Kidney Transplant: Functional Assessment with Diffusion-Tensor MR Imaging at 3T 1

Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights. Original Research n Genitourinary Imaging Rotem S. Lanzman, MD Alexandra Ljimani Gael Pentang, MSc Panagiota Zgoura, MD Hakan Zenginli, MD Patric Kröpil, MD Philipp Heusch, MD Julia Schek, MD Falk R. Miese, MD Dirk Blondin, MD Gerald Antoch, MD Hans-Jörg Wittsack, PhD Kidney Transplant: Functional Assessment with Diffusion-Tensor MR Imaging at 3T 1 Purpose: Materials and Methods: To evaluate the feasibility of diffusion-tensor (DT) imaging at 3 T for functional assessment of transplanted kidneys. This study was approved by the local ethics committee; written informed consent was obtained. Between August 2009 and October 2010, 40 renal transplant recipients were prospectively included in this study and examined with a clinical 3-T magnetic resonance (MR) imager. An echo-planar DT imaging sequence was performed in coronal orientation by using five b values (0, 200, 400, 600, 800 sec/mm 2 ) and 20 diffusion directions. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were determined for the cortex and medulla of the transplanted kidney. Relationships between FA, ADC, and allograft function, determined by the estimated glomerular filtration rate (egfr), were assessed by using Pearson correlation coefficient. ADC and FA were compared between patients with good or moderate allograft function (group A; egfr. 30 ml/min/1.73 m 2 ) and patients with impaired function (group B; egfr 30 ml/min/1.73 m 2 ) by using a student t test. P,.05 indicated a statistically significant difference. Results: Conclusion: Mean FA of the renal medulla and cortex was significantly higher in group A (0.39 6 0.06 and 0.17 6 0.4) compared with group B (0.27 6 0.05 and 0.14 6 0.03) (P,.001 and P =.009, respectively). Mean ADCs of renal cortex and medulla were significantly higher in group A than in group B (P =.007 and P =.01, respectively). In group B, mean medullary FA was significantly lower in patients whose renal function did not recover (0.22 6 0.02) compared with those with stable allograft function at 6 months (0.29 6 0.05, P <.001). There was significant correlation between egfr and medullary FA (r = 0.65, P,.001), cortical ADC (r = 0.43, P =.003), and medullary ADC (r = 0.35, P =.01). DT imaging is a promising noninvasive technique for functional assessment of renal allografts. FA values in the renal medulla exhibit a good correlation with renal function. q RSNA, 2012 1 From the Department of Diagnostic and Interventional Radiology, University Düsseldorf, Medical Faculty, Moorenstr. 5, 40225 Düsseldorf, Germany. Received November 23, 2011; revision requested January 3, 2012; revision received June 1; accepted July 2; final version accepted July 24. Address correspondence to R.S.L. (e-mail: rotemshlomo@yahoo.de). q RSNA, 2012 218 radiology.rsna.org n Radiology: Volume 266: Number 1 January 2013

Transplantation is the therapy of choice in patients with end-stage chronic kidney disease. Owing to advances in immunosuppressive therapy and postoperative monitoring, the half-life of renal allografts has improved significantly over the past 20 years and is reported to range between 8.8 and 11.9 years (1). Although sonography is generally used as the primary imaging modality in the follow-up of renal transplant recipients, magnetic resonance (MR) imaging may be used for further evaluation of specific complications, such as transplant renal artery stenosis (2,3). In addition to detailed depiction of posttransplantation anatomy, functional information may be provided by the use of MR imaging. Information on allograft oxygenation and perfusion may be obtained by using blood oxygen level dependent and arterial spin labeling techniques (4 8). Furthermore, diffusion-weighted (DW) imaging has emerged as a promising noninvasive functional imaging technique for renal allografts (8,9). By using DW imaging, the Brownian motion Advances in Knowledge nn Fractional anisotropy (FA) and apparent diffusion coefficients (ADCs) are higher in renal allografts with good or moderate function (estimated glomerular filtration rate [egfr]. 