Diagnostic value of contrast-enhanced ultrasound (CEUS) in kidney allografts – 12 years of experience in a tertiary referral center

Abstract

BACKGROUND:

B-Mode and Doppler ultrasound are standard diagnostic techniques for early postoperative monitoring and long-term follow-up of kidney transplants. In certain cases, contrast-enhanced ultrasound (CEUS) is used to clarify unclear Doppler findings.

OBJECTIVE:

To investigate the diagnostic performance of CEUS in the workup of renal allograft pathologies.

METHODS:

A systematic search for CEUS examinations of renal transplants conducted in our department between 2008 and 2020 was performed using the following inclusion criteria: i) patient age ≥18 years and ii) confirmation of diagnosis by biopsy and histopathology, imaging follow-up by CEUS, contrast-enhanced computed tomography (ceCT), contrast-enhanced magnetic resonance imaging (ceMRI), or angiography, or intraoperative findings. Exclusion criteria were: i) CEUS performed in the setting of a study and ii) CEUS for other indications than dedicated renal transplant examination. Statistical analysis was performed separately for subgroups with different indications (focal vs non-focal).

RESULTS:

Overall, 78 patients were included in the statistical analysis, which revealed high sensitivity (92.2%, 95% -confidence interval [CI] 81.5–96.9%) and high specificity (88.9%, 95% -CI 71.9–96.1%) of CEUS.

CONCLUSIONS:

The high diagnostic performance demonstrated here and the superficial location of kidney allografts advocate the additional use of CEUS in the follow-up of renal transplant recipients.

Keywords

Renal ultrasound contrast-enhanced ultrasound CEUS sensitivity specificity renal transplant

1 Introduction

In renal transplant imaging, Doppler and B-mode ultrasound (US) are the primary modalities and can be used for both intraoperative imaging and through monitoring from early postoperative period to long-term follow-up [1, 2]. If US findings are inconclusive, Sugi et al. recommend magnetic resonance imaging (MRI), contrast-enhanced ultrasound (CEUS), and biopsy as further diagnostic options [1]. Ghonge et al. also advocate multimodality imaging, emphasizing the many advantages of US including its inexpensiveness and simple accessibility, which allows bedside examination, for instance [2].

Along with the advantages of US, rapid technical innovations in this field have led to the advent of further sonographic submodalities and multiparametric US (mpUS) protocols that combine various US parameters for comprehensive assessment [3]. One component of mpUS is CEUS [3]. These submodalities have been shown to be useful in postinterventional imaging as well [4]. A major benefit of CEUS is that it allows real-time dynamic imaging of perfusion, for example, of the renal allograft [2]. However, the use of CEUS in kidney transplants is off-label. Nevertheless, in their 2017 guidelines, the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) report strong consensus regarding the use of CEUS for identifying vascular complications and renal cysts or characterizing intermediate lesions in kidney transplants [5].

There is growing evidence confirming the value of CEUS in the diagnosis of renal transplant complications. For example, Mueller-Peltzer et al. investigated the diagnostic accuracy of CEUS in 22 patients with suspected renal transplant malignancy using computed tomography (CT) or MRI as reference standard [6]. They reported 100% sensitivity and 94.4% specificity for CEUS in this setting [6]. For use of CEUS in transplant recipients with suspected vascular rejection of the kidney allograft, the same investigators found 85.7% sensitivity and 100% specificity considering histopathology as the gold standard [7]. Moreover, CEUS has also been shown to improve the accuracy of Doppler US in the evaluation of transplant renal artery stenosis [8]. Overall, available evidence suggests that CEUS is beneficial in the diagnostic evaluation of both focal and non-focal conditions affecting renal transplants.

The aim of this study was to systematically investigate the clinical role of CEUS in the diagnostic evaluation of kidney transplants in general and in the detection of transplant pathology in particular.

2 Material and methods

This retrospective analysis was registered at the local ethical committee of our institution (EA1/320/20).

2.1 Study population

As part of the routine clinical procedure at our department, all patients gave written informed consent to anonymized use of their data prior to imaging. All study data were collected in compliance with the principles expressed in the 2002 Declaration of Helsinki.

