Renal Functional MRI: Are We Ready for Clinical Application?

Genitourinary Imaging Perspective Chandarana and Lee Renal Functional MRI Genitourinary Imaging Perspective FOCUS ON: Hersh Chandarana 1 Vivian S. Lee Chandarana H, Lee VS Keywords: blood oxygen level dependent MRI, diffusion-weighted imaging, functional renal imaging, MR renography DOI:1.2214/AJR.9.239 Received January 2, 29; accepted without revision January 2, 29. 1 Both authors: Department of Radiology, New York University Medical Center, 53 First Ave., MRI, New York, NY 116. Address correspondence to H. Chandarana (hersh.chandarana@nyumc.org). AJR 29; 192:155 1557 361 83X/9/1926 155 American Roentgen Ray Society Renal Functional MRI: Are We Ready for Clinical Application? OBJECTIVE. We review the basics of functional renal imaging and highlight a few clinical applications. CONCLUSION. Techniques such as contrast-enhanced MR renography, diffusionweighted imaging, and blood oxygen level dependent MRI have been investigated in animal models and in a few human studies. Functional renal imaging is a rapidly growing field that has the potential to provide new insight into the pathophysiology of renal disease. T he primary role of the kidney is to maintain homeostatic balance of bodily fluids by filtering and secreting metabolites and minerals from the blood and excreting them along with water as urine. Serum creatinine concentration is used to calculate glomerular filtration rate (GFR), which although imprecise, is considered the reference standard in the evaluation of kidney function. Serum creatinine concentration, however, is a late marker of renal dysfunction, especially in chronic renal disease, and becomes abnormal in response to substantial and sometimes irreversible renal damage. Furthermore, blood tests depend on body mass index and age and cannot be used to assess single-kidney function [1 3]. Because of the limitations of serum markers, imaging can play an important role in the evaluation of renal disease. Ultrasound and CT provide good anatomic images but limited functional information. CT also requires use of iodinated contrast material and exposure to ionizing radiation. Nuclear medicine examinations provide functional information but lack spatial resolution. MRI has the unique ability to show both structure and function [4, 5]. Functional renal imaging techniques, such as contrast-enhanced MR renography, and unenhanced techniques, such as diffusion-weighted imaging (DWI) and blood oxygen level dependent (BOLD) imaging have shown considerable promise in the evaluation of renal function in health and disease. We review potential applications of these techniques in the clinical setting. We also present examples of diagnostic algorithms for the evaluation of suspected renovascular disease, allograft dysfunction, and split renal function measurements to suggest how functional MRI techniques can be integrated into clinical practice. Contrast-Enhanced MR Renography Dynamic contrast-enhanced MRI of the kidneys, or MR renography, is used to monitor the transit of contrast material, typically a gadolinium chelate, through the renal cortex, the medulla, and the collecting system. Most gadolinium contrast agents are cleared by glomerular filtration and pass through capillaries and the renal tubules causing the signal intensity of the renal tissues to increase. Through analysis of the enhancement of the renal tissues as a function of time, clinically important singlekidney parameters such as renal blood flow, GFR, and cortical and medullary blood volumes can be determined [6 8]. Technique There is no consensus regarding an optimal technique for MR renography. Various groups have proposed varied acquisition techniques. Most of these techniques require the following steps: acquisition of dynamic images before, during, and after administration of gadolinium chelate; conversion of the signal intensity of the renal tissue to gadolinium concentration; and plotting of gadolinium concentration versus time to generate various functional parameter curves. The total acquisition time for MR renography of healthy kidneys ranges from 3 to 155 AJR:192, June 29