30 ml/ min/1.73 m 2 ) compared with allografts that have heavily impaired function (egfr 30 ml/min/1.73 m 2 ). nn FA values in the medulla of transplanted kidneys correlate better with allograft function that is assessed by measuring egfr (r = 0.65) than do ADCs of the renal cortex (r = 0.43) and medulla (r = 0.35). nn Medullary FA values differ significantly between patients whose renal function recovers or remains stable (0.29 6 0.05) and those with chronic allograft (0.22 6 0.02, P,.001) failure at 6 months following the MR examination. of water in the extracellular space can be measured. While the mean apparent diffusion coefficient (ADC) is calculated as a quantitative parameter from DW images and depends on tissue microstructure (10,11), it does not account for the directionality of molecular motion. However, in kidneys, diffusion properties may be anisotropic because main anatomic structures, like vessels and tubules, exhibit a radial orientation. The fractional anisotropy (FA) of tissues, which is a measure of the directionality of diffusion, is assessed by using diffusion-tensor (DT) imaging. Studies in human kidneys have shown higher FA values in the renal medulla than in the renal cortex, which reflects the high potential for DT imaging to aid in the assessment of the radial microstructure in the renal medulla (12 15). Cheung et al (16) showed significant changes in medullary FA values in an animal renal ischemia and reperfusion model, which highlighted the potential use of DT imaging for functional renal imaging. The purpose of our study was to evaluate the feasibility of DT imaging at 3 T in the functional assessment of renal allografts. Materials and Methods This prospective study was approved by the local ethics committee, and written informed consent was obtained. Included in this study were 40 consecutive renal transplant recipients (mean age, 49.6 years 6 14.9), composed of 25 men (mean age, 52.0 years 6 15.3) and 15 women (mean age, 45.7 years 6 13.2) who between August 2009 and October 2010 either had undergone transplantation less than 1 month previously (n = 28) or presented to our inpatient or outpatient department for transplant-related complications (n = 12). Because contrast material was Implication for Patient Care nn As an unenhanced functional imaging technique, diffusion-tensor imaging may help to improve noninvasive monitoring of renal allograft recipients. not applied, patients were included irrespective of allograft function. The general contraindications for MR imaging were applied. No patients were excluded in the present study. The time interval between renal transplantation and the MR examination ranged between 3 days and 11 years, with a median of 16 days. Patients were assigned to two groups according to allograft function: Group A was composed of patients with good or moderate allograft function, determined according to chronic kidney disease stage I III (estimated glomerular filtration rate [egfr]. 30 ml/min/1.73 m 2 ), whereas patients with heavily impaired renal function (chronic kidney disease stage IV V [egfr 30 ml/min/1.73 m 2 ]) were assigned to group B. In all patients, blood samples were obtained on the day of the MR examination, and egfr was calculated by using the modification of diet in renal disease equation (17). Clinical status and renal function as determined by egfr were monitored every 1 4 weeks in the 1st year after transplantation and at least every 3 months thereafter. A minimum of 6 months of follow-up was available for all patients. Published online before print 10.1148/radiol.12112522 Content code: Radiology 2013; 266:218 225 Abbreviations: ADC = apparent diffusion coefficient DT = diffusion tensor DW = diffusion weighted egfr = estimated glomerular filtration rate FA = fractional anisotropy Author contributions: Guarantors of integrity of entire study, R.S.L., D.B., H.J.W.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, R.S.L., A.L., P.Z., P.K., P.H., F.R.M., D.B., G.A.; clinical studies, R.S.L., A.L., P.Z., H.Z., P.H., F.R.M., G.A.; experimental studies, P.H., H.J.W.; statistical analysis, R.S.L., A.L., G.P., P.K., P.H., H.J.W.; and manuscript editing, R.S.L., G.P., P.Z., H.Z., P.K., P.H., J.S., F.R.M., D.B., G.A., H.J.W. Conflicts of interest are listed at the end of this article. Radiology: Volume 266: Number 1 January 2013 n radiology.rsna.org 219

