Contrast-Induced Nephropathy: What Do We Know? A Literature Analysis

Contrast-induced nephropathy (CIN)/acute kidney injury (AKI) is the third leading cause of hospital-acquired acute renal failure. As diagnostic imaging increases in interventional procedures such as coronary and peripheral angiography, along with an ever-increasing number of high-risk patients, CIN remains a major source of hospital morbidity and mortality, and associated healthcare costs. Associated costs are not just an increased length of stay, but may include advanced interventional treatment such as dialysis. This incidental increase in costs is also driven by patients with pre-existing comorbidities such as hypotension, hypovolemia, diabetes, and congestive heart failure. Clinicians engaged in radiologic procedures need to be able to recognize predisposing risk factors, use effective and appropriate prophylactic peri-procedural treatment, and effectively manage CIN in patients who are clinically symptomatic. It is essential that medical staff (physicians and nurses) possess an understanding of 1) patients at risk for CIN, 2) identification of the onset of CIN, and 3) how to implement treatment strategies prophylactically in the outpatient setting and evidence-based management within the acute care setting.¹  

Literature Evaluation

The following articles were chosen and reviewed for their contribution to the formulation of a general understanding of CIN/AKI pathophysiology, patient populations, treatment modalities, and how the research literature may impact patient care. Literature citations are the result of using various combinations of the following keywords: contrast, nephropathy, risk, strategies, and hydration. A database search was conducted utilizing a hospital-based medical librarian and the following limitations were imposed: citations were required to be from peer-reviewed journal publications and cited research articles needed to be within the last 8 years. Additional citations were gathered through the PubMed database which is a part of Medline, the United States National Library of Medicine national database concentrating on biomedicine by the Literature Selection Technical Review Committee (LSTRC), Cochrane Library, and other relevant databases providing peer-reviewed journals.

What Do We Know About Assessing for Risk of CIN?

Ideally, clinicians would have available a reliable and easily utilizable and interpretable method of assessing and identifying patient risk factors for developing CIN within the interventional cardiology environment. For patients undergoing elective procedures, there is a window of opportunity for assessing risk and initiating prophylactic measures to reduce CIN. For patients undergoing emergent percutaneous coronary intervention (PCI) risk assessment, identification and interventions to reduce CIN are initiated only after acute kidney injury (AKI) may have been sustained after exposure to radiographic contrast media during the procedure. Chang et al review key concepts in CIN²: 

1. CIN can be defined as a ≥0.5 mg/dl rise in serum creatinine (SC) or a 25% increase within 48 to 72 hours post administration of contrast media. (Note: although this is the most prevalent definition of CIN within the literature, it is not universally accepted or utilized); 
2. The pathogenesis of CIN has not been clearly elucidated. It is hypothesized that toxic effects of contrast media create oxidative stress in the form of radical oxygen species (ROS) and subsequent hypoxia-induced renal tubular damage.  

Azzalini et al³ have identified specific biomarkers that are potentially indicative of CIN: cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and pro-calcitonin. Identifying the presence of these biomarkers is a distinct advantage over monitoring serum creatinine levels over days. Their presence may be detectable within hours; currently, however, there are no defined, standardized levels considered prognostic of CIN.^2,3

Clinicians need to be keenly aware of the pathophysiological and clinical factors that culminate in a complex matrix that puts patients at risk for developing CIN in the clinical setting. Several schemas have been proposed to include/identify comorbidities contributing to the potential for developing CIN. Rashid et al4 conducted a retrospective analysis of intensive care unit (ICU) patients who received intravenous contrast during computerized tomography (CT). Central to the assessment of risk is the ability to identify modifiable risk factors (here, researchers considered amount of contrast used and sequential studies) and non-modifiable risk factors (considered were hypertension, chronic renal impairment, diabetes, sepsis, and age). Interestingly, Rashid et al reported 139 incidences of ICU patients developing CIN where 70% had two or more risk factors, and yet, multivariate analysis indicated age as the only commonality in predicting the incidence of CIN (P=0.04). Predictive value in using the described risk factors could not be shown. The authors noted that their analysis applies to patients in the ICU setting and suggested that further research is needed to identify the potential linkage between risk factors and the development of CIN in the ICU patient undergoing CT. This study is indicative of the difficulty and ambiguity in identifying and predicting development of CIN within select subsets of patients.⁴  

