Review

Could MRI Be Used To Image Kidney Fibrosis? A Review of Recent Advances and Remaining Barriers

General Leung, Anish Kirpalani, Stephen G. Szeto, Maya Deeb, Warren Foltz, Craig A. Simmons and Darren A. Yuen
CJASN June 2017, 12 (6) 1019-1028; DOI: https://doi.org/10.2215/CJN.07900716

Abstract

A key contributor to the progression of nearly all forms of CKD is fibrosis, a largely irreversible process that drives further kidney injury. Despite its importance, clinicians currently have no means of noninvasively assessing renal scar, and thus have historically relied on percutaneous renal biopsy to assess fibrotic burden. Although helpful in the initial diagnostic assessment, renal biopsy remains an imperfect test for fibrosis measurement, limited not only by its invasiveness, but also, because of the small amounts of tissue analyzed, its susceptibility to sampling bias. These concerns have limited not only the prognostic utility of biopsy analysis and its ability to guide therapeutic decisions, but also the clinical translation of experimental antifibrotic agents. Recent advances in imaging technology have raised the exciting possibility of magnetic resonance imaging (MRI)–based renal scar analysis, by capitalizing on the differing physical features of fibrotic and nonfibrotic tissue. In this review, we describe two key fibrosis-induced pathologic changes (capillary loss and kidney stiffening) that can be imaged by MRI techniques, and the potential for these new MRI-based technologies to noninvasively image renal scar.

The Importance of Fibrosis as a Final Common Pathway of Chronic Kidney Injury

Fibrosis is a final common injury pathway that drives CKD progression, for which no safe and effective therapies exist. Epidemiologic studies have consistently demonstrated that fibrotic burden is an important predictor of adverse renal outcomes (1). However, because kidneys are endowed with significant nephron reserve, renal fibrosis often progresses silently, with no overt manifestations such as increases in BP, serum creatinine, or urinary albumin excretion, until much of the kidney has already been replaced by scar.

Quantification of fibrotic burden during this “silent” scarring phase could theoretically identify patients at high risk for progression even before the development of significant renal dysfunction. As many new antifibrotic agents are being developed, this early identification might in the future enable intervention to prevent the subsequent development of renal dysfunction. Moreover, having the ability to monitor fibrosis progression could enable accurate tracking of the efficacy of these agents.

Even when patients present with impaired kidney function, measurement of renal fibrotic burden is still warranted, as clinicians currently have no means to separate the contributions of scarring from other reversible forms of injury, such as inflammation. Such distinctions are important, as quantification of irreversible scar burden could help predict the degree of renal function recovery after treatment of reversible injury, and thus could guide: (1) whether potentially toxic therapies for reversible disease should be used, and (2) the timing of RRT initiation. For example, in the setting of renal allograft rejection, clinicians may make different decisions regarding the use of antirejection therapies (that come with risks of over-immunosuppression) for a patient with a kidney that is 15% scarred versus a kidney that is 85% scarred. Thus, being able to quantify renal scar burden may not only expedite the future development of new antifibrotic agents, but also aid in present-day clinical decision-making.

Kidney Biopsy, the Gold Standard for Renal Fibrosis Assessment, Is Fraught with Limitations

The only current way to examine renal scar burden is the histologic evaluation of needle biopsy samples. Although a biopsy is often performed to establish the cause of renal dysfunction, its use as a way to quantify scar burden is fraught with limitations. First, biopsy is associated with significant bleeding risk. Second, because biopsy samples are only 2 mm in diameter, even “satisfactory” samples represent much <1% of one kidney, and almost never include the medulla. As fibrosis is often heterogeneously distributed, renal biopsy analysis is thus inherently subject to sampling bias.

Given these safety and sampling concerns, patients are often reluctant to undergo a biopsy. For similar reasons, clinicians reserve biopsy for situations when noninvasive testing fails to provide a diagnosis, meaning that in many cases, fibrotic burden is never assessed. Thus, clinicians are often left without a critical piece of information that would help with management, resulting in undue reliance on nonspecific measures such as eGFR that provide no insight into the underlying renal pathophysiology. Importantly, these same safety and sampling issues have also been major barriers to recruitment for studies of novel antifibrotic agents, impeding the clinical translation of promising new drugs. Taken together, although biopsy is the current gold standard for renal scarring assessment, it is imperfect from both a clinical and a research perspective. New, noninvasive methods that safely and accurately assess whole-kidney fibrotic burden are clearly needed.

