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review http://www.kidney-international.org & 2013 International Society of Nephrology

New magnetic resonance imaging methods in nephrology Jeff L. Zhang1, Glen Morrell1, Henry Rusinek2, Eric E. Sigmund2, Hersh Chandarana2, Lilach O. Lerman3, Pottumarthi V. Prasad4, David Niles5, Nathan Artz5, Sean Fain5, Pierre-Hugues Vivier6, Alfred K. Cheung7 and Vivian S. Lee1

1Department of , University of Utah, Salt Lake City, Utah, USA; 2Department of Radiology, New York University, New York, New York, USA; 3Department of Nephrology and , Mayo , Rochester, MN, USA; 4Department of Radiology, North Shore University, Evanston, Illinois, USA; 5Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin, USA; 6Department of Radiology, Rouen University , Rouen, France and 7Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah, USA

Established as a method to study anatomic changes, such as Long established as a method to study structural changes in renal tumors or atherosclerotic , magnetic disease, such as renal tumors or atherosclerotic vascular resonance imaging (MRI) to interrogate renal function has disease, magnetic resonance imaging (MRI) to interrogate only recently begun to come of age. In this review, we briefly renal function has only recently begun to come of age. introduce some of the most important MRI techniques for Functional renal MR approaches render added value for MRI renal functional imaging, and then review current findings on over other conventional imaging modalities, with emerging their use for diagnosis and monitoring of major applications in nephrology. As an example, low doses of diseases. Specific applications include renovascular disease, the conventional used in MRI—gadolinium , renal transplants, renal masses, acute chelates—can be used to measure glomerular filtration kidney injury, and pediatric anomalies. With this review, we rate (GFR) in individual kidneys.1,2 Techniques borrowed hope to encourage more collaboration between from functional brain mapping known as blood oxygen nephrologists and radiologists to accelerate the development level–dependent (BOLD) MRI have recently been applied to and application of modern MRI tools in nephrology . interrogate renal oxygenation and metabolic rate.3,4 Renal Kidney International (2014) 85, 768–778; doi:10.1038/ki.2013.361; perfusion can be measured using MRI either by intravenous published online 25 September 2013 injection of an exogenous tracer or with endogenous blood KEYWORDS: glomerular filtration rate; kidney; magnetic resonance imaging; labeling methods that do not require contrast injection. perfusion; tissue oxygenation In this article, we briefly review the principles of MR imaging, introduce some of the most important MRI techniques, and then review current findings on their use for diagnosis and monitoring of major kidney diseases. Specific applications include renovascular disease (RVD), diabetic nephropathy (DN), renal transplants, renal masses, , and pediatric anomalies. Our purpose is to accelerate the application of modern MRI tools in the clinic and to strengthen the collaboration between MRI physicists, radiologists, and nephrologists. We refer the reader to other reviews5–14 and the cited papers for more technical details.

MRI PRINCIPLES AND TECHNIQUES Modern clinical MRI scanners are typically equipped with a large superconducting magnet, which provides a stable homogeneous magnetic field (1.5–3.0T), and multiple coils for different purposes, including signal transmission, recep- Correspondence: Jeff L. Zhang, Department of Radiology, University of tion, and creating magnetic field gradients. For abdominal Utah, 729 Arapeen Drive, Salt Lake City, Utah 84108, USA. imaging, surface coils are available to be applied to the E-mail: [email protected] abdomen to improve signal reception. Owing to the strong Received 29 May 2013; revised 16 July 2013; accepted 17 July 2013; magnetic field, pacemakers are usually contraindicated with published online 25 September 2013 MRI scans, but most vascular stents are compatible.

