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Advances of Contrast-Enhanced Ultrasonography and Elastography in Kidney Transplantation: From Microscopic to Microcosmic
ARTICLE IN PRESS Ultrasound in Med. & Biol., Vol. 00, No. 00, pp. 18, 2020 Copyright © 2020 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. Printed in the USA. All rights reserved. 0301-5629/$ - see front matter
https://doi.org/10.1016/j.ultrasmedbio.2020.07.025
Review Article ADVANCES OF CONTRAST-ENHANCED ULTRASONOGRAPHY AND ELASTOGRAPHY IN KIDNEY TRANSPLANTATION: FROM MICROSCOPIC TO MICROCOSMIC TAGEDPRUOCHEN QI,*,y,z CHENG YANG,*,z and TONGYU ZHU*,zTAGEDEN
* Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; y Shanghai Medical College, Fudan University, Shanghai, China; and z Shanghai Key Laboratory of Organ Transplantation, Shanghai, China (Received 22 April 2020; revised 2 June 2020; in final from 22 July 2020)
Abstract—Kidney transplantation is the best choice for patients with end-stage renal disease. To date, allograft biopsy remains the gold standard for revealing pathologic changes and predicting long-term outcomes. However, the invasive nature of transplant biopsy greatly limits its application. Ultrasound has been a first-line examination for evaluating kidney allografts for a long time. Advances in ultrasound in recent years, especially the growing number of studies in elastography and contrast-enhanced ultrasonography (CEUS), have shed new light on its application in kidney transplantation. Elastography, including strain elastography and shear wave elastography, is used mainly to assess allograft stiffness and, thus, predict renal fibrosis. CEUS has been used extensively in evaluating blood microperfusion, assessing acute kidney injury and detecting different complications after transplantation. Requiring the use of microbubbles also makes CEUS a novel method of gene transfer and drug delivery, enabling promising targeted diagnosis and therapy. In this review, we summarize the advances of elastography and CEUS in kidney transplantation and evaluate their potential efficiency in becoming a better complement to or even substitute for transplant biopsy in the future. (E-mail: [email protected]. cn) © 2020 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. Key Words: Kidney transplantation, Contrast-enhanced sonography, Elastography, Diagnosis, Ultrasound-targeted microbubble destruction, Targeted therapy.
allograft biopsy remains the gold standard in revealing the status of the transplant kidney, for instance, T cellmediated rejection, antibody-mediated rejection (AMR) and virus infection, its invasive nature also increases the risk of hemorrhage, vascular injury and loss of nephrons. Thus, it is vital to develop a non-invasive method that reveals the status of the transplant kidney and different complications. Ultrasonography is a tolerable and non-invasive examination and has been widely used to monitor different kidney diseases. Its application has extended from native kidneys to allografts (Correas et al. 2003). Advances in ultrasonography in recent years have made it possible not only to “take a glance” at the allograft, but also to provide abundant information on the transplant kidney. Among various new techniques, elastography and contrast-enhanced ultrasonography (CEUS) are well recognized in monitoring of the transplant kidney (Cantisani et al. 2015; Gungor et al. 2019). Elastography takes advantage of the altered elasticity of soft organs in pathologic conditions and, thus, is used mainly to determine
INTRODUCTION Kidney transplantation is the best choice for end-stage renal disease patients and can greatly improve their quality of life. In past decades, improvements in immunosuppressive agents and surgical techniques have led to relatively satisfactory allograft survival and overall survival rates in kidney transplant recipients (Correas et al. 1999). However, despite these successes, the nature of the transplant kidney as an allograft, inappropriate immunosuppression and the operation itself cause a wide range of complications among kidney recipients (Wang et al. 2017). These complications, including but not limited to vascular, urinary, lymphatic and infectious complications, malignant lesions and chronic rejection, greatly threaten the allograft kidney and usually result in early diagnosis. However, some lesions of the transplant could be latent and difficult to recognize. Though Address correspondence to: Tongyu Zhu, Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 2000032, China. E-mail: [email protected]
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interstitial fibrosis/tubular atrophy (IF/TA), formerly known as chronic allograft nephropathy (Menzilcioglu et al. 2015). Elastography can be further classified as strain elastography and shear wave elastography (SWE); the latter includes transient elastography (TE) and acoustic radiation force impulse (ARFI) imaging (Morgan et al. 2018), depending on the operating principles. CEUS requires intravenous injection of contrast agent, the microbubbles (MBs), which is later excreted via respiration (Morgan et al. 2018). These MBs, unlike the contrast agents used in computed tomography (CT) or magnetic resonance imaging (MRI) that redistribute to tissue from blood vessels to enhance tissue imaging, are pure intravascular agents and enhance the imaging of small vasculatures. MBs enable an accurate display of renal perfusion, thus indicating different lesions (Rennert et al. 2014). All references cited in this review were searched on PubMed. The search strategy was constructed as follows: (kidney transplantation[Title/Abstract] OR renal transplantation[Title/Abstract] OR kidney transplant[Title/ Abstract] OR renal transplant[Title/Abstract] OR kidney allograft[Title/Abstract]) AND (contrast enhanced ultrasonography[Title/Abstract] OR CEUS[Title/Abstract] OR elastography[Title/Abstract] OR microbubble[Title/ Abstract] OR UTMD[Title/Abstract]). Articles and reviews published in the past 5 y were mainly included. Every study cited in this review had institutional review board approval. ELASTOGRAPHY Strain elastography Strain elastography, including real-time elastography (RTE), is the first applied ultrasound elastic examination and has been widely used. In this method, external compression is applied with the transducer, resulting in an axial change in length in the examined organ. Ultrasound echoes before and after compression are compared to yield a qualitative strain map. Usually, the Young’s modulus (YM) is employed to assess the elasticity (Asano et al. 2014). Chronic kidney diseases (CKDs), together with IF/ TA, are characterized by worsened renal function and tubulo-interstitial fibrosis (TIF). Several studies have examined the efficacy of strain elastography in distinguishing CKDs and their stages. One study successfully used the strain index (SI) to differentiate CKD patients from normal controls. However, that study failed to reveal statistical differences in the SI among different CKD stages (Menzilcioglu et al. 2015). Another study found that YM is significantly higher in the CKD group compared with the control group. Moreover, the YMs of the renal cortex and medulla are positively correlated
