Abstract
BACKGROUND:
Despite of the more potent immunosuppressive medication, vascular rejection is still a major issue after renal transplantation. Renal biopsy is the gold standard diagnostic to evaluate acute and chronic allograft rejection. As it is an invasive diagnostic there is the risk of complications like haematoma, arteriovenous fistulas, active bleeding or infection. Contrast-enhanced ultrasound is a non-invasive imaging modality that allows visualising renal transplant perfusion.
OBJECTIVE:
To analyse the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) compared to biopsy as gold standard in diagnosing vascular rejection in renal transplant patients.
METHODS:
A total of 57 renal transplant recipients with poor renal allograft function with initial diagnostic imaging between 2006 and 2017 were included in the study. Clinical data and imaging studies were analysed retrospectively. The diagnostic accuracy of CEUS in diagnosing vascular rejection of the renal transplant was compared to renal biopsy as gold standard. Out of 57 patients 7 patients showed signs of vascular rejection in biopsy. In 6 out of these 7 patients CEUS described irregularities in renal perfusion suspicious of vascular rejection.
RESULTS:
CEUS showed a sensitivity of 85.7%, a specificity of 100%, a positive predictive value (PPV) of 100%, and a negative predictive value (NPV) of 98.0%.
CONCLUSIONS:
CEUS is a safe, non-nephrotoxic imaging modality for the initial imaging of renal transplant recipients with elevated kidney function parameters suspicious of vascular rejection. Compared to renal biopsy as gold standard CEUS shows a high specificity and PPV in detecting signs of vascular rejection. Since sub-types of vascular rejection with cellular and humoral components with greater risk for allograft loss have been described renal biopsy is inevitable in these cases.
Introduction
Allograft rejection following renal transplantation continues to be a major issue for allograft function even though the incidence decreased significantly over the past years. Despite of the availability of more potent immunosuppressive medication, the outcomes in cases of acute vascular rejection remain poor. Histologically different subtypes of transplant rejection are being differentiated by using the Banff classification. Acute vascular recjection (AVR) can be attributed to cellular and/or humoral immunity and is characterised by intimal and transmural endarteritis. The severity of vessel involvement influences the treatment response, thus it determines the outcome of the allograft function [1, 2].
Gold standard for diagnosing acute vascular rejection is renal biopsy with subsequent histologic evaluation. Usually biopsy is performed under ultrasound guidance using a 14 to 18 gauges needle with automated biopsy device. Due to the invasive character of this diagnostic procedure complications may occur. Minor complications are seen in 1.9–24.2 % and include asymptomatic haematoma and haematuria, perinephric infection or arteriovenous fistulas. Major complications include sepsis and bleeding or large haematoma requiring blood transfusion or therapeutic procedures. Those complication are less common and seen in 0.36–6.6% of all cases. After the procedure the patient has to rest for at least 6 to 8 hours and vital signs must be checked. Depending on the kidney function tests and the clinical presentation renal biopsy might be repeatedly performed to monitor therapy. [3]. Therefore, non-invasive methods are needed to reduce the number of biopsies. Standard ultrasound and colour-Doppler are part of the follow-up examinations renal transplant recipients undergo regularly. As part of the examination routine the measurement of the renal segmental arterial resistance index of the renal transplant is well-established. An elevated resistance index is associated with poor allograft performance. But the informative value of non-enhanced ultrasound is limited [4, 5]. Contrast-enhanced ultrasound combines the advantages of standard ultrasound as fast, cost-effective, non-invasive imaging modality with the possibility to visualise renal transplant perfusion in real-time. Furthermore, it allows a quantitative evaluation of parenchymal microcirculation [6–9]. Using this quantitative analysis CEUS has been shown to be superior in evaluating renal transplant dysfunction compared to standard ultrasound [10, 11].
This retrospective analysis study has been performed to assess the sensitivity and specificity of CEUS in the diagnosis of vascular rejection in renal transplant recipients in comparison to biopsy as gold standard.
Materials and methods
Between October 2006 and May 2017 a total of 57 renal transplant patients with poor renal allograft function had undergone CEUS imaging as well as renal biopsy as gold standard.
Prior to each imaging examination oral and written consent of the patient was obtained. The local ethic committee approved the study protocol and study data were collected according to the principles of the Helsinki/Edinburgh Declaration of 2002. The authors followed the ethical guidelines fur publication in Clinical Hemorheology and Microcirculation [12]. Ultrasound guided biopsies and histologic analysis were performed in accordance with the valid techniques, protocols and classifications at the time of the examination. CEUS imaging was performed using a low mechanical index (always <0.4) to avoid unintentional early destruction of the microbubbles. High-end ultrasound systems (GE Healthcare: LOGIQ E9; Philips Ultrasound HDI 5000, iU22, EPIQ 7, Affiniti; Samsung: RS80A 50 Prestige, RS80A Prestige; Siemens Ultrasound: Sequoia, S2000, S3000) equipped with up-to date CEUS specific protocols available at the time of the examinations were used for CEUS examinations. The ultrasound probes used included CA1-7A, C6-1 HD, C5-1, C4-1 and V4-1 probes, all available at the time of the examinations.