768 Kidney International (2014) 85,768–778 JL Zhang et al.: New MRI methods in nephrology review

Most MRI signals originate from hydrogen nuclei or ab protons, which behave like tiny magnets in the MRI system’s magnetic field and their behavior in response to changing magnetic fields forms the basis of MRI. MRI image contrast is achieved by manipulating the magnetic properties of hydrogen protons and thereby distinguishing among various tissue characteristics, including intrinsic MR properties such as the relaxation times T1 and T2. Compared with tissues, water (e.g. cysts, cerebrospinal fluid) typically has longer T1 Figure 1 | Conventional anatomic magnetic resonance imaging and T2 times (Figure 1). (MRI) of kidney. The cyst, (a) with long T1, is dark on a T1-weighted Using MRI, we can also visually distinguish tissues based image, and (b) with long T2, bright on a T2-weighted image. on other inherent tissue properties such as diffusivity of water within those tissues, capillary perfusion, blood flow determine GFR. For more refined measurements, signal or velocity, and even oxygenation. In addition, with the intensities can be recorded from the renal cortex, medulla, administration of exogenous contrast agents, other tissue and collecting system. With more detailed data, the transit of characteristics can be explored. Exogenous agents such as the bolus of contrast from the artery to the renal cortex can gadolinium (Gd)-based chelates are useful for MR angio- be used to estimate renal perfusion; the transit from cortex to graphy and in MR renography (MRR), because they shorten medulla reflects glomerular filtration; and finally from the T1 relaxation time, and for many years they were regarded as medulla into the collecting system reflects tubular function. one of the safest agents used in . About a decade To extract these functional measurements from signal ago, the associations between high doses (typically double intensities in the kidney, the method typically assumes a tight and triple the standard doses) of Gd contrast in patients with bolus of contrast entering the renal artery. Gd contrast is renal failure and nephrogenic systemic fibrosis (NSF) were administered intravenously, and therefore accurate measure- first reported.15 Recommendations have been made on the ment of renal function depends on knowing the shape of use of Gd contrast in patients with renal impairment.16,17 In the bolus of contrast as it arrives in the abdominal aorta, the past few years, with adherence to guidelines, no report of following dispersion during transit through the pulmonary new NSF cases has been published.18 circulation, heart, and thoracic aorta. Direct measurement of Below, we review some of the MRI techniques most widely the bolus as it arrives at the level of the renal arteries can be explored for applicability to functional renal imaging. Their taken from images of the abdominal aorta and is termed characteristics are summarized in Table 1. arterial input function (AIF). Using a mathematical opera- tion called deconvolution, we can eliminate the variable MRR and dynamic contrast-enhanced MRI effects of bolus dispersion, as quantified by AIF, on the MRR is a term used to describe one application of dynamic measurements of tracer in the kidney. Compartmental contrast-enhanced (DCE) MRI, specifically the use of modeling is typically used to extract renal physiological Gd-based contrast agents for the noninvasive measurement parameters such as GFR from enhancement curves. The of GFR. Most Gd chelates have favorable renal properties: details of the models and their comparison can be found in they are freely filtered at the glomeruli without tubular literature.2,21–25 secretion or resorption. This means that with the continuous Several studies have shown good agreement between MRR acquisition of high-resolution images through the kidney measurements of GFR and reference methods. Hackstein every few seconds, renal function can be visualized as the et al.26 found a correlation coefficient of 0.83 between passage of contrast material from the aorta through the MRR-GFR and GFR measured by iopromide plasma kidney and out of the collecting system. Calculation clearance. Using low Gd dose (4 ml) and multiple- of the extraction fraction of the Gd contrast allows compartment modeling technique, Lee et al.2,21,24 measured determination of GFR. Several technical limitations have MRR-GFR with correlation coefficient of 0.82–0.84 slowed the widespread adoption of this method, although with 99mTc-DTPA (99mTc-diethylenetriamine pentaacetic recent developments are promising. We review some of the acid) plasma clearance. challenges below. One major issue with MRR is imprecise measurement of Unlike computed tomography or , where AIF. Cutajar et al.27 found that AIF errors could severely tracer concentration is approximately linear to signal lower the precision of the estimated GFR and renal blood intensity, in DCE MRI, the relationship is more complex flow. Zhang et al.28 proposed a technique of using patient’s and it depends on the specific pulse sequence used. Methods cardiac output (measured using phase-contrast MRI) and converting MR signal intensity to concentrations of tracer increased the correlation coefficient between two have been reviewed elsewhere.19,20 Because of the sensitivity independent MRR-GFR measurements from 0.83 to 0.92. of MRI to Gd contrast agents, 3–4ml of Gd contrast agent The cardiac-output approach28 is promising in correcting for suffices for accurate renal functional measurements. In MRR, AIF errors, but measurement of the patient’s cardiac output signal intensities can be recorded from the whole kidney to with phase-contrast MRI can be cumbersome.29 The other

