Introduction
Recent clinical commentaries suggest that acute kidney injury (AKI) is more likely to occur following cardiac catheterisation and intervention than with contrast-enhanced computed tomography (CECT), especially in renally compromised patients [
1,
2]. Some have questioned whether the differential rates of AKI are the result of contrast-induced nephropathy (CIN) or factors related to the cardiac catheterisation procedure itself, and/or the greater degrees of pre-existing comorbidities found in patients with cardiac disease [
1‐
5]. Post cardiac catheterisation cerebral emboli have been described in up to 15% of patients detected by transcranial Doppler and diffusion-weighted magnetic resonance imaging (MRI) [
6,
7] and myocardial microinfarcts in 28% detected by MR [
8‐
10]. We are not aware of any imaging studies that have assessed possible analogous renal complications, although they would seemingly be likely to occur.
Focal, segmental nephrograms on delayed CT scans have been uncommonly reported, but are believed to be a possible indication of AKI, related to focal renal ischemia. Yamazaki et al. [
11] and Monsky et al. [
12] observed segmental, wedge-shaped nephrograms, as well as global nephrograms on delayed CT scans following transarterial chemoembolisation (TACE), with the global nephrograms being associated with AKI. Monsky et al. [
12] postulated that the delayed CT segmental nephrograms could represent foci of renal injury secondary to renal emboli related to the catheterisation procedure itself.
Other studies have suggested that a persistent nephrogram is an indicator of significant AKI. Older et al. [
13] and Love et al. [
14] reported that persistent, bilateral and global nephrograms detected by either plain radiography or delayed CT are indicative of acute renal failure (ARF) related to CIN.
The meaning remains unclear whether there is a correlation with the incidence of CIN or cardiac catheterisation. We describe the 24-h delayed nephrographic CT findings and compare these with procedure time, amount of contrast material (CM) administered and changes in the serum creatinine (SCr).
Discussion
We report a frequent occurrence of persistent nephrograms detected by CT 24 h after cardiac catheterisation with or without intervention. Focal nephrograms were observed in 34% (10/29) and bilateral global nephrograms in 45% (13/29) of patients. Positive correlations were found between fluoroscopic procedure time for focal nephrograms and both CM dose and fluoroscopic procedure time for the global nephrograms. There was no correlation between global nephrograms and baseline renal function defined by the eGFR. Increases in SCr at 24–72 h post cardiac catheterisation did not show a relationship to the occurrence of global nephrograms. Four of 29 (14%) of subjects experienced either one or both an increase in SCr ≥44 μmol/l (0.5 mg/dl) and ≥25%. These are significant enough transient changes in kidney function to qualify for the criteria defined for CIN [
16], although the numbers are too small to establish a direct link to the CM, alone, versus other potential risk factors. No subjects required extended hospitalisation or additional medical management.
Segmental, wedge-shaped nephrograms on delayed imaging studies have been uncommonly reported. Anecdotal case reports were described by Ishikawa et al. [
17] in 1985, by Pazimiño et al. [
18] in 1983, by Braedel et al. [
19] in 1987, and by Trueba-Arguinareña et al. [
20] in 1977. Yamazaki et al. [
21] reported focal residual contrast media in 16% (17/105) of patients by delayed CT at 24 h following abdominal angiography and found no association with CIN. The focal nephrograms were related to larger volumes of contrast media. No specific etiology for these findings was offered.
Monsky et al. [
12] described wedge-shaped or linear peripheral nephrograms in 24-h delayed CT scans in 23.3% (14/60) of patients having undergone TACE and found a statistically significant (
P = 0.029) relationship with procedure time. These authors postulated that these foci represent segmental ischemia and trapped CM in the tubular lumen. Possible etiologies include emboli from either blood or cholesterol plaques from the catheterisation procedure itself.
The well-perfused parenchyma clears the CM, which has a normal biologic half-time of about 1.5 h. However, in the areas with segmental ischemia, the CM does not empty, and sodium and water continue to be reabsorbed from the tubular lumen and with a persistence or even an increase in CM concentration. This results in accentuation of the focally ischemic region in comparison with the normal parenchyma (Figs.
2a, b,
3a-c and
4a, b). Cholesterol emboli have been reported to occur in association with angiographic procedures [
22,
23]. Furthermore, clots can form around the indwelling catheter. Research has shown that angiographic techniques can lead to the release of particles, presumably made up of bits of clot and fatty plaque material, into the blood. It has also been reported that cholesterol emboli are a known cause of ARF [
23].
We do not have a control group of subjects having delayed non-contrast CT scans after CECT, but Jakobsen et al. [
24] studied 60 healthy male volunteers by delayed CT at varying doses of iodixanol at four time points up to 5 days after injection. These investigators reported global, but no focal nephrograms.