Renal Functional MRI 3 Cortex 25 Medulla Fig. 1 MR renography. A, 83-year-old woman with renal artery stenosis imaged with contrast-enhanced MRI. Coronal maximum-intensity-projection renal MR angiographic image shows severe stenosis at origin of left renal artery. B, Plot of signal intensity time curves at baseline and after injection of angiotensin-converting enzyme inhibitor (ACEI) shows signal intensity is higher after ACEI injection because 8 ml of contrast material was used. C, Plot of gadolinium concentration time curves at baseline and after ACEI injection shows decrease in glomerular filtration rate (GFR) consistent with hemodynamically significant renal artery stenosis. Three-compartment tracer kinetic model was used to calculate GFR at baseline and after ACEI injection. D, 67-year-old woman without evidence of renal artery stenosis. Plots of gadolinium concentration time curves at baseline and after ACEI injection show GFR calculated with three-compartment tracer kinetic model at baseline is unchanged after ACEI injection. 1 minutes. The highest GFR precision is achieved at an approximately.2 mmol/kg (~ 4 ml) dose of gadolinium in healthy persons and approximately.25 mmol/kg (~ 5 ml) in patients with decreased renal function [9]. High doses of gadolinium chelate should be avoided because of the T2* susceptibility effect caused by concentrated con trast material. Current and Potential Applications Renal artery stenosis MRI perfusion parameters, such as mean transit time, maximum up-slope, and time to peak signal intensity, can be calculated from first-pass tracer kinetics and have been used in evaluation of renal artery stenosis (RAS). A study by Michaely et al. [1] showed significant differences in these parameters in patients with high-grade RAS compared with healthy persons and patients with low-grade stenosis. Furthermore, these perfusion parameters exhibited significant correlation with serum A Signal Intensity Gadolinium Concentration (mmol/l) Gadolinium Concentration (mmol/l) 2 15 1 5.8.7.6.5.4.3.2.1.8.7.6.5.4.3.2.1 2 4 6 8 Baseline with 4 ml of gadolinium Cortex Medulla 2 Cortex Medulla 2 GFR 17 ml/min 4 6 8 Baseline with 4 ml of gadolinium GFR 44 ml/min 4 6 8 Baseline with 4 ml of gadolinium 1 2 Time (min) 1 2 Time (min) 1 2 Time (min) 22 24 26 28 After ACEI injection with 8 ml of gadolinium 22 GFR 8 ml/min 24 26 28 After ACEI injection with 8 ml of gadolinium 22 24 GFR 45 ml/min 26 28 After ACEI injection with 8 ml of gadolinium 3 B 3 C 3 D AJR:192, June 29 1551

Chandarana and Lee creatinine levels. Our group has implemented an angiotensin-converting enzyme inhibitor (ACEI) injection protocol for evaluation of RAS. Patients with hemodynamically significant RAS have a decrease in GFR measured at MR renography after ACEI injection. Patients without significant RAS do not have a change in response to ACEI injection (Fig. 1). ACEI administration thus can be used to differentiate hemodynamically significant stenosis from insignificant stenosis [11]. Allograft dysfunction Acute tubular necrosis (ATN) and acute rejection are the two most common causes of allograft dysfunction in the early postoperative period. It can be difficult to discriminate these two entities clinically, and renal biopsy is often required for diagnosis. Because of the risks associated with renal biopsy, noninvasive techniques such as MR perfusion imaging have been explored. Patients with ATN have maintained cortical and medullary perfusion despite the presence of renal insufficiency. However, patients with acute rejection have significantly decreased cortical and medullary perfusion [12]. MR renography can be useful in the diagnosis of these conditions in early transplant dysfunction, eliminating the risk of percutaneous biopsy. Limitations The limitations of functional contrast-enhanced MRI include quantification of gadolinium concentration from signal intensity, image postprocessing problems such as spatial registration of the dynamic data and tissue segmentation, and lack of consensus about a protocol and method of analysis. These problems have inhibited widespread use of MR renography in clinical practice. Unenhanced Functional Imaging In light of the association between gadolinium contrast agents and nephrogenic sclerosing fibrosis [13 15], there has been renewed interest in exploring unenhanced techniques in evaluation of renal function. Diffusion MRI DWI is based on thermally induced brownian motion of water molecules in tissue. The apparent diffusion coefficient (ADC) calculation can be used for in vivo quantification of the combined effects of capillary perfusion and diffusion [16]. DWI historically has been used in stroke imaging and in the evaluation of intracranial mass lesions. With improvements in hardware and software, including parallel imaging, there has been considerable interest in the use of DWI in abdominal imaging, especially in the evaluation of diffuse liver disease and focal liver lesions [17 2]. A handful of studies have tried to characterize focal renal lesions with DWI, and these studies have shown more restricted diffusion and lower ADC in neoplastic lesions [21 23]. The role of DWI in the evaluation of renal function has become a subject of exploration [24 26]. Technique Single-shot echo-planar imaging is the sequence most frequently used for DWI. Diffusion can be quantified with ADC calculation, for which at least two images are required: one with and one without application of a diffusion gradient. The ADC calculation is based on the negative natural logarithm (ln) of the