Key Pathologic Features of the Fibrosing Kidney

Capillary Dropout and Reduced Microvascular Blood Flow

As the kidney scars, progressive capillary loss also occurs in parallel, leading to hypoperfusion of the renal parenchyma (2). An unfortunate consequence of this reduced microvascular blood flow is diminished oxygen delivery to tubular epithelial cells, which can lead to apoptosis, inflammation, and release of profibrotic stimuli that drive further fibrogenesis in a positive feedback loop (3). Thus, capillary dropout and hypoperfusion are not only key features of the fibrosing kidney, but also drivers of further fibrosis-associated injury (Figure 1).

Figure 1.
Figure 1.

Multiple physical changes occur in the kidney as it scars. As the tubulo-interstitium scars, the deposited extracellular matrix fibrils compress and obliterate surrounding capillaries, resulting in reduced blood flow and oxygen delivery, diminished tissue water mobility, and an increased diffusion distance for oxygen to reach tubular epithelial cells. Progressive ischemic tubular injury leads to tubular cell apoptosis, and tubular atrophy/dilation. These processes reduce oxygen consumption, which can normalize blood oxygen levels in the chronically injured kidney, and induce the production of profibrotic stimuli that drive further fibrosis in a positive feedback loop. Replacement of compliant kidney cells with stiff, crosslinked extracellular matrix increases the stiffness of the scarring kidney, a phenomenon that also induces further fibrogenesis. Novel magnetic resonance imaging modalities can image a variety of these physical changes to provide estimates of whole-kidney scar burden.

Increased Kidney Stiffness

A second important, but often overlooked, feature of the fibrosing kidney is an increase in renal stiffness (Figure 1). Organ stiffening is driven by the replacement of compliant cells with rigid matrix (4), and is further increased by crosslinking of these matrix fibrils (Figure 1) (4). Interestingly, recent data suggest that fibrosis requires this stiffening to occur. Fibroblasts respond to TGF-β, a profibrotic stimulus, only when grown in a stiff environment similar to an injured, fibrotic organ, whereas fibroblasts grown on a soft, healthy organ-like surface fail to respond (5). These results suggest that kidney stiffening, like capillary dropout, is not just a manifestation of the fibrotic process, but also an important contributor to fibrosis progression.

Novel Gadolinium-Free Magnetic Resonance Imaging–Based Modalities for Kidney Fibrosis Imaging

Conventional magnetic resonance imaging (MRI) has generally failed to image fibrosis, in part because of the often diffuse distribution of scar tissue. Recent advances, combined with an improved understanding of fibrosis pathophysiology, however, have raised the exciting possibility of using MRI to image scar. At the forefront of these advances has been the use of gadolinium-enhanced MRI, which has become an accepted means of imaging cardiac fibrosis (6). Unfortunately, because of the risks of gadolinium in patients with renal dysfunction, these techniques have not been easily translatable to the kidney. Fortunately, other gadolinium-free techniques which show promise for renal fibrosis imaging have also been developed. Several articles have reviewed the use of a number of these gadolinium-free techniques in the kidney (7,8), including an excellent review of renal functional MRI by Ebrahimi et al. (9). Recognizing the importance of microvascular loss and renal stiffening to kidney fibrosis, in this review we will summarize recent advances in renal MRI that focus on these two key pathophysiologic processes.