Prior studies have indicated the observation that microemboli occur in the brain and the heart, making it highly likely that renal emboli may likely occur. Büsing et al. [
6] prospectively evaluated the incidence of embolic cerebral infarction 12–48 h following diagnostic and interventional coronary angiography in 48 patients using diffusion weighted cerebral MR imaging finding an incidence of 15% (7/48), all of whom were asymptomatic. There was a statistically significant (
P = 0.017) association with the cardiac catheterisation procedure time. They postulated that cerebral emboli associated with catheterisation could be the result of loosened atherosclerotic plaque caused by catheter manipulation, thrombus formation at the catheter, air embolism or, in rare circumstance, foreign material from the catheter or guidewire. The femoral approach was used in all cases.
Lund et al. [
7], using multifrequency transcranial Doppler, detected cerebral emboli in 15% of 47 patients undergoing left heart catheterisation. Neuropsychological assessment of 42 of these subjects showed that seven (16.7%) had post catheterisation cognitive impairment.
Myocardial microinfarcts have also been identified after percutaneous coronary intervention [
8‐
10]. Selvanayagam et al. [
8] studied 50 subjects after intervention and found that 28% of them had delayed enhancement on cardiac MR images.
We excluded patients with chronic kidney disease (CKD) defined as an eGFR <60 ml/min per 1.73 m
2, subjects [
25] who are known to have a much greater risk for AKI following cardiac catheterisation and intervention. This may explain our low rate of AKI as determined by changes in SCr. Further, subjects with CKD require a lesser degree of AKI (change in GFR) to manifest changes in SCr due to the non-linear relationship between GFR and SCr. Changes in the eGFR metric cannot be used to assess AKI, since it established only in steady state CKD subjects [
15]. We have not used the term “CIN” in reporting manifestations of AKI as we agree with others that “CIN” presumes causality that may not exist [
2,
4,
5,
26].
The diagnosis of AKI related to CIN is usually based on an elevation of SCr of either ≥44 μmol/l (0.5 mg/dl) and/or an increase ≥25% over 24–72 h after the initial insult [
16,
27]. However, it is well known that SCr is a poor marker of early renal dysfunction because its concentration is influenced by numerous non-renal factors [
5,
28]. It is of even lesser utility in AKI because patients are not in a steady state and substantial rises are not detected until 48–72 h after the initial insult. Significant renal disease can exist with minimal change in SCr because of renal reserve and enhanced tubular secretion of creatinine [
29,
30]. On the other hand, significant random SCr fluctuations can occur as “background noise,” as pointed out by Newhouse et al. [
2]. It is, thus, possible that the nephrographic patterns detected by non-contrast CT are more sensitive indicators of AKI and should be compared with urinary biomarkers, rather than SCr.
The bilateral global nephrographic pattern is possibly less easy to understand. Some previous reports have equated this observation to ARF and CIN [
13,
14]. Our review of that literature and the current results of this study do not necessarily document a clear association with either (Table
7). The poor sensitivity of SCr, especially in mild cases of AKI, may be an explanation for the lack of consistently proven association between persistent nephrograms and AKI.
Table 7
Summary of reports on persistent global nephrograms
| Persistent nephrograms on plain films 24 h after angiography in 17/90 (19%) of patients of which 9/17 (53%) did have and 8/17 (47%) did not have significant change in renal function | ↑SCr ≥20% or 26.40 μmol/l | HOCM |
| Delayed CT cortical enhancement of 141.6 HU 22–26 h after angiography in 1/50 (2%) with any significant change in renal function. Cortical enhancement of 55–110 HU classified as “subclinical renal impairment” | ↑SCr = 150% of baseline or 88 μmol/l | HOCM and LOCM |
Jakobsen et al. (1992) [ 24] | Cortical attenuation of 52 ± 6 HU at 8–32 h in 40 healthy male volunteers after CECT. No change in renal function. (No focal CT nephrograms reported) | ↑SCr, Cr Cl and urinary biomarkers | LOCM, LOCM ionic dimer |
Yamazaki et al. (2001) [ 11] | Delayed CT cortical enhancement 16–21 h after TACE in 81/180 (45%) and nephropathy in 11/180 (6%) of treatments. Minimal cortical retention >50 HU and severe retention >100 HU | ↑SCr ≥44 μmol/l or ≥25% | HOCM, LOCM, LOCM ionic dimer |
Monsky et al. (2009) [ 12] | CT renal nephrograms 24 h post TACE in 14/60 (23.3%) treatments. Global nephrograms associated with significant (p = 0.031) change in SCr at 24 h. (Delayed segmental nephrograms associated with procedural factors) | ↑SCr at 24 h and 24 h from baseline pre-TACE values | IOCM and LOCM |
Love et al. [
14] proposed a cortical attenuation of 55–110 HU at 24 h to identify patients with subclinical renal impairment and attenuations in excess of 140 HU to be an early indicator of CIN. On the other hand, Jakobsen et al. [
24] demonstrated persistence of the cortical nephrogram by sequentially timed delayed CT scans and postulated that retention of CM occurred in the proximal tubular cells and was greater for the nonionic dimer, iodixanol, in comparison with nonionic monomers. The HU levels we have observed and those reported by Yamazaki et al. [
11] and Monsky et al. [
12] are generally much higher. More than 98% of the iodixanol administered should be excreted within the first 24 h.