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Table 1 | A summary of major MRI techniques and their capabilities Techniques Capability Parameters DCE MRI Tracer transit through vascular space and tubules GFR, perfusion, vascular, and tubular MTTs BOLD Direct measure of deoxyhemoglobin, and reflects blood and Spin–spin relaxation rate (R2* ¼ 1/T2*), medulla–cortex R2* ratio (MCR ¼ tissue pO2 R2*Med/R2*Cx) ASL Perfusion without injecting tracer Perfusion DWI Water diffusion in interstitial space; capillary flow ADC, anisotropy, perfusion fraction Abbreviations: ADC, apparent diffusion coefficient; ASL, arterial spin labeling; BOLD, blood oxygen level–dependent; DCE, dynamic contrast-enhanced; DWI, diffusion- weighted imaging; GFR, glomerular filtration rate; MCR, medullary-to-cortical ratio; MRI, magnetic resonance imaging; MTT, mean transit time; pO2, partial pressure of oxygen. parameters such as vascular and tubular mean transit times ab 40 (MTTs) measure the time it takes for unfiltered and filtered tracers to go through a kidney, respectively. Although 30 clinically able to distinguish different renal ,30 the accuracy of these parameters has not been validated. 20 Another hurdle to the clinical use of MRR is the absence of dedicated processing software in commercial workstations. 10 For pediatric applications, several programs are freely downloadable on the web.31,32 In addition, for analysis of 0 adult data, recent software developments appear promising in their simplicity of use and potential widespread Figure 2 | Kidney T2* maps from blood oxygen level–dependent (BOLD) imaging. The scale on the right side is T * value, with unit of dissemination.33,34 2 milliseconds. Higher T2* corresponds to lower deoxyhemoglobin concentration. (a) Typical T2* map with conventional BOLD scan (20-s 2 Blood oxygen level dependent breath-hold, matrix size 256256, field of view (FOV) 3232 cm ). (b) T2* map with free-breathing prospectively navigated sequence Renal BOLD MRI is a method similar to functional imaging (10-m imaging time, matrix size 512 512, FOV 50 50 cm2). 35 in the brain that forms images of a particular tissue The free-breathing images offer greater image quality. characteristic, the transverse relaxation time constant T2*. T2* is strongly affected by deoxyhemoglobin, whose paramagnetic effect shortens T2*. This gives a potential of BOLD MRI. One such challenge is the low signal-to-noise window into the oxygen level throughout the kidney. ratio of conventional renal BOLD images. The kidneys move Some investigators prefer the use of R2*(¼ 1/T2*). Higher during respiration, and this excursion limits BOLD imaging R2* (or low T2*) theoretically corresponds to higher deoxy- to a single breath hold. A short imaging time results in the and, in turn, lower tissue pO2 (partial pressure low signal-to-noise ratio and consequently decreases in the of oxygen) level. precision of T2* estimation. To overcome this problem, we Several groups have demonstrated the sensitivity of BOLD have recently developed a new BOLD imaging technique imaging to different physiologic states in both human and during free breathing,49 which allows longer imaging times, animal kidneys. Hypoxia in the of rat and pig thus improving the T2* precision significantly (Figure 2). models, measured with oxygen probes, has been shown to Another factor that may have caused the contradiction in the improve after administration of the loop diuretic furose- publications is the multiple confounding factors other than 36,37 50,51 mide. Corresponding increases in medullary T2* (increase tissue pO2 that influence T2*, such as blood perfusion, in oxygenation) with furosemide administration or with water intrinsic transverse relaxation not due to deoxyhemoglobin, have been reported in animal models37,38 and normal volume fraction of blood in a voxel, and magnetic field 3 humans. Some studies have shown that the changes in T2* strength (1.5 vs. 3 signal-to-noise ratio T). To quantify after furosemide administration or water diuresis are absolute tissue oxygenation based on BOLD T2*, it is attenuated in diabetic kidneys39,40 and in elderly subjects.41 necessary to measure the above confounding factors in vivo Some other studies have shown that the basal T2* values and address their effects. In addition, the BOLD signal, which (without diuretic challenge) negatively correlate with the is primarily due to the microscopic susceptibility effect of degree of DN ( estimated GFR level in humans,42 and days deoxyhemoglobin, could sometimes be superimposed by after induction of in a rat model43). signals from macroscopic susceptibility artifact. Magnetic Given the central role of hypoxia in the progression of field shimming to improve the magnetic field homogeneity52 chronic (CKD),44–46 the prospect of assessing can help reduce the impact of such artifact. renal parenchymal oxygenation level by noninvasive techniques is exciting. However, published renal BOLD data Arterial spin labeling appear to be somewhat contradictory, with some studies Originally used in the brain for perfusion and functional failing to show these aforementioned effects.47,48 The imaging, arterial spin labeling (ASL) MR imaging53,54 uses contradictions may be partly due to the technical challenges arterial blood as an endogenous contrast agent, and obviates