The patients were grouped according to their calculated egfr: Group A included 23 patients (mean age, 50.6 years 6 14.3), composed of 16 men (mean age, 52.1 years 6 15.4) and seven women (mean age, 47.1 years 6 9.5); group B included 17 patients (mean age, 48.3 years 6 16.3), composed of nine men (mean age, 51.8 years 6 15.2) and eight women (mean age, 44.4 years 6 15.6). Of the 23 patients assigned to group A, 17 patients with good and stable allograft function were imaged in the early postoperative period within 4 weeks after transplantation, and six patients were imaged between 5 weeks and 1.3 years after transplantation. Four patients had a mild ureteral obstruction caused by lymphoceles, one patient had pneumonia, and one patient had a urinary tract infection. A mild deterioration in renal function had been observed in the latter two patients prior to the MR examination. Of the 17 patients that were assigned to group B, 11 patients with delayed allograft function were imaged within 4 weeks after transplantation; this included one patient in whom acute rejection was clinically suspected, who subsequently developed severe hemolytic uremic syndrome, and one patient with severe stenosis of the transplant renal artery. In the other six patients (imaged between 6 weeks and 11 years after transplantation), poor allograft function was caused by urosepsis (n = 2), mild ureteral obstruction due to lymphocele (n = 1), perinuclear antineutrophil cytoplasmic antibody associated vasculitis within the renal allograft (n = 1), prior surgery for nephrectomy of the native kidney (n = 1), and clinically suspected rejection (n = 1), although this could not be confirmed in the biopsy specimen. MR Imaging All patients were examined in the supine position with a clinical 3-T MR imager (Magnetom Trio; Siemens, Erlangen, Germany) with a six-element surface coil, and with the spine coil Figure 1 integrated into the imager table. In all patients, a transverse T2-weighted half-fourier rapid acquisition with relaxation enhancement sequence was performed (repetition time msec/echo time msec, 2000/96; section thickness, 4 mm; 30 sections; field of view, 380 3 340 mm 2 ; in-plane resolution, 1.5 3 1.2 mm 2 ). In cases where ureteral obstruction was suspected, an additional MR urogram was acquired by using a T2-weighted three-dimensional imaging sampling perfection with application optimized contrasts using different flip angle evolutions, or SPACE, sequence (2400/712; field of view, 350 3 350 mm 2 ; 80 sections; resolution, 0.9 3 0.9 3 0.9 mm 3 ). DT images were acquired with a coronal echo-planar imaging sequence with the following imaging parameters: 1500/90; section thickness, 6 mm; 10 sections; field of view, 400 3 400 mm 2 ; b = 0, 200, 400, 600, and 800 sec/mm 2 ; 20 diffusion Figure 1: Images in a 52-year-old man with good function of cadaveric allograft 10 days after transplantation (from group A). (a) T2-weighted image shows renal allograft in right iliac fossa. (b) FA map shows excellent corticomedullary differentiation (medullary FA = 0.48). (c) ADC map shows homogeneously high signal intensity (cortical ADC = 1824 3 10 26 mm 2 /sec). directions; two signals acquired; partial Fourier acquisitions, 6/8; matrix, 192 3 192; echo spacing, 0.77 msec; parallel imaging factor, two; bandwidth, 2170 Hz/pixel. Total acquisition time for the echo-planar imaging sequence was 4 minutes 11 seconds. No respiratory gating was used because motion is negligible in transplanted kidney owing to their location in the iliac fossa. Image Analysis For image postprocessing, parametric ADC and FA maps were calculated inline. All images were transferred to a workstation for analysis (Leonardo; Siemens). Diffusion measurements along 20 axes were calculated inline to a 3 3 3 matrix, which corresponded to the diffusion tensor. The eigenvectors (v 1, v 2, v 3 ) and eigenvalues (l 1, l 2, l 3 ) of the diffusion tensor were 220 radiology.rsna.org n Radiology: Volume 266: Number 1 January 2013

Table 1 Comparison of Mean egfr, FA, and ADC Group FA Medulla FA Cortex ADC Medulla (10 26 mm 2 /sec) ADC Cortex (10 26 mm 2 /sec) A (n = 23) 0.39 6 0.06* 0.17 6 0.04 1817 6 126 1857 6 107 B (n = 17) 0.27 6 0.05 0.14 6 0.03 1699 6 149 1723 6 164 *P,.001, compared with group B. P,.05, compared with group B. Figure 2 section through the renal allograft by an author (R.S.L., 5 years of experience with abdominal MR imaging) who was blinded to clinical data. Three ellipsoid ROIs of approximately 10 15 pixels were placed in the medulla, and an ROI of 60 100 pixels was drawn to cover the renal cortex on 0-b-value images and FA maps. These ROIs were subsequently transferred to the parametric ADC map. The average of the three ROIs was used to quantify ADC and FA of the renal medulla. Statistical Analysis The student t test was used to assess differences in FA and ADC, as well as egfr between group A and group B. Pearson correlation coefficients were calculated to analyze the relationship between ADC, as well as FA values, and renal function as estimated by egfr. In addition, a multivariate regression analysis was performed with egfr as a dependent variable and ADC and FA as simultaneous predictors. P,.05 was considered to indicate a statistically significant difference. determined. FA parametric maps were calculated to depict the degree of diffusion anisotropy: FA = with 3 2 ( λ λ) + ( λ λ) + ( λ λ), 2 2 2 1 2 3 2 2 2 λ1 + λ2 + λ3 λ = λ1 + λ2 + λ 3. 