Contrast Associated Kidney Injury in the Critically Ill: a multicenter retrospective cohort study

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Author

Adam Wolf

Under mentorship from

Robert Frithiof

September 6, 2018

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Populärvetenskaplig Sammanfattning

Jodinnehållande kontrastmedel har använts sedan 1920-talet för att förstärka

röntgenundersökningar. Jod är mycket mer röntgentät än kroppens vävnader, vilket gör att det skapar starka kontraster vid röntgenbelysning. Detta gör att undersökningarna får bättre förmåga att upptäcka avvikande detaljer, som kanske hade missats om man inte använde kontrastmedel. Kontrastmedel kan ges genom blodet, urinröret, eller även genom att svälja det. Olika vägar används beroende på önskad undersökning.

Precis som medicin i sin helhet har utvecklats under åren så har även kontrastmedel. Det som användes i tidigt 1900-talet var skadligt för njurarna, som måste filtrera ut kontrastmedel från blodet och utsöndra det i urinen. Nuförtiden används betydligt mindre farliga ämnen. Det finns dock fortfarande risker som associeras med kontrastmedel, där en av de mest kända inom medicin är akut njursvikt.

Under en lång tid har akut njursvikt varit en fruktad komplikation efter en kontrast undersökning, men mer och mer data pekar på att riskerna är avsevärt lägre än vad som tidigare ansetts.

Sjukdomar i andra organsystem påverkar oftast njurarna, och det kan leda till att en patient utvecklar akut njursvikt utan att ens ha fått kontrastmedel. Det finns studier som visar att akut njursvikt förekommer lika ofta hos patienter som inte fått kontrastmedel som hos patienter som fått kontrastmedel.

Vi tittade på svårt sjuka patienter som låg på intensivvårdsavdelningen, IVA, i Gävle och Uppsala. Patienterna som genomgick röntgenundersökningar och fick kontrast jämfördes med patienter som inte fick kontrast. Flera mätvärden noterades men det som vi var mest intresserade av var förekomsten av akut njursvikt.

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Abstract

Contrast media associated kidney injury is a feared complication in any patient. The role of contrast media has been challenged by several researchers in the field who have examined various risk factors in patients who have developed acute kidney injury. Critically ill patients often have several risk comorbidities when compared to the general ward patient. A retrospective dual-center cohort study was performed on ICU patients treated at Uppsala University Hospital and Gävle County Hospital to examine contrast media as an independent risk factor in AKI. Long-term kidney function was also noted as a secondary area of interest. Contrast

administration was neither a significant risk factor in the development of AKI in the 3 days post-examination nor did it have a significant effect on 3-month creatinine values. Although this study has its limitations, the results are in-line with large meta-analyses suggesting that contrast media does not play a significant role in the development of AKI among critically ill patients. The long term effect of contrast media on creatinine is an understudied field that would greatly benefit from further research.

Glossary and Abbreviations

AKI - Acute Kidney Injury

S-Cr - Serum creatinine

KDIGO - Kidney Disease Improving Global Outcomes Baseline S-Cr - Serum creatinine 3 months before exam Long term S-Cr - Serum creatinine 3 months after exam CM - Contrast media

LOCM - Low osmolality contrast media

SAPS III - Simplified Acute Physiology Score, an ICU scoring system for disease severity RIFLE – Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease classification

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Disclaimer: It is difficult to remain impartial in discussing the role of contrast media in kidney injury, as the two most common terms are “Contrast Associated AKI” and “Contrast Induced AKI”. Choosing to use one is akin to choosing a side. The author of this paper has chosen to use the term which best reflects the findings of this paper.