Diffusion MRI: Imaging the Mobility of Tissue Water Molecules

Using magnetic field gradients to measure water molecule movements, diffusion MRI is a noncontrast technique that images both directional water motion such as blood and urine flow, and also random motion of intra- and extracellular water, via “diffusion weighting.” This weighting is reflected in the b value, with higher b values increasing the sensitivity to water motion. The most commonly used diffusion MRI metric is the apparent diffusion coefficient (ADC), which integrates both random diffusion and directed flow of water into a quantitative parameter. Recognizing that different diseases can alter random and directional water movement in divergent ways, two common methods to separate these phenomena have been developed. In the first, diffusion MRI images are acquired using low (<300 s/mm2) and high b values (>300 s/mm2) to estimate the contributions of directional flow and diffusion, respectively (10). In the second strategy, postprocessing techniques such as intravoxel incoherent motion imaging are applied. With these methods, investigators have estimated the individual contributions of diffusion (ADCdiffusion) and perfusion (ADCperfusion) to the total ADC value. The remarkable sensitivity of diffusion MRI has permitted the imaging of diminished blood flow (reduced ADCperfusion), increased cell density due to cellular infiltration and/or proliferation (reduced ADCdiffusion due to more cell membranes), and even disrupted cell integrity (increased ADCdiffusion). A further variant of diffusion MRI, called diffusion tensor imaging, measures water mobility along different axes using a parameter called fractional anisotropy. Disruption of ordered structures that favor water movement in certain directions, such as axons in the brain or tubules in the kidney, can thus be theoretically captured using diffusion tensor imaging. Given this multitude of applications, diffusion MRI has been extensively used in neuro-imaging, especially in the early detection of ischemic brain injury (11), and for tumor imaging (12).

The processes that lead to renal fibrosis, including microvascular loss, but also fibroblast proliferation and matrix deposition, would be expected to: (1) decrease water mobility, either by impairing perfusion or water diffusion (Figure 2); and (2) disrupt the ordered structure of the renal parenchyma. Multiple case-control studies have indeed reported lower ADCtotal levels (13–17) and fractional anisotropy (18–20) in a variety of CKDs as compared with healthy controls, with ADCtotal, ADCperfusion, and fractional anisotropy falling with worsening renal function (Table 1) (13,15–17,20). When correlated with histology, ADCtotal levels were found to decrease with progressive fibrosis in mice subjected to unilateral ureteral obstruction (10) and allogeneic kidney transplantation (Table 1) (21). Similarly, several studies have found moderately strong correlations between increasing fibrosis and declining ADC in humans (Table 1) (13,15,21).

Figure 2.
Figure 2.

Diffusion-weighted magnetic resonance imaging detects reduced microvascular perfusion in fibrotic kidneys. (A) Representative pseudo-colorized apparent diffusion coefficient (ADCperfusion) map from a kidney allograft with minimal fibrosis, and (B) representative ADCperfusion map showing reduced microvascular perfusion in a kidney allograft with severe fibrosis. These images demonstrate the potential ability of diffusion-weighted magnetic resonance imaging to visualize the progressive reduction in microvascular blood flow that occurs as a result of kidney scarring. The color scale bar reflects the percentage of signal in a voxel that exhibits perfusion-like behavior at small b value diffusion gradient. Echo planar spin echo images were acquired with a water excitation pulse and a repetition time/echo time = 3500 ms/68 ms over a 380 × 380 mm field of view. Thirty-five-millimeter slices were acquired with a resolution of 1.5 × 1.5 mm, with a 20% gap between each slice. This acquisition was repeated with multiple diffusion gradients with increasing weighting of b = 0, 50, 100, 300, 600, 800, 1000 s/mm2.

View this table:
Table 1.

Summary of novel magnetic resonance imaging modalities and their ability to image renal fibrosis

Although these studies suggest that reduced ADCtotal and ADCperfusion are modestly associated with scar burden and kidney dysfunction, their results are somewhat disappointing given the much stronger relationship between ADC and tissue injury in other settings (22). A potential explanation for this poorer performance is that, despite the simplistic model described above, multiple processes in the chronically injured kidney can affect ADC measurements in a dynamic and complex manner. Renal blood flow, for example, can be affected by intravascular volume and medications such as diuretics and renin-angiotensin-aldosterone system blockers. Because these parameters can vary between patients and within a patient over time, their influence on ADC measurements may be highly relevant. To further complicate matters, the kidney, unlike other organs, contains a second fluid conduction system composed of tubules that carry urine. The effects of tubular urinary flow and water diffusion, which can change in response to hemodynamic, hormonal, or mechanical stimuli, have not been examined in detail, although a recent report suggested that tubular dilation in the chronically injured kidney may increase ADCdiffusion (23). A second reason why renal ADC measures have not correlated tightly with fibrosis may be that scar burden has historically been measured by biopsy. Studies correlating ADC values with biopsy fibrosis scores typically measured whole-kidney ADC, without matching to the area that was sampled by biopsy (13,15). As fibrosis is often heterogeneously distributed, it is not surprising that these studies demonstrated only a modest correlation between whole-kidney ADC and biopsy-derived fibrotic burden (13,15). Future studies will be required to test whether ADC values taken from the area sampled by biopsy correlate more tightly with biopsy-derived fibrosis scores.