3 Figure 2: Images in a 36-year-old man with impaired function of cadaveric allograft in early posttransplantation period (day 6, from group B). (a) T2-weighted MR image shows allograft was transplanted to left iliac fossa. (b) FA map shows low FA values of 0.25 in renal medulla, with moderate differentiation between renal cortex and medulla. (c) ADC map shows homogeneous signal intensity (cortical ADC = 1788 3 10 26 mm 2 /sec). FA is generally used as a quantifiable measure of diffusion anisotropy, and it is on a scale of 0 (isotropic) to 1 (fully anisotropic). A monoexponential analysis of trace images was used to determine ADCs. For quantification of ADC and FA, regions of interest (ROIs) were defined on images with b of 0 sec/mm 2 and parametric FA maps on a central Results Image acquisition was successfully completed in all patients (Figs 1, 2). Mean egfr was significantly higher in group A (49.0 ml/min/1.73 m 2 6 18.3) compared with group B (17.1 ml/min/1.73 m 2 6 6.4) (P,.001, Table 1). Mean ADCs of the renal cortex and medulla were significantly higher in group A (1857 3 10 26 mm 2 /sec 6 107 and 1817 3 10 26 mm 2 /sec 6 126) than in group B (1723 3 10 26 mm 2 / sec 6 164 and 1699 3 10 26 mm 2 /sec 6 149) (P =.007 for cortex; P =.01 for medulla). Mean FA of the renal medulla was significantly higher in group A (0.39 6 0.06) than in group B (0.27 6 0.05) (P,.001). In addition, there was a significant difference between cortical FA in group A (0.17 6 0.4) and that in group B (0.14 6 0.03) (P =.009) (Fig 3). Concordantly, the corticomedullary difference in FA values was lower Radiology: Volume 266: Number 1 January 2013 n radiology.rsna.org 221

Figure 3 Figure 3: Box and whisker plots that compare group A with group B by showing higher FA of the (a) medulla and (b) cortex, as well as higher ADC of the (c) medulla and (d) cortex. in group B (0.13 6 0.05) than group A (0.21 6 0.08, P,.001). There was a significant correlation between egfr and the ADC of the renal cortex (r = 0.43, P =.003) as well as the ADC of the renal medulla (r = 0.35, P =.01). Furthermore, FA of the medulla exhibited a high correlation with egfr (r = 0.65, P,.001), while no correlation was found between egfr and FA of the renal cortex (r = 0.15, P =.37) (Fig 4). In a multivariate regression model, FA of the medulla was found to correlate significantly better with renal function than did FA of the cortex and ADC values (P,.001). All patients in group A and 12 of 17 patients (71%) in group B had stable allograft function at 6 months after the MR examination and did not require hemodialysis. In five of the 17 patients (29%) in group B, allograft function did not recover, and permanent hemodialysis was required; in three of these patients, the renal allograft was explanted within 2 months after the MR examination. Chronic allograft failure in these five patients was caused by clinically suspected allograft rejection (two patients; one of these patients developed hemolytic uremic syndrome), severe transplant renal artery stenosis (one patient), perinuclear antineutrophil cytoplasmic antibody associated vasculitis in the transplanted kidney (one patient), and deterioration of allograft function following surgery (one patient). Mean medullary FA values were significantly lower in the five patients whose function did not recover (0.22 6 0.02) compared with the 12 patients in group B with stable allograft function at 6 months (0.29 6 0.05, P,.001) (Fig 5), while egfr, FA of the cortex, and ADCs were not significantly different (Table 2). Discussion Renal MR imaging is shifting from pure visualization of anatomy to assessment of physiologic and functional parameters of the kidney (18,19). Beside blood oxygen level dependent and arterial spin labeling MR imaging, DW imaging has emerged as a promising noninvasive functional technique in renal imaging 222 radiology.rsna.org n Radiology: Volume 266: Number 1 January 2013