The retrospective analysis included patients who underwent CEUS of their kidney allograft in our department from 2008 to 2020. Inclusion criteria were: i) patient age ≥18 years and ii) confirmation of diagnosis by biopsy and histopathology, imaging follow-up by CEUS, contrast-enhanced computed tomography (ceCT), contrast-enhanced magnetic resonance imaging (ceMRI), or angiography, or intraoperative findings. Exclusion criteria were: i) CEUS performed in the setting of a study and ii) CEUS for other indications than dedicated renal transplant examination.

Clinical information including sex, age (of recipient), date of kidney donation, living or cadaver donation, donor age, and cold ischemia time, if available, were collected. The interval been transplantation and time of CEUS examination was categorized as follows: up to 2 weeks; over 2 weeks to 3 months; and over 3 months.

2.2 Diagnostic performance

For all patients, the written reports on CEUS examinations were reviewed for to the final diagnosis. If the diagnosis was inconclusive, we additionally evaluated documented US images. For subgroup analysis, we defined a group with focal transplant lesions and a group with nonfocal conditions. In addition, CEUS findings were subdivided into further categories: infarction, cortical necrosis, rejection or acute tubular necrosis, renal artery stenosis, renal vein thrombosis, tumor, inflammation, and organ scar.

2.3 Imaging protocol

Gray-scale B-mode imaging of transplant kidneys was performed using a convex array transducer to assess renal size, echogenicity, and homogeneity.

Standardized Doppler US was performed to assess venous outflow and arterial circulation and to calculate resistance indices (RI) for different segmental arteries (at the pyeloparenchymal border). Power Doppler imaging was used to identify focal perfusion loss.

CEUS examinations were performed as part of clinical routine using high-end ultrasound systems (Aplio 500/i900, Canon Medical Systems Corporation, Tochigi, Japan; Acuson Sequoia/S3000, Siemens Healthineers, Mountain View, CA, USA; GE Logiq E9, GE Healthcare, Chicago, Illinois, USA) with state-of-the-art CEUS-specific protocols available at the time of examination. All convex transducers employed in study patients were required to be for abdominal use with a frequency range of 1–6 MHz. The very-low-mechanical-index (< 0.1) technique was used to avoid early microbubble destruction. A bolus of 1.2–1.6 mL of ultrasound contrast agent (SonoVue®, Bracco Imaging, Milan, Italy) was injected up to three times, if necessary. Immediately after contrast agent injection, the kidney allograft was scanned for at least five minutes to capture the late contrast phase.

2.4 Reference standard

Histopathology, CEUS, ceCT, ceMRI, percutaneous angiography, and intraoperative findings were defined as adequate reference standard methods. Biopsies were taken only when clinically indicated. Histopathological examinations in suspicion of rejection followed the respectively valid BANFF-classification [9]. Multiphase ceCT examinations (arterial, portal-venous, and/or venous/delayed phase) were performed in a multidetector CT scanner using a standard protocol and ceMRI was performed at 1.5 T or 3.0 T using phased-array body coils and protocols for perfusion analysis. All cross-sectional imaging scans were performed after injection of weight-adapted doses of contrast agent.

2.5 Statistical analysis

Continuous variables are reported as median and interquartile range (IQR), and categorical variables are reported as proportion of absolute number (n/N) and percentage.

Sensitivity and specificity were calculated using cross-tabulation of CEUS findings versus the reference standard.

Equivalently, sensitivity and specificity were determined separately in the above defined subgroups (focal versus non-focal and categories of CEUS findings).

All statistical analysis was performed using the SPSS software (IBM Corp., released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp.).

3 Results

3.1 Study population

Overall, our systematic search retrieved a total of 151 patients who underwent CEUS of their kidney allograft. A total of 73 patients were excluded: 10 patients because they underwent CEUS as part of a study protocol, 53 patients did not have a follow-up examination as defined above, and another 10 patients had a different indication for CEUS or an pathological findings of the renal transplant as secondary findings. A total of 78 patients finally met the criteria for inclusion in our statistical analysis of this investigation. An overview of baseline characteristics of the final study population is provided in Table 1.