770 Kidney International (2014) 85,768–778 JL Zhang et al.: New MRI methods in nephrology review

ab

Figure 3 | Difference images obtained from renal arterial spin labeling (ASL) scans. (a) Acquired at 800 ms after arterial blood labeling, when the labeled blood is mostly in the renal cortex; (b) acquired at 1000 ms after the labeling, and some labeled blood reaches the renal medulla. The images were acquired by a modified TrueFISP FAIR ASL (true-fast imaging with steady-state precession flow-sensitive alternating inversion recovery arterial spin labeling) sequence (eight averages, acquisition time B24 s, with breath-hold). any exogenous agent as in DCE MRI. In this approach, the MR system is used to regionally label inflowing arterial blood by altering its magnetic state. The labeled blood then transits Figure 4 | Kidney diffusion-weighted imaging using diffusion to the tissue where its magnetization affects the measured tensor imaging (DTI) methods. Following imaging processing, signal intensity, and the degree of signal change reflects tissue color-coded primary diffusion eigenvectors display radial pattern perfusion. of medullary tubules. Typically, ASL requires two types of images: label and control. The two images are acquired in exactly the same way, except that before acquiring the label image magnetization of Recent studies have tested ASL in native and transplanted some arterial blood is altered or labeled. Subtraction of the kidneys with both normal and altered function.55,60–62,64–80 control from the label images provides a difference image, and Two main ASL methods have been used—FAIR (flow- the difference is solely due to the labeled magnetization of sensitive alternating inversion recovery) ASL and pCASL arterial blood in the part of the body being imaged. Examples (pseudocontinuous ASL)—the details of which can be of difference image are shown in Figure 3.55,56 To estimate found elsewhere.81,82 Renal perfusion measured using renal perfusion, the labeling is typically done at the a FAIR ASL scheme, first demonstrated in the kidneys abdominal aorta, and the labeled blood transits through by Martirosian et al.,55 has correlated with renal artery renal vascular space, such as an exogenous tracer. Unlike an stenosis (RAS) grades,69 renal plasma flow,69,76 and exogenous tracer, the altered magnetization of labeled blood microsphere perfusion measurements.65 Artz et al.64 found recovers toward its baseline prelabeled state within a few that FAIR-ASL yielded reproducible cortical perfusion seconds owing to T1 relaxation. This means that the transit results in native and transplanted kidneys, although the time for the labeled arterial blood to move into the perfused reproducibility for medulla was moderate to poor. ASL has organ should be short enough to maintain measurable detected significantly lower perfusion in allografts versus difference signals. healthy kidneys,60 native diseased versus healthy kidneys,74,78 Owing to concerns about NSF,57–59 non-contrast imaging and in renal allografts experiencing an acute decrease in techniques such as ASL are particularly attractive for patients renal function (420% increase in serum ) with advanced renal diseases, as well as allograft dysfunction, compared with allografts with good function (serum where it can be used for longitudinal perfusion evaluation creatinine o2 mg/dl).73 A background-suppressed, pCASL (see ‘Renal Transplants’ section). One technical challenge method61 has helped characterize renal masses75 and enabled with kidney ASL is the respiratory motion associated with distinction between histopathological diagnoses such as long scan time (minutes) for achieving sufficient signal-to- oncocytomas and renal cell carcinomas (RCCs).72 Finally, noise ratio. These errors can be mitigated, however, using ASL measurements have correlated with clinical outcome in a variety of approaches including synchronized breathing, patients with metastatic RCC undergoing antiangiogenic respiratory triggering, or retrospective sorting based on .67 respiratory position.60–62 For example, Gardener and Overall, although early clinical ASL results appear Francis63 proposed a rapid multislice ASL technique for the promising for differentiating different disease states, valida- kidneys and used retrospective image sorting to correct for tion and development of robust quantitative perfusion the respiratory motion artifact. methods remain under investigation.