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with the progression of CKD (Peng et al. 2017). Two other studies covering diabetic nephropathy, kidney transplant and glomerulonephritis, also found that strain elastography/RTE revealed a positive correlation between elastography score and renal function in CKD patients (Lin et al. 2017; Gungor et al. 2019). Regarding allograft fibrosis, two independent studies revealed that strain elastography could effectively discriminate patients with mild allograft fibrosis from those with moderate and severe fibrosis (Kahn et al. 2013; Orlacchio et al. 2014). Ozkan et al. (2013) also observed a positive correlation between parenchymal stiffness examined by RTE and two Doppler parameters, allograft resistive index (RI) and pulsatility index. In addition to CKDs and IF/TA, strain elastography has been applied in other transplant-related disease models, including acute vein occlusion and brain death-associated kidney injury (Gao et al. 2015; Tang et al. 2017). There are still limitations to strain elastography. One study reported that this method had wide range intra- and low inter-observer agreement in the examination of kidney allografts (Ozkan et al. 2013). Morgan et al. (2018) found that the position, heterogenicity and intrinsic anatomic complexity of the allograft make it difficult to obtain accurate and reproducible elastography data. Also, the stiffness of the allograft can be easily influenced by kidney perfusion, hydronephrosis and edema of the surrounding tissue (Morgan et al. 2018). Moreover, application of different elastography indexes in different studies also makes it difficult to develop a uniform and standardized strategy. Shear wave elastography SWE, including TE and ARFI imaging, is now the most widely used elastography method in evaluation of kidney transplants. In SWE, a dynamic stress generated by the transducer is used to elicit shear waves parallel or perpendicular to the organ being investigated. The shear waves are then tracked by the transducer to calculate the stiffness of the tissue (Early et al. 2017). The speed of the shear wave, known as shear wave velocity (SWV), is positively correlated with tissue stiffness. Numerous studies have been conducted to examine the validity of SWE in examining CKDs, renal fibrosis and allograft function; however, the results remain controversial. Several studies involving animal and clinical experiments have indicated that an increase in SWV could predict a worsened estimated glomerular filtration rate (eGFR) as well as renal fibrosis in both CKD and transplant patients (Moon et al. 2015; Samir et al. 2015; Ma et al. 2018; Muttray et al. 2018; Leong et al. 2019). Other researchers have found that increased SWV could help differentiate subclinical rejection from stable allograft function (Kim et al. 2018). Two other studies did not find that
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significant correlation. One study indicated that only the median medulla SWE was associated with renal fibrosis, while the mean cortical, median cortical and mean medullary SWE values did not correlate with fibrosis (Early et al. 2018). Grenier et al. (2012) found that renal cortical stiffness did not correlate with any clinical parameters, pathologic changes or renal fibrosis; the only association observed was between renal cortical stiffness and total allograft lesions. However, several other studies yielded contradictory results. These studies indicated that lower SWVs were observed in patients with worsened eGFR, CKDs, hydronephrosis and allograft dysfunction compared with healthy controls (Asano et al. 2014; Bob et al. 2015; Habibi et al. 2017; Marticorena Garcia et al. 2018; Grosu et al. 2019). Some proposed that this difference might be attributed to decreased kidney perfusion in some CKD and transplant patients (Asano et al. 2014). These contradictions also raised doubt about the efficacy of applying SWE in renal transplantation. Several researchers have proposed that the SWV of the kidney could be largely influenced by a variety of factors, including renal blood flow (RBF), age, body mass index, depth of the allograft, kidney intracapsular pressure and hydronephrosis (Grass et al. 2017; Habibi et al. 2017; Kashani et al. 2017; Muttray et al. 2018; Jarv et al. 2019). Lack of guidance of the monodimensional SWE technique also limited its application (Early et al. 2017). Thus, to make SWE a feasible method for examining kidney allograft, many factors must be considered and clinical experiments with larger study populations might be required. Recent advances have also shed light on the application of a new technique in the kidney, 2-D SWE (2-DSWE). Instead of generating a single focal zone, used in classic point SWE, 2-D-SWE produces multiple focal zones and creates a shear wave cone in the detected area (Sigrist et al. 2017). This allows simultaneous observation of kidney structures as well as quantitative elastography assessment (Gao et al. 2020). A recent study reported that the SWV measured by 2-D-SWE was decreased in a CKD population compared with healthy controls (Grosu et al. 2019). CONTRAST-ENHANCED ULTRASONOGRAPHY Basic principle: Monitoring graft microperfusion Similar to contrast-enhanced CT or MRI, CEUS also requires intravenous injection of contrast agent. The difference is that the agent used is gas-filled MBs and has no nephrotoxicity or risk of allergy (Jimenez et al. 2008). In the examination of kidney allografts, the renal artery is enhanced first, followed in order by the renal cortex and medulla. The entire perfusion cycle of the kidney is completed in 23 min (Morgan et al. 2018). A
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timeintensity curve (TIC) can be generated by detecting the perfusion of MBs of a selected area. Several parameters derived from TIC are often used to analyze renal transplants, including the slope rate of the ascending curve and descending curve, the area under the curve (AUC), peak intensity (PI), arrival time (AT) and time to peak (TTP) (Correas et al. 2003; Cantisani et al. 2015). Enhanced echo enables CEUS to detect renal macro- and microperfusion more accurately; thus, this technique has been widely used in kidney allografts (Fig. 1). Animal experiments have indicated that CEUS could effectively detect impaired renal parenchymal perfusion in acute renal congestion as well as chronic ischemia renal disease models (Dong et al. 2013; Komuro et al. 2018). Parameters of CEUS indicating renal microcirculation also sensitively change in response to different vasoactive agents (Schneider et al. 2012). Studies covering animal and clinical experiments have reported that CEUS displays renal allograft microcirculation better and can detect small foci of ischemia usually neglected or underestimated by conventional color Doppler and B-flow ultrasound (Grzelak et al. 2011a, 2013; Wang et al. 2015, Greenbarg et al. 2018). Several studies have also indicated that CEUS parameters may reveal pathologic changes of the allograft and predict long-term graft survival. Grzelak et al. (2011b) reported that CEUS could differentiate patients with biopsy-proven acute rejection (AR) and acute tubular necrosis (ATN) from patients with early graft function. Another study developed a novel index derived from the delta time among regions of interest to help in diagnosis of AR and ATN after transplantation (Jin et al. 2015). The same group also created a new index derived from the TIC that could discriminate chronic rejection from AR (Yang et al. 2019) Research indicated that RBF estimated by CEUS 1 wk after transplantation correlates well with allograft function 1 y later. Moreover, RBF was found to be associated with biopsy-proven vascular fibrosis and intimal thickening of the allograft (Schwenger et al. 2014). Furthermore, TIC parameters could indicate IF/TA and allograft fibrosis even before the elevation of serum creatinine level, and the parameters correlated well with the expression of fibrosis-associated proteins within the kidney (Zhang et al. 2016). A study including CKD patients reported that quantitative parameters derived from CEUS, especially PI, could help assess the severity of pathologic changes in native kidneys (Yang et al. 2018). This raises the hope that perhaps in the future, CEUS, a non-invasive examination, might replace the protocol biopsy (Yang et al. 2018). Advances in recent years have given birth to a new technique, 3-D CEUS. A series of studies conducted by Stenberg et al. (2014, 2017) revealed that 3-D CEUS could effectively detect global perfusion and small
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Fig. 1. Schematic view of the application of contrast-enhanced ultrasonography in renal allografts. The nature of microbubbles enables CEUS to be widely used in evaluating kidney allografts. The characteristic of revealing microperfusion makes it available to detect small foci of ischemia. Changes in CEUS-derived parameters could also be used to indicate acute kidney injury (AKI) and acute or chronic rejection. Enhancement of the renal parenchyma allows detection of a variety of surgical complications as well as transplant malignancies after transplantation. Moreover, application of ultrasound-targeted microbubble destruction makes targeted diagnosis and therapy possible in the allograft.
