DOI: 10.1148/radiol.2363041080
(Radiology 2005;236:911-919.)
© RSNA, 2005
Assessment of Acute Renal Transplant Rejection with Blood Oxygen Level–Dependent MR Imaging: Initial Experience1
Elizabeth A. Sadowski, MD,
Sean B. Fain, PhD,
Sara K. Alford, MS,
Frank R. Korosec, PhD,
Jason Fine, PhD,
Rebecca Muehrer, RN, MS,
Arjang Djamali, MD,
R. Michael Hofmann, MD,
Bryan N. Becker, MD and
Thomas M. Grist, MD
1 From the Departments of Radiology (E.A.S., S.B.F., F.R.K., J.F., T.M.G.), Medical Physics (S.B.F., S.K.A., F.R.K., T.M.G.), Nephrology (R.M., A.D., R.M.H., B.N.B.), and Biostatistics (J.F.), University of Wisconsin, 600 Highland Ave, E3/311 CSC, Madison, WI 53792. Received June 18, 2004; revision requested August 27; revision received October 8; accepted November 15.
Address correspondence to E.A.S. (e-mail: ea.sadowski{at}hosp.wisc.edu).
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ABSTRACT
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PURPOSE: To prospectively assess the oxygenation state of renal transplants and determine the feasibility of using blood oxygen level–dependent (BOLD) magnetic resonance (MR) imaging to differentiate between acute tubular necrosis (ATN), acute rejection, and normal function.
MATERIALS AND METHODS: This HIPAA-compliant study had institutional human subjects review committee approval, and written informed consent was obtained from all patients. BOLD MR imaging was performed in 20 patients (age range, 21–70 years) who had recently received renal transplants. Six patients had clinically normal functioning transplants, eight had biopsy-proved rejection, and six had biopsy-proved ATN. R2* (1/sec) measurements were obtained in the medulla and cortex of transplanted kidneys. R2* is a measure of the rate of signal loss in a specific region and is related to the amount of deoxyhemoglobin present. Statistical analysis was performed by using a two-sample t test. Threshold R2* values were identified to discriminate between transplanted kidneys with ATN, those with acute rejection, and those with normal function.
RESULTS: R2* values for the medulla were significantly lower in the acute rejection group (R2* = 15.8/sec ± 1.5) than in normally functioning transplants (R2* = 23.9/sec ± 3.2) and transplants with ATN (R2* = 21.3/sec ± 1.9). The differences between the acute rejection and normal function groups (P = .001), as well as between the acute rejection and ATN groups (P < .001), were significant. Acute rejection could be differentiated from normal function and ATN in all cases by using a threshold R2* value of 18/sec. R2* values for the cortex were higher in ATN (R2* = 14.2/sec ± 1.4) than for normally functioning transplants (R2* = 12.7/sec ± 1.6) and transplants with rejection (R2* = 12.4/sec ± 1.2). The difference in R2* values in the cortex between ATN and rejection was statistically significant (P = .034), although there was no threshold value that enabled differentiation of all cases of ATN from cases of normal function or acute rejection.
CONCLUSION: R2* measurements in the medullary regions of transplanted kidneys with acute rejection were significantly lower than those in normally functioning transplants or transplants with ATN. These results suggest that marked changes in intrarenal oxygenation occur during acute transplant rejection.
© RSNA, 2005
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INTRODUCTION
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Kidney transplantation remains the optimal means of renal replacement therapy for individuals with end-stage renal disease and prolongs both survival and quality of life in these patients. Although advances in both surgical technique and immunosuppressive therapy have resulted in 1-year survival rates of greater than 90%, graft dysfunction in the early posttransplant period remains an important clinical problem (1). Early graft dysfunction due to rejection and acute tubular necrosis (ATN) occurs in approximately 30% of patients. Early characterization of the underlying cause of graft dysfunction is important because delayed treatment can lead to irreversible loss of nephrons and hasten graft loss over time (2–4).
Percutaneous renal transplant biopsy is currently the only means of differentiating between ATN and acute rejection. Unfortunately, biopsies are invasive and painful and can result in complications such as bleeding, infection, and, rarely, graft loss (4). Development of a noninvasive alternative to biopsy would decrease the likelihood of complications. Moreover, having a noninvasive tool for assessing transplanted kidneys would enable more patients to be screened for acute rejection and potentially lead to earlier initiation of treatment.
Invasive measurements of kidney function and oxygenation obtained in animals have revealed a correlation between intrarenal oxygenation and the functional activity of the kidney (5–10). Owing to their invasive nature, these types of studies are not possible in humans. Recently, blood oxygen level–dependent (BOLD) magnetic resonance (MR) imaging has been used as a noninvasive method of assessing tissue oxygenation, thus enabling the study of intrarenal oxygenation in humans. BOLD MR imaging has been used in native kidneys and has revealed differences in medullary oxygenation during renal artery occlusion, water diuresis, and pharmacologic stimulation with lasix, acetazolamide, and nitric oxide (11–17).