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Diffusion-weighted MRI but this attenuation is difficult to determine in subjects with Diffusion-weighted MRI (DWI) probes micron-scale water low basal signal enhancement. To overcome this barrier, a motion in the tissue.83 During the imaging period, relative multicompartmental modeling method for analyzing dual- displacement of water molecules due to diffusion in the injection MRI data has been developed to allow for GFR presence of magnetic field gradients results in a decay in the determinations in human kidneys with significant stenotic DWI signals. Such decay can be quantified by the ‘apparent renal arteries and has shown that angiotensin-converting diffusion coefficient’ (ADC), which is computed as the decay enzyme inhibitor caused a significant decrease in GFR constant of the exponential signal decay. ADC is influenced averaging B26% in a group of kidneys with RAS X50%.98 by microstructural barriers. In the case of anisotropic diff- The effects of RVD on intrarenal hypoxia have been usion in ordered structures such as renal medulla, diffusion evaluated using BOLD MRI. Although it is relatively preserved tensor imaging (DTI)84–86 can be applied to measure both the in moderate RVD,99 a decrease in renal oxygenation becomes magnitude and the three-dimensional direction of diffusion evident once severe stenosis develops.4,100 This is possibly (Figure 4). DTI requires more data using multiple gradient because, in severe vascular occlusion that threatens cortical directions. In another variant of DWI with MR parameters perfusion, processes of compensating tissue oxygenation designed to be highly sensitized to perfusion, referred to become overwhelmed. Histogram-based analysis over large as intravoxel incoherent motion imaging,87 both tissue cortical and medullary regions can be used to evaluate the diffusion- and perfusion-like characteristics can be distribution of tissue oxygenation in these regions and reduces extracted from DWI images. sampling error.101 Moreover, a furosemide challenge enables DWI has recently found increasing application extracra- the study of tubular oxygen–dependent transport,37 which is nially including characterization of kidney function.88–90 blunted in damaged kidneys102 but enhanced in hyperfiltering Progress to date indicates promising sensitivity of DWI to kidneys.103 Hence, BOLD MRI may be useful to assess the renal function,70,91 but further experiments and analysis are functional integrity of the renal medullary tubules.104 needed to disentangle the relevant biophysical mechanisms Other methods have also been explored in RVD. Magnetic and yield further diagnostic specificity. resonance elastography utilizes the translocation of mechan- ical shear waves to estimate elasticity, which may decrease in APPLICATIONS FOR KIDNEY DISEASES fibrotic kidneys. Interestingly, in swine with RVD, overall Renovascular diseases kidney stiffness is unaltered, because a fall in renal blood flow Renal MR has long been established as an reduces renal turgor and masks decreased elasticity.105 In accurate, clinically acceptable method for depicting RAS.92–94 contrast, medullary elasticity appears to be less dependent on Because of the high incidence of asymptomatic renal artery hemodynamic variables, and may reflect kidney fibrosis.106 stenosis, several methods have been investigated as adjuncts DWI detects changes in tissue property based on its to anatomic imaging to help determine the functional sensitivity to restriction of free-water diffusion. In patients significance of the stenosis, to monitor therapy, and to with RVD,107 but not hypertension alone,108 ADC declines and develop predictive indices to identify patients likely to benefit correlates with the extent of RVD, suggesting that significant from revascularization. kidney injury is required to become detectable by DWI. To assess the functional significance of the RVD, renal The noninvasive and versatile nature of MRI positions this blood flow can be measured using ASL or DCE MRI, using modality at the forefront for evaluation of RVD in humans. Gd contrast agents or ultrasmall paramagnetic iron-oxide The rapid progress in this field will hopefully inspire the particles that stay in the intravascular space. Using ultrasmall development of molecular and metabolic probes to assess paramagnetic iron-oxide–enhanced imaging, Schoenberg mechanisms of injury and viability of the poststenotic kidney. et al.95,96 found that with renal artery diameter narrowing These developments would be for identifying the subset of o80%, intrarenal cortical perfusion did not change patients with RVD who may benefit from revascularization significantly (average 513 ml/100 g/min), whereas artery of stenotic renal arteries.109 The determination of tissue narrowing 480% caused a fall of more than 200 ml/100 g/min perfusion and oxygenation may facilitate the decision to in cortical perfusion.95,96 ASL-MRI uses spin-labeled arterial perform the revascularization procedure and monitoring of blood as the tracer, thereby avoiding the potential adverse the kidney responses after the procedure. effects of exogenous contrast agents. Its value in RVD remains to be determined. Diabetic nephropathy The management of RVD, often asymmetric in nature, Recent advances suggest that progressive CKD eventually may benefit from the determination of single-kidney GFR results in peritubular capillary injury, tubular hypoxia and using MRR. The detection of hemodynamically significant atrophy, and interstitial fibrosis,110 independent of the type RAS, often corresponding to 470% decrease in diameter, of underlying primary kidney disease. DN is the most can be facilitated by the administration of angiotensin- common form of CKD, and functional renal MRI is an converting enzyme inhibitors. Angiotensin-converting attractive opportunity for noninvasive diagnosis and enzyme inhibitor attenuates GFR and thus the magnitude monitoring of potential therapeutic interventions. Most of signal enhancement in the presence of significant RAS,97 studies have focused on hypoxia using BOLD MRI,111,112