Deek et al⁵ provided a critique and review of current evidence to inform clinicians of best practice. Researchers completed an integrative database review for research taking place between 2000-2013. The likelihood of patients developing CIN increases with multiple risk factors: chronic kidney disease, i.e., glomerular filtration rates (GFR) <30ml/min (representing the patients at highest risk), age >70 years, diabetes, dehydration, sepsis, and nephrotoxic drugs. Conflicting information remains regarding the potential nephrotoxic effects of ACE-I/ARB therapy and the incidence of CIN, evidenced in a review by Kalyesubula et al6. The risk of death from CIN is 34% in high-risk patients compared to 7% in low-risk patients, strengthening the idea that multiple risk factors increase the likelihood of patients developing CIN. Erring on the side of proactive cautionary measures would seem prudent in the face of ambiguous or conflicting information. The needed increased vigilance in assessing risk will assist in identifying subsets of patients who are more vulnerable.^5,6

The development of CIN is clearly multifactorial, involving modifiable and non-modifiable risk factors. The increasing use of contrast media in the clinical setting punctuates the need for assessment tools capable of providing the clinician with an estimate of the probability of patients developing CIN. Kim et al⁷ developed a nomogram for assessing risk of CIN after abdominal contrast-enhanced CT, with a predictive value at a 95% confidence interval. This risk assessment tool is designed for a certain subset of patients receiving contrast media and has shown good internal validity, but without expanded use of this nomogram and follow-up statistical analysis, generalizability and external validity may not yield the same predictive value. Gurm et al8 developed a 46-item risk assessment tool (along with a scaled-down 15-item version) for use by clinicians at bedside in predicting the occurrence of CIN in patients undergoing PCI. These researchers utilized a random forest regression model, which utilizes a classification method in determining consensus prediction for each item. Advantages of this type of random regression analysis are evidenced by the predictive value, accounting for overfitting, evaluating large numbers of predictors, and exploiting potential interactions between predictors. Full and abbreviated models demonstrated good concordance between observed and predicted risk of CIN, with each model obtaining a 95% confidence interval in discriminating for CIN. This model also has the advantage of stratifying patients into low, intermediate and high risk categories. Deek et al⁵ reported on a risk factor scoring scheme where eight risk factors were identified and assigned a numeric value, producing a stratified numeric risk assessment score, which was then translated into a percent risk of developing CIN. The authors indicated that testing and validation was situationally valid after being utilized on a select subset of patients ≥70 years and above.^5,7,8

Pharmacological Treatment Strategies Tested for CIN Reduction 

We know CIN/AKI when we see it. The clinical manifestations can be diagnosed and quantified, but the exact mechanisms of the pathophysiology behind the development of CIN remain theoretical and speculative. Theories of oxidative stress and radical oxygen species (ROS) in relation to the cause of medullary hypoxia-induced renal tubular damage remain as prime speculative culprits in the incidence of CIN/AKI. After these proposed mechanisms of damage were put forward, treatment strategies for reducing CIN have centered on attenuating the effects of oxidative stress. Sun et al⁹ conducted a meta-analysis of randomized, controlled trials using intravenous (IV) N-acetylcysteine (NAC) in the treatment and prevention of CIN based on the antioxidant properties of NAC and the inhibition of ROS. It is important to note that oral administration of NAC and its bioavailability is limited by first pass conversion in the liver to cystine and then glutathione, which also exhibits antioxidant activity against free radicals. The authors’ meta-analysis is unable to conclude the efficacy of IV NAC, based on the potential for publication bias resulting in overestimation of true treatment effect, and inherit heterogeneity between study subjects. Boucek et al¹⁰ conducted a prospective, randomized, double-blind controlled study of sodium chloride (NaCl) hydration (standard treatment) and sodium bicarbonate (NaHCO3) (therapy) in diabetic patients with impaired renal function undergoing elective cardiac procedures. Major risk factors for the development of CIN include diabetes and the comorbidity of impaired renal function. NaHCO3 has been proposed as a mediator in reducing free-radical facilitated renal injury. The occurrence of CIN, in 7 (11.5%) and 5 (8.5%) patients between the NaHCO₃ and NaCl groups, respectively, did not reach the level of statistical significance (P= 0.76). Researchers concluded that sodium HCO3 did not confer protection against CIN in patients with diabetes and impaired renal function.^9,10