BOLD MR imaging involves using the paramagnetic properties of deoxyhemoglobin to image the local tissue oxygen concentration. Previous investigators have shown that, as the deoxyhemoglobin concentration in blood increases, the T2* relaxation time of the protons decreases and more dephasing occurs in the surrounding tissues (18–20). This produces measurable signal loss in areas of increased deoxyhemoglobin concentration. In the kidney, this loss of signal intensity can be well demonstrated on a series of T2*-weighted images in which each image is acquired with a different echo time. R2* is a measure of the rate of signal loss and is calculated as the slope of a line produced by plotting the logarithm MR signal intensity versus echo time for the series of T2*-weighted images. The higher the concentration of deoxyhemoglobin, the greater the rate of signal loss and the larger the R2*. These parameters have been introduced and applied to the measurement of oxygenation in the cortex and medulla of native kidneys (11–15); however, to the best of our knowledge, BOLD MR imaging has not yet been used for evaluation of renal transplant function and oxygenation. Thus, the purpose of our study was to assess the oxygenation state of renal transplants and determine the feasibility of using BOLD MR imaging to differentiate between ATN, acute rejection, and normal function.
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MATERIALS AND METHODS
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Patients
Our Health Insurance Portability and Accountability Act–compliant study was approved by our institutional human subjects review committee, and written informed consent was obtained from all patients. BOLD MR imaging was performed between January 2003 and April 2004 in 20 consecutive patients who had recently received renal transplants. All patients had received their transplants less than 3 months previously. All patients had received induction therapy with alemtuzumab, basiliximab, thymoglobulin, or antithymocyte globulin before transplantation. After transplantation, 16 of 20 patients (80%) were receiving triple immunosuppression therapy (prednisone plus mycophenolate mofetil or azathioprine plus cyclosporine, tacrolimus, or sirolimus) and four of 20 patients (20%) were receiving two immunosuppressants only (prednisone plus mycophenolate mofetil).
Six patients had clinically normal functioning transplants, as determined with laboratory evaluation and by the consulting transplant nephrologist (B.N.B., A.D., or R.M.H. [average experience, 11 years]), while eight patients had acute rejection and six had ATN, as determined with percutaneous renal transplant biopsy. The patient population consisted of 11 men and nine women who ranged in age from 21 to 70 years. Four of six patients in the normal function group, all patients in the ATN group, and six of eight patients in the acute rejection group had received kidney transplants from deceased donors. The remaining patients had received kidney transplants from living related donors. The mean creatinine level was 1.6 mg/dL (141.4 µmol/L) in the normal function group, 4.7 mg/dL (415.5 µmol/L) in the ATN group, and 3.3 mg/dL (291.7 µmol/L) in the acute rejection group.
Normal function or graft dysfunction was determined by the transplant nephrologist. In cases of graft dysfunction, cyclosporine toxicity, infection, vascular compromise, and ureteral obstruction were excluded on a clinical, laboratory, and imaging basis. Ultrasonography (US) was routinely performed before biopsy to exclude hydronephrosis, perirenal fluid collections, and vascular occlusion. The indications for biopsy early after transplantation included an increasing serum creatinine or ß2-microglobulin level in the absence of other causes of kidney transplant dysfunction. If percutaneous renal transplant biopsy was clinically indicated, two 18-gauge biopsy core samples were obtained at the time of biopsy by the transplant nephrologist with real-time US guidance. One 18-gauge core sample was used entirely for histologic assessment. Half of the second core sample was paraffin-embedded for immunohistochemical analysis. The other half of the second core sample was stored at –70°C for additional mRNA studies. In addition, C4d immunostaining, which is part of the standard of care at our institution, was performed for each sample.
The time from transplantation to MR imaging varied between 2 weeks and 3 months for all patients. All patients refrained from water or intravenous fluid intake for 4 hours prior to the BOLD MR imaging examination. BOLD MR imaging was performed within 48 hours of the clinically indicated biopsy in 11 of the 14 patients who required biopsy, with the biopsy always preceding MR imaging. Three patients underwent BOLD MR imaging 5–7 days after their biopsy, and all had a stable condition in the interim. Two of these three patients were found to have ATN at biopsy and had a stable creatinine level from the time of biopsy to the time of MR imaging. One patient had acute rejection, and, although the creatinine level had improved somewhat between the biopsy and MR imaging, we decided to keep this patient's data in our investigation because the R2* measurements were still markedly abnormal at the time of the BOLD MR imaging study. This was agreed to by the primary author (E.A.S.) and the consulting nephrologists (B.N.B., A.D., and R.M.H.).
MR Imaging Technique
MR imaging was performed with a 1.5-T system (Signa; GE Healthcare, Waukesha, Wis) and a four-element torso phased-array surface coil. BOLD MR imaging was performed by using a multi–gradient-recalled-echo sequence with 16 echoes at a gap of 1 mm and a 5-mm section thickness that was prescribed in the coronal plane. The scanning parameters were as follows: repetition time msec/echo time msec, 87/8–41.8; flip angle, 40°; bandwidth, ±62.5 kHz; field of view, 32–34 cm; matrix, 256 x 128; and number of signals acquired, one. Each set of 16 T2*-weighted images was acquired during an 11-second breath hold. Three sections were obtained in the coronal plane for each transplanted kidney. The coronal plane was chosen because of the authors' preference.
Data Analysis
Results of the biopsy were not available at the time of R2* analysis but were available approximately 1 week after biopsy. The renal status of the patients was known to the reader of the BOLD MR images. Mean R2* values were recorded in units of 1/sec. With Functool on the Advantage workstation (GE Healthcare), color R2* maps were generated and regions of interest (ROIs) were placed in the medulla and cortex by a radiologist (E.A.S.) with 4 years of experience in BOLD MR imaging. More specifically, three sections were obtained through the transplanted kidney in the coronal plane and up to four ROIs were placed per section in the medulla and in the cortex. A total of six to 10 ROIs were placed in the medulla, and six to 10 ROIs were placed in the cortex, resulting in 12–20 ROIs per kidney per patient.