ratio of signal intensities of the two images, weighted by the diffusion factor, or b value, as follows: ADC = ( 1/b)[ln(S 1 / S )], where ADC is measured in square millimeters per second, b is the diffusion factor, S is the signal at b =, and S 1 is the signal intensity after application of the diffusion gradient. Although at high b values, ADC is dominated by diffusion effects, it is well known that DWI is influenced by perfusion effects at lower diffusion factors (b values). Le Bihan et al. [27 29], in their works on intravoxel incoherent motion (IVIM) modeling of diffusion, suggested that movement of blood in the microvasculature can be modeled as pseudo diffusion and that this perfusion effect can be separated if both low (< 2 s/mm 2 ) and high b values are used in DWI. Currently most investigators routinely use higher b values (b = 4 8 s/mm 2 ) to exclude the perfusion effect and to obtain true diffusion measurements. Some investigators, however, have tried to exploit the perfusion information of DWI in the evaluation of renal function [25]. Current and Potential Applications Renal insufficiency Namimoto et al. [24] initially found that ADC values in both the cortex and the medulla of patients with acute and chronic renal failure were significantly lower than the values in normal kidneys. Furthermore, their initial study showed good linear correlation between serum creatinine level and the ADC value of the cortex (r =.75) and weaker linear correlation between serum creatinine level and the ADC of the medulla (r =.6). A subsequent study [26] also showed good correlation between GFR and renal ADC values. The results of these studies highlight the potential role of renal ADC values in the evaluation of renal dysfunction in native kidneys. Another advantage of DWI is its ability to investigate the function of each kidney separately and to acquire split function information. Many diseases such as RAS and ureteral obstruction are unilateral. GFR estimates based on serum creatinine concentration do not provide split renal function results; thus the function of the diseased kidney is overestimated and that of the healthy kidney is underestimated. A study by Bozgeyik et al. [3] showed that obstructed kidneys had lower ADCs than did normal kidneys. Similarly, in the evaluation of patients with hydronephrosis, another study [31] showed that hydronephrotic kidneys with moderate and severe decreases in renal function as assessed with renal scintigraphy had much lower ADCs than hydronephrotic kidneys with maintained renal function. Thoeny et al. [25] performed diffusion imaging with a large number of b values, including low (range, 1 s/mm 2 ) and high values (range, 5 1, s/mm 2 ). In their study, there was a decrease in renal cortical and medullary ADC measurements calculated with both low and high b values for both the cortex and the medulla of dysfunctioning kidneys. As suggested by the IVIM model of diffusion, low b values contain perfusion information, whereas as high b values contain true diffusion information. Thus DWI with a large number of b values can potentially provide simultaneous perfusion and diffusion information, and both of these parameters have been found to change with renal dysfunction. Renal allograft DWI has been used in the evaluation of renal allografts. In an animal model [32], decreases in renal cortical and medullary ADC values were found in allografts over an 8-hour period starting on day 4 after surgery. In renal allografts, the mean total ADC, true diffusion, and perfusion fraction were identical in the cortex and medulla. However, in normal native kidneys, total ADC and the perfusion fraction were usually higher in the cortex than in the medulla (Fig. 2). These decreases in cortical ADC and perfusion fraction in the allograft have been attributed to loss of autonomic innervation [33]. With an increase in serum creatinine concentration there is a decrease 1552 AJR:192, June 29

Renal Functional MRI in cortical ADC and perfusion fraction in both the cortex and the medulla, as in native kidneys. Thus, DWI has potential for evaluation of renal allograft dysfunction without the use of exogenous contrast agents, but this possibility has to be further investigated in a larger study. Renal artery stenosis Animal studies have shown a decrease in renal ADC in response to decreased renal perfusion. With the IVIM model of diffusion, it is possible to calculate the perfusion fraction with DWI without an exogenous contrast agent. Powers et al. [34] found correlation between perfusion fraction at DWI and renal blood flow in a canine model of unilateral renal artery obstruction. Yildirim et al. [35] used DWI with both low and high b values to examine patients with suspected RAS. They found that patients with RAS had significantly lower ADC values, which were calculated with average, low, and