Although these limitations must be addressed, diffusion MRI offers a number of exciting, and as yet untapped, opportunities. First, unlike biopsy analysis, which samples a highly-restricted area, MRI can serially examine both kidneys in their entirety. Sequential ADC studies could thus potentially be used to analyze changes in the patterns of perfusion and diffusion as fibrosis progresses. Although ADC levels differ between the cortex and medulla likely because of differences in perfusion and/or tissue architecture (24), how ADC patterns evolve over time may shed light on where fibrosis develops in different types of CKD. Second, given that microvascular loss drives renal injury and fibrosis, whole-kidney changes in perfusion and diffusion may also permit better prediction of the risk of fibrosis and CKD progression. Future studies examining these potential applications of diffusion MRI are clearly warranted.

Arterial Spin Labeling: Evaluation of Microvascular Perfusion

The success of diffusion MRI in measuring perfusion changes has fueled the development of other MRI-based techniques that measure blood flow. One method, called arterial spin labeling (ASL), has shown particular promise. In ASL, a combination of radiofrequency and magnetic gradient pulses is used to tag inflowing blood without gadolinium. Images are acquired with and without this tagging, and a subtraction between the two acquisitions provides information on the volume of tagged blood that flows into the imaged slice (25).

Application of ASL in animals (26) and humans (27) has demonstrated that this technique provides reasonable and reproducible estimates of renal cortical microvascular blood flow when compared with gold-standard measurements. In the setting of CKD, ASL-derived microvascular flow rates are decreased, with varying degrees of correlation with eGFR (Table 1) (28–30). Given that fibrosis is associated with capillary loss and impaired microvascular perfusion, the decrease in ASL-derived blood flow seen in CKD may be a surrogate measure of whole-kidney fibrotic burden, and may also predict progression risk. Correlation of ASL measurements with histologic injury has been limited, however, with only one study showing reduced cortical blood flow after ischemia-reperfusion injury in mouse kidneys (Table 1) (31). To our knowledge, no studies have examined whether ASL-measured renal blood flow reduction correlates with fibrotic burden.

Although renal ASL represents a potential addition to our fibrosis imaging armamentarium, further study is clearly required. In addition to more detailed imaging-histology correlation studies, a number of limitations need to be addressed. First, ASL measurements are plagued by poor signal-to-noise ratios and consequently low resolution, which limit their ability to separately assess the cortex and medulla, especially in chronically injured kidneys with cortical thinning. Second, ASL measures of medullary perfusion are difficult to perform because the medulla receives only 10% of total renal blood flow, making the ASL signal generally weaker than in the cortex. Moreover, much of the transient ASL label can decay before reaching the medulla because most blood flowing to the medulla must first pass through glomerular capillaries. Multiple acquisitions can be performed to improve signal measurement, but this prolongs scan time, rendering ASL more sensitive to respiratory motion artifact. This susceptibility is relevant, as ASL is a subtraction technique that requires the pretagging and post-tagging images to be superimposable. Respiratory motion compensation techniques have thus been developed to minimize patient motion between images. Finally, as with diffusion MRI, we need a better understanding of how ASL measures might be affected by hemodynamic and neurohormonal stimuli that can dynamically alter cortical and medullary blood flow independent of fibrotic burden.