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fibrosis using DWI, tubular damage using DTI,113,114 or a which (ATN) and acute allograft combination of BOLD MRI and DWI.115,116 A recent rejection (AR) are the most common. Szolar et al.121 preliminary report applied ASL to show reduced cortical observed that the first-pass cortical signal enhancement blood flow in patients with CKD.62 using DCE MRI was markedly reduced in allografts with AR Studies using BOLD-MRI in rodent models suggest that, at compared with normally functioning kidneys, whereas least in the early stages, type 1 and type 2 DN is associated allografts with ATN showed no difference compared with with increased hypoxia.116–118 DWI that measures water normal cases. Using a similar approach, Wentland et al.122 diffusion in the interstitial space, however, has failed to show reported lower cortical and medullary blood flow in AR any changes in early-stage DN.116 Part of the reason may be compared with normal kidneys and lower medullary blood related to the specific parameters of the diffusion MRI flow in AR compared with ATN. Most recently, by applying method.119 a multicompartmental tracer kinetic model to DCE MR Clinical results of BOLD MRI in DN have been strikingly images, Yamamoto et al.30 showed that MTTs could variable. Consistent with rodent studies, one recent BOLD differentiate normal allografts from AR or ATN, where AR MRI study of 46 patients with type 2 diabetes using 3.0 T MRI cases had a higher ratio of vascular MTT over whole-kidney found that the ratios of medullary-to-cortical R2*(MCR)were MTT, whereas ATN cases had higher ratio of tubular MTT higher in stages 1 and 2 CKD compared with controls,112 over whole-kidney MTT. suggesting a greater than expected medullary tissue hypoxia Several studies have investigated the diagnosis of acute relative to the cortex. Interestingly, the MCR values were lower dysfunction using non-contrast techniques such as BOLD at later stages (3–5) of CKD compared with controls. The MRI. Sadowski et al.123 and Han et al.124 performed BOLD reason for this paradox is not apparent, but it may provide MRI in recent kidney transplant recipients and observed interesting clues to the understanding of the pathophysiology significantly lower medullary R2*, or higher oxygenation, in of DN. Another study of 20 diabetic patients (14 with stages cases of AR compared with ATN. As the authors suggested, 3–5 CKD) performed using 1.5 T MRI confirmed lower MCR this could be due to preferential blood shunting toward values than healthy subjects.111 Yet another study of type 2 the medulla during acute rejection or reduced oxygen diabetic patients (CKD stages 1–4) using 3.0 T MRI found no consumption rate owing to subclinical medullary tubular change in MCR compared with controls reported in the injury or both. Taken together, the results consistently show literature.120 As noted above (BOLD section), the apparently differentiation between ATN and AR based on perfusion and contradictory results of BOLD imaging in these patients is oxygenation parameters; however, robust differentiation of likely due to technical challenges such as image artifacts and ATN from normally functioning allografts has not been 6 the oversimplification of interpretation of R2*(orT2*) values. demonstrated. Therefore, Chandarana et al. have proposed a Diffusion-weighted imaging has also been applied to DN follow-up role for MRI only after acute dysfunction has been patients. A recent study of CKD patients with (n ¼ 43) or implicated by other tests such as elevated serum creatinine. without (n ¼ 76) diabetes found a statistically significant Studies of long-term allograft function have combined correlation between ADC and estimated GFR values in both multiple functional MRI techniques, including BOLD, DWI, groups of patients.115 However, this correlation was only seen in and ASL MRI. In a cross-sectional BOLD MRI study of healthy the nondiabetic patients and not in the diabetic patients. A volunteers and transplant recipients with chronic allograft recent DTI study suggested changes in fractional anisotropy in nephropathy, Djamali et al.125 observed significantly reduced 114 the renal medulla with different levels of DN probably related cortical and medullary R2*, indicating increased oxygenation, to , interstitial fibrosis, and tubular damage.113 in allografts affected by chronic allograft nephropathy. Long- Overall, these reports clearly demonstrate the complexities term longitudinal studies, however, have produced mixed involved in translating results from animal models to results. Vermathen et al.126 reported stable DWI parameters humans. In addition to technical challenges inherent in the and an increase of cortical R2* (decrease in oxygenation) in MR methods, these discrepancies may also be related to allografts between 7 and 32 months after transplant. In a small differences species, pathogenesis of diabetes, severity of pilot study involving matched donor and recipient pairs, 127 kidney disease, comorbid conditions, use of Malvezzi et al. observed a reduction in cortical R2*inboth such as renin–angiotensin system blockers, hydration, and groups and a reduction in medullary R2* (increase in other preparations for imaging. Further refinement and oxygenation) in the transplanted kidney 1 month after validation of these techniques and their applications to larger, transplant. In a recent study of 14 donor and recipient pairs, 112,115 128 well-designed clinical studies may establish their utility Niles et al. observed a reduction in both medullary R2* in clinical research of DN and routine clinical use. (increase in oxygenation) and ASL-estimated cortical perfusion in transplanted kidneys 3 months after transplant, Renal transplants and this reduction persisted for at least 2 years. The clinical MRI has emerged as an attractive approach for evaluating the significance of these changes was unclear, as all allografts were function of renal allografts owing to its noninvasiveness and functioning well based on conventional clinical biomarkers. suitability for repeated application. The most promising Further longitudinal studies with larger sample sizes will be results have involved near-term allograft complications, of necessary to determine whether long-term changes in MRI

