Acute effects of Iodixanol on renal function after intra-arterial administration in patients with end-stage kidney disease

Abstract

BACKGROUND:

Contrast-induced acute kidney injury (CI-AKI), a potentially life-threatening complication of iodinated contrast media in patients with impaired renal function, has attracted increasing attention in recent years. There is overwhelming evidence that the most important pre-disposing factor for a contrast-medium induced nephropathy is the pre-existence of a renal impairment.

METHODS:

The registry was performed as a part of a quality management project in the Dresden-Friedrichstadt heart catheter laboratory. In compliance with the Declaration of Helsinki/Somerset West, 9,026 patients were included between 2010 and 2015. 100 patients of these were participants in a chronic dialysis program. All patients were dialyzed on the day before angiography. In all patients a coronary angiography, in 28 patients a stent implantation and in 12 patients a surgical reconstruction had to be performed. Prior to the intervention and one, two and three days thereafter the serum creatinine was measured.

RESULTS:

Up to the third day after application of the iodinated contrast medium no significant changes of the serum creatinine (baseline value: 423.3±42.6μmol/l) occurred (ANOVA for repeated measures: p = 0.507). On average, a slight decrease of the serum creatinine was found.

All patients remained in their routine dialysis-program. 18 out of 100 died during the next three months after the procedure.

CONCLUSION:

The study revealed that the coronary angiography using Iodixanol as iodinated contrast medium did not result in an increase of serum creatinine, which was drastically elevated in these patients before application of the iodinated contrast medium.

Keywords

Keywords: Iodixanol renal insufficiency dialysis serum creatinine

1 Introduction

The assessment of contrast-induced acute kidney injury (CI-AKI) is controversial in the literature and ranges from the judgement “There is no CI-AKI” to “CI-AKI is the leading cause of hospital-aquired renal failure (ARF)”. Reasons for this seem to be that very different groups of patients (outpatient - inpatient, coronary patients, orthopaedic patients, etc.) received different iodinated contrast media (CM) or very different amounts of CM (or repeated doses), which were administered intravenously or -arterially and with or without prior hydration. But also differences in the definition of CI-AKI itself contribute to this. This could explain the considerable differences in CI-AKI prevalence reported between >2% in the total population and 20% –30% in high-risk patients (overview in [1]).

It is generally acknowledged that in individuals with normal renal function, the risk of CI-AKI is negligible and it seems that the risk of CI-AKI after intravenous application has been overestimated [2, 3]. However, high-risk patients (such as patients with accompanying kidney disease, diabetics, patients with heart failure or patients of very advanced age) are considered at risk for a CI-AKI [4 –17]. According to the recommendations of the updated ESUR Contrast Medium Safety Committee guidelines (European Society of Urogenital Radiology) [16] the principal risk factor for CI-AKI is impaired renal function [16], especially, when repeated CM injections were performed in a short period (48–72 h) [16].

Beyond, chronic kidney disease (CKD) is an independent risk factor for the development of coronary artery disease and the leading cause of death in CKD-patients [18, 19], with increasing risk as renal function declines. However, patients with end-stage kidney disease must also be examined using CM when there is a clear indication for coronary angiography. Within the scope of the present register, the renal function of patients with end-stage renal failure who were referred for coronary artery disease, for coronary angiography or for stent implantation was therefore analyzed after intra-arterial X-ray contrast medium application.

2 Material and methods

2.1 Study objectives

The aim of the study was to determine the prevalence of CI-AKI after iodixanol application during coronary angiography or coronary intervention in patients with end-stage kidney disease. In addition, the course over time of serum creatinine was examined after the procedure.

2.2 Study design

The registry was performed as a part of a quality management project in the heart catheter lab of the hospital Dresden-Friedrichstadt between March 2012 and December 2016 in compliance with the declaration of Helsinki [20]. During this period, a total of n = 9,026 patients were included. 100 of these patients, who were in a chronic dialysis program, were included in the present analysis. All patients were to be well hydrated before angiography according to their heart and kidney function. It was recommended, but not required, that patients received 500 ml of water orally, 500 ml of saline intravenously, or both before the angiography, followed by 1 liter of 0.9 percent saline or similar fluids intravenously from the start of the procedure.