Background

A Brief History of Iodinated Contrast Agents

After the accidental discovery of iodine as a radiopaque agent in the early 1920s by Osborne et al (Osborne et al., 1923), iodinated contrast agents have undergone several iterations and

developments. Iodinated contrast agents can be classified by osmolality, water solubility, and structural makeup. Low-osmolality contrast agents are associated with a decreased risk of nephrotoxicity compared to high-osmolality contrast agents, regardless of pre-existing renal insufficiency. (Barrett and Carlisle, 1993)

LOCM can be divided into monomeric or dimeric, characterized by either a single or double tri-iodinated benzene ring. (“Organic Chemistry - Jonathan Clayden, Nick Greeves, Stuart Warren - Google Books,” n.d.) The agents are then further classified by their water solubility as ionic or non-ionic. Ionic agents have a higher toxicity due in part to the fact that they dissociate into positive and negative ions. These have not seen widespread use in the last decades. Non-ionic agents do not dissociate and are thus less toxic and better suited for widespread use. (Caschera et al., 2016) The two most readily available contrast agents in Sweden include the non-ionic, low-osmolality Iohexol, and the non-ionic, iso-osmolar agent Iodixanol. (“Jodkontrastmedel vid röntgenundersökningar,” n.d.)

Dangers Associated with Contrast Media

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Pathophysiology

The exact pathophysiology behind contrast-associated kidney injury is not known in its entirety. It is however understood that hemodynamically induced medullary hypoxia, formation of reactive oxygen species, and tubular cell toxicity play a role in the development of tubular necrosis after CM administration in in-vitro studies. (Geenen et al., 2013). One of the better understood mechanisms revolves around the interplay between vasoregulatory molecules such as nitric oxide, prostglandin PGE2, endothelin, and adenosine. Only a relatively small amount (10%) of renal blood flow reaches the medulla (Evans et al., 2008). Proper regulation of this system is therefore crucial to ensure medullary perfusion and prevent hypoxia.

Administration of LOCM (iohexal) has been shown in rats to create hemodynamic changes in the kidney; a 3 hour vasoconstriction follows a shorter initial vasodilation. The overall end result is a 40% decrease in blood flow to the outer medulla (Nygren, 1992). In a system highly sensitive to changes, a 40% alteration is quite significant. This is only one example of the pathophysiology behind CA-AKI. However appealing it may seem to assign the pathogenesis to a single

mechanism, the reality is that a complex series of in- and interdependent factors affect the development of CIN.

Epidemiology

It has long been known that contrast agents carry risk of nephrotoxicity, and two meta-analyses have shown the incidence of Post-Contrast AKI in the general ward patient to be 5-6%. Risk factors identified (in order of decreasing odds ratio) included NSAID use, age over 65, diabetes, malignancy, and lastly renal insufficiency. Hypertension, anemia and chronic heart failure were not associated with an increased risk (Kooiman et al., 2012; Moos et al., 2013).

Definition of Contrast-Associated Acute Kidney Injury

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increase in S-Cr to ≥ 1.5 times baseline or urine volume ≤ 0.5ml/kg/h for 6 hours (“KDIGO Clinical Practice Guideline for Acute Kidney Injury,” 2012). See table 1.

Contrast-Induced AKI is widely defined in literature and by the ESUR (European Society of Urogenital Radiology) as an increase in S-Cr by ≥0.5mg/dl (≥ 44 µmol/l) or a 25% increase from baseline value within 48 hours after administration of contrast media during a radiologic

procedure (“KDIGO Clinical Practice Guideline for Acute Kidney Injury,” 2012; Stacul et al., 2011). However, since the development of the KDIGO guidelines the recommendation is to use the standard AKI staging definition for the 72 hours following contrast administration. If AKI criteria are fulfilled during the 72 hours, the patient is considered to have suffered from contrast associated AKI.

Table 1: Staging of AKI. The highest stage achieved between either S-Cr and urine production is considered.

Stage S-Creatinine Urine production

1 1.5-1.9 x baseline creatinine OR

≥0.3 mg/dl (≥26.5µmol/l) increase within 48 hours

<0.5ml/kg/h for 6-12 hours

2 2.0-2.9 x baseline creatinine <0.5ml/kg/h for ≥12 hours 3 3.0 x baseline creatinine OR Increase of S-Cr to or above 4.0 mg/dl (353.6µmol/l) OR Start of RRT OR

Patients under 18 who experience a decrease of eGFR to <35ml/min/1.73m2

<0.3ml/kg/h for ≥24 hours OR

Anuria ≥12 hours

Contrast Induced or Contrast Associated?

