis of randomized clinical trials demonstrated that oral hydration with water was as effective as hydration using i.v. saline.43 Statins, oral sodium citrate, atrial natriuretic peptide, ascorbic acid, theophylline, and nifedipine have all been studied and failed to show any benefit against CIN.41,42,44
Logistical barrier to contrast-induced nephropathy prevention
While i.v. hydration has been reported to be the single most important element in halting CIN, from a purely opinion-based point of view, there are several barriers that create a problem for the implementation of this strategy in clinical practice (Table 2). Often, procedures are scheduled in an emergency and at times with coexisting confounding factors (congestive heart failure, etc.,) limiting the use of i.v. hydration. In addition, the lack of space in radiology suites to provide i.v. hydration adds to the complexity in implanting strategies to prevent CIN. The infusion centers provide an alternative for i.v. hydration; however, these centers are often overbooked with other critically important therapeutic infusions (i.v. iron, blood transfusions, chemotherapy, etc.,). It is worth mentioning that there is always an opportunity for improved coordination of care between clinicians and radiologists. For instance, a preprocedure practice of disallowing oral fluid intake for 12-h before any contrast imaging study can potentially lead to subclinical volume depletion and thereby increase the risk of CIN. Implementing strategies to improve coordination will have a positive impact on minimizing the risk of CIN.
Rightfully so, there are practical and logistical complexities at multiple levels (Figure 1). From the radiology perspective, the question is who would write the order for i.v. fluids and who would administer and monitor? There are several imaging studies performed on a daily basis in hospitals worldwide. The required space and personnel to administer i.v. hydration would stress the limited existing resources. From the clinician’s standpoint, at times, the exact time of the study is not known. Hence, i.v. hydration orders are difficult to implement. Throughout the world, clinicians in the hospital frequently carry a busy ward service making it difficult to keep up with the changes in imaging study times. Importantly, some of the imaging services are performed on an outpatient basis. In this context, from a hospital standpoint, a 12-h hydration cannot be performed unless the patient is brought to the hospital at least 12 h before the procedure. Such an approach introduces short-term admission and use of limited resources. Finally, from the billing standpoint, preprocedure billing of such a patient further complicates the situation.
While challenging, a closer look at the factors highlighted above might bring ideas that would have a positive impact on ameliorating CIN. At a minimum, oral hydration is something that could be encouraged before a contrast imaging study.
Contrast material continues to be a common cause of AKI. Patients with preexisting renal dysfunction, diabetes, advanced age, and intravascular volume depletion are at a particularly high risk for developing contrast-induced renal injury. There is no definitive treatment of CIN. In this context, identification of high-risk patients and institution of preventive measures are of critical importance. i.v normal saline is the best available solution for the prevention of CIN. However, oral hydration is equally effective. N-acetylcysteine has failed to show conclusive benefit against CIN. Finally, prophylactic dialysis therapy cannot be recommended to protect against the development of CIN. If contrast administration is absolutely contraindicated, then carbon dioxide angiography should be considered.
Conflict of interest:
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