The number of ROIs per section depended on the amount of bowel gas artifact present on the images obtained in a specific patient. Susceptibility artifacts caused by bowel gas are often marked, and sometimes portions of a section were noninterpretable owing to the presence of such an artifact. Areas of obvious susceptibility artifact, which appeared as broad areas of red or complete black in the cortex on the color map, were avoided. Both T1-weighted gray-scale and color maps were used to place ROIs properly. The gray-scale image was the first image of the set of 16 multi–gradient-recalled-echo images obtained during BOLD MR imaging and had a repetition time of 87 msec and an echo time of 8 msec.
In the medulla, ROIs were placed over areas that contained the gradient of green, yellow, and red on the color map and had decreased signal intensity compared with the signal intensity of the cortex on the gray-scale image. Areas of red near an obvious vessel in the hilum of the kidney were avoided because these were areas of dephasing caused by moving blood in the vessel and were not related to the deoxyhemoglobin concentration. In transplanted kidneys with rejection, the gradient of green to red was not evident, and ROIs were placed in regions that appeared mostly green on the color map and had decreased signal intensity on the gray-scale image. In the cortex, ROIs were placed over areas that appeared blue on the color map and had increased signal intensity compared with the signal intensity of the medulla on the gray-scale image. In addition to obtaining quantitative R2* measurements in the cortex and medulla, we visually inspected the cortical medullary differentiation of each transplanted kidney on the color R2* map.
Further comment on the use of color R2* maps is necessary. The color R2* map was windowed to provide a visual range of R2* values from low to high, with blue representing the lowest R2* value (area of lowest deoxyhemoglobin concentration) and red representing the highest R2* value (area of highest deoxyhemoglobin concentration). This aided in the discrimination of cortex from medulla and prevented the inclusion of volume-averaged pixels that contained both cortex and medulla. Volume averaging occurs because the kidney is a three-dimensional structure and because the medullary pyramids are not perfectly coronal or perfectly axial. In addition, columns of cortex interdigitate themselves between the medullar pyramids. Therefore, some medullar pyramids will have more areas of cortex averaged with areas of medulla than others. Instead of a true medullary reading, information from the cortex is averaged in the data, causing an underestimation of the R2* value for the medulla. An example of volume averaging and proper ROI placement is given in Figure 1.
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Figure 1a. (a) Color R2* map of coronal section obtained in normally functioning transplanted kidney. ROI 1 is placed properly on a pyramid that shows the green to yellow to red gradient on the color map and has an R2* value of 23.6/sec. ROI 2 is not placed properly because the pyramid is entirely green, signifying that it includes some volume averaging from adjacent cortex either anterior or posterior to this point in space. Note that ROI 2 has a R2* value of only 18.0/sec. ROI 1 is placed over the same medullary pyramid in a–d. ROI 2 is also placed over the same medullary pyramid in a–d. Images a and c (section thickness, 5 mm; gap, 1 mm) were obtained in only slightly different anterior-to-posterior locations. (b) Coronal gradient-echo T1-weighted MR image corresponding to a. On this gray-scale image, both pyramids corresponding to ROIs 1 and 2 appear to have lower signal intensities compared with the signal intensity of the cortex and could be used improperly if no reference were made to the color map. (c) Color R2* map of coronal section obtained just anterior to a. ROI 1 now contains pixels that are averaged with cortical pixels, which is obvious on both the color map because of the lack of yellow or red and the gray-scale image (d) by the fact that the signal intensity in the ROI is closer to that of cortex. ROI 1 now has a lower R2* value of 20.7/sec. In contrast, ROI 2 has now come into a better plane and has less volume averaging, as seen by the fact that a proper color gradient is present on the color map and the higher R2* value of 26.0/sec. (d) Coronal gradient-echo T1-weighted image corresponding to c. On this gray-scale image, ROI 1 is difficult to separate from cortex because of the volume averaging that is occurring. In contrast, ROI 2 is now in a better plane and is in a region that has darker signal intensity than does the cortex, meaning this region has less volume averaging with cortex anterior or posterior to this point in space.
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Figure 1b. (a) Color R2* map of coronal section obtained in normally functioning transplanted kidney. ROI 1 is placed properly on a pyramid that shows the green to yellow to red gradient on the color map and has an R2* value of 23.6/sec. ROI 2 is not placed properly because the pyramid is entirely green, signifying that it includes some volume averaging from adjacent cortex either anterior or posterior to this point in space. Note that ROI 2 has a R2* value of only 18.0/sec. ROI 1 is placed over the same medullary pyramid in a–d. ROI 2 is also placed over the same medullary pyramid in a–d. Images a and c (section thickness, 5 mm; gap, 1 mm) were obtained in only slightly different anterior-to-posterior locations. (b) Coronal gradient-echo T1-weighted MR image corresponding to a. On this gray-scale image, both pyramids corresponding to ROIs 1 and 2 appear to have lower signal intensities compared with the signal intensity of the cortex and could be used improperly if no reference were made to the color map. (c) Color R2* map of coronal section obtained just anterior to a. ROI 1 now contains pixels that are averaged with cortical pixels, which is obvious on both the color map because of the lack of yellow or red and the gray-scale image (d) by the fact that the signal intensity in the ROI is closer to that of cortex. ROI 1 now has a lower R2* value of 20.7/sec. In contrast, ROI 2 has now come into a better plane and has less volume averaging, as seen by the fact that a proper color gradient is present on the color map and the higher R2* value of 26.0/sec. (d) Coronal gradient-echo T1-weighted image corresponding to c. On this gray-scale image, ROI 1 is difficult to separate from cortex because of the volume averaging that is occurring. In contrast, ROI 2 is now in a better plane and is in a region that has darker signal intensity than does the cortex, meaning this region has less volume averaging with cortex anterior or posterior to this point in space.