defects in porcine kidneys undergoing in vitro hypothermic perfusion, and the parameters corresponded well with those seen in vivo (Stenberg et al. 2011). Furthermore, 3-D CEUS was able to find more perfusion defects missed by Tc-DTPA scan and also quantified the volume of the perfusion defects with respect to total renal volume (Stenberg et al. 2014, 2017). Detecting acute kidney injury Acute kidney injury (AKI), characterized by a rapid loss of kidney function, is not rare in the clinical setting and can be caused by a variety of injuries including hypovolemia, cardiovascular surgery and sepsis. AKI leads to increased patient mortality and is an important factor in progression to CKD. Thus, early diagnosis and adjustment of the therapeutic strategy without delay are vital. The superiority of CEUS in displaying perfusion, especially microcirculation within the kidney, makes it a suitable technique to detect AKI. Experiments in mice on ischemiareperfusion injury (IRI) revealed that CEUS could detect the decrease in renal perfusion only 1 h after AKI, and the decrease in blood flow was positively correlated with subsequent renal fibrosis (Cao et al. 2017). In another IRI experiment in mice, new
analytical software was developed that enabled high resolution and pixel-by-pixel analysis on each imaging clip. This analysis applied a pixel-by-pixel Fourier transform approach during spectral analysis and provided a kidney perfusion map of the relative blood volume in each pixel (Fischer et al. 2016). The same study also indicated that perfusion in the outer medulla, instead of the cortex, decreased most significantly after IRI (Fischer et al. 2016). Another two studies revealed changes in CEUSderived parameters, including PI, AT, TTP and AUC, after IRI. And these parameters were strongly correlated with pathologic severity and expression of ICAM-1, an AKI molecular indicator (Li et al. 2015; Lee et al. 2017). CEUS has also been introduced at the beside in the clinical setting. Application of CEUS peri-operatively detected decreased renal perfusion within 24 h after surgery, manifested by a decreased perfusion index and increased mean transit time (mTT). However, the study did not find any correlation between the perfusion index and the serum creatinine level (Schneider et al. 2013; Hobson et al. 2017). Harrois et al. (2018) found similar parameter changes and reported that mTT could be used as an indicator of AKI in patients with septic shock. A clinical experiment examining the efficacy of CEUS in
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sepsis-associated AKI is also in progress (Liu et al. 2019b). Thus, because it is portable and is not nephrotoxic, CEUS might become a powerful tool for screening for AKI in high-risk patients, especially in the intensive care unit (Gocze et al. 2014). Convenient choice during follow-up The efficacy of CEUS in detecting a wide range of acute and subacute complications after kidney transplantation has also been extensively studied. Poorly perfused renal parenchyma was found to be an indicator of acute pyelonephritis in allografts (Granata et al. 2011). CEUS could also detect perirenal hematomas more sensitively than conventional B-mode ultrasound by revealing the increased difference in echogenicity between the hematoma and renal parenchyma (Grzelak et al. 2013). Moreover, CEUS was found to be capable of diagnosing acute renal vein thrombosis and other vascular complications after transplantation (Grzelak et al. 2011a; Mueller-Peltzer et al. 2017). Kidney recipients also have an increased risk of allograft malignancies because of immunosuppression. Though enhanced CT and MRI play the dominant role in diagnosing renal carcinoma, the nephrotoxicity and concern over inducing AKI associated with the contrast agents limit their application in kidney recipients. One study revealed that CEUS had a sensitivity of 100% and a specificity of 94.4% in detecting renal malignancies in transplant recipients (MuellerPeltzer et al. 2018). Another study found that CEUS could discriminate between complex kidney cysts and malignant masses that could not be clearly defined with conventional ultrasound (Paudice et al. 2012). Thus, CEUS might be a potent tool in follow-up of different complications after kidney transplantation. MOLECULAR TARGETED DIAGNOSIS AND TREATMENT Ultrasound-targeted microbubble destruction (UTMD) is a new technique that evolved from CEUS in recent years. MBs can carry a variety of cargo, including plasmid, siRNA, shRNA and even drugs, to the local tissue. Given that RBF accounts for a large amount of total cardiac output, the kidney is an ideal place for MB enrichment. Ultrasound generated from the transducer causes cavitation of the MBs, creating shock waves that permeabilize surrounding biological barriers together with release of cargo (Huang et al. 2019). Several studies found that UTMD led to increased permeabilization of kidney interstitial capillaries and MBs remained mainly in the tubular region (Li et al. 2013). The increased permeabilization of the capillary was found to be transient and reversible and did not lead to increases in hematuria or proteinuria (Zhang et al. 2014). Another study
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applying b-galactosidase plasmid also found that the gene transferred was expressed mainly in the tubular cells in the interstitium (Chen et al. 2012), further indicating the target region of UTMD within the kidney. Several studies have used UTMD to alleviate renal fibrosis, either by inducing Smad7 expression or by downregulating connective tissue growth factor (Lan et al. 2003; Hou et al. 2005; Wei et al. 2016). Because IF/TA of the kidney transplant is also manifested with TIF, this might be an effective way to treat allograft fibrosis. Capillary permeabilization increased by MBs has been found to enhance the homing ability of several stem cells, including mesenchymal stem cells and bone marrow stromal cells, to the kidney parenchyma, ameliorating renal injures (Zhang et al. 2013; Wang et al. 2016). UTMD has also been reported to enhance the efficiency of viral gene transfer into tumor tissue (Li et al. 2014) and delivery of tacrolimus specifically to the transplant (Liu et al. 2019a). In addition to the therapeutic effects of UTMD and MBs, a recent study has shed light on their role in diagnosis by designing C4d-targeted MBs. This study found that these targeted MBs could quantify the deposition of C4d in the kidney allograft, indicating AMR (Liao et al. 2019). In conclusion, though all of the studies discussed above were conducted in animal models, given its abilities to increase capillary permeabilization and take on different cargo, UTMD might become an efficient diagnostic and therapeutic method in kidney allografts in the future.
CONCLUSIONS AND PERSPECTIVE Advances in ultrasonography have resulted in powerful tools for examining kidney allografts. Among them, the most outstanding new techniques are elastography and CEUS. Strain elastography was the first elasticity examination applied in kidney transplants. However, because of its susceptibility to other factors and poor repeatability, its application was largely limited. SWE improved some of the defects of strain elastography though its application was still restricted in measuring allograft stiffness, detecting fibrosis and, to some extent, predicting allograft survival, while CEUS is playing an increasingly important role in the field of kidney transplantation. Because it can accurately depict the microcirculation of the allograft, CEUS can efficiently monitor kidney perfusion and different complications, detect AKI and predict long-term prognosis. Moreover, advances in MBs have shed light on a new application of CEUS, UTMD, for molecular targeted diagnosis and treatment. This novel and promising strategy might complement or even substitute for protocol allograft biopsy in the future.