Since the first reports of contrast induced nephropathy in the 1950s by Bartel et al has CM been implicated in renal injury. As contrast agents have evolved to non-ionic, low-osmolality

molecules, the definitive role of contrast media has been strongly questioned.

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contrast agents played as large a role as previously believed. Several studies have since been performed in an attempt to further elucidate the risk, or lack thereof, of iodinated contrast agents (Katzberg and Newhouse, 2010)

One difficulty facing cohort analyses is the multitude of potentially confounding factors that affect whether or not a patient undergoes a contrast-enhanced CT versus an unenhanced CT. Some of these (such as dehydration, shock, renal insufficiency, diabetes) may increase risk of AKI, regardless of contrast administration. In 2013 both Davenport et al (Davenport et al., 2013) and McDonald et al (McDonald et al., 2013) used a method of propensity score matching to account for such differences. McDonald performed a large retrospective study in which patients were divided into groups based on S-Cr level, and found no significant difference in AKI risk regardless of S-Cr level (McDonald et al., 2013). Meanwhile Davenport et al (Davenport et al., 2013) found that risk of AKI began at pre-CT serum creatinine levels of 132.6µmol/L, and increased with increasing creatinine, with contrast medium administration remaining an

independent risk factor. Both studies were large and well-designed and although attempts have been made, the discrepancies are difficult to fully explain (Newhouse and RoyChoudhury, 2013). There is still no clear consensus on whether or not the administration of contrast media

contributes to the development of AKI, and there are high quality studies supporting both sides (Ehrmann et al., 2018; Kashani et al., 2018; Weisbord and Cheryon, 2018).

Critically Ill Patients: Risk of AKI

The aforementioned studies have largely been performed on general ward patients. Patients treated at the ICU are sicker and have greater comorbidities than the general ward patient. Few recent studies have been performed on contrast-associated kidney injury in the ICU patient after the adoption of RIFLE/AKIN criteria, making it difficult to compare against previous studies. There have however been a few high quality studies performed.

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understanding of the risks associated with AKI is therefore required to maintain a high standard of care.

Perhaps the largest and most recent epidemiological study was performed by Hoste et al (Hoste et al., 2015). Their 2016 multinational cross-sectional study on ICU patients using full KDIGO criteria found that AKI occurred in 57% of ICU patients. Hypertension and diabetes were the two comorbidities associated with AKI. Amongst various drug administration was contrast media present during 2.1% of AKI incidents, overshadowed by diuretics (32.4%), NSAID (11.9%) and aminoglycosides (6.8%) (Hoste et al., 2015). These findings suggest that contrast media

administration play an insignificant role in the development of AKI when placed into context at an ICU.

Critically Ill Patients: Contrast Associated, or Contrast Induced

In 2017 McDonald et al published a propensity score-adjusted study examining post-contrast AKI in ICU patients. Using a total of 6877 patients and the KDIGO definition of AKI, they found that IV contrast was not associated with an increased risk of AKI, dialysis, or short-term mortality assuming an estimated GFR of over 45 (McDonald et al., 2017). They did however find an increased rate of dialysis in patients with eGFR <45 who received contrast. These results are in accordance with a meta-analysis of three studies which concluded that acute kidney injury in the ICU patient could not be attributed to administration of contrast medium (Ehrmann et al., 2017).

Long-term effects of contrast medium administration in ICU patients

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Hypothesis

Is contrast media an independent risk factor in the development of AKI among critically ill patients?

Also of Interest

Is there a tangible effect on long-term creatinine after administration of contrast media on patients in the ICU setting?

Methods

Study Design

This study was a multicenter retrospective cohort study, analyzed and approved by the Regional ethical committee. Patients treated at Gävle County Hospital during 2015-2017 and Uppsala University Hospital 2013- 2016 were included.

Data Collection

Data from Gävle was obtained using the e-journal program Melior and the intensive care program PASIVA. Uppsala data was collected through the e-journal system Cosmic and PASIVA. Missing data was complemented through photocopied journals scanned into KOVIS when available. For Uppsala patients a list from radiology was obtained detailing any radiologic exams and the amount of contrast used. In Gävle a list of ICU transports was obtained and contrast type and amount retrieved from the radiology program SECTRA.