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Figure 1c. (a) Color R2* map of coronal section obtained in normally functioning transplanted kidney. ROI 1 is placed properly on a pyramid that shows the green to yellow to red gradient on the color map and has an R2* value of 23.6/sec. ROI 2 is not placed properly because the pyramid is entirely green, signifying that it includes some volume averaging from adjacent cortex either anterior or posterior to this point in space. Note that ROI 2 has a R2* value of only 18.0/sec. ROI 1 is placed over the same medullary pyramid in a–d. ROI 2 is also placed over the same medullary pyramid in a–d. Images a and c (section thickness, 5 mm; gap, 1 mm) were obtained in only slightly different anterior-to-posterior locations. (b) Coronal gradient-echo T1-weighted MR image corresponding to a. On this gray-scale image, both pyramids corresponding to ROIs 1 and 2 appear to have lower signal intensities compared with the signal intensity of the cortex and could be used improperly if no reference were made to the color map. (c) Color R2* map of coronal section obtained just anterior to a. ROI 1 now contains pixels that are averaged with cortical pixels, which is obvious on both the color map because of the lack of yellow or red and the gray-scale image (d) by the fact that the signal intensity in the ROI is closer to that of cortex. ROI 1 now has a lower R2* value of 20.7/sec. In contrast, ROI 2 has now come into a better plane and has less volume averaging, as seen by the fact that a proper color gradient is present on the color map and the higher R2* value of 26.0/sec. (d) Coronal gradient-echo T1-weighted image corresponding to c. On this gray-scale image, ROI 1 is difficult to separate from cortex because of the volume averaging that is occurring. In contrast, ROI 2 is now in a better plane and is in a region that has darker signal intensity than does the cortex, meaning this region has less volume averaging with cortex anterior or posterior to this point in space.
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Figure 1d. (a) Color R2* map of coronal section obtained in normally functioning transplanted kidney. ROI 1 is placed properly on a pyramid that shows the green to yellow to red gradient on the color map and has an R2* value of 23.6/sec. ROI 2 is not placed properly because the pyramid is entirely green, signifying that it includes some volume averaging from adjacent cortex either anterior or posterior to this point in space. Note that ROI 2 has a R2* value of only 18.0/sec. ROI 1 is placed over the same medullary pyramid in a–d. ROI 2 is also placed over the same medullary pyramid in a–d. Images a and c (section thickness, 5 mm; gap, 1 mm) were obtained in only slightly different anterior-to-posterior locations. (b) Coronal gradient-echo T1-weighted MR image corresponding to a. On this gray-scale image, both pyramids corresponding to ROIs 1 and 2 appear to have lower signal intensities compared with the signal intensity of the cortex and could be used improperly if no reference were made to the color map. (c) Color R2* map of coronal section obtained just anterior to a. ROI 1 now contains pixels that are averaged with cortical pixels, which is obvious on both the color map because of the lack of yellow or red and the gray-scale image (d) by the fact that the signal intensity in the ROI is closer to that of cortex. ROI 1 now has a lower R2* value of 20.7/sec. In contrast, ROI 2 has now come into a better plane and has less volume averaging, as seen by the fact that a proper color gradient is present on the color map and the higher R2* value of 26.0/sec. (d) Coronal gradient-echo T1-weighted image corresponding to c. On this gray-scale image, ROI 1 is difficult to separate from cortex because of the volume averaging that is occurring. In contrast, ROI 2 is now in a better plane and is in a region that has darker signal intensity than does the cortex, meaning this region has less volume averaging with cortex anterior or posterior to this point in space.
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There were two patients in our study who were individually evaluated. One patient was examined twice: once during a time of normal function and once during an episode of acute rejection, which occurred approximately 2 months apart. The second patient had markedly elevated R2* values in the cortex compared with these values in the other patients in the study. This patient's biopsy and MR imaging results were correlated.
Statistical Analysis
R2* values (1/sec) are expressed as means ± standard deviations. Statistical analysis of cortical and medullary R2* values was formally performed by using a two-sample t test with S-Plus, version 3.4 (Insightful, Seattle, Wash). Normal function versus acute rejection, normal function versus ATN, and acute rejection versus ATN were evaluated. To better understand the ability of R2* values in the medulla and cortex to enable discrimination between kidney transplants with acute rejection, those with ATN, and those with normal function, we identified thresholds and computed the probabilities of correct classification with these thresholding rules.
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RESULTS
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R2* Measurements
Results of R2* measurements in the medulla and cortex of patients with normally functioning transplanted kidneys, patients with ATN, and patients with acute rejection, along with the numbers of living and deceased donors and the average ages and creatinine and hematocrit levels in each group, are summarized in Table 1. In brief, the R2* measurements in the medulla were highest in normally functioning transplants (23.9/sec ± 3.2), lower in transplants with ATN (21.3/sec ± 1.9), and lowest in transplants with rejection (15.8/sec ± 1.5). The R2* values in the cortex of normally functioning transplants and transplants with acute rejection were similar, at 12.7/sec ± 1.6 and 12.4/sec ± 1.2, respectively. Transplants with ATN had a slightly elevated R2* value of 14.2/sec ± 1.4 in the cortex. One of the patients with ATN had a markedly elevated R2* in the cortex. This patient was excluded from the analyses involving cortical R2* because of this irregularity, which was thought to be caused by superimposed cortical ischemia. The difference in the mean R2* values in the medulla was statistically significant between normally functioning transplants and transplants with acute rejection (P = .001) and between transplants with ATN and transplants with acute rejection (P < .001) (Fig 2a). The difference in the mean R2* values in the cortex was statistically significant between transplants with acute rejection and transplants with ATN (P = .034) (Fig 2b).