Table 1
Baseline characteristics of the total study population

Variable Proportion

Age [years] 56 (46.75–66)

Female sex 19/78 (24.4%)

Renal allograft

Living donation^* 25/59 (42.4%)

Cold ischemia time [hh:mm]^* 03:30 (02:24–11:00)

Donor age [years]^* 59 (47–64.5)

Interval between CEUS and transplant

up to 2 weeks postoperatively^* 25/74 (33.8%)

> 2 weeks to 3 months postoperatively^* 13/74 (17.6%)

> 3 months postoperatively^* 36/74 (48.6%)

Variable	Proportion
Age [years]	56 (46.75–66)
Female sex	19/78 (24.4%)
Renal allograft
Living donation^*	25/59 (42.4%)
Cold ischemia time [hh:mm]^*	03:30 (02:24–11:00)
Donor age [years]^*	59 (47–64.5)
Interval between CEUS and transplant
up to 2 weeks postoperatively^*	25/74 (33.8%)
> 2 weeks to 3 months postoperatively^*	13/74 (17.6%)
> 3 months postoperatively^*	36/74 (48.6%)

Continuous variables are given as median (IQR), categorical variables as absolute/total numbers (n/N) and percentages in brackets. ^*where available. Abbreviations: IQR denotes interquartile range.

The reference modality used was histopathology in 43 cases (55.1%), CEUS follow-up in 16 cases (20.5%), ceCT in 14 cases (17.9), ceMRI in two cases (2.6%), and intraoperative findings or angiography in three cases (3.8%). Histopathological examination was the reference standard in the subgroup of kidney transplant recipients with rejection / acute tubular necrosis (24/25 patients).

The mean interval between the index CEUS examination and the reference examination was 5 days in the subgroup with non-focal indications (n = 55; overall 0–359 days, IQR 1–20 days). In the subgroup of focal lesions, reference imaging modality or histopathology was used for suspicious findings and long-term FU (minimum of two years) for assessment of stable disease to clarify benign findings.

3.2 CEUS examination

In 29.5% of cases (n = 23), CEUS was requested to clarify a focal lesion, whereas, in 70.5% of cases (n = 55), it was requested for clarification of non-focal pathology (perfusion, rejection/ATN). The subgroup of transplants with tumors included 13 cystic lesions, eight non-cystic lesions, one case with both cystic and non-cystic lesions, and one case with a parenchymal scar.

3.3 Overall diagnostic performance

For the total study population, CEUS had a sensitivity of 92.2% (47 of 51 participants, 95% -CI 81.5–96.9%) and a specificity of 88.9% (24 of 27 participants, 95% -CI 71.9–96.1%), see Table 2.

Table 2
Diagnostic accuracies by subgroup

Subgroup Sensitivity Specificity

Infarction 10/11 (90.9%) 2/3 (66.7%)

Cortical necrosis 8/8 (100.0%) 1/1 (100.0%)

Rejection / acute tubular necrosis 20/21 (95.2%) 2/4 (50.0%)

Renal artery stenosis 2/2 (100.0%) 1/1 (100.0%)

Renal vein thrombosis 0/0 (–) 1/1 (100.0%)

Tumor 4/6 (66.7%) 16/16 (100.0%)

Inflammation 3/3 (100.0%) 0/0 (–)

Scar 0/0 (–) 1/1 (100.0%)

Overall 47/51 (92.2%, 95% -CI 81.5–96.9%) 24/27 (88.9%, 95% -CI 71.9–96.1%)

Subgroup	Sensitivity	Specificity
Infarction	10/11 (90.9%)	2/3 (66.7%)
Cortical necrosis	8/8 (100.0%)	1/1 (100.0%)
Rejection / acute tubular necrosis	20/21 (95.2%)	2/4 (50.0%)
Renal artery stenosis	2/2 (100.0%)	1/1 (100.0%)
Renal vein thrombosis	0/0 (–)	1/1 (100.0%)
Tumor	4/6 (66.7%)	16/16 (100.0%)
Inflammation	3/3 (100.0%)	0/0 (–)
Scar	0/0 (–)	1/1 (100.0%)
Overall	47/51 (92.2%, 95% -CI 81.5–96.9%)	24/27 (88.9%, 95% -CI 71.9–96.1%)

Variables are given as absolute/total numbers (n/N) and percentages in brackets.