Patient demographics and clinical history were obtained through e-journals. Laboratory values such as serum creatinine (baseline, admittance, examination, post exam, and 3 month) were obtained through e-journals. PASIVA, a stand-alone intensive care journal system, was used to obtain parameters during ICU treatment, such as lowest median arterial pressure, lowest

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from radiology. Post-examination diuretics and the presence of nephrotoxic drugs were not routinely recorded in e-journals, but were retrieved (when present) through photocopied journals in KOVIS.

Data Workup

Baseline S-Cr was considered the most recent stable S-Cr value from at least 3 months prior to examination. When several values were present, an average was obtained. For patients lacking recorded baseline values, estimation was calculated using the KDIGO recommended formula. Skin color was, in contrast to the recommendation, not considered during calculation. Long-term S-Cr values were recorded as the earliest stable value at least 3 months after examination. In the case of several values an average was recorded.

Nephrotoxic drugs were included if administered 24 hours before or after radiologic

examination. Drugs considered nephrotoxic for the purpose of this study are listed in Table 3.

Table 3: Drugs considered nephrotoxic at clinically relevant doses, compiled in cooperation with intensivists.

Aminoglycosides Mannitol

Vancomycin Cyclosporins

Amphotericin B Tacrolimus

Acyclovir Hydroxy-ethyl-starch

ACE-inhibitors NSAID

ARB Polymyxin E (Colistin)

Diuretics Gadolinium

Vasoactive drugs included Adrenaline, Noradrenaline, dopamine, dobutamine, atropine, vasopressin, and ephedrine administered 24 hours before and after examination. Diuretics 48 hours after examination were noted, when available. Mechanical ventilation was included if administered 24 hours before or after exam. SAPS III, a measure of disease severity at admittance was obtained through PASIVA.

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Study Population and Exclusion Criteria

A total of 989 separate radiological exams were recorded, with 402 marked for exclusion for various reasons, see Table 2. This resulted in 587 separate exams. 394 were first-time

examinations, while 193 were recurrent occasions. The first occasion was recorded and analyzed for each patient. 11 of these first-time examinations lacked creatinine values for the day of CT and were thus excluded from analysis. Thus a total of 383 patients were included in the AKI baseline table, with 130 from Gävle and 250 from Uppsala.

Table 2: Exclusion criteria

Reason for Exclusion Total

Dialysis 24 h before exam 158

Time of care <48 h 199

Age <16 28

Lack of Sufficient data 17

Statistical Analysis

Statistical analysis was carried out by Johan Westerbergh of Uppsala Clinical Research Center. Patient baseline characteristics were compared using Fisher’s exact test or a Wilcoxon signed-rank test to determine significant differences. Fisher’s exact test was used to analyze qualitative yes/no values and Wilcoxon for ordered numerical values. A p-value of < 0.05 was considered significant. The tests were non-parametric analyses used on non-parametric data.

To analyze the effect of various factors on AKI and account for intervariable correlation a

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Results

Patient Baselines

The combined average age of patients was 66 years old, with 36% female. Cause of admission is detailed in table 4.

Table 4: Cause of admission. “Other” includes but is not limited to: esophageal rupture, intoxication, unclear loss of consciousness, ketoacidosis, electrolyte imbalances, and ruptured abdominal aorta aneurysm.

Cause of Admission Total (%)

Circulatory failure 21(5.5%) Cardiac arrest 38 (10.0%) Infection 87 (22.9%) Respiratory failure 107 (28.2%) Trauma 62(16.3%) Other 65 (17.1%) Patient comorbidities

The two most common comorbidities in the examined group were hypertension (37.0%) and diabetes (17.3%). These are both slightly lower than reported by Hoste et al, which found 47.6% and 25.3% respectively (Hoste et al., 2015). There was even a significant difference between Gävle County Hospital and Uppsala University Hospital regarding the prevalence of

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Who Receives Contrast

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Baseline creatinine was lower (78 v 89.3, p= 0.001) in patients who received contrast (table 5). Creatinine at CT was also significantly lower (77 v 92, p<0.001) in patients who received contrast. This difference is even reflected in the association between AKI staging at CT and contrast administration. AKI incorporates both creatinine and urine production (see table 1). 82.6% of patients who received contrast had no AKI at the time of CT, compared to 68.9% of patients who did not receive contrast (p<0.001). SAPS III score and acute heart failure were also correlated to contrast, with a higher SAPS III score and presence of Acute heart failure

correlating with a lower chance to receive contrast. The administration of vasoactive drugs was significantly higher in patients who received contrast (78.8% v 68.2%, p=0.027). There was no significant difference between hospitals in the rates of contrast administration.