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Figure 2a. (a) Bar graph shows range of medullary R2* values in transplanted kidneys with normal function, ATN, or acute rejection. R2* values are noted as means ± standard deviations (which are also indicated by the error bars). Note that the R2* values decrease from normal function to ATN to acute rejection. The differences in mean medullary R2* value between normally functioning transplants and transplants with acute rejection (P = .001) and between transplants with ATN and transplants with acute rejection (P < .001) were significant. (b) Bar graph shows range of cortical R2* values in transplanted kidneys with normal function, ATN, or acute rejection. R2* values are noted as means ± standard deviations (which are also indicated by the error bars). Note that the R2* values are highest in the transplanted kidneys with ATN. The difference in mean cortical R2* value between transplanted kidneys with ATN and those with acute rejection was significant (P = .034). ** = Excluding one patient with ATN who had cortical ischemia and an R2* of 41.2/sec.
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Figure 2b. (a) Bar graph shows range of medullary R2* values in transplanted kidneys with normal function, ATN, or acute rejection. R2* values are noted as means ± standard deviations (which are also indicated by the error bars). Note that the R2* values decrease from normal function to ATN to acute rejection. The differences in mean medullary R2* value between normally functioning transplants and transplants with acute rejection (P = .001) and between transplants with ATN and transplants with acute rejection (P < .001) were significant. (b) Bar graph shows range of cortical R2* values in transplanted kidneys with normal function, ATN, or acute rejection. R2* values are noted as means ± standard deviations (which are also indicated by the error bars). Note that the R2* values are highest in the transplanted kidneys with ATN. The difference in mean cortical R2* value between transplanted kidneys with ATN and those with acute rejection was significant (P = .034). ** = Excluding one patient with ATN who had cortical ischemia and an R2* of 41.2/sec.
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So that we could better understand the ability of R2* values in the medulla and cortex to enable discrimination between transplanted kidneys with ATN, those with acute rejection, and those with normal function, we identified thresholds for discriminating between these groups. For R2* values in the medulla, all (100%) of the eight transplanted kidneys with acute rejection had values of less than 18/sec, while none (0%) of the six transplanted kidneys with ATN and none (0%) of the six transplanted kidneys with normal function had values above this threshold. Use of the R2* values for the medulla at the threshold defined above yielded the correct decision for eight of eight kidneys (100%) (Fig 3a). In the cortex, four of five transplanted kidneys with ATN (80%) had an R2* value of 13.9 or higher, while one of eight transplanted kidneys with acute rejection (13%) and one of six transplanted kidneys with normal function (17%) had R2* values higher than 13.9 (Fig 3b).
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Figure 3a. (a) Scatterplot of medullary R2* values in transplanted kidneys with normal function, ATN, or acute rejection. Note that the medullary R2* values of all transplanted kidneys with acute rejection are below the threshold value of 18/sec. (b) Scatterplot of cortical R2* values in transplanted kidneys with normal function, ATN, or acute rejection. Note that the cortical R2* values in four of the five transplanted kidneys with ATN are higher than the threshold value of 13.9/sec, whereas the values in seven of the eight kidneys with acute rejection are lower than 13.9/sec.
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Figure 3b. (a) Scatterplot of medullary R2* values in transplanted kidneys with normal function, ATN, or acute rejection. Note that the medullary R2* values of all transplanted kidneys with acute rejection are below the threshold value of 18/sec. (b) Scatterplot of cortical R2* values in transplanted kidneys with normal function, ATN, or acute rejection. Note that the cortical R2* values in four of the five transplanted kidneys with ATN are higher than the threshold value of 13.9/sec, whereas the values in seven of the eight kidneys with acute rejection are lower than 13.9/sec.
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Figure 4 illustrates the visual difference noted between groups when the same scale for the color R2* maps was applied. In normally functioning transplants there was obvious differentiation between cortex and medulla, with the cortex (the site of the lowest R2* value) appearing blue, the outer part of the medulla appearing green, and the inner part of the medulla (the site of the highest R2* values) appearing yellow or red (Fig 4a). This differentiation became less apparent in ATN (Fig 4b) and was not present in acute rejection (Fig 4c).
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Figure 4a. (a) Coronal color R2* map of normally functioning transplanted kidney. Blue represents the lowest R2* value, and green, yellow, and red represent increasing R2* values. Note that the cortex is blue, signifying a lower R2* value (lower deoxyhemoglobin concentration). This is in contrast to the medulla, where there is a gradient of green, yellow, and red that signifies an increase in R2* values from the outer to the inner medulla. (b) Coronal color R2* map of transplanted kidney with ATN. Notice some loss of yellow and red in the medulla. (c) Coronal color R2* map of transplanted kidney with rejection. Note the loss in the medulla of yellow and red—colors that are seen in both transplanted kidneys with normal function and transplanted kidneys with ATN. The blue/green color of the medullary pyramids in rejection corresponds to lower R2* values and signifies that less deoxyhemoglobin is present in rejection than is present in normally functioning kidneys or kidneys with ATN. The color map scale is similar in a–c.