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Acknowledgments—This study was supported by the National Natural Science Foundation of China (81770746 to C.Y.), the National Key R&D Program of China (2018 YFA0107502 to C.Y.), the Medical and Health Talents Training Plan for the Excellent Youth of Shanghai Municipal (2018 YQ50 to C.Y.), Shanghai RisingStar Program (19 QA1406300 to C.Y.) and China Organ Transplantation Development Foundation Elite Program (2019 JYJH05 to C.Y.). Conflict of interest disclosure—The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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ARTICLE IN PRESS US Advances in Kidney Transplantation R. QI et al. Kahn J, Slowinski T, Thomas A, Filimonow S, Fischer T. TSI ultrasound elastography for the diagnosis of chronic allograft nephropathy in kidney transplanted patients. J Ultrasonogr 2013;13:253–262. Kashani KB, Mao SA, Safadi S, Amiot BP, Glorioso JM, Lieske JC, Nyberg SL, Zhang X. Association between kidney intracapsular pressure and ultrasound elastography. Crit Care 2017;21:251. Kim BJ, Kim CK, Park JJ. Non-invasive evaluation of stable renal allograft function using point shear-wave elastography. Br J Radiol 2018;91 20170372. Komuro K, Seo Y, Yamamoto M, Sai S, Ishizu T, Shimazu K, Takahashi Y, Imagawa S, Anzai T, Yonezawa K, Aonuma K. Assessment of renal perfusion impairment in a rat model of acute renal congestion using contrast-enhanced ultrasonography. Heart Vessels 2018;33:434–440. Lan HY, Mu W, Tomita N, Huang XR, Li JH, Zhu HJ, Morishita R, Johnson RJ. Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasoundmicrobubble system in rat UUO model. J Am Soc Nephrol 2003;14:1535–1548. Lee G, Jeon S, Lee SK, Cheon B, Moon S, Park JG, Cho KO, Choi J. Quantitative evaluation of renal parenchymal perfusion using contrast-enhanced ultrasonography in renal ischemia-reperfusion injury in dogs. J Vet Sci 2017;18:507–514. Leong SS, Wong JHD, Md Shah MN, Vijayananthan A, Jalalonmuhali M, Ng KH. Comparison of shear wave elastography and conventional ultrasound in assessing kidney function as measured using 51 Cr-ethylenediaminetetraacetic acid and 99Tc-dimercaptosuccinic acid. Ultrasound Med Biol 2019;45:1417–1426. Li P, Gao Y, Zhang J, Liu Z, Tan K, Hua X, Gong J. Renal interstitial permeability changes induced by microbubble-enhanced diagnostic ultrasound. J Drug Target 2013;21:507–514. Li F, Jin L, Wang H, Wei F, Bai M, Shi Q, Du L. The dual effect of ultrasound-targeted microbubble destruction in mediating recombinant adeno-associated virus delivery in renal cell carcinoma: Transfection enhancement and tumor inhibition. J Gene Med 2014;16:28–39. Li M, Luo Z, Chen X, Xuan J, Ye F, Liu H, Chen K. Use of contrastenhanced ultrasound to monitor rabbit renal ischemia-reperfusion injury and correlations between time-intensity curve parameters and renal ICAM-1 expression. Clin Hemorheol Microcirc 2015;59:123–131. Liao T, Zhang Y, Ren J, Zheng H, Zhang H, Li X, Liu X, Yin T, Sun Q. Noninvasive quantification of intrarenal allograft C4d deposition with targeted ultrasound imaging. Am J Transplant 2019;19:259–268. Lin HY, Lee YL, Lin KD, Chiu YW, Shin SJ, Hwang SJ, Chen HC, Hung CC. Association of renal elasticity and renal function progression in patients with chronic kidney disease evaluated by real-time ultrasound elastography. Sci Rep 2017;7:43303. Liu J, Chen Y, Wang G, Jin Q, Sun Z, Lv Q, Wang J, Yang Y, Zhang L, Xie M. Improving acute cardiac transplantation rejection therapy using ultrasound-targeted FK506-loaded microbubbles in rats. Biomater Sci 2019a;7:3729–3740. Liu N, Zhang Z, Hong Y, Li B, Cai H, Zhao H, Dai J, Liu L, Qian X, Jin Q. Protocol for a prospective observational study on the association of variables obtained by contrast-enhanced ultrasonography and sepsis-associated acute kidney injury. BMJ Open 2019b;9 e023981. Ma MK, Law HK, Tse KS, Chan KW, Chan GC, Yap DY, Mok MM, Kwan LP, Tang SC, Choy BY, Chan TM. Non-invasive assessment of kidney allograft fibrosis with shear wave elastography: A radiological-pathological correlation analysis. Int J Urol 2018;25:450–455. Marticorena Garcia SR, Guo J, Durr M, Denecke T, Hamm B, Sack I, Fischer T. Comparison of ultrasound shear wave elastography with magnetic resonance elastography and renal microvascular flow in the assessment of chronic renal allograft dysfunction. Acta Radiol 2018;59:1139–1145. Menzilcioglu MS, Duymus M, Citil S, Avcu S, Gungor G, Sahin T, Boysan SN, Altunoren O, Sarica A. Strain wave elastography for
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evaluation of renal parenchyma in chronic kidney disease. Br J Radiol 2015;88 20140714. Moon SK, Kim SY, Cho JY, Kim SH. Quantification of kidney fibrosis using ultrasonic shear wave elastography: Experimental study with a rabbit model. J Ultrasound Med 2015;34:869–877. Morgan TA, Jha P, Poder L, Weinstein S. Advanced ultrasound applications in the assessment of renal transplants: Contrast-enhanced ultrasound, elastography, and B-flow. Abdom Radiol (NY) 2018;43:2604–2614. Mueller-Peltzer K, Rubenthaler J, Fischereder M, Habicht A, Reiser M, Clevert DA. The diagnostic value of contrast-enhanced ultrasound (CEUS) as a new technique for imaging of vascular complications in renal transplants compared to standard imaging modalities. Clin Hemorheol Microcirc 2017;67:407–413. Mueller-Peltzer K, Negrao de Figueiredo G, Fischereder M, Habicht A, Rubenthaler J, Clevert DA. 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;69:69–75. Muttray J, Mehrabi A, Hafezi M, Saffari A, Bui-Ta TTT, Meyburg J, Wuhl E, Schenk JP. ARFI shear-wave elastography with simulation of acute urinary tract obstruction in an ex vivo porcine kidney model. Diagn Interv Radiol 2018;24:308–315. Orlacchio A, Chegai F, Del Giudice C, Anselmo A, Iaria G, Palmieri G, Di Caprera E, Tosti D, Costanzo E, Tisone G, Simonetti G. Kidney transplant: Usefulness of real-time elastography (RTE) in the diagnosis of graft interstitial fibrosis. Ultrasound Med Biol 2014;40:2564–2572. Ozkan F, Yavuz YC, Inci MF, Altunoluk B, Ozcan N, Yuksel M, Sayarlioglu H, Dogan E. Interobserver variability of ultrasound elastography in transplant kidneys: Correlations with clinicalDoppler parameters. Ultrasound Med Biol 2013;39:4–9. Paudice N, Zanazzi M, Agostini S, Bertelli E, Caroti L, Carta P, Moscarelli L, Tsalouchos A, Salvadori M, Bertoni E. Contrastenhanced ultrasound assessment of complex cystic lesions in renal transplant recipients with acquired cystic kidney disease: Preliminary experience. Transplant Proc 2012;44:1928–1929. Peng L, Zhong T, Fan Q, Liu Y, Wang X, Wang L. Correlation analysis of renal ultrasound elastography and clinical and pathological changes in patients with chronic kidney disease. Clin Nephrol 2017;87:293–300. Rennert J, Farkas S, Georgieva M, Loss M, Dornia C, Jung W, Stroszczynski C, Jung EM. Identification of early complications following pancreas and renal transplantation using contrast enhanced ultrasound (CEUS)—First results. Clin Hemorheol Microcirc 2014;58:343–352. Samir AE, Allegretti AS, Zhu Q, Dhyani M, Anvari A, Sullivan DA, Trottier CA, Dougherty S, Williams WW, Babitt JL, Wenger J, Thadhani RI, Lin HY. Shear wave elastography in chronic kidney disease: A pilot experience in native kidneys. BMC Nephrol 2015;16:119. Schneider AG, Hofmann L, Wuerzner G, Glatz N, Maillard M, Meuwly JY, Eggimann P, Burnier M, Vogt B. Renal perfusion evaluation with contrast-enhanced ultrasonography: Nephrology, dialysis, transplantation. 