The second-generation blood pool contrast agent SonoVue®(Bracco, Milan, Italy) was used in all CEUS examinations. The contrast agent was injected as a bolus followed by a flush of 5 to 10 ml of 0.9% sodium chloride solution via a 20–22 G needle placed in an antecubital vein. 1.6 to 2.4 ml contrast agent were administered in a single examination in most cases, with a minimum of 1.0 ml and a maximum of 5.0 ml. A single dose of contrast agent was sufficient in the majority of cases. In individual cases the injection of contrast agent was repeated up to two times. After the administration of SonoVue® no critical adverse reactions were observed. The mean examination time ranged from 3 to 5 minutes.
CEUS examinations were documented by acquiring cine loops, which were stored in the picture archiving and communication system (PACS) of our institution. All CEUS imaging studies were performed successfully with satisfactory image quality in all cases. No patient case had to be excluded due to incomplete data or poor image quality. Imaging studies and patient record files of all patients were retrieved from the archiving system of our institution. Imaging results were analysed retrospectively.
All CEUS examinations were performed and interpreted by a single radiologist with more than 15 years of experience in CEUS.
The 57 patients included in this study underwent renal transplantation between 1984 and 2016. Out of the 57 patients 22 (36.6%) were female and 35 patients (61.4%) were male. Mean age at the time of CEUS was 53.5 years ranging between 20 years and 76 years (SD±15.7 years). Mean period of time between renal transplantation and CEUS examination was 26.7 months (SD±65.7 months). Mean period of time between CEUS and biopsy was 12.5 days (SD±18.5 days). The underlying kidney diseases causing chronic renal failure were diabetic nephropathy, IgA nephropathy, polycystic kidney disease, dysplastic kidneys of unknown cause, granulomatosis with polyangiitis, Lupus nephritis, congenital reflux nephropathy, sepsis or nephropathy due to analgesic abuse.
Diagnostic accuracy of CEUS was tested using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) compared to biopsy as gold standard.
Results
Imaging was completed successfully in all 57 patients. In 7 out of 57 patients signs of vascular rejection were reported in the histologic analysis of the biopsy material. CEUS depicted significantly abnormal perfusion in 6 out of these patients suspecting signs of rejection (Fig. 1–4). In 1 case with histologically signs of vascular rejection renal transplant perfusion appeared regular. Histological subtypes of cellular and/or humoral immunity could not be differentiated by CEUS. Biopsy showed no signs of acute vascular rejection in 50 patients. These patients showed normal perfusion imaging of the renal transplant in CEUS.
B-mode ultrasound in a patient after renal transplantation with signs of a vascular rejection. The B-mode ultrasound reveals no major abnormalities.
CEUS showed a sensitivity of 85.7%, a specificity of 100%, a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 98.0% in comparison to biopsy.
Same patient as in Fig. 1. Color-Doppler shows no major perfusion deficits with normal vascularization patterns of the renal transplant.
Same patient as in Fig. 1–3. Contrast-enhanced ultrasound in the venous phase shows continuous peripheral hypoperfusion (white arrows) of the renal transplant in line with sonographic features of a vascular rejection after renal transplantation. This result was later on histopathologically confirmed after biopsy.
The incidence of severe, acute allograft rejections in renal transplant recipients decreased over the last years due to the availability of stronger immunosuppressant drugs. Nevertheless, acute allograft rejection can lead to allograft loss and needs to be diagnosed and treated promptly [2]. Diagnosis of acute rejection in patients with poor allograft function is based on allograft biopsy as gold standard. Renal biopsy is an invasive and painful diagnostic, which can cause complications including haematomas, active bleedings, infections or arteriovenous fistulas [2, 3]. Measuring the resistance index of the renal transplant is a methodical approach for an imaging based suspicion of acute vascular rejection. But the resistance index in the renal allograft is influenced by patients characteristics like the vascular compliance, which is strongly associated with a higher age, the heart rhythm and heart rate [13]. Using contrast-enhanced ultrasound it is possible to visualise renal transplant perfusion in real-time [14]. Furthermore, perfusion parameters can be quantified and compared intra- and interindividually [9].
To summarise, our study is in line with several other studies regarding this topic demonstrating that CEUS is a promising imaging modality to visualise and quantify perfusion abnormalities in renal transplants suspicious of acute vascular rejection [9–11]. This might help to reduce the number of biopsies performed in renal transplant recipients. However, CEUS imaging is limited due to patient characteristics such as obesity and bowel gas interposition as well as due to the skills and experience of the performing radiologist [15]. A considerable advantage is that SonoVue® shows no nephrotoxic effects and can be administered if the renal function is limited. Furthermore, CEUS is a safe and non-invasive imaging modality that can be performed as bedside examination [16].
The retrospective mono-centre study design is a limiting factor of this study. Moreover, the ultrasound systems used for CEUS varied among the examined patients.
Conclusion
In line with other studies we demonstrate that CEUS is a promising imaging modality to visualise and quantify renal perfusion abnormalities suspicious of acute vascular rejection of the renal allograft. At the present time renal biopsy represents the gold standard for diagnosing renal transplant rejection and CEUS might help to reduce the number of biopsies required in patients with poor allograft function.