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Figure 1: Odds ratios for various factors accounted for in a multivariate analysis. Numbers after the hyphen represent the 2nd and 3rd quartile interval.

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Acute Kidney Injury

The overall percentage of AKI in this population was 37.5% within 3 days of a radiologic exam (see table 5). When comparing the baseline characteristics between patients who suffered acute kidney injury and those who did not, we found no significant difference in the administration of contrast on the presence of AKI.

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Hypertension and diabetes were significantly associated with the presence of AKI. This is in line with several large studies examining the risks of AKI. For the purposes of this study,

hypertension was not included. Although the data could not prove statistical significance, there was a trend towards a greater number of patients who received contrast not having a resulting AKI episode, demonstrating a seemingly counterintuitive protective effect of CM. This is however only evident on the baseline table, which does not account for intervariable correlation. Accounting only for S-Creatinine at CT and the administration of CM shows a trend that contrast increases risk for AKI, although this did not prove to be statistically significant (figure 2).

Figure 2: Odds ratio of Creatinine at CT compared to Contrast at CT and associated p-values.

At first glance it would appear that the baseline table and the odds-ratio analysis are

incompatible. The baseline table hints that contrast is a protective factor against AKI while the odds ratio analysis hints at the opposite. Whereas the baseline table does not account for intervariable correlation, the small adjustment accounts for two variables. In order to further examine the differences a full adjustment was performed with several other factors, listed in figure 3.

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Figure 3: Odds ratios for selected variables. Chi-square analysis can be found in Appendix B.

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Contrast and AKI

Figure 4: regression analysis of creatine changes from baseline after Day 1-3, clockwise.

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group. A difference in groups would be represented by a difference in the slope of the lines. There is an obvious difference on Day 1, but a multivariate regression analysis showed that contrast was not a significant factor (see Appendix C).

Long-term Effects on Creatinine

Long term creatinine was elevated in patients who had had an AKI episode versus those who had not (78µmol/l vs. 69µmol/l, p=0.003), table 6. In determining factors of significance for long-term elevation of creatinine, a multivariate regression analysis was used.

Figure 5: Regression analysis plotting difference in long-term creatinine to baseline based on creatinine at CT.

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Discussion

Primary Hypothesis

The primary goal of this paper was to examine whether or not contrast media administration was a credible risk factor in the development of acute kidney injury amongst ICU patients. A control group of patients who was subjected to a CT examination but did not receive contrast was

identified and compared to the study group, patients who received contrast. Multivariate analyses and linear regressions of the data were unable to support the claim that CM use increases AKI risk. It was determined that several other factors carry much greater risk in the development of AKI, including creatinine levels at CT, AKI at CT, and vasoactive medications. With other factors accounted for, contrast media use was not a significant risk factor. There are however discrepancies and limitations which need to be addressed.

Long-term Creatinine Values

A secondary goal of this study was to examine the effects of contrast media administration on long-term creatinine values, comparing the control and study groups. These results found no significant difference in long-term creatinine levels between patient groups. This study accounted only for contrast administered during the first recorded radiologic exam. Some patients received multiple contrast-enhanced exams and higher doses of contrast, whereas some control patients received contrast during their treatment time. This results in an underestimation of contrast media usage, much like what was discussed earlier.

Patients with Creatinine at CT over 150µmol/l

A total of 11 patients with creatinine over 150 received contrast. 4 of these had values for long-term serum creatinine, and 3 of them experienced an increase from baseline no greater than 27%. The 4th experienced a decrease of roughly 30%. Although tempting, the number of observations is simply too small to draw any conclusions as to the long-term effects of contrast-media in these patients. This is an interesting topic for future research as the long-term effects of CM are widely understudied in critically ill patients with decreased kidney function at time of contrast

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does not pose an immediate increased risk to the critically ill patient, then the potential long-term effects should be of consideration when ordering radiological exams. More research is desired.