2012;27:674681. Schneider AG, Goodwin MD, Schelleman A, Bailey M, Johnson L, Bellomo R. Contrast-enhanced ultrasound to evaluate changes in renal cortical perfusion around cardiac surgery: A pilot study. Crit Care 2013;17:R138. Schwenger V, Hankel V, Seckinger J, Macher-Goppinger S, Morath C, Zeisbrich M, Zeier M, Kihm LP. Contrast-enhanced ultrasonography in the early period after kidney transplantation predicts longterm allograft function. Transplant Proc 2014;46:3352–3357. Sigrist RMS, Liau J, Kaffas AE, Chammas MC, Willmann JK. Ultrasound elastography: Review of techniques and clinical applications. Theranostics 2017;7:1303–1329. Stenberg B, Talbot D, Khurram M, Kanwar A, Ray C, Mownah O, White K, Elliott ST. A new technique for assessing renal transplant perfusion preoperatively using contrast-enhanced ultrasound (CEUS) and three-dimensional ultrasound (3 DUS)—A porcine model pilot study. Ultraschall Med 2011;32(Suppl 2):E8–E13.
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Stenberg B, Chandler C, Wyrley-Birch H, Elliott ST. Post-operative 3-dimensional contrast-enhanced ultrasound (CEUS) versus Tc99 m-DTPA in the detection of post-surgical perfusion defects in kidney transplants—Preliminary findings. Ultraschall Med 2014;35:273–278. Stenberg B, Wilkinson M, Elliott S, Caplan N. The prevalence and significance of renal perfusion defects in early kidney transplants quantified using 3D contrast enhanced ultrasound (CEUS). Eur Radiol 2017;27:4525–4531. Tang Y, Zhao J, Liu D, Niu N, Yu H. Evaluation of early kidney damage caused by brain death using real-time ultrasound elastography in a bama pig model. Ultrasound Med Biol 2017;43:2395–2401. Wang X, Yu Z, Guo R, Yin H, Hu X. Assessment of postoperative perfusion with contrast-enhanced ultrasonography in kidney transplantation. Int J Clin Exp Med 2015;8:18399–18405. Wang G, Zhang Q, Zhuo Z, Wu S, Liu Z, Xia H, Tan K, Zou L, Gan L, Gao Y. Effects of diagnostic ultrasound-targeted microbubble destruction on the homing ability of bone marrow stromal cells to the kidney parenchyma. European radiology 2016;26:3006–3016. Wang Z, Yang H, Suo C, Wei J, Tan R, Gu M. Application of ultrasound elastography for chronic allograft dysfunction in kidney transplantation. Journal Ultrasound Med 2017;36:1759–1769. Wei S, Xu C, Rychak JJ, Luong A, Sun Y, Yang Z, Li M, Liu C, Fu N, Yang B. Short hairpin RNA knockdown of connective tissue
Volume 00, Number 00, 2020 growth factor by ultrasound-targeted microbubble destruction improves renal fibrosis. Ultrasound Med Biol 2016;42:2926–2937. Yang WQ, Mou S, Xu Y, Xu L, Li FH, Li HL. Quantitative parameters of contrast-enhanced ultrasonography for assessment of renal pathology: A preliminary study in chronic kidney disease. Clin Hemorheol Microcirc 2018;68:71–82. Yang C, Wu S, Yang P, Shang G, Qi R, Xu M, Rong R, Zhu T, He W. Prediction of renal allograft chronic rejection using a model based on contrast-enhanced ultrasonography. Microcirculation 2019;26: e12544. Zhang Y, Ye C, Wang G, Gao Y, Tan K, Zhuo Z, Liu Z, Xia H, Yang D, Li P. Kidney-targeted transplantation of mesenchymal stem cells by ultrasound-targeted microbubble destruction promotes kidney repair in diabetic nephropathy rats. BioMed Res Int 2013;2013 526367. Zhang Y, Ye C, Xu Y, Dong X, Li J, Liu R, Gao Y. Ultrasound-mediated microbubble destruction increases renal interstitial capillary permeability in early diabetic nephropathy rats. Ultrasound Med Biol 2014;40:1273–1281. Zhang Q, Yu Z, Xu Y, Zeng S, Zhang Z, Xue W, Wang W, Zhang X, Hu X. Use of contrast-enhanced ultrasonography to evaluate chronic allograft nephropathy in rats and correlations between time-intensity curve parameters and allograft fibrosis. Ultrasound Med Biol 2016;42:1574–1583.
https://doi.org/10.1016/j.ultrasmedbio.2020.07.025
Review Article ADVANCES OF CONTRAST-ENHANCED ULTRASONOGRAPHY AND ELASTOGRAPHY IN KIDNEY TRANSPLANTATION: FROM MICROSCOPIC TO MICROCOSMIC TAGEDPRUOCHEN QI,*,y,z CHENG YANG,*,z and TONGYU ZHU*,zTAGEDEN
* Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; y Shanghai Medical College, Fudan University, Shanghai, China; and z Shanghai Key Laboratory of Organ Transplantation, Shanghai, China (Received 22 April 2020; revised 2 June 2020; in final from 22 July 2020)
Abstract—Kidney transplantation is the best choice for patients with end-stage renal disease. To date, allograft biopsy remains the gold standard for revealing pathologic changes and predicting long-term outcomes. However, the invasive nature of transplant biopsy greatly limits its application. Ultrasound has been a first-line examination for evaluating kidney allografts for a long time. Advances in ultrasound in recent years, especially the growing number of studies in elastography and contrast-enhanced ultrasonography (CEUS), have shed new light on its application in kidney transplantation. Elastography, including strain elastography and shear wave elastography, is used mainly to assess allograft stiffness and, thus, predict renal fibrosis. CEUS has been used extensively in evaluating blood microperfusion, assessing acute kidney injury and detecting different complications after transplantation. Requiring the use of microbubbles also makes CEUS a novel method of gene transfer and drug delivery, enabling promising targeted diagnosis and therapy. In this review, we summarize the advances of elastography and CEUS in kidney transplantation and evaluate their potential efficiency in becoming a better complement to or even substitute for transplant biopsy in the future. (E-mail: [email protected]. cn) © 2020 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. Key Words: Kidney transplantation, Contrast-enhanced sonography, Elastography, Diagnosis, Ultrasound-targeted microbubble destruction, Targeted therapy.