Blood Oxygenation Level–Dependent MRI: Evaluating Oxygen Delivery to the Kidney

With reductions in blood flow, oxygen delivery is compromised, which in turn can lead to local changes in blood and tissue oxygenation. Taking advantage of this phenomenon, Ogawa et al. (32) described a technique sensitive to changes in blood oxygenation. Called blood oxygenation level–dependent (BOLD) MRI, this technique depends on the difference in magnetic properties between oxy- and deoxyhemoglobin. Hemoglobin in red blood cells becomes paramagnetic when deoxygenated, reflected by a decrease in the observed transverse relaxation time (T2*), which takes into account magnetic field inhomogeneity/susceptibility and is shorter than the inherent T2 of tissue. Acquiring images weighted by T2* thus allows estimation of tissue oxygen levels, and indeed BOLD MRI has been extensively validated as a measure of brain oxygenation (32).

Prasad et al. were the first to test BOLD MRI in the kidney, demonstrating that the medulla exhibits a lower T2* signal than the cortex (33), in line with the fact that the medulla operates in near hypoxic conditions. Later reports demonstrated reasonable correlation between T2* and directly measured tissue pO2 (34,35). Multiple studies have thus examined whether BOLD MRI could be used to noninvasively detect hypoxia in the injured kidney as decreased T2* signal. Somewhat surprisingly, although a number of early studies demonstrated that renal T2* is decreased in CKD (15,36,37), growing evidence now suggests that T2* is generally either preserved or even increased in both animals and humans with CKD, declining only in very late-stage disease (Table 1 and Figure 3) (38–45).

Figure 3.
Figure 3.

Blood oxygenation level–dependent magnetic resonance imaging (BOLD MRI) detects basal differences in renal blood oxygenation only in the setting of severe fibrosis. Representative pseudo-colorized BOLD MRI–derived T2* images of (A) a transplant kidney with minimal fibrosis, (B) a transplant kidney with moderate fibrosis, and (C) a transplant kidney with severe fibrosis. T2* is the observed transverse relaxation time, which takes into account magnetic field inhomogeneity/susceptibility and is shorter than the inherent T2 of tissue. Note that T2* does not differ between kidneys with minimal versus moderate fibrosis, but is significantly reduced when fibrosis is severe. These images suggest that in the absence of a pharmacologic stress, BOLD MRI can detect only severe kidney scarring, when renal blood flow (and hence blood oxygenation) is significantly compromised. The color scale bar denotes T2* signal intensity in milliseconds. T2* imaging was acquired using a two dimensional gradient echo sequence (repetition time/echo time = 100 ms/20 echoes with first echo 0.67 ms, and equally spaced echos every 1.2 ms thereafter). Quantitative T2* maps were reconstructed from an exponential fit to the acquired data.

This normalization of T2* in CKD is likely due to multiple processes. First, although blood flow and oxygen delivery are reduced due to capillary dropout in CKD, the effects of this change can be offset. In particular, reduced glomerular filtration due to glomerulosclerosis leads to lower sodium reabsorption by downstream tubules. This phenomenon, combined with tubular cell apoptosis, decreases oxygen consumption, which counteracts the effects of reduced oxygen delivery. Thus, renal T2* will decrease only at very late stages of disease, when renal blood flow (and thus oxygen delivery) is extremely compromised. Second, a decline in hemoglobin concentration is often observed in CKD because of erythropoietin deficiency. With a decreased hemoglobin concentration, for any given renal pO2, absolute deoxyhemoglobin levels will also decrease, leading to increased T2*. Finally, because of their effects on renal blood flow and tubular function, diuretics, non-steroid anti-inflammatory drugs, and renin-angiotensin-aldosterone system antagonists have all been shown to influence T2* (44,46–48). Taken together, these data suggest that BOLD MRI, on its own, may not be a useful measure of renal fibrotic burden.