high b values. These early findings suggest RAS can be diagnosed on the basis of the ADC value of the kidney without contrast-enhanced MR angiography. A Fig. 2 Diffusion-weighted imaging. A, 45-year-old man with no known renal disease and normal serum creatinine concentration. Apparent diffusion coefficient (ADC) image shows normal corticomedullary differentiation with lower ADC (lower signal intensity) of medulla with respect to cortex. B, 29-year-old man with normally functioning renal allograft. Diffusion-weighted image shows loss of corticomedullary differentiation with decrease in cortical ADC, which has been attributed to loss of autonomic innervation. Limitations One of the major limitations to widespread use of DWI is the lack of consensus regarding the selection of b values for renal imaging. Calculated ADC measurements depend on the b value, and this lack of consensus has made it difficult to compare results of different studies and to generate standardized ADC values for disease and health. Further work also needs to be done in the evaluation of the precision and accuracy of ADC values obtained with different MRI systems. The results will allow investigators to reliably compare studies and confidently apply DWI in clinical practice. Diffusion Tensor Imaging ADC measurements generated with DWI have a scalar property, that is, they have magnitude but no direction. However, diffusion of B A water molecules is a 3D process having both magnitude and direction. This directionality of diffusion, or anisotropy, can be measured by application of diffusion gradients in at least six directions. Anisotropy can provide structural and flow information, expressed as fractional anisotropy (FA). FA values range from to 1, being isotropic diffusion without directionality and 1 being completely anisotropic diffusion in only one direction. The renal medulla is composed of closely packed radially oriented renal tubules and vasa recta. There is directionality to the flow of the glomerular filtrate within these tubules and the blood in the vessels as they travel from the corticomedullary junction to the renal papilla and back. Knowledge of the structure and function of these tubules acquired with a noninvasive technique such as renal diffusion tensor imaging is important because it may provide insight into the pathophysiologic mechanism of renal disease. A small number of investigators [36 39] have found higher FA of the medulla than of the cortex in healthy volunteers. It is unclear, however, whether medullary FA is predominantly a measure of tubular structural arrangement or is substantially influenced by tubular flow. Our group and others are investigating the contribution of flow and structure in the measurement of FA. The role of diffusion tensor imaging in the evaluation of renal disease in native and transplanted kidneys is also under investigation (Fig. 3). Fig. 3 Diffusion tensor imaging. A, 28-year-old woman with normally functioning renal allograft. Fractional anisotropy (FA) map on diffusion tensor image shows higher signal intensity (FA) in medulla with respect to cortex (arrow). FA of medulla in allograft measured.4. B, 47-year-old man with renal dysfunction secondary to acute T-cell mediated rejection after renal transplantation (calculated glomerular filtration rate, 27 ml/min). Diffusion tensor image shows loss of corticomedullary differentiation on FA map with decrease in medullary FA, which measured.2. B AJR:192, June 29 1553

Chandarana and Lee BOLD MRI The renal medulla functions in a hypoxic milieu and is susceptible to changes in blood flow and blood oxygenation. Medullary hypoxia has been implicated as a common pathway in renal failure in animal models of various renal diseases, including hypertension and diabetes [4 42]. Most studies in animal models have been conducted with invasive electrodes, which are clearly not feasible for human studies. BOLD MRI, however, can be used for noninvasive but indirect measurement of renal oxygenation. It exploits the paramagnetic effect of deoxyhemoglobin for acquisition of images sensitive to local oxygen concentration. With an increase in tissue deoxyhemoglobin concentration, there is more dephasing and a decrease in the T2* relaxation time of the protons in the surrounding tissues [43]. In other words, higher tissue oxygenation results in increased T2* relaxation time and a correspondingly shorter R2* value. Technique A multiple gradient-recalled echo (GRE) sequence is currently the most widely used technique for renal BOLD MRI [44]. In the 2D multiple GRE technique, about eight to 16 echoes are acquired after each excitation pulse. For an optimal signal-to-noise ratio, the maximum TE should be equal to the T2* value of the organ of interest. For renal imaging, this value is approximately 5 milliseconds at 1.5 T and 25 milliseconds at 3 T on the basis