3.4 Diagnostic performance by subgroup

In the subgroup with focal lesions (n = 23), CEUS had 66.7% sensitivity (4 of 6 participants, 95% -CI 30.0–90.3%) and 100.0% specificity (17 of 17 participants, 95% -CI 81.6–100.0%). In the subgroup with non-focal pathologies (n = 55, Fig. 1), there was 95.6% sensitivity (43 of 45 participants, 95% -CI 85.2–98.8%) and 70.0% specificity (7 of 10 participants, 95% -CI 39.7–89.2%).

Fig. 1

CEUS in the confirmation of renal vein thrombosis. Ultrasound examination of a 47-year old male patient on day 5 after cadaver transplantation. Color-coded Doppler Ultrasound showed no renal venous outflow and were only able to depict central arteries (a). On Duplex Ultrasound, the arterial flow was triphasic with a Resistance Index > 1 (b). On CEUS, only the central arteries showed contrast enhancement, while neither cortical nor medullar contrast enhancement were noticed.

Analysis by category of CEUS findings as described above yielded the following diagnostic accuracy results for the two largest subgroups with non-focal renal graft lesions: in the subgroup of infarction diagnosed by CEUS (n = 14 participants), we found 90.9% sensitivity (10 of 11 participants, 95% -CI 62.3–98.4%) and 66.7% specificity (2 of 3 participants, 95% -CI 20.8–93.9%). Wherein the group where CEUS diagnosed rejection or acute tubular necrosis (n = 25), there was 95.2% sensitivity (20 of 21 participants, 95% -CI 77.3–99.2%) and 50% specificity (2 of 4 participants, 95% -CI 15.0–85.0%), respectively. Subgroup results are summarized in Table 2.

4 Discussion

The main findings of the present study can be summarized as follows: CEUS has an overall diagnostic accuracy of 91.0% in the assessment of kidney allografts with high sensitivity of 95.2% in recipients with rejection or acute tubular necrosis (96.0% correlated with histopathological examination as reference standard) and high specificity of 100% in the subgroup with tumor lesions.

In contrast to these findings, Mueller-Peltzer et al. reported a significantly higher specificity in patients with vascular rejection and a significantly higher sensitivity in patients with suspected malignancy, whereas they found a similar specificity in patients with suspected malignancy as in the present study [6, 7].

Hai et al. performed a meta-analysis of the value of CEUS in the assessment of complications after kidney transplantation [10]. They included 12 diagnostic accuracy studies with a total of 542 cases and found a pooled sensitivity of 86% (95% -CI 78–92%) and specificity of 90% (95% -CI 82–94%) [10]. Overall, external validity was rather heterogenous. The meta-analysis of Hai et al. is comparable to our analysis in that the cases included were not restricted to certain entities or groups of entities [10]. While specificities are comparable, we found approx. 6% higher sensitivity than Hai et al. The difference might be attributable to the high experience of the uroradiologists performing CEUS examinations in our department.

An example of a complication after kidney transplantation which has been diagnosed with mpUS is visualized in Fig. 2.

Fig. 2

Pre- and postoperative 3D CEUS assessment. CEUS examination of a 51-year old female patient on day 4 after cadaver transplantation. The low Resistance Index of 0.42 (a) was suggestive for renal artery stenosis. 3D imaging after injection of 1.6 ml Sonovue® showed a “s-shaped” kinking of the proximal artery (b). Surgical findings during nephropexy confirmed the kinking and urologists re-fixed the renal transplant in a more superficial position. Five hours after surgery, the Resistance Index increased to 0.70 with short acceleration time (c) and 3D imaging after contrast injection revealed no persistence of the kinking.

There was no case of acute pyelonephritis in the present study. This entity was investigated by Granata et al. [10, 11], who reported a limited role of non-enhanced US in this field while they found 95% sensitivity and 100% specificity for CEUS compared with unenhanced MRI as diagnostic reference in 37 patients with pyelonephritis in a total study population of 56 patients [11].

In the present study, 53 cases had to be excluded because no reference was available, accounting for 35.1% of all cases initially considered for inclusion. The reason for this amount of excluded cases is the role of CEUS in our Department as an established modality for renal transplant assessment without need for further imaging.