Although basal BOLD T2* measurements may not be that informative, changes in T2* after a pharmacologic challenge may be of more utility. Furosemide has shown particular promise as a pharmacologic stimulus, because it is commonly used and reduces medullary sodium reabsorption, a process that is energy-dependent and hence consumes oxygen. By blocking sodium reabsorption, furosemide increases renal oxygenation, primarily in the medulla. BOLD MRI detects this improved medullary oxygenation in young, healthy adults as an increase in medullary T2* (47). Interestingly, this furosemide-induced increase in medullary T2* was not seen in settings that can be associated with renal fibrosis, such as in elderly but otherwise healthy adults (47), patients with essential hypertension (40), CKD (40), or hemodynamically significant renal artery stenosis (Table 1) (43). Although in CKD the attenuated effect of furosemide may have been due to reduced diuretic tubular exposure, taken together these results suggest that medullary oxygen homeostasis may be impaired with chronic renal injury. This altered oxygen balance, which is not apparent using standard clinical measures, suggests that tubules in the fibrotic kidney could already be dysfunctional. Future studies will be required to clarify whether furosemide-enhanced BOLD MRI can detect early functional changes associated with renal fibrosis, especially in patients with CKD.

Magnetic Resonance Elastography: As Kidneys Scar, They Stiffen

As alluded to previously, organ stiffening is a common but under-recognized complication of fibrosis (4). This stiffening can be captured using elastography, a technique that involves the external application of a gentle compressive or vibratory force over the organ of interest, followed by imaging of the resulting deformation. When vibratory forces are applied, shear waves are generated in the underlying tissue that can be captured by motion-synchronized imaging. The velocity of wave propagation varies according to tissue stiffness, with stiffer, fibrotic tissues propagating more rapidly moving waves of longer wavelength than softer, healthy tissues (49). These wave differences are then converted into a stiffness map (Figure 4).

Figure 4.
Figure 4.

Magnetic resonance elastography detects increases in kidney stiffness as a surrogate measure of renal fibrosis. (A) In magnetic resonance elastography, a gentle acoustic vibrational wave is applied on the skin overlying the kidney. The magnetic resonance imaging scanner acquires images at a frequency matched to that of the generated vibrational wave, capturing the small displacements in the vibrating organ. Taking advantage of the fact that these waves are longer and travel more rapidly in stiff organs than in soft organs, kidney stiffness can be calculated on the basis of the measured displacements and the amount of vibrational force applied to create “stiffness maps” (elastograms) of the imaged kidney. Sample pseudo-colorized displacement images are shown to the left and right of the magnetic resonance scanner in (A), with blue and red depicting alternating phases of the displacement waves. Below each displacement image is the corresponding pseudo-colorized elastogram (stiffness map), with blue depicting soft, and red depicting stiff tissue. (B) In these representative images of healthy (left panels) and fibrotic (right panels) transplant kidneys, standard transverse relaxation time (T2)-weighted images are shown in the top row. Note that no obvious differences can be identified. In contrast, in the bottom row, pseudo-colorized elastogram stiffness maps are shown of the same two kidneys, with red color reflecting stiffer tissue. The color bar is scaled from 0 kPa (blue) to red (8 kPa). Note the significant increases in stiffness in the fibrotic kidney. Phase images were acquired with a gradient echo sequence (repetition time/echo time = 50/20.79 ms) using a 12° flip angle. Acquired resolution of 1.5 × 1.5 × 5 mm over a 380 mm2 field of view. Four separate phase delays were acquired over the 60.1 Hz cycle of the acoustic driver and reconstructed to yield stiffness images. The T2-weighted image was acquired using a two dimensional Half-Fourier-Acquired Single-shot Turbo spin Echo (2D HASTE) sequence using a repetition time/echo tine of 1400/90 ms for over 40 slices with a reconstructed resolution of 1.6 × 1.6 × 4.5 mm. Partial Fourier reconstruction was used over a 256-squared encoding matrix.

MRI-based elastography (MRE) techniques that capitalize on these principles were initially developed for imaging of the liver, a large, homogenous, superficial organ, with multiple studies demonstrating its utility as a measure of liver fibrosis (50,51). More recently, MRE has also been applied to deeper organs such as the kidney (Figure 4) (52–56). In initial animal studies, for example, MRE was used to detect kidney stiffening induced by nephrocalcinosis in rats, a condition that is associated with mild fibrosis (54), as well as medullary fibrosis induced by chronic renal artery stenosis in swine (56). Preliminary human studies have demonstrated that MRE-measured kidney stiffness in healthy volunteers correlates with stiffness values predicted from ex vivo biomechanical measurements of animal kidneys (52,57). Finally, in a small study of eleven renal transplant patients with varying degrees of renal dysfunction undergoing protocol biopsies, whole-kidney MRE stiffness scores were higher in patients with moderate versus mild fibrosis, although considerable variability existed (53). Taken together, MRE-derived kidney stiffness measurements show promise as a measure of scar burden.