allograft biopsy remains the gold standard in revealing the status of the transplant kidney, for instance, T cellmediated rejection, antibody-mediated rejection (AMR) and virus infection, its invasive nature also increases the risk of hemorrhage, vascular injury and loss of nephrons. Thus, it is vital to develop a non-invasive method that reveals the status of the transplant kidney and different complications. Ultrasonography is a tolerable and non-invasive examination and has been widely used to monitor different kidney diseases. Its application has extended from native kidneys to allografts (Correas et al. 2003). Advances in ultrasonography in recent years have made it possible not only to “take a glance” at the allograft, but also to provide abundant information on the transplant kidney. Among various new techniques, elastography and contrast-enhanced ultrasonography (CEUS) are well recognized in monitoring of the transplant kidney (Cantisani et al. 2015; Gungor et al. 2019). Elastography takes advantage of the altered elasticity of soft organs in pathologic conditions and, thus, is used mainly to determine
INTRODUCTION Kidney transplantation is the best choice for end-stage renal disease patients and can greatly improve their quality of life. In past decades, improvements in immunosuppressive agents and surgical techniques have led to relatively satisfactory allograft survival and overall survival rates in kidney transplant recipients (Correas et al. 1999). However, despite these successes, the nature of the transplant kidney as an allograft, inappropriate immunosuppression and the operation itself cause a wide range of complications among kidney recipients (Wang et al. 2017). These complications, including but not limited to vascular, urinary, lymphatic and infectious complications, malignant lesions and chronic rejection, greatly threaten the allograft kidney and usually result in early diagnosis. However, some lesions of the transplant could be latent and difficult to recognize. Though Address correspondence to: Tongyu Zhu, Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 2000032, China. E-mail: [email protected]
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interstitial fibrosis/tubular atrophy (IF/TA), formerly known as chronic allograft nephropathy (Menzilcioglu et al. 2015). Elastography can be further classified as strain elastography and shear wave elastography (SWE); the latter includes transient elastography (TE) and acoustic radiation force impulse (ARFI) imaging (Morgan et al. 2018), depending on the operating principles. CEUS requires intravenous injection of contrast agent, the microbubbles (MBs), which is later excreted via respiration (Morgan et al. 2018). These MBs, unlike the contrast agents used in computed tomography (CT) or magnetic resonance imaging (MRI) that redistribute to tissue from blood vessels to enhance tissue imaging, are pure intravascular agents and enhance the imaging of small vasculatures. MBs enable an accurate display of renal perfusion, thus indicating different lesions (Rennert et al. 2014). All references cited in this review were searched on PubMed. The search strategy was constructed as follows: (kidney transplantation[Title/Abstract] OR renal transplantation[Title/Abstract] OR kidney transplant[Title/ Abstract] OR renal transplant[Title/Abstract] OR kidney allograft[Title/Abstract]) AND (contrast enhanced ultrasonography[Title/Abstract] OR CEUS[Title/Abstract] OR elastography[Title/Abstract] OR microbubble[Title/ Abstract] OR UTMD[Title/Abstract]). Articles and reviews published in the past 5 y were mainly included. Every study cited in this review had institutional review board approval. ELASTOGRAPHY Strain elastography Strain elastography, including real-time elastography (RTE), is the first applied ultrasound elastic examination and has been widely used. In this method, external compression is applied with the transducer, resulting in an axial change in length in the examined organ. Ultrasound echoes before and after compression are compared to yield a qualitative strain map. Usually, the Young’s modulus (YM) is employed to assess the elasticity (Asano et al. 2014). Chronic kidney diseases (CKDs), together with IF/ TA, are characterized by worsened renal function and tubulo-interstitial fibrosis (TIF). Several studies have examined the efficacy of strain elastography in distinguishing CKDs and their stages. One study successfully used the strain index (SI) to differentiate CKD patients from normal controls. However, that study failed to reveal statistical differences in the SI among different CKD stages (Menzilcioglu et al. 2015). Another study found that YM is significantly higher in the CKD group compared with the control group. Moreover, the YMs of the renal cortex and medulla are positively correlated
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with the progression of CKD (Peng et al. 2017). Two other studies covering diabetic nephropathy, kidney transplant and glomerulonephritis, also found that strain elastography/RTE revealed a positive correlation between elastography score and renal function in CKD patients (Lin et al. 2017; Gungor et al. 2019). Regarding allograft fibrosis, two independent studies revealed that strain elastography could effectively discriminate patients with mild allograft fibrosis from those with moderate and severe fibrosis (Kahn et al. 2013; Orlacchio et al. 2014). Ozkan et al. (2013) also observed a positive correlation between parenchymal stiffness examined by RTE and two Doppler parameters, allograft resistive index (RI) and pulsatility index. In addition to CKDs and IF/TA, strain elastography has been applied in other transplant-related disease models, including acute vein occlusion and brain death-associated kidney injury (Gao et al. 2015; Tang et al. 2017). There are still limitations to strain elastography. One study reported that this method had wide range intra- and low inter-observer agreement in the examination of kidney allografts (Ozkan et al. 2013). Morgan et al. (2018) found that the position, heterogenicity and intrinsic anatomic complexity of the allograft make it difficult to obtain accurate and reproducible elastography data. Also, the stiffness of the allograft can be easily influenced by kidney perfusion, hydronephrosis and edema of the surrounding tissue (Morgan et al. 2018). Moreover, application of different elastography indexes in different studies also makes it difficult to develop a uniform and standardized strategy. Shear wave elastography SWE, including TE and ARFI imaging, is now the most widely used elastography method in evaluation of kidney transplants. In SWE, a dynamic stress generated by the transducer is used to elicit shear waves parallel or perpendicular to the organ being investigated. The shear waves are then tracked by the transducer to calculate the stiffness of the tissue (Early et al. 2017). The speed of the shear wave, known as shear wave velocity (SWV), is positively correlated with tissue stiffness. Numerous studies have been conducted to examine the validity of SWE in examining CKDs, renal fibrosis and allograft function; however, the results remain controversial. Several studies involving animal and clinical experiments have indicated that an increase in SWV could predict a worsened estimated glomerular filtration rate (eGFR) as well as renal fibrosis in both CKD and transplant patients (Moon et al. 2015; Samir et al. 2015; Ma et al. 2018; Muttray et al. 2018; Leong et al. 2019). Other researchers have found that increased SWV could help differentiate subclinical rejection from stable allograft function (Kim et al. 2018). Two other studies did not find that