Figure 4 Figure 4: Scatterplots show FA values of (a) renal medulla and (b) cortex, as well as ADC plotted with egfr of (c) medulla and (d) cortex. (11,20). Initial studies have demonstrated its high potential for monitoring renal allografts by showing a decrease in the ADC in patients with allograft rejection and acute tubular necrosis (8). In our study, we found a significant difference between cortical and medullary ADCs of recipients with an egfr greater than 30 ml/min/1.73 m 2 (group A) and those with poor allograft function (group B, egfr 30 ml/min/1.73 m 2 ). However, because DW imaging does not account for the directionality of diffusion properties, there is only a relatively small difference between the ADC of the cortex and the medulla of native kidneys, and this difference can be absent even in transplanted kidneys (8,21). Recent studies in native kidneys have shown that the directionality of diffusion (ie, FA) is higher in the renal medulla than in the renal cortex, which probably reflects the radial arrangement of tubules, vessels, and collecting ducts (12 15). Concordantly, in our study, FA values in the medulla were significantly higher than FA values in the cortex of transplanted kidneys. Furthermore, cortical and medullary FA values, as well as the corticomedullary difference in FA values, were significantly reduced in patients with an egfr of 30 ml/min/1.73 m 2 or less compared with patients with an egfr greater than 30 ml/min/1.73 m 2. The reduction in medullary FA values, as well as the corticomedullary difference, ranged between 30% and 40% and was more pronounced than the reduction in ADC values. Furthermore, in group B, medullary FA values were lower in patients whose renal function did not recover than in patients who had stable renal function at 6 months, while ADC and egfr did not differ significantly. These findings suggest that DT imaging may be more sensitive than DW imaging for detection of pathologic changes in renal microstructure. This assumption is supported by the significant correlation that was observed between medullary FA and egfr (r = 0.65, P,.001) in our study. A similar correlation was reported by Hueper et al (22) in an initial DT imaging study in 15 renal allograft recipients examined Radiology: Volume 266: Number 1 January 2013 n radiology.rsna.org 223

Table 2 Comparison of egfr, FA, and ADC by Allograft Function at 6 Months in Group B Patients Allograft Function at 6 Months egfr (ml/min/1.73 m 2 ) FA Medulla FA Cortex Figure 5 Figure 5: Box and whisker plot show significantly reduced FA values in patients from group B who had chronic allograft failure at 6 months after the MR examination compared with patients who had stable allograft function at 6 months. at 1.5 T. In contrast to that initial study, we also observed a significant correlation between egfr and ADC of the renal medulla (r = 0.35, P =.01) and cortex (r = 0.43, P =.003), which might be attributed to the higher number of patients included in our study. There are limited data on the use of DW imaging in renal allograft recipients, and the results with respect to the correlation between renal ADC and kidney function are variable. While Eisenberger et al (21) showed no correlation between ADC and egfr, other authors have reported a correlation between ADC and laboratory measures of renal allograft function (8,9). Explanations for this variation may relate to differences in imager geometry and to the ADC Medulla (10 26 mm 2 /sec) ADC Cortex (10 26 mm 2 /sec) Recovery (n = 12) 17.5 6 7.1 0.29 6 0.05* 0.15 6 0.03 1699 6 154 1752 6 164 Chronic failure (n = 5) 16.2 6 3.2 0.22 6 0.02 0.12 6 0.02 1696 6 118 1652 6 121 Note. Comparison of egfr, FA, and ADC in group B at the time of the MR examination in patients with stable allograft function and patients with chronic allograft failure 6 months following the MR examination. *P,.001, compared with patients with chronic allograft failure at 6 months. use of various b values in the different studies. Both tissue microperfusion and diffusion contribute to the signal decay in DW imaging of kidneys (23). Low b values (,200 sec/mm 2 ) contribute mainly to microperfusion, and higher b values (.200 sec/mm 2 ) contribute to pure diffusion. Therefore, the number and strength of b values have a large effect