Quantification of perfusion using CEUS has been investigated for many applications including renal transplants [5, 12]. For example, in their study investigating CEUS in the assessment of early transplant function in 19 patients, Elec et al. suggest that quantitative CEUS parameters might supplement Doppler parameters in assessing kidney allograft vascularization [12]. While data on quantitative CEUS of the renal transplant are still sparse [5] it is an interesting field of research since quantification can reduce the examiner dependency of US [13]. Initial data show that quantitative parameters offer relevant clinical advantages, for example, in the detection of renal allograft rejection [14].

Given the scarcity of scientific data, studies that investigate the reproducibility of typical radiological signs in established contrast-enhanced modalities may be helpful in assessing the significance of CEUS in renal transplant imaging –the reverse rim sign in renal cortical necrosis is a case in point [15, 16].

In this era of limited healthcare resources, the fact that CEUS is the least expensive modality next to contrast-enhanced CT and MRI also plays a role in the follow-up of kidney graft recipients [17].

CEUS may also have a role in long-term follow-up, even if its significance in this area is significantly lower than that of B-mode and Doppler sonography. In a study of 39 kidney transplants, Mori et al. showed the resistive index to have a high sensitivity in relation to loss of graft function, while CEUS showed a higher specificity [18]. The authors attribute the higher specificity of CEUS to the detection of good perfusion [18].

5 Limitations

The present study is limited by its retrospective single-center design and examinations without additional imaging (especially in assessment of early postoperative complications) since CEUS is an established modality appreciated by urologists and nephrologists. Nevertheless, this compromise is justified by ethical concerns since a prospective study would involve additional contrast agent administration in tomographic imaging or histopathological examination in every patient.

6 Conclusions

CEUS is a reliable tool in the diagnosis of renal transplant pathologies suspected on the basis of clinical findings or when initial unenhanced US is inconclusive.

Footnotes

Acknowledgments

The authors thank Ms. Bettina Herwig for language editing of the manuscript.

Conflict of interest

None of the authors reports a relationship with industry and other relevant entities–financial or otherwise–that might pose a conflict of interest in connection with the submitted article. The following authors report financial activities outside the submitted work:

Markus H. Lerchbaumer reports having received payments for lectures from Canon Medical Imaging.

Thomas Fischer reports having received consultancy honoraria from Bracco and Canon Medical Imaging.

Deniz Uluk reports no conflict of interest.

Frank Friedersdorff reports no conflict of interest.

Bernd Hamm reports having received consultancy honoraria from Canon Medical Imaging.

Paul Spiesecke reports no conflict of interest.

References

Sugi

, Joshi

, Maddu

, Dahiya

, Menias

Imaging of renal transplant complications throughout the life of the allograft: Comprehensive multimodality review. RadioGraphics [Internet]. 2019;39(5):1327–1355. Available from: https://doi.org/10.1148/rg.2019190096

Ghonge

, Goyal

, Vohra

, Chowdhury

. Renal transplant evaluation: Multimodality imaging of post-transplant complications. Br J Radiol [Internet]. 2021;94(1124):20201253. Available from: https://doi.org/10.1259/bjr.20201253

Sidhu

Multiparametric ultrasound (MPUS) imaging: Terminology describing the many aspects of ultrasonography. Vol. 36, Ultraschall Med. Germany; 2015, pp. 315–317.

Jung

, Wertheimer

, Putz

, Jung

, Kammerer

, Pregler

, Luerken

, Stroszczynski

, Beyer

. Contrast enhanced ultrasound (CEUS) with parametric imaging and time intensity curve analysis (TIC) for evaluation of the success of prostate arterial embolization (PAE) in cases of prostate hyperplasia. Clin Hemorheol Microcirc.. 2020;76(2):143–153.

Sidhu

, Cantisani

, Dietrich

, Gilja

, Saftoiu

, Bartels

, Bertolotto

, Calliada

, Clevert

D-AD-A

, Cosgrove

, Deganello

, D’Onofrio

, Drudi

, Freeman

, Harvey

, Jenssen

, Jung

E-M

, Klauser

, Lassau

,et al. The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update (Long Version). Ultraschall in Med. 2018;39(2):e2–e44.