Khaledifar et al¹¹ conducted a randomized trial assessing the preventative strategies of reducing CIN through the effects of NAC, ascorbic acid (AA), and IV normal saline (NS) on patients scheduled for elective coronary angiography. Researchers argued further investigation was needed to evaluate antioxidant agents on the formation of CIN given that previous studies produced conflicting results. The study subjects were divided into three groups: group A (oral NAC + NS), group B (oral AA +NS), and group C (IV NS). There was no statistical difference between groups in pre-procedure serum creatinine (P=0.661) and glomerular filtration rate (GFR) (P=0.785), and no statistical difference between groups post-procedure. Serum creatinine (P=0.771) showed an increase with a corresponding decline in GFR (P=0.876). The addition of these antioxidants did not yield an advantage over sodium chloride in preventing CIN.¹¹

The landmark study conducted in 2011, the acetylcysteine for contrast-induced nephropathy trial (ACT), is one of the largest randomized, controlled trials conducted to address a specific strategy in reducing CIN. ACT was a multisite, double-blind, randomized, controlled trial studying the effects of oral N-acetylcysteine or placebo in patients undergoing coronary or peripheral angiogram with at least one risk factor for developing CIN. Enrollment was 2308 patients with 1172 allocated to the acetylcysteine arm and 1136 patients to placebo. The primary endpoint, contrast-induced acute kidney injury, occurred in 27% of the study subjects in both arms (relative risk, 1.00, 95% confidence interval, 0.812-1.25, P=0.97). ACT demonstrated that NAC had no efficacy in preventing CIN and advanced the notion that hydration remains the single key ingredient in reducing CIN incidence.¹²  

The controversy surrounding the efficacy of antioxidant agents such as NAC or NaHCO₃ continues to garner considerable disagreement between various studies and meta-analyses. Researchers continue to examine other modifiable risk factors, such as the type and amount of contrast media used during the procedure; ambiguity remains regarding safe levels of contrast media. Gurm et al¹³ are critical of current determinants of maximal acceptable contrast dose (MACD) as calculated by 5 ml of contrast media/kg of body weight/baseline serum creatinine (mg/dl), noting that 1) it is not routinely utilized in clinical practice and 2) a significant number of cases of CIN occur even when MACD is not exceeded. The authors propose the ratio of contrast volume (CV)/calculated creatinine clearance (CCC) and established patient cohorts on ratio values of <2, 2 to 2.9, and ≥3. Results of the study indicated:

• <2% of patients with a ratio <2 develop CIN
• Approximately 2% of patients with a ratio of 2 to 2.9 go on to develop CIN
• Nearly 6% patients with a ratio ≥3 went on to develop CIN
• The ratio of CV/CCC was statistically a better predictor of CIN compared with MACD (P<0.05).¹³

The critical role of hydration in ameliorating the effects of contrast media was exemplified in the study conducted by Jurado-Roman et al¹⁴ for patients undergoing primary PCI for ST-segment elevation myocardial infarction (STEMI). Patients were assigned to one of two groups: one arm received IV NS intra/post-procedure (NS+) and the other received no IV treatment (NS).  Development of CIN was 21% in the NS- group and 11% in the NS group+, reaching statistical significance (P=0.016). In a multivariate analysis, hydration presented as the only predictor of CIN (OR=0.29[0.14 to 0.66]; P=0.003).¹⁴

Non-Pharmacological Treatment Strategies Tested for CIN Reduction 

Emerging from the status of current research, we find:

1. The goal of reducing CIN is in early intervention and preventative measures, but the role of antioxidants remains ambiguous at best and hydration appears to be a critical key. 
2. The ability to assess risk and limit modifiable treatments/interventions is critical in reducing the occurrence of CIN.
3. Prevention remains the cornerstone of CIN management.  