on both the renal ADC that is calculated with a monoexponential fit and the parameters that are obtained from a biexponential fit (24 26). Studies on human brains have demonstrated that the choice of b value influences the ADC, not the FA, of anatomic structures (27). In a previous study, Notohamiprodjo et al (13) showed that a b value of 50 sec/mm 2 that was added to a DT imaging protocol that consisted of two b values (0 and 300 sec/mm 2 ) caused a significant change in the ADC of native kidneys, but did not affect FA values. Concordantly, by using five b values (0 800 sec/mm 2 ) in our DT imaging protocol, the calculated ADCs in native kidneys were lower than those in previous studies, whereas FA values were comparable to previous results in native and transplanted kidneys (12,13,15,22). According to these findings, FA seemed to be a more stable functional parameter than was ADC, and it may improve the comparability of functional parameters that are obtained with different imagers and with different imaging protocols. One substantial advantage of DT imaging is its noninvasive character; injection of gadolinium-based contrast material is not required. This is relevant to renal allograft recipients because patients with poor renal function may develop nephrogenic systemic fibrosis after administration of gadolinium-based contrast material (28). Nephrogenic systemic fibrosis has been reported to possibly affect transplant recipients even without prior gadolinium-based contrast agent administration (29). The extent to which accumulated risk factors (eg, vascular surgery and contrast material administration) may increase the risk of nephrogenic systemic fibrosis remains unclear. However, a special caution for gadolinium-based contrast material administration in transplant recipients is warranted. Our study had limitations. First, the underlying pathologic conditions that led to impaired renal function were heterogeneous. Thus, the potential for DT imaging to differentiate between pathologic conditions (eg, acute rejection, acute tubular necrosis) cannot be derived from our results. Furthermore, we did not standardize the hydration state of our patients. Chandarana et al (18) recently showed that the hydration state may have an influence on measured renal FA values. By performing two DT imaging acquisitions in healthy patients who first refrained from fluid intake for 6 hours and then underwent water loading, 224 radiology.rsna.org n Radiology: Volume 266: Number 1 January 2013

the authors observed a variation from 10% 15% in FA values. Although differences in hydration state of allograft recipients may have biased our results, we do not expect a systematic bias because all patient groups were affected equally. In conclusion, FA values of the renal medulla differed significantly between allograft recipients with heavily impaired renal function (chronic kidney disease stage IV and V) and those with moderate or mild impairment in renal function (chronic kidney disease stage I III). The high correlation between FA values of the renal medulla and allograft function highlights the potential of DT imaging for noninvasive functional assessment of transplanted kidneys. However, the clinical value of DT imaging to differentiate between different pathologic conditions of transplanted kidneys (eg, acute rejection, acute tubular necrosis) requires further investigation. Disclosures of Conflicts of Interest: R.S.L. No relevant conflicts of interest to disclose. A.L. No relevant conflicts of interest to disclose. G.P. No relevant conflicts of interest to disclose. P.Z. No relevant conflicts of interest to disclose. H.Z. No relevant conflicts of interest to disclose. P.K. No relevant conflicts of interest to disclose. P.H. No relevant conflicts of interest to disclose. J.S. No relevant conflicts of interest to disclose. F.R.M. No relevant conflicts of interest to disclose. D.B. No relevant conflicts of interest to disclose. G.A. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: receives payment for lectures from Bayer HealthCare, Siemens Healthcare, Nordion, Novartis Oncology. Other relationships: none to disclose. H.J.W. No relevant conflicts of interest to disclose. References 1. Lodhi SA, Meier-Kriesche HU. Kidney allograft survival: the long and short of it. Nephrol Dial Transplant 2011;26(1):15 17. 2. Lanzman RS, Voiculescu A, Walther C, et al. 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