Iodixanol (Visipaque320trademark) was used as CM. Prior to the procedure and at the 1., 2. and 3. day after the procedure serum creatinine was measured. After 12 months, a telephone enquiry was made regarding the survival of the patients. In addition, demographic, clinical and procedural data were recorded.

The study was performed in compliance with the ethical guidelines of Clinical Hemorheology and Microcirculation [21].

3 Quantification methods

Serum creatinine (sCrea) was measured according to Jaffe’s photometric method [22]. Interassay coefficients of variations (CV) for normal creatinine concentrations were 4.1% for normal or 1.3% for high creatinine concentration. The reference range is between 63 and 100μmol/l for men and between 48 - 85μmol/l for women [23].

The glomerular filtration rate (GFR) is the total volume of primary urine that is filtered by all glomeruli of both kidneys together, in a defined time unit. The GFR is the most important parameter for estimating the renal function. It was calculated according to the MDRD formula [24].

GFR [ml/min/1.73 m²] = 186 * sCrea^–^1,154 * Age^0,203 * F

With: F := 0.742 when it’s a female patient, males 1.0.

4 Statistical analysis

Descriptive statistics (sample size, mean value, standard deviation, median, minimum and maximum values) were used to summarise continuous variables, frequency counts and percentages were used to summarise ordinal data (visual scores).

The t-test for unpaired samples was performed for two-sample problems and a one-factorial variance analysis with post-hoc analyses for multiple-sample problems. Results of the test statistics are considered significant if p was less than 0.05.

Linear correlations were performed between creatinine – increase, demographic data (age, sex), clinical data (glomerular filtration rate, baseline creatinine, diabetes mellitus, vascular disease) and procedural data (amount of contrast medium).

5 Results

5.1 Patients

Of the 9,026 patients, 100 had end-stage renal disease. All were in a chronic dialysis program. The patients were aged between 54 and 92 years (64±37 years), 84 were male. The average size was 171±18 cm, the body weight 85±21 kg. At the time, two patients of coronary angiography were in stage 2 (GFR mildly decreased), 4 patients were in stage 3 (GFR moderately decreased), 29 in stage 4 (GFR severely decreased) and 65 in stage 5 (kidney failure) according to the GFR category of the US National Kidney foundation [25].

89 patients had arterial hypertension, 60 had diabetes mellitus, 63 had hyperlipidemia and 10 were smokers.

All patients had an indication for coronary angiography (acute coronary syndrome (24), angina pectoris / dyspnea (34/8), condition after resuscitation (7), limited ejection fraction (EF) / stress examination (19/6), others (16)). An average of 64±37 ml Iodixanol was applied to patients undergoing angiography alone and 128±70 ml to patients undergoing intervention (Table 2).

Table 1
Glomerular filtration rate categories in chronic kidney disease [25]

Stage GFR [ml/min/1.73M²] Characterization

Stage 1 >90 Normal or high GFR

Stage 2 60–89 Mildly decreased GFR

Stage 3 30–59

A 45–59 Mildly to moderately decreased GFR

B 30–45 Moderately to severely decreased GFR

Stage 4 15–29 Severe kidney disease

Stage 5 <15 kidney failure

Stage	GFR [ml/min/1.73M²]	Characterization
Stage 1	>90	Normal or high GFR
Stage 2	60–89	Mildly decreased GFR
Stage 3	30–59
A	45–59	Mildly to moderately decreased GFR
B	30–45	Moderately to severely decreased GFR
Stage 4	15–29	Severe kidney disease
Stage 5	<15	kidney failure

Table 2

Angiographic findings

Iodixanol–group	n=100
no stenosis	6
stenosis < 30%	18
1–vessel disease	14
2–vessel disease	26
3–vessel disease	37

28 of the patients received at least one coronary stent, 12 patients had to undergo cardiac surgery and all other patients further received conservative treatment.Fig. 1 shows the initial serum creatinine values in μmol/l of the included patients.

Fig.1

Serum creatinine values [μmol/l] prior to coronary angiography (The red line marks the reference range).

In 60 of the 100 patients, creatinine levels were followed-up (the remaining 40 patients left the hospital). The mean serum creatinine concentration during the three days after coronary angiography is shown in Fig. 2.