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significant correlation. One study indicated that only the median medulla SWE was associated with renal fibrosis, while the mean cortical, median cortical and mean medullary SWE values did not correlate with fibrosis (Early et al. 2018). Grenier et al. (2012) found that renal cortical stiffness did not correlate with any clinical parameters, pathologic changes or renal fibrosis; the only association observed was between renal cortical stiffness and total allograft lesions. However, several other studies yielded contradictory results. These studies indicated that lower SWVs were observed in patients with worsened eGFR, CKDs, hydronephrosis and allograft dysfunction compared with healthy controls (Asano et al. 2014; Bob et al. 2015; Habibi et al. 2017; Marticorena Garcia et al. 2018; Grosu et al. 2019). Some proposed that this difference might be attributed to decreased kidney perfusion in some CKD and transplant patients (Asano et al. 2014). These contradictions also raised doubt about the efficacy of applying SWE in renal transplantation. Several researchers have proposed that the SWV of the kidney could be largely influenced by a variety of factors, including renal blood flow (RBF), age, body mass index, depth of the allograft, kidney intracapsular pressure and hydronephrosis (Grass et al. 2017; Habibi et al. 2017; Kashani et al. 2017; Muttray et al. 2018; Jarv et al. 2019). Lack of guidance of the monodimensional SWE technique also limited its application (Early et al. 2017). Thus, to make SWE a feasible method for examining kidney allograft, many factors must be considered and clinical experiments with larger study populations might be required. Recent advances have also shed light on the application of a new technique in the kidney, 2-D SWE (2-DSWE). Instead of generating a single focal zone, used in classic point SWE, 2-D-SWE produces multiple focal zones and creates a shear wave cone in the detected area (Sigrist et al. 2017). This allows simultaneous observation of kidney structures as well as quantitative elastography assessment (Gao et al. 2020). A recent study reported that the SWV measured by 2-D-SWE was decreased in a CKD population compared with healthy controls (Grosu et al. 2019). CONTRAST-ENHANCED ULTRASONOGRAPHY Basic principle: Monitoring graft microperfusion Similar to contrast-enhanced CT or MRI, CEUS also requires intravenous injection of contrast agent. The difference is that the agent used is gas-filled MBs and has no nephrotoxicity or risk of allergy (Jimenez et al. 2008). In the examination of kidney allografts, the renal artery is enhanced first, followed in order by the renal cortex and medulla. The entire perfusion cycle of the kidney is completed in 23 min (Morgan et al. 2018). A
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timeintensity curve (TIC) can be generated by detecting the perfusion of MBs of a selected area. Several parameters derived from TIC are often used to analyze renal transplants, including the slope rate of the ascending curve and descending curve, the area under the curve (AUC), peak intensity (PI), arrival time (AT) and time to peak (TTP) (Correas et al. 2003; Cantisani et al. 2015). Enhanced echo enables CEUS to detect renal macro- and microperfusion more accurately; thus, this technique has been widely used in kidney allografts (Fig. 1). Animal experiments have indicated that CEUS could effectively detect impaired renal parenchymal perfusion in acute renal congestion as well as chronic ischemia renal disease models (Dong et al. 2013; Komuro et al. 2018). Parameters of CEUS indicating renal microcirculation also sensitively change in response to different vasoactive agents (Schneider et al. 2012). Studies covering animal and clinical experiments have reported that CEUS displays renal allograft microcirculation better and can detect small foci of ischemia usually neglected or underestimated by conventional color Doppler and B-flow ultrasound (Grzelak et al. 2011a, 2013; Wang et al. 2015, Greenbarg et al. 2018). Several studies have also indicated that CEUS parameters may reveal pathologic changes of the allograft and predict long-term graft survival. Grzelak et al. (2011b) reported that CEUS could differentiate patients with biopsy-proven acute rejection (AR) and acute tubular necrosis (ATN) from patients with early graft function. Another study developed a novel index derived from the delta time among regions of interest to help in diagnosis of AR and ATN after transplantation (Jin et al. 2015). The same group also created a new index derived from the TIC that could discriminate chronic rejection from AR (Yang et al. 2019) Research indicated that RBF estimated by CEUS 1 wk after transplantation correlates well with allograft function 1 y later. Moreover, RBF was found to be associated with biopsy-proven vascular fibrosis and intimal thickening of the allograft (Schwenger et al. 2014). Furthermore, TIC parameters could indicate IF/TA and allograft fibrosis even before the elevation of serum creatinine level, and the parameters correlated well with the expression of fibrosis-associated proteins within the kidney (Zhang et al. 2016). A study including CKD patients reported that quantitative parameters derived from CEUS, especially PI, could help assess the severity of pathologic changes in native kidneys (Yang et al. 2018). This raises the hope that perhaps in the future, CEUS, a non-invasive examination, might replace the protocol biopsy (Yang et al. 2018). Advances in recent years have given birth to a new technique, 3-D CEUS. A series of studies conducted by Stenberg et al. (2014, 2017) revealed that 3-D CEUS could effectively detect global perfusion and small
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Fig. 1. Schematic view of the application of contrast-enhanced ultrasonography in renal allografts. The nature of microbubbles enables CEUS to be widely used in evaluating kidney allografts. The characteristic of revealing microperfusion makes it available to detect small foci of ischemia. Changes in CEUS-derived parameters could also be used to indicate acute kidney injury (AKI) and acute or chronic rejection. Enhancement of the renal parenchyma allows detection of a variety of surgical complications as well as transplant malignancies after transplantation. Moreover, application of ultrasound-targeted microbubble destruction makes targeted diagnosis and therapy possible in the allograft.