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Figure 4b. (a) Coronal color R2* map of normally functioning transplanted kidney. Blue represents the lowest R2* value, and green, yellow, and red represent increasing R2* values. Note that the cortex is blue, signifying a lower R2* value (lower deoxyhemoglobin concentration). This is in contrast to the medulla, where there is a gradient of green, yellow, and red that signifies an increase in R2* values from the outer to the inner medulla. (b) Coronal color R2* map of transplanted kidney with ATN. Notice some loss of yellow and red in the medulla. (c) Coronal color R2* map of transplanted kidney with rejection. Note the loss in the medulla of yellow and red—colors that are seen in both transplanted kidneys with normal function and transplanted kidneys with ATN. The blue/green color of the medullary pyramids in rejection corresponds to lower R2* values and signifies that less deoxyhemoglobin is present in rejection than is present in normally functioning kidneys or kidneys with ATN. The color map scale is similar in a–c.
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Figure 4c. (a) Coronal color R2* map of normally functioning transplanted kidney. Blue represents the lowest R2* value, and green, yellow, and red represent increasing R2* values. Note that the cortex is blue, signifying a lower R2* value (lower deoxyhemoglobin concentration). This is in contrast to the medulla, where there is a gradient of green, yellow, and red that signifies an increase in R2* values from the outer to the inner medulla. (b) Coronal color R2* map of transplanted kidney with ATN. Notice some loss of yellow and red in the medulla. (c) Coronal color R2* map of transplanted kidney with rejection. Note the loss in the medulla of yellow and red—colors that are seen in both transplanted kidneys with normal function and transplanted kidneys with ATN. The blue/green color of the medullary pyramids in rejection corresponds to lower R2* values and signifies that less deoxyhemoglobin is present in rejection than is present in normally functioning kidneys or kidneys with ATN. The color map scale is similar in a–c.
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R2* Measurements in Same Patient during Normal Function and Acute Rejection
One patient was examined shortly after he received a living donor transplant during a time of normal kidney function and again during a subsequent episode of mild acute rejection that occurred approximately 2 months after transplantation. This patient's medullary R2* value during normal function was 24.1/sec, while during the acute rejection episode the R2* decreased to 16.9/sec (Fig 5).
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Figure 5a. (a) Coronal color R2* map shows transplanted kidney during normal function (2 weeks after transplantation). Note that the cortex is blue and the medullary pyramids have a green/yellow color. The three ROIs (1–3) placed in the upper pole, midpole, and lower pole have R2* values above 18/sec. (b) Gradient-echo T1-weighted MR image obtained during normal function shows ROIs placed over areas of lower signal intensity that correspond to medulla. (c) Coronal color R2* map shows same kidney as in a and b. This kidney is now experiencing mild rejection (2 months after transplantation). Note the subtle loss of green and yellow in the medullary pyramids of the upper and lower poles, with corresponding decreased R2* values (16.0/sec in ROI 1 and 17.3/sec in ROI 3). There is a midpole medullary pyramid (ROI 2) that maintains its green and yellow coloration and has a R2* value of more than 18/sec. (d) Gradient-echo T1-weighted MR image obtained during mild rejection shows ROIs placed over areas of lower signal intensity that correspond to medulla.
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Figure 5b. (a) Coronal color R2* map shows transplanted kidney during normal function (2 weeks after transplantation). Note that the cortex is blue and the medullary pyramids have a green/yellow color. The three ROIs (1–3) placed in the upper pole, midpole, and lower pole have R2* values above 18/sec. (b) Gradient-echo T1-weighted MR image obtained during normal function shows ROIs placed over areas of lower signal intensity that correspond to medulla. (c) Coronal color R2* map shows same kidney as in a and b. This kidney is now experiencing mild rejection (2 months after transplantation). Note the subtle loss of green and yellow in the medullary pyramids of the upper and lower poles, with corresponding decreased R2* values (16.0/sec in ROI 1 and 17.3/sec in ROI 3). There is a midpole medullary pyramid (ROI 2) that maintains its green and yellow coloration and has a R2* value of more than 18/sec. (d) Gradient-echo T1-weighted MR image obtained during mild rejection shows ROIs placed over areas of lower signal intensity that correspond to medulla.
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Figure 5c. (a) Coronal color R2* map shows transplanted kidney during normal function (2 weeks after transplantation). Note that the cortex is blue and the medullary pyramids have a green/yellow color. The three ROIs (1–3) placed in the upper pole, midpole, and lower pole have R2* values above 18/sec. (b) Gradient-echo T1-weighted MR image obtained during normal function shows ROIs placed over areas of lower signal intensity that correspond to medulla. (c) Coronal color R2* map shows same kidney as in a and b. This kidney is now experiencing mild rejection (2 months after transplantation). Note the subtle loss of green and yellow in the medullary pyramids of the upper and lower poles, with corresponding decreased R2* values (16.0/sec in ROI 1 and 17.3/sec in ROI 3). There is a midpole medullary pyramid (ROI 2) that maintains its green and yellow coloration and has a R2* value of more than 18/sec. (d) Gradient-echo T1-weighted MR image obtained during mild rejection shows ROIs placed over areas of lower signal intensity that correspond to medulla.