Researchers/clinicians remain concerned with what methods or combination of hydration methods provide nephron-protective effects and efficacy, i.e., oral hydration as preconditioning, IV hydration peri-procedural, and/or combinations of oral and IV hydration to achieve the best possible outcomes. Cheungpasitporn et al15 conducted a systematic review and meta-analysis of randomized, controlled trials addressing the question of oral hydration for prevention of CIN, finding six randomized, controlled trials meeting criteria. Statistical analysis revealed the pooled risk ratio (RR) of CIN in oral hydration versus IV fluid treatment of 0.94 (95% CI, 0.38-2.31). Of note, the investigators reported only moderate statistical heterogeneity and an assessed absence of publication bias. These findings are suggestive that an oral fluid regimen may be considered as an outpatient treatment option for the prevention of CIN in patients with normal to moderately impaired kidney function.¹⁵ 

Cho et al¹⁶ conducted a prospective, randomized, single-center study to establish that oral hydration and bicarbonate would be comparable to IV prevention strategies. Subjects were assigned to one of four groups: groups 1 and 2 were designated as control or standard of care, receiving IV normal saline and IV normal saline with IV sodium bicarbonate, and groups 3 and 4, considered the experimental intervention, received oral hydration only or oral hydration and sodium bicarbonate, respectively. The investigators report no statistical difference between IV normal saline and oral hydration alone or with oral sodium bicarbonate (P=0.617 and 0.342, respectively); similarly, IV normal saline and IV sodium bicarbonate compared to the intervention arms was not statistically significant (P=0.835 and 0.525, respectively). The defined standard of care regimen did not show a statistically significant benefit as compared to oral strategies in preventing CIN. Nijssen et al¹⁷ in a phase 3 non-inferiority trial, A MAstricht Contrast-Induced Nephropathy Guideline (AMACING), studied the safety and cost-effectiveness pre-procedure IV hydration versus no pre-procedural treatment. Researchers found no significant difference between groups, with a 2.7% (n=307) incidence of CIN in the IV prophylaxis group versus 2.6% (n=296) in the non-hydrated group.^16,17

CIN/AKI is an iatrogenic disorder shown to have transient and persistent sequelae that increase the mortality risk for elderly patients and especially those with comorbidities such as renal insufficiency, diabetes, and hypertension. As a direct consequence, the rising use of radiographic contrast in the face of increasingly complex interventional procedures is putting patients at risk for AKI and increased mortality, while identifying best practice remains elusive. Shoukat et al¹⁸ produced a review article reiterating that AKI continues to plague patients with renal insufficiency undergoing coronary interventions. They note that the volume of contrast media remains the most modifiable risk factor and that volume administration is a key factor in the prevention of CIN. Additionally, the use of antioxidants such as NAC present ambiguous and mixed results, with a consensus leading toward the non-efficacy of NAC administration.¹⁸ 

Yellen et al¹⁹ utilized Roger’s theory of diffusion of innovations to engage staff in a quality improvement (QI) project to reduce the incidence of CIN in patients undergoing CT imaging. Utilizing current evidence for increasing intravascular volume and associated reduction in incidence of CIN, the authors identified five key elements related to changing current policy and updating specific aspects of patient care: 1) type of IV fluid, 2) cutoff points for IV fluid hydration, 3) location of IV intervention with concomitant safe, feasible, and reduced duration of stay, 4) implementation of oral hydration, and 5) improvement of renal outcomes. The QI project achieved a cost savings of approximately $70,000 per year and none of the study subjects (n=521) developed renal impairment.¹⁹

Within the literature, it continues to be demonstrated that non-pharmacological means of preventing CIN/AKI, along with modifiable risks, may prove to be the standard of care. The literature contains quality studies indicating the efficacy of interventions such as intravascular volume expansion, early risk assessment, and instigating modifiable risk such as volume reduction in use of contrast media and the accompanying reduction in CIN/AKI. Ozsvath et al²⁰ provide a compelling review indicating that the preconditioning is one key concept in preventing CIN. In attenuating renal vasoconstriction and/or directly reducing the toxic effects of contrast media on renal cells, treatment is directed toward increasing intravascular volume peri-procedurally. Intravascular volume expansion may be considered preconditioning of patients prior to administration of contrast media. The authors conclude that pre-procedural risk assessment along with preconditioning in the form of intravascular volume expansion are necessary precautionary measures to reduce the incidence of AKI/CIN.²⁰  