of the T2* relaxation time of the renal medulla. The R2* value can be obtained by measurement of the slope of the line fit of natural log of signal intensity versus TE [45]. With calculation of the R2* value on a pervoxel basis, an R2* map can be easily generated on commercially available workstations. Regions of interest defined on the anatomic template can be used for estimation of R2* value in the renal medulla and cortex. Current and Potential Applications Renal artery stenosis BOLD MRI can be used to detect the changes of renal hypoxia in an animal model. In an elegant study, Juillard et al. [46] found a graded increase in cortical and medullary R2* value in response to a decrease in renal blood flow in a pig model. They also found a decrease in cortical and medullary R2* value with return to baseline values in response to resolution of renal artery occlusion. BOLD MRI also has been investigated in the evaluation of RAS in humans. Textor et al. [47] found A that normal-sized kidneys with high-grade RAS had improved oxygenation in response to furosemide administration. This finding suggests maintenance of functional reserve in kidneys even in the presence of reduced GFR. However, atrophic kidneys distal to the totally occluded renal arteries had a low R2* value (or improved oxygenation) that did not respond to furosemide challenge. Thus, response to furosemide can serve as a marker of maintained renal function in the presence of RAS. Whether these patients are more likely to benefit from therapy remains to be investigated, and use of BOLD MRI may facilitate appropriate patient selection. Renal allograft dysfunction Renal transplantation has become the treatment of choice of patients with end-stage renal disease. The medullary R2* value in patients who have undergone transplantation is lower than that in healthy volunteers, implying relatively improved oxygenation in transplanted kidneys. This phenomenon has been attributed to reduced tubular fractional reabsorption of sodium and an increase in blood flow due to allograft denervation [33]. In early renal dysfunction after transplantation, differentiating acute rejection from ATN is an important but difficult clinical endeavor because the initial manifestations of both of these conditions are abnormal serum creatinine concentration and a decrease in GFR. Sadowski et al. [48] found that patients with acute rejection have significantly lower R2* values (higher oxygenation) in the medulla than patients with ATN and normal allografts. Using an R2* cutoff of 18 seconds 1 or lower, the investigators diagnosed acute rejection with 1% sensitivity and specificity. This decrease in renal hypoxia in acute rejection has been attributed to decreased oxygen utilization or increased corticomedullary shunting of blood. In contrast, patients with ATN have higher cortical R2* value than patients with normal transplants and patients with acute rejection, likely because of ischemic insult. Having a noninvasive means of determining the presence of acute rejection may allow patients to be evaluated without the concerns associated with percutaneous biopsy. Djamali et al. [49] found that BOLD MRI can be used for evaluation of chronic allograft nephropathy. There is a loss of corticomedullary differentiation on R2* maps of patients with chronic allograft nephropathy with a decrease in medullary R2* values that approaches cortical R2* values. These changes may reflect a decrease in deoxyhemoglobin in the medulla due to decreased tubular work and underutilization of oxygen. Diabetic nephropathy Diabetic nephropathy is the leading cause of chronic renal failure and end-stage renal disease in the United States. Renal hypoxia is considered an important factor in the development and progression of renal failure in diabetes. Animal studies [41, 42] have shown medullary hypoxia, increased oxygen consumption, and up-regulation of the sodium potassium Fig. 4 29-year-old woman with no known renal disease who underwent blood oxygen level dependent (BOLD) MRI. A, T2*-weighted image at baseline in dehydrated state shows medulla to be more hypoxic with lower T2* relaxation time and lower signal intensity than cortex. B, T2*-weighted image obtained after physiologic water-loading challenge shows improvement in medullary hypoxia with increase in signal intensity and corresponding loss of corticomedullary differentiation. B 1554 AJR:192, June 29