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Figure 5d. (a) Coronal color R2* map shows transplanted kidney during normal function (2 weeks after transplantation). Note that the cortex is blue and the medullary pyramids have a green/yellow color. The three ROIs (1–3) placed in the upper pole, midpole, and lower pole have R2* values above 18/sec. (b) Gradient-echo T1-weighted MR image obtained during normal function shows ROIs placed over areas of lower signal intensity that correspond to medulla. (c) Coronal color R2* map shows same kidney as in a and b. This kidney is now experiencing mild rejection (2 months after transplantation). Note the subtle loss of green and yellow in the medullary pyramids of the upper and lower poles, with corresponding decreased R2* values (16.0/sec in ROI 1 and 17.3/sec in ROI 3). There is a midpole medullary pyramid (ROI 2) that maintains its green and yellow coloration and has a R2* value of more than 18/sec. (d) Gradient-echo T1-weighted MR image obtained during mild rejection shows ROIs placed over areas of lower signal intensity that correspond to medulla.
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R2* Measurements in Patient with Cortical Ischemia
One patient in the ATN group was noted to have a markedly elevated cortical R2* of 41.2/sec, with a medullary R2* value of 20.3/sec—a value that was neither elevated nor decreased compared with the average values in the ATN group. The cortex in this patient was red on the color map, signifying a high R2* and therefore a high deoxyhemoglobin level. This was in contrast to our findings for the remaining study patients, whose cortical R2* values were much lower (range, 9.8/sec to 15.9/sec). In this patient, biopsy revealed ATN, in addition to arteriolosclerosis and the early changes of transplant glomerulopathy. This patient subsequently underwent angiography that did not reveal large-vessel renal artery disease. However, the arteriolosclerotic changes in the microvasculature seen at transplant biopsy, along with the constriction of preglomerular blood flow by calcineurin inhibition that is known to occur during ATN, likely contributed to changes in cortical blood flow and the perceived ischemia seen at BOLD MR imaging. Within 2 weeks the patient required dialysis because of a "failed" transplanted kidney, as determined with laboratory values and by the consulting transplant nephrologist.
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DISCUSSION
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Our data demonstrate the feasibility of using BOLD MR imaging as a noninvasive test for assessing the oxygenation state of transplanted kidneys. R2* values in the medulla are significantly lower in transplanted kidneys with acute rejection than in those with normal function or ATN. This suggests the presence of an increased oxygen concentration in the medullae of transplanted kidneys with acute rejection. The intense local inflammation, oxidative stress, and cytokine profile observed during acute rejection could alter corticomedullary hemodynamics, leading to preferential blood shunting toward the medulla and increased oxygen content. Alternatively, there may be subclinical medullary tubular injury that reduces local oxygen consumption. Using invasive techniques, other investigators have noted corticomedullary shunting of blood flow—as well as a decreased glomerular filtration rate and, therefore, a decreased tubular workload—in transplanted kidneys with rejection (21–24).
All transplanted kidneys with acute rejection had medullary R2* values of less than 18/sec, while all transplanted kidneys with ATN or normal function had R2* values of greater than 18/sec. This is important because if MR imaging can help exclude acute rejection, a substantial number of percutaneous transplant biopsies could be avoided. Furthermore, clinicians weigh their concern that acute rejection is actually present against the risks of percutaneous biopsy. Patients are often watched over a period of time so that trends in laboratory values can be evaluated before a decision is made to proceed with biopsy. Having a noninvasive means of determining the presence of acute rejection would allow patients to be evaluated without the concerns associated with percutaneous biopsy. This, in turn, would lead to an increase in the screening of patients and, potentially, earlier detection of kidney transplant rejection.
Cortical R2* values were significantly higher in transplanted kidneys with ATN than in kidneys with acute rejection. Elevated R2* values correspond to increased deoxyhemoglobin levels and decreased oxygen content in the cortex. ATN occurs secondary to an ischemic event. After the initial insult, cortical blood flow is decreased by varying degrees depending on the amount of cellular and tubular damage that has occurred (25–28). This would explain the perceived decrease in oxygen content at BOLD MR imaging. In contrast, BOLD MR imaging revealed a normal oxygenation state in the medulla of transplanted kidneys with ATN. This is likely due to the well-known ability of the medulla to survive in hypoxic conditions by balancing blood flow and resorptive workload to maintain a normal oxygen gradient (5–10). The cortex receives up to 90% of total renal blood flow in normal conditions and does not have the same ability to balance blood flow and resorptive workload to maintain a normal oxygen concentration gradient (28). This would account for the apparent decrease in cortical oxygenation and the lack of change in medullary oxygenation in transplanted kidneys with ATN.
Although it was not statistically significant, there was also a trend toward higher R2* values in the cortices of kidney transplants with ATN than in the cortices of kidney transplants with normal function. The lack of statistical significance was likely due to the small sample size and the larger standard deviation in the normal function group.
The subject of R2* measurements in the medulla requires further comment. Hemoglobin saturation is affected by many factors, including pH and PO2. The kidney has an oxygen gradient from the cortex to the inner part of the medulla, with the PO2 being approximately 50 mm Hg in the cortex and approximately 20 mm Hg in the inner part of the medulla (5,7,29). This places hemoglobin on different parts of its dissociation curve in the cortex and medulla (30). In the medulla, where the PO2 is less than 40 mm Hg, small changes in medullary oxygenation result in large changes in the concentration of oxyhemoglobin versus deoxyhemoglobin. As an example, as PO2 increases from 20 to 25 mm Hg, the hemoglobin saturation increases from 30% to 45%, decreasing the availability of oxygen. These are the changes that are detected with BOLD MR imaging, although to date oxygen content, PO2, and oxyhemoglobin concentration cannot be directly quantified with BOLD MR imaging. Therefore, one can only comment on the relative hypoxia of the medulla to the cortex, or, in the case of this study, the relative increase in oxygen content in the medullae of transplanted kidneys with acute rejection compared with that in the medullae of transplanted kidneys with other conditions.