Mueller-Peltzer

, Negrão de Figueiredo

, Fischereder

, Habicht

, Rübenthaler

, Clevert

D-A

. Contrast-enhanced ultrasound (CEUS) as a new technique to characterize suspected renal transplant malignancies in renal transplant patients in comparison to standard imaging modalities. Clin Hemorheol Microcirc. 2018;69(1–2):69–75.

Mueller-Peltzer

, Negrão de Figueiredo

, Fischereder

, Habicht

, Rübenthaler

, Clevert

D-A

. Vascular rejection in renal transplant: Diagnostic value of contrast-enhanced ultrasound (CEUS) compared to biopsy. Clin Hemorheol Microcirc. 2018;69(1–2):77–82.

Pan

F-S

, Liu

, Luo

, Tian

W-S

, Liang

J-Y

, Xu

, Zheng

Y-L

, Xie

X-Y

. Transplant renal artery stenosis: Evaluation with contrast-enhanced ultrasound. Eur J Radiol. 2017;9042–49.

Loupy

, Haas

, Roufosse

, Naesens

, Adam

, Afrouzian

, Akalin

, Alachkar

, Bagnasco

, Becker

, Cornell

, Clahsen-van Groningen

, Demetris

, Dragun

, Duong van Huyen

J-P

, Farris

, Fogo

, Gibson

, Glotz

, et al. The Banff Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2020;20(9):2318–2331.

10.

Hai

, Chong

, Liu

J-B

, Forsberg

, Eisenbrey

. The diagnostic value of contrast-enhanced ultrasound for monitoring complications after kidney transplantation-a systematic review and meta-analysis. Acad Radiol. 2021;28(8):1086–1093.

11.

Granata

, Andrulli

, Fiorini

, Basile

, Logias

, Figuera

, Sicurezza

, Gallieni

, Fiore

. Diagnosis of acute pyelonephritis by contrast-enhanced ultrasonography in kidney transplant patients. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2011;26(2):715–720.

12.

Elec

, Elec

, Bolboaca

, Socaciu

, Muntean

, Iacob

, Moisoiu

, Zaro

, Andries

A-I

, Badulescu

, Ignat

, Badea

. Contrast-enhanced ultrasonography in the initial evaluation of the kidney graft function: A pilot study. Med Ultrason. 2020;22(3):272–278.

13.

Jacobsen

, Nolsøe

, Konge

, Graumann

, Dietrich

, Sidhu

, Piscaglia

, Gilja

, Laursen

. Contrast-enhanced ultrasound: Development of syllabus for core theoretical and practical competencies. Ultrasound Med Biol [Internet].-Available from. 2020;46(9):2287–2292. Available from: https://www-sciencedirect-com-443.web.bisu.edu.cn/science/article/pii/S0301562920302209

14.

Como

, Da Re

, Adani

, Zuiani

, Girometti

. Role for contrast-enhanced ultrasound in assessing complications after kidney transplant. World J Radiol. 2020;12(8):156–171.

15.

Fernandez

, Ripolles

, Martinez

, Blay

, Pallardó

, Gavela

. Diagnosis of acute cortical necrosis in renal transplantation by contrast-enhanced ultrasound: A preliminary experience. Ultraschall der Medizin - Eur J Ultrasound. 2012;34(04):340–344.

16.

Spiesecke

, Münch

, Fischer

, Hamm

, Lerchbaumer

. Multiparametric ultrasound findings in acute kidney failure due to rare renal cortical necrosis. Sci Rep. 2021;11(1):2060.

17.

Spiesecke

, Reinhold

, Wehrenberg

, Werner

, Maxeiner

, Busch

, Fischer

, Hamm

, Lerchbaumer

. Cost-effectiveness analysis of multiple imaging modalities in diagnosis and follow-up of intermediate complex cystic renal lesions. BJU Int. 2021;128(5):575–585.

18.

Mori

, Granito

, Favali

, Cappelli

. Long-term prognostic impact of contrast-enhanced ultrasound and power doppler in renal transplantation. Transplant Proc [Internet].-Available from. 2015;47(7):2139–2141. Available from: https://www-sciencedirect-com-443.web.bisu.edu.cn/science/article/pii/S0041134515006521