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measures of allograft function are associated with clinical recently been defined and classified more specifically by the outcomes. RIFLE (risk, injury, failure, loss, end stage) criteria.148,149 Causes of AKI include renal ischemia and renal parenchymal Renal tumors diseases such as contrast-induced nephropathy and ATN. AKI Renal masses are increasingly discovered incidentally, which predisposes the patients to CKDs.150,151 is largely attributable to the increased use of medical Although DCE MRI with low Gd dose is capable of imaging.129,130 Because tumors differ in biologic behavior, measuring single-kidney GFR with higher accuracy than aggressiveness, and ,131,132 their increased detection serum creatinine, it is typically not used for assessing AKI, as has led to a management dilemma. Accurate characterization lowered GFR in severe AKI patients could potentially increase of tumor aggressiveness can guide management. Although the risk of NSF. He et al.152 developed an innovative non- CT is most widely used to diagnose renal lesions in clinical contrast MRI technique for estimating GFR based on ASL. practice, advantages of MRI include superior soft tissue Although not yet validated against any gold standard, this contrast, avoidance of ionizing radiation and iodinated approach showed a promising 28% increase in the estimated contrast media, and most importantly the availability GFR after protein loading, as would be expected. In a rat of different techniques such as DCE, DWI, and BOLD MRI model of ischemic AKI, Zimmer et al.153 observed that to probe different aspects of tumor such as vascularity, although their ASL-estimated cortical perfusion was B30% microstructure, and oxygenation (6). lower than that from DCE MRI, both were able to Widely used clinically, DCE MRI is one of the most robust differentiate between healthy and AKI cases. Prowle et al.154 techniques for evaluating the aggressiveness of renal tu- used phase-contrast MRI, a non-contrast MRI method to mors.133,134 Studies have shown that by imaging at three time measure blood flow rate through the renal artery, and points following contrast administration, the low level and found that renal blood flow in ischemic AKI patients was homogeneous enhancement of papillary RCC can help significantly lower than that in normal volunteers (335–1137 distinguish it from clear cell RCC.135,136 With a higher vs. 791–1750 ml/min). temporal resolution of B30 s per acquisition, a distinct Tissue oxygenation is another physiologic parameter of pattern of enhancement was identified for angiomyolipomas: interest for AKI.155,156 BOLD MRI enables noninvasive an early enhancement peak followed by lower-level mapping of renal tissue oxygenation for human subjects enhancement.137 Using a two-compartmental model to (section ‘BOLD MRI’). Assessment of ATN by BOLD is also analyze the high temporal resolution data, Notohamiprodio discussed in section ‘Renal Transplants’. Contrast-induced et al.138 estimated perfusion and permeability of renal tumors. nephropathy is another form of AKI. Using BOLD and a rat These parameters could help differentiate tumor subtypes and model of contrast-induced nephropathy, Li et al.157 found identify tumor features such as necrosis and vessel invasion. that BOLD measurements could detect the effects of viscosity Cellular renal lesions, such as RCC, restrict water diffusion and dose of iodinated contrast on subsequent contrast- in interstitial space, which explains the associated lower ADC induced nephropathy. values in the lesion compared with normal tissue.139–141 Kim et al.142 found significantly lower ADC values in malignant Pediatric kidney imaging lesions compared with benign lesions (1.75±0.57 vs. Congenital anomalies of the kidney and urinary tract are 2.50±0.5310–3 mm2/s).142 Sandrasegaran et al.143 found frequent in children. Ultrasonography remains the primary similar results. Taouli et al. reported lower ADC values in imaging modality to image these disorders. An extension of Bosniak category 3 and 4 lesions compared with category 1 MRR, MR urography (Figure 5), is increasingly used in simple cysts, although a statistically significant difference practice as a complementary tool, as it can combine between Bosniak 2F and 3–4 lesions was not detected.140 Low exquisite anatomic depiction and functional evaluation in a ADC values have been shown in the papillary subtype of RCC single examination without radiation exposure. Heavily 140 144 compared with non-papillary subtypes. Wang et al. T2-weighted images allow a complete visualization of the found that clear-cell RCCs showed a significantly higher urinary tract in a few seconds (with two-dimensional mean ADC (1.8510 3 mm2/s) than papillary acquisitions) to few minutes (with three-dimensional acqui- (1.0910 3 mm2/s) and chromophobe (1.3110 3 mm2/s) sitions and respiratory synchronization). With three-dimen- RCCs. ADC has also been reported to be significantly lower sional isotropic acquisitions, multiplanar and volumetric in high nuclear-grade (III and IV) than low nuclear-grade reconstructions that are easily understandable for urologists (I and II) clear-cell RCCs.145 With advanced DWI methods, have made intravenous urography obsolete. In addition, the Chandarana et al.146,147 showed that DWI has potential in renal parenchyma can be studied in detail: corticomedullary assessing renal tumor cellularity, as well as vascularity, and differentiation, thickness, cortical scarring, and cysts. can help discriminate RCC subtypes.146,147 In pediatric , one of the most challenging issues is to identify whether dilated systems have true obstruction and Acute kidney injury therefore require . True chronic obstruction is AKI, previously termed as acute renal failure, refers to a rapid defined in practice by a decrease in the split (differential) and reversible decline of GFR within days or weeks and has renal function on serial functional imaging, such as renal