Differences between Hospitals

There were several differences in baseline characteristics between hospitals. Significant variations were found in rates of hypertension between Gävle and Uppsala (26.2% vs. 42.4% respectively) and prevalence of AKI within 3 days (45.4% vs. 34.0%, respectively), see table 7.

Table 7: Baseline characteristics between hospitals

Hypertension

The reason for discrepancies between hypertension in Gävle and Uppsala was underreporting of hypertension. This was due mainly to a system wide e-journal update which resulted in

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hypertension rates between study groups. The underreporting of hypertension at Gävle County Hospital should not have a significant effect on the results of this study, and if anything would lead to an overestimation of the risk of contrast media in the development of AKI found in this study.

AKI within 3 days

This study was neither designed to observe or explain inter-hospital differences nor function as a quality control study. The prevalence of AKI in this patient population was 45.4% at Gävle, and 34.0% at Uppsala. This is however markedly less than the prevalence reported in the

multinational AKI-EPI study of 57.3%. Due to the nature of the study it is difficult to draw any conclusion as to why there exists a discrepancy, and nor is it the main focus of this paper. Interesting to note, however, is that in a multivariate analysis of factors influencing AKI risk, hospital choice was only a significant factor on Day 1. On Day 2 and Day 3 post-examination there was no significant effect of hospital choice. See Appendix C.

Limitations

Selection of Control Group

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remain unchanged. This should even result in a slight decrease of total AKI incidence in the control group, but due to the relative size of the sample group this number is highly unlikely to have a significant effect on the data. The author does however believe that such contingencies should be accounted for in future studies, either by excluding such patients or placing them in the study group.

Urine Production as a Definition of AKI

Due to the nature of the documentation program PASIVA, urine production is recorded as a 24 hour total. According to KDIGO, AKI is defined in 6-12 hour increments, which are missed by the 24 hour total. This means that a patient who is anuric for 6 hours may then produce enough urine under the following 18 hours to generate a 24- hour average that does not fill AKI criteria. It is difficult to determine how significant a role the underestimation played in this study. There is no logical reason that there should be a difference between the control and study group, as urine measurement is standardized for all patients treated at the ICU at both hospitals. As such this should not have had a significant effect on the results of this study.

Estimation of Baseline Creatinine

135 (35.2%) of patients had no recorded baseline creatinine and were given an estimated value using the Modification of Diet in Renal Disease (MDRD) Study equation. The MDRD formula considers race, which was not used in this study as the data is not readily available. The formula can be used to calculate a baseline creatinine based on an assumed GFR of 75ml/min/1.73m2 and has been validated in studies (Závada et al., 2010). It is however known that the formula

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Future Prospects

Isolation of CM risk in development of AKI is a monumental task primarily due to the number of confounding variables and difficulty in identifying a reliable control group. The holy grail of clinical research, a double-blind randomized control trial, is near unthinkable in the ICU setting due to the sensitive nature of the care provided. This forces researchers to employ creative means to develop and perform high-quality studies. Large retrospective cohort studies are a viable alternative and should include a matched control group and use the widely supported definition of acute kidney injury as detailed in the KDIGO report (“KDIGO Clinical Practice Guideline for Acute Kidney Injury,” 2012). Although most ICU care is concerned with the immediate risk to patient life, long-term implications should be considered. It would be of interest to perform a prospective study where serum creatinine levels are recorded 3 and 6 months after ICU treatment. This would provide a relatively simple and cheap way to ensure reliable data and evaluate quality of treatment in the long term.

Concluding remarks

This study was unable to demonstrate an increased risk of AKI after administration of contrast media in critically ill patients. We have shown that the risk of contrast media in the context of AKI pales in comparison to factors of greater importance. Of continued interest is the effect of contrast media on long-term creatinine values. Despite its limitations this study was able to hint that contrast media had no effect on long-term creatinine values. Continued research is desired to further enhance patient care in both the short term and the long term.

Special thanks

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Appendix A

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Appendix C

Short term effects on Creatinine, significance analysis