defects in porcine kidneys undergoing in vitro hypothermic perfusion, and the parameters corresponded well with those seen in vivo (Stenberg et al. 2011). Furthermore, 3-D CEUS was able to find more perfusion defects missed by Tc-DTPA scan and also quantified the volume of the perfusion defects with respect to total renal volume (Stenberg et al. 2014, 2017). Detecting acute kidney injury Acute kidney injury (AKI), characterized by a rapid loss of kidney function, is not rare in the clinical setting and can be caused by a variety of injuries including hypovolemia, cardiovascular surgery and sepsis. AKI leads to increased patient mortality and is an important factor in progression to CKD. Thus, early diagnosis and adjustment of the therapeutic strategy without delay are vital. The superiority of CEUS in displaying perfusion, especially microcirculation within the kidney, makes it a suitable technique to detect AKI. Experiments in mice on ischemiareperfusion injury (IRI) revealed that CEUS could detect the decrease in renal perfusion only 1 h after AKI, and the decrease in blood flow was positively correlated with subsequent renal fibrosis (Cao et al. 2017). In another IRI experiment in mice, new
analytical software was developed that enabled high resolution and pixel-by-pixel analysis on each imaging clip. This analysis applied a pixel-by-pixel Fourier transform approach during spectral analysis and provided a kidney perfusion map of the relative blood volume in each pixel (Fischer et al. 2016). The same study also indicated that perfusion in the outer medulla, instead of the cortex, decreased most significantly after IRI (Fischer et al. 2016). Another two studies revealed changes in CEUSderived parameters, including PI, AT, TTP and AUC, after IRI. And these parameters were strongly correlated with pathologic severity and expression of ICAM-1, an AKI molecular indicator (Li et al. 2015; Lee et al. 2017). CEUS has also been introduced at the beside in the clinical setting. Application of CEUS peri-operatively detected decreased renal perfusion within 24 h after surgery, manifested by a decreased perfusion index and increased mean transit time (mTT). However, the study did not find any correlation between the perfusion index and the serum creatinine level (Schneider et al. 2013; Hobson et al. 2017). Harrois et al. (2018) found similar parameter changes and reported that mTT could be used as an indicator of AKI in patients with septic shock. A clinical experiment examining the efficacy of CEUS in
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sepsis-associated AKI is also in progress (Liu et al. 2019b). Thus, because it is portable and is not nephrotoxic, CEUS might become a powerful tool for screening for AKI in high-risk patients, especially in the intensive care unit (Gocze et al. 2014). Convenient choice during follow-up The efficacy of CEUS in detecting a wide range of acute and subacute complications after kidney transplantation has also been extensively studied. Poorly perfused renal parenchyma was found to be an indicator of acute pyelonephritis in allografts (Granata et al. 2011). CEUS could also detect perirenal hematomas more sensitively than conventional B-mode ultrasound by revealing the increased difference in echogenicity between the hematoma and renal parenchyma (Grzelak et al. 2013). Moreover, CEUS was found to be capable of diagnosing acute renal vein thrombosis and other vascular complications after transplantation (Grzelak et al. 2011a; Mueller-Peltzer et al. 2017). Kidney recipients also have an increased risk of allograft malignancies because of immunosuppression. Though enhanced CT and MRI play the dominant role in diagnosing renal carcinoma, the nephrotoxicity and concern over inducing AKI associated with the contrast agents limit their application in kidney recipients. One study revealed that CEUS had a sensitivity of 100% and a specificity of 94.4% in detecting renal malignancies in transplant recipients (MuellerPeltzer et al. 2018). Another study found that CEUS could discriminate between complex kidney cysts and malignant masses that could not be clearly defined with conventional ultrasound (Paudice et al. 2012). Thus, CEUS might be a potent tool in follow-up of different complications after kidney transplantation. MOLECULAR TARGETED DIAGNOSIS AND TREATMENT Ultrasound-targeted microbubble destruction (UTMD) is a new technique that evolved from CEUS in recent years. MBs can carry a variety of cargo, including plasmid, siRNA, shRNA and even drugs, to the local tissue. Given that RBF accounts for a large amount of total cardiac output, the kidney is an ideal place for MB enrichment. Ultrasound generated from the transducer causes cavitation of the MBs, creating shock waves that permeabilize surrounding biological barriers together with release of cargo (Huang et al. 2019). Several studies found that UTMD led to increased permeabilization of kidney interstitial capillaries and MBs remained mainly in the tubular region (Li et al. 2013). The increased permeabilization of the capillary was found to be transient and reversible and did not lead to increases in hematuria or proteinuria (Zhang et al. 2014). Another study
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applying b-galactosidase plasmid also found that the gene transferred was expressed mainly in the tubular cells in the interstitium (Chen et al. 2012), further indicating the target region of UTMD within the kidney. Several studies have used UTMD to alleviate renal fibrosis, either by inducing Smad7 expression or by downregulating connective tissue growth factor (Lan et al. 2003; Hou et al. 2005; Wei et al. 2016). Because IF/TA of the kidney transplant is also manifested with TIF, this might be an effective way to treat allograft fibrosis. Capillary permeabilization increased by MBs has been found to enhance the homing ability of several stem cells, including mesenchymal stem cells and bone marrow stromal cells, to the kidney parenchyma, ameliorating renal injures (Zhang et al. 2013; Wang et al. 2016). UTMD has also been reported to enhance the efficiency of viral gene transfer into tumor tissue (Li et al. 2014) and delivery of tacrolimus specifically to the transplant (Liu et al. 2019a). In addition to the therapeutic effects of UTMD and MBs, a recent study has shed light on their role in diagnosis by designing C4d-targeted MBs. This study found that these targeted MBs could quantify the deposition of C4d in the kidney allograft, indicating AMR (Liao et al. 2019). In conclusion, though all of the studies discussed above were conducted in animal models, given its abilities to increase capillary permeabilization and take on different cargo, UTMD might become an efficient diagnostic and therapeutic method in kidney allografts in the future.
CONCLUSIONS AND PERSPECTIVE Advances in ultrasonography have resulted in powerful tools for examining kidney allografts. Among them, the most outstanding new techniques are elastography and CEUS. Strain elastography was the first elasticity examination applied in kidney transplants. However, because of its susceptibility to other factors and poor repeatability, its application was largely limited. SWE improved some of the defects of strain elastography though its application was still restricted in measuring allograft stiffness, detecting fibrosis and, to some extent, predicting allograft survival, while CEUS is playing an increasingly important role in the field of kidney transplantation. Because it can accurately depict the microcirculation of the allograft, CEUS can efficiently monitor kidney perfusion and different complications, detect AKI and predict long-term prognosis. Moreover, advances in MBs have shed light on a new application of CEUS, UTMD, for molecular targeted diagnosis and treatment. This novel and promising strategy might complement or even substitute for protocol allograft biopsy in the future.
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Acknowledgments—This study was supported by the National Natural Science Foundation of China (81770746 to C.Y.), the National Key R&D Program of China (2018 YFA0107502 to C.Y.), the Medical and Health Talents Training Plan for the Excellent Youth of Shanghai Municipal (2018 YQ50 to C.Y.), Shanghai RisingStar Program (19 QA1406300 to C.Y.) and China Organ Transplantation Development Foundation Elite Program (2019 JYJH05 to C.Y.). Conflict of interest disclosure—The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Ultrasound in Medicine & Biology
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Volume 00, Number 00, 2020 growth factor by ultrasound-targeted microbubble destruction improves renal fibrosis. Ultrasound Med Biol 2016;42:2926–2937. Yang WQ, Mou S, Xu Y, Xu L, Li FH, Li HL. Quantitative parameters of contrast-enhanced ultrasonography for assessment of renal pathology: A preliminary study in chronic kidney disease. Clin Hemorheol Microcirc 2018;68:71–82. Yang C, Wu S, Yang P, Shang G, Qi R, Xu M, Rong R, Zhu T, He W. Prediction of renal allograft chronic rejection using a model based on contrast-enhanced ultrasonography. Microcirculation 2019;26: e12544. Zhang Y, Ye C, Wang G, Gao Y, Tan K, Zhuo Z, Liu Z, Xia H, Yang D, Li P. Kidney-targeted transplantation of mesenchymal stem cells by ultrasound-targeted microbubble destruction promotes kidney repair in diabetic nephropathy rats. BioMed Res Int 2013;2013 526367. Zhang Y, Ye C, Xu Y, Dong X, Li J, Liu R, Gao Y. Ultrasound-mediated microbubble destruction increases renal interstitial capillary permeability in early diabetic nephropathy rats. Ultrasound Med Biol 2014;40:1273–1281. Zhang Q, Yu Z, Xu Y, Zeng S, Zhang Z, Xue W, Wang W, Zhang X, Hu X. Use of contrast-enhanced ultrasonography to evaluate chronic allograft nephropathy in rats and correlations between time-intensity curve parameters and allograft fibrosis. Ultrasound Med Biol 2016;42:1574–1583.