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Figure 5 | Primitive right megaureter on a bifid ureter in a 6-month-old boy. (a) T2-weighted image with fat saturation. (b) Coronal view of volume-rendered T2-weighted images. (c) Oblique view of volume-rendered T2-weighted images. (d) Maximum intensity projection of T1-weighted images at excretory phase. (e) Renography before contrast arrival. (f) Renography at arterial phase. (g) Renography at tubular phase. (h) Renography at excretory phase. Symmetric enhancement and excretion of contrast bilaterally suggests that the marked dilatation of the right collecting system and ureter is not a functional obstruction.

, MRR, or MR urography.158–160 Using Gd facts, the development of appropriate physiologic models to contrast agents and a tracer compartmental model of interpret the BOLD data will be critical. The jury is still out analysis, the relative filtration of the parenchyma can be on methods such as ASL and DWI, both of which have either calculated for each side with classical scintigraphic-derived technical challenges or image interpretation issues. Given the estimates such as the integral method and/or the prevalence and growing rate of renal diseases together with Rutland–Patlak method.32,161,162 These results have to take MRI’s advantages of providing both high-resolution ana- into account the volume of renal parenchyma on both sides. tomic imaging without exposure to ionizing radiation, As with scintigraphy, many estimates have been developed to functional renal MRI is worthy of intensive research effort, assess the drainage, such as the shape of the renograms or which will be most successful where nephrologists and transit times.163,164 These parameters turned out to be of poor urologists collaborate with radiologists and MR scientists. value, and the presence of chronic obstruction remains based on an evolving decrease in split (differential) renal function. DISCLOSURE All the authors declared no competing interests. CONCLUSION With high diagnostic reliability, anatomic MRI of the kidneys REFERENCES and their blood vessels has achieved widespread clinical 1. Lee VS, Rusinek H, Johnson G et al. MR renography with low-dose adoption. On the other hand, the functional MRI techniques gadopentetate dimeglumine: feasibility. Radiology 2001; 221: 371–379. 2. Lee VS, Rusinek H, Bokacheva L et al. Renal function measurements from for the kidneys require more work for their clinical MR renography and a simplified multicompartmental model. Am application. Of the functional methods available, the low- JPhysiol 2007; 292: F1548–F1559. 3. Prasad PV, Edelman RR, Epstein FH. Noninvasive evaluation of intrarenal dose Gd-enhanced imaging (MRR or MR urography) is oxygenation with BOLD MRI. Circulation 1996; 94: 3271–3275. closest to clinical adoption. In , these methods have 4. Textor SC, Glockner JF, Lerman LO et al. The use of magnetic resonance been proven to be useful for determining functional to evaluate tissue oxygenation in . J Am Soc Nephrol 2008; 19: 780–788. obstruction in the setting of or ureterectasis. 5. Prasad PV. Functional MRI of the kidney: tools for translational studies of In both pediatrics and adults, numerous studies have pathophysiology of renal disease. Am J Physiol 2006; 290: F958–F974. validated the high agreement between the glomerular 6. Chandarana H, Lee VS. Renal functional MRI: Are we ready for clinical application? Am J Roentgenol 2009; 192: 1550–1557. filtration of Gd chelates as a marker of GFR and other more 7. Grenier N, Basseau F, Ries M et al. Functional MRI of the kidney. Abdom established techniques. Among the other functional methods, Imag 2003; 28: 164–175. 8. Kalb B, Martin DR, Salman K et al. : structural and BOLD imaging promises the most valuable insights into renal functional evaluation using MR nephro-urography. J Magn Reson disease with the opportunity to measure hypoxia noninva- Imaging 2008; 28: 805–822. sively. Addressing technical challenges for BOLD is the focus 9. Nikken JJ, Krestin GP. MRI of the kidney—state of the art. Eur Radiol 2007; 17: 2780–2793. of many laboratories, and it is likely that, in addition to 10. Li LP, Halter S, Prasad PV. Blood oxygen level-dependent MR imaging of improving acquisition techniques for reducing image arti- the kidneys. Magnet Resonan Imag Clin N Am 2008; 16: 613–625.

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