It is possible that the persistent global nephrogram is not specific for AKI, but can be a manifestation of significant physiological alteration. Catheter manipulation, intraluminal aortic pressure changes due to bolus injections, temperature changes and CM effects on the endothelium could result in significant stimulation of a richly innervated visceral/endoluminal sympathetic nervous system leading to bilateral renal vasoconstriction [
31]. This could lead to stagnation of CM in the tubular lumen and with a prolonged retention time. The medullary region could “flush” the distal tubular CM by persistent and possibly enhanced tubular secretion. This could be an explanation for the unexpected higher cortical than medullary attenuation. Indeed, it has been shown that the tubular secretion of endogenous creatinine increases significantly with ARF and acute glomerular diseases [
29,
30,
32]. The expected typical CT nephrographic pattern following a CM i.v. bolus, for example, at 4 ml/s, is an immediate corticomedullary differentiation followed by a homogenous nephrogram.
It might seem a reasonable possibility that the poorer the baseline renal function, the longer the retention of CM. However, we did not observe a statistically significant correlation between baseline eGFR and the presence of the persistent nephrograms. These results suggest, on the other hand, the higher probability of other factors that are procedurally related as a cause.
The strengths of this study include its prospective nature, the comprehensive clinical data, especially a close monitoring of renal function, and the high rates of persistent nephrograms. The latter observations provide a foundation for a potentially rich opportunity for future investigation. The ability to detect focal nephrograms would appear useful to detect the side effects of renal emboli, providing a scoring system for guiding further innovations in cardiac catheterisation techniques. Persistent global nephrograms appear to reflect important alterations in renal physiology. Extreme alterations, especially in more vulnerable subjects with renal insufficiency could then manifest as AKI.
Weaknesses in this study include the small patient population. However, this is a pilot study and, as noted above, the findings of persistent nephrograms have been observed to be at surprisingly high rates. Only four subjects manifested significant changes in renal function as measured by their SCr. Thus, no firm conclusions can be made about any specific risk factors or relationships to CIN. The major risk factor for CIN is pre-existing renal insufficiency which was not an enrollment criterion in this study. Also, and as emphasised by Newhouse et al. [
2], one must be cautious not to attribute all cases of AKI to the CM, per se, in order to avoid the post hoc, ergo propter hoc logical fallacy. Future studies will expand enrollment to include these subjects.
We did not acquire pre-cardiac catheterisation CT scans as baseline and we may have overestimated the occurrence of global nephrograms. However, we derived our subjective nephrogram ratings regarding this aspect of the study from our previous work where we did have access to this information, as reported by Monsky et al. [
12]. Also, the delayed renal attenuation, we observed and defined as positive nephrograms, is similar to that reported and summarised in Table
7. It is unlikely that we have over-estimated the focal nephrogram findings since no patient was enrolled if they had had CM with 72 h of their cardiac catheterisation procedure.
Dual-energy scan data were inadvertently lost in 11/29 patients. We used a methodology described in the “
Electronic supplementary material” section that employed a novel technique of training sets derived from the data on the successfully acquired dual-energy data sets. We believe iodine quantification is a valuable approach, noting high correlation coefficients between our total renal iodine determinations and right and left kidneys, cortical HUs, global nephrograms, CM dose and fluoroscopic procedure times.
We estimate an additional radiation dose of approximately 3.4 mSv for these CT scans, which is another negative aspect of our study. However, the incremental dose compared with the cardiac catheterisation procedure is small, the images are limited to the kidneys, and can be rapidly performed.
In conclusion, delayed CT nephrograms post cardiac catheterisation and intervention manifest a high positive occurrence of both segmental and global nephrograms. These findings correlate with procedural factors such as fluoroscopic time and total amount of contrast medium utilised. Our data, and what has been previously reported, are yet too limited to prove a relationship between the global nephrogram and CIN.