Fig.2

Serum creatinine concentration [μmol/l] after CM application followed up to 72 hours.

The mean serum creatinine concentration did not change after the injection of Iodixanol during the follow-up period of three days (p = 0.693), although 56 of the 60 patients were in a stage of severe GFR decrease or had kidney failure, and only 4 of the patients were in a moderately decreased GFR stage. In total, there was an increase in 32 patients and a decrease in creatinine levels in 28 patients. In 22 of the patients there was an increase of more than 44.2μmol/l relative to the starting value of serum creatinine. In 15 of these patients the increase relative to the starting value was even greater than 25%. The changes in the creatinine values – shown are the maximum changes in creatinine values as an increase or decrease during the three-day follow-up period –are related to the respective baseline values and are shown in Fig. 3.

Fig.3

Serum creatinine [μmol/l] with 95% confidence intervals in relation to the maximal change of creatinine during the three days of follow-up.

There was no correlation between the creatinine baseline values and the maximum changes in the post-angiography phase up to the third day (r = 0.001; p > 0.9931). This applied, both, to patients only undergoing angiography (r = 0.0019; p = 0.901) and to patients undergoing interventions (r = 0.052; p = 0.8542).

The maximum change in creatinine values during the follow-up period seem to be negligible on average at 25.6±190.0 [μmol/l]. However, Fig. 3 shows that sometimes considerable increases or decreases in creatinine values, ranging from a maximum decrease of 386 [μmol/l] up to an increase of 721 mol/l occurred.

Of the 100 patients, 18 died in the observation period of one year (9 after acute myocardial infarction, two after pulmonary embolism, two succumbed to a tumor disease and 4 patients died of septic shock). The cause of death could not be determined for 1 patients.

6 Discussion

The administration of CM can have an immediate negative impact on the physiology of the kidney, including vasoconstriction [26], diminished perfusion in different areas of the kidney (superficial, midcortical and iuxtamedullar [27, 28]) including the microcirculation [26], an increase in apoptotic pathways and oxidative stress [29, 30]. Therefore, CI-AKI remains an important cause of sudden impairment of renal function.

Far from being just a transient phenomenon, CI-AKI has consistently been shown to be associated with adverse outcomes. In individuals with normal renal function the risk of CI-AKI seems to be negligible, however, a pre-existing renal disease is its greatest independent risk factor [3 –15]. However, there are only scarce data about CI-AKI in patients with severe kidney disease or kidney failure. Most of the studies included patients with moderately elevated serum creatinine. The first study to suggest that there was a reduced incidence of nephropathy after iodixanol application was published by Chalmers and Jackson, who investigated 124 patients with serum creatinine concentrations of more than 1.7 mg per deciliter [31]. In that unblinded study, the incidence of nephropathy (defined by an increase of 25 percent or more in the serum creatinine concentration) in the Iodixanol group was 3.7 percent. The Nephric study [32] involved 129 diabetic patients with serum creatinine concentrations between 1.5 and 3.5 mg per deciliter who underwent coronary or aorto-femoral angiography. Two of the 64 patients in the Iodixanol group (3%) had an increase in the creatinine concentration of 44.2μmol/l or more, extending the results of the Chalmers-study to a population at higher risk for contrast-medium–induced nephropathy.

Our study was performed in patients with severe kidney disease, where 93.3% of all patients were in stage 4 (severely decreased GFR) or 5 (kidney failure) according to the GFR category of the US National Kidney foundation [25]. The study revealed that coronary angiography using Iodixanol as iodinated contrast medium in patients with end-stage kidney disease did not result in an increase of serum creatinine on average.

In the CRIC study, 4.85% of 1,705 patients with a glomerular filtration rate of less than 30 ml/min/1.73m² died per year [33]. For those patients who additionally participated in a dialysis program 9% died per year. In our study, GFR was even less than 15% in 60% of the patients, so that the increased mortality rate of 18% per year could possibly be explained by very advanced renal failure. Also, the advanced age of the patients could certainly contribute to this since 39% of the patients were older than 80 years.

7 Conclusion

These data underline and extend the statement of Ewing & Eidt [36] that Iodixanol, especially, can be utilized when alternate diagnostic or therapeutic options are comparatively ineffective or even hazardous in patients with severe kidney dysfunction.

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