Brar et al’s randomized, controlled trial, the Prevention of Contrast Renal Injury with Different Hydration Strategies (POSEIDON), looked at a hemodynamic-guided fluid administration for the prevention of AKI/CIN.²¹ The authors devised a post cardiac cath IV supplementation regimen driven by left ventricular end-diastolic pressure measurements. Primary endpoints were defined as a >25% or 0.5 mg/dL increase in the serum creatinine concentration over a 1- to 4-day period post-procedure as compared to baseline. Statistical analysis showed AKI/CIN occurred less frequently in the experimental group, 6.7%, and 16.3% in the control group. Statistical significance was achieved between treatment and standard of care (CI 95% and P=0.005). The results suggest intravenous administration of normal saline guided by left ventricular end-diastolic pressure is well tolerated and may substantially reduce the incidence of CIN, leading to an overall decrease in major adverse clinical events in patients undergoing cardiac catheterization.²¹

Conclusions and Looking Ahead

Reviews of physiology, pathophysiology, pharmacology, and current strategies in treating/preventing CIN, as well as clinical studies, all stress the need for continued research and examination of novel treatments and methodologies in preventing and treating CIN. The literature supports 1) that hydration remains an important component to reducing the incidence of CIN; 2) that CIN is a major health care concern as a significant contributor to in hospital acute renal failure and medical expenditure; 3) health care practitioners and patients need to be made aware of risk through increased educational efforts; and 4) adopting effective strategies in reducing the incidence of CIN is of benefit to patients and healthcare institutions.  

Assessment of patients at risk for developing CIN requires a multifaceted approach, requiring critical thinking skills and flexibility in utilizing and developing novel approaches for the prevention and treatment of CIN. A standardization of the clinical definition of CIN needs to be developed, along with elucidating biomarkers specific to identifying and detecting the early onset of AKI/CIN. Clinicians need to be vigilant in identifying modifiable and non-modifiable risk factors. Tools developed in assessing and scoring patient’s risk for developing CIN need to be predictive throughout the continuum of care (pre, intra, and post-procedural) and easily interpreted without consuming a vast amount of resources and/or clinician time. With clinically useful patient assessment tools such as the Mehran contrast-induced nephropathy risk score22-23, patients at risk can be more easily identified and stratified, but without consistent application of scoring systems, patient risk of developing CIN will continue to be unidentified or misidentified. 

An overriding theme is the need for large-scale, multicenter, randomized, controlled trials to evaluate which treatment strategies and/or hydration protocols positively affect the incidence of contrast-induced nephropathy. One concern that still eludes researchers is a clear understanding of the exact pathophysiological mechanisms underlying the development of CIN. Identifying specific biomarkers associated with CIN/AKI may prove beneficial, much like troponin has advanced the diagnosis of acute myocardial infarction. What remains unclear is to what degree oxidative stress plays a role, if any. Adequate hydration is the one controllable factor clinicians can utilize in reducing the incidence/deleterious effects of CIN. It remains to be investigated whether combining treatments focused on reducing oxidative stress, along with what constitutes an optimal peri-procedural fluid repletion protocol, will ultimately prove efficacious in reducing the incidence of CIN.

References

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21. Brar SS, Aharonian V, Mansukhani P, Moore N, Shen AY, Jorgensen M, et al. Haemodynamic-guided fluid administration for the prevention of contrast-induced acute kidney injury: the POSEIDON randomised controlled trial. Lancet. 2014 May 24; 383(9931): 1814-1823. doi: 10.1016/S0140-6736(14)60689-9.
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23. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol. 2004 Oct 6;44(7):1393-1399.

Michael O’Bleness, MBA, MSN, RN, can be contacted at michael.obleness@gmail.com