In contrast to the medulla, the cortex functions at a PO2 of greater than 50 mm Hg in normal physiologic conditions (5,7). Hemoglobin is therefore on a shallower portion of its dissociation curve, where changes in PO2 from 50 to 55 mm Hg only change the hemoglobin saturation from 85% to 87% (30). Hence, small changes in oxygen content in the cortex do not affect the hemoglobin saturation to the same degree and may not be detectable with BOLD MR imaging. However, if the cortex is in ischemic conditions, the PO2 may be lower than 50 mm Hg, and, therefore, changes in oxygen content would affect the hemoglobin levels to a greater degree. Consequently, in transplanted kidneys with ATN in which the oxygen content and therefore the PO2 appear to be lower, changes in oxygen content would potentially be detectable with BOLD MR imaging. This would make the trend of elevated R2* values in the cortex of transplanted kidneys with ATN important as a measure of kidney recovery or dysfunction.
One limitation in this pilot study was the small population (n = 20). Despite the small population, there were large differences in mean R2* values in the medullae of transplanted kidneys when acute rejection was present. Most important, BOLD MR imaging enabled differentiation of acute rejection from ATN and normal function in all cases.
This study also had the limitation of being a point-in-time analysis. Oxygenation is likely a dynamic characteristic of the kidney that is influenced by a number of stimuli that change in response to local and systemic events. A point-in-time study can only capture a single moment of this physiologic spectrum and thus has discrete limitations in assessing a biologic process. Further investigations are necessary to determine if analysis of one point in time will enable one to accurately diagnosis the presence of acute rejection or if a series of time points are necessary. We also cannot comment on whether or not rejection can be distinguished from all other causes of renal transplant dysfunction in an unselected population. The oxygenation of the renal parenchyma is complex and there is a spectrum of changes that occur in both corticomedullary perfusion and tubular function when the kidney is stressed. It is possible that with other causes of renal dysfunction, such as infection and ureteral obstruction, oxygenation to the medulla is altered. A larger unselected population would need to be examined to document the transplanted kidney's response to different types of injury.
Other limitations to this study were related to data acquisition and analysis. Intraobserver variability was not calculated in this pilot study. ROIs were placed manually by the user for the medulla and cortex, and therefore the technique is prone to errors owing to improper or varied ROI placement. Our calculated R2* values in the cortex are consistent with values obtained by other authors who studied native human kidney function (11,13,14,16). Our calculated R2* values in the medullae of transplanted kidneys are higher than values published by these same authors (Table 2). It is unclear whether other authors used both gray-scale images and color maps to place ROIs in the medulla, as we outlined in the Materials and Methods section of this article—a factor that might also account for variation in the R2* values. As explained in the Materials and Methods section, volume averaging can occur, and awareness of this when placing ROIs is helpful in minimizing underestimations of R2* measurements in the medulla. An alternative explanation for the elevated R2* values in the medullae of transplanted kidneys with normal function compared with the values in the medullae of normal native kidneys in other studies is that there may be inherent differences between transplanted and native kidneys. This can only be addressed in formal comparative studies that are designed to assess native versus transplanted kidneys by using BOLD MR imaging and studies that include intraobserver variability measurements.
In conclusion, BOLD MR imaging appears to be a rapid, noninvasive method for assessing renal oxygen status in transplanted kidneys and determining the presence of acute rejection. Decreased R2* values in the medullae of kidneys with rejection correspond to increased oxygen concentration. This may be due to altered corticomedullary hemodynamics and/or to reduced local O2 consumption secondary to decreased tubular function. Further studies to assess BOLD MR imaging in the setting of kidney transplantation are warranted because BOLD MR imaging may constitute a noninvasive means of differentiating transplanted kidneys with acute rejection from both transplanted kidneys with normal function and transplanted kidneys with ATN. Additionally, MR perfusion studies coupled with BOLD MR imaging may help elucidate the underlying mechanisms of acute rejection and ATN and explain the changes seen at BOLD MR imaging.
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ACKNOWLEDGMENTS
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We thank Pottumarthi Prasad, PhD, and Jason Polzin, PhD, for their help with sequence parameters and processing, as well as for enlightening discussions about functional imaging of the kidney. We also thank Orhan Unal, PhD, for help with data analysis on the GE Advantage workstation.
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FOOTNOTES
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Abbreviations: ATN = acute tubular necrosis • BOLD = blood oxygen level dependent • ROI = region of interest
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, E.A.S., S.B.F., T.M.G.; study concepts, E.A.S., S.B.F., B.N.B., T.M.G.; study design, all authors; literature research, E.A.S.; clinical studies, E.A.S., B.N.B., T.M.G.; data acquisition, E.A.S., S.K.A., F.R.K., R.M., A.D., T.M.G.; data analysis/interpretation, E.A.S., S.K.A., F.R.K., R.M.H., B.N.B., T.M.G.; statistical analysis, E.A.S., F.R.K., J.F.; manuscript preparation, E.A.S., S.B.F., S.K.A., T.M.G.; manuscript definition of intellectual content, E.A.S., S.B.F., T.M.G.; manuscript editing and final version approval, all authors; manuscript revision/review, E.A.S., S.B.F., S.K.A., F.R.K., J.F., B.N.B., T.M.G.
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TOP
ABSTRACT
INTRODUCTION