Renal Functional MRI pump in diabetic kidneys with maintenance of renal blood flow. Using BOLD MRI, Ries et al. [4] found significantly lower oxygenation in the renal medulla of diabetic rats than in a control group as early as 5 days after induction. BOLD MRI has also been used to evaluate humans with diabetes. Epstein et al. [5] found a significant increase in oxygenation of the renal medulla in healthy subjects in response to water diuresis (Fig. 4). This response was absent in the diabetic patients. It is hypothesized that early in the disease, before observed changes in GFR, diabetic patients have loss of autoregulation with impairment of adaptive vasodilatation in response to water loading. Studies are being conducted to explore the role of nitric oxide synthase and nitric oxide inhibitors in animal models and diabetic patients to better understand the role of nitric oxide in the pathogenesis of diabetes. Limitations BOLD signal intensity is an indirect marker of renal oxygenation, and various factors influence signal intensity on BOLD images. These factors include oxygen supply and consumption, blood flow, hematocrit, and plasma oxygen (Po 2). Therefore, direct calibration of R2* value versus Po 2 is unreliable. More work needs to be done to better understand whether changes in BOLD signal intensity in renal disease result from changes in oxygen supply or oxygen consumption. Furthermore, the absolute magnitude of the R2* value is less reliable in practice than the relative changes observed in response to various physiologic and pharmacologic challenges. Future work should be directed at developing physiologic and pharmacologic challenges that help to elucidate changes in renal physiology in renal diseases such as diabetes and hypertension. This findings not only will allow us to better understand the pathogenesis of renal disease but also will provide another paradigm to evaluate disease progression and treatment efficacy. Clinical Practice Algorithms Renal Artery Stenosis RAS (Fig. 5) can be diagnosed with contrast-enhanced MRI or CT. MR renography with an ACEI can help discriminate hemodynamically significant from insignificant RAS. If significant RAS is present, BOLD imaging with furosemide challenge can depict kidneys with maintained functional reserve despite a decrease in renal function. Although unproven, this protocol may allow Decrease in GFR Significant RAS MR renography ACEI BOLD MRI with furosemide challenge Decrease in R2* No change in R2* Maintained renal function Atrophic kidney with no functional reserve selection of patients who are more likely to benefit from revascularization. In patients who are unable to receive gadolinium chelate owing to renal insufficiency, DWI may help in the diagnosis of moderate to severe RAS because patients with this degree of disease have lower ADC values. Acute Allograft Dysfunction Patients with acute allograft dysfunction (Fig. 6) have an abnormal serum creatinine concentration and hence a low GFR. In this setting, BOLD imaging will help discriminate cases of acute rejection from ATN noninvasively and without use of an exogenous contrast agent. If the diagnosis is unclear at BOLD imaging, MR renography can be used for patients who are able to receive a gadolinium contrast agent. RAS No change in GFR Normal or insignificant RAS Decrease in ADC DWI Significant RAS If gadolinium contraindicated Normal ADC Normal vessels or insignificant RAS Fig. 5 Clinical practice functional MRI algorithm for renal artery stenosis (RAS). ACEI = angiotensinconverting enzyme inhibitor, DWI = diffusion-weighted imaging, GFR = glomerular filtration rate, ADC = apparent diffusion coefficient, BOLD = blood oxygen level dependent. Decreased in R2* valve (increased oxygenation) Acute Allograft Dysfunction Acute rejection BOLD MRI Increased in R2* valve (decreased oxygenation) ATN Fig. 6 Clinical practice functional MRI algorithm for acute allograft dysfunction. BOLD = blood oxygen level dependent, ATN = acute tubular necrosis. MR renography GFR estimate Split Renal Function If gadolinium contraindicated DWI Cortical and medullary ADC and perfusion fraction measurements Kidney with lower cortical ADC and perfusion fraction suggests decreased GFR Fig. 7 Clinical practice functional MRI algorithm for split renal function. DWI = diffusion-weighted imaging, GFR = glomerular filtration rate, ADC = apparent diffusion coefficient. Split Renal Function Split renal function (Fig. 7) can be evaluated with MR renography with one of a variety of analysis techniques. Diffusion imaging can help in estimating split renal function in patients who are unable to receive exogenous gadolinium contrast material. Conclusion Noninvasive imaging techniques such as contrast-enhanced MR renography, DWI, and BOLD MRI have great potential in the evaluation of renal function. These techniques have shown considerable promise in research studies and despite some challenges are ready to be explored on a larger scale to answer clinical questions. A clear understanding of these techniques will allow us as radiologists to better serve our clinical colleagues and patients by providing another paradigm in the evaluation of renal function beyond anatomic structural imaging. AJR:192, June 29 1555

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