Although these initial studies are certainly encouraging, a number of questions remain. First, unlike the relatively homogenous liver, the kidney is structurally very heterogeneous. Thus, whether MRE stiffness measurements taken from the biopsy-sampled pole (rather than the entire kidney) might correlate better with biopsy-derived fibrosis scores needs to be examined. Second, the kidney is subject to injury-induced processes besides fibrosis that can also affect stiffness, including renal blood flow changes, collecting system dilation, and edema formation. Whether MRE can detect fibrosis in these clinically relevant scenarios is not clear, and in fact initial studies in pigs suggest that reduced blood flow may interfere with MRE measurements (55). Thus, although MRE shows promise as a noninvasive tool to image renal fibrosis, further work is required to better characterize its utility and applicability.

Other MRI-Based Techniques with Potential as Fibrosis Imaging Modalities

Whereas our review focused specifically on MRI modalities that image either changes in microvascular perfusion/oxygenation or renal stiffening, MRI-based techniques that examine other properties of fibrosing tissue are also under development. For example, longitudinal relaxation time (T1), an MRI parameter that increases with progressive scarring, has been shown to correlate with cardiac fibrosis (58). Studies of this so-called T1 fibrosis mapping, however, have not been performed in the kidney to date. A modification of this T1 mapping approach that takes advantage of the different magnetic properties of water protons that are attached to macromolecules like matrix proteins (as compared with protons of free water molecules), called magnetization transfer imaging, has also been developed. Interestingly, a recent study has demonstrated that magnetization transfer imaging can detect renal fibrosis in a murine model of renal artery stenosis (59), although clinical application of this technique has not yet been reported. Finally, the recent development of nongadolinium contrast agents may enable the use of “molecular MRI” strategies that directly image scar by using contrast-tagged probes that bind to matrix proteins such as collagen (60). Clearly, many new promising strategies are being explored that deserve further study.

MRI offers a wide range of possibilities for the noninvasive imaging of whole-kidney scar burden, potentially overcoming the safety and sampling bias limitations of biopsy analysis. We have highlighted four MRI-based techniques that image the consequences of two important pathologic features of the fibrosing kidney: capillary dropout and renal stiffening. Each of these techniques has been validated for various uses in extrarenal organs such as the brain and the liver. Several issues specific to the kidney, including its anatomic complexity, respiration-induced motion, and a unique system of microvessels and tubules that is tightly controlled by multiple neurohormonal regulators, have made translation of these techniques to the kidney not a simple task. In recent years, however, a number of studies have demonstrated that these noncontrast MRI modalities may have the potential to image renal scar.

Moving forward, further validation studies need to be performed, beginning in animal models to enable comparison of MRI-based measurements with histologic assessment of the entire kidney, rather than using biopsy samples that are subject to sampling bias. The use of preclinical models would also permit a better understanding of the effects of potential nonfibrotic confounding variables such as fluid status and medications. In addition, as these MRI sequences can all be performed during a single, short imaging session, studies testing whether diagnostic accuracy is improved by combining these techniques into a multiparametric test should also be performed.

Fibrosis is major cause of chronic renal injury, which currently is quantified in a limited and invasive manner via renal biopsy histologic analysis. As described above, MRI holds promise as a novel modality to noninvasively image whole-kidney fibrotic burden, and thus could become an important research and clinical tool for the study of renal fibrosis.

Disclosures

S.G.S. was supported by an National Sciences and Engineering Research Council of Canada (NSERC) Canada Graduate Scholarship (Master’s). C.A.S. is the Canada Research Chair in Mechanobiology. D.A.Y. is supported by a Kidney Research Scientist Core Education and National Training (KRESCENT) program New Investigator and Canadian Diabetes Association Clinician Scientist Award, and is also a recipient of a Canadian Institutes of Health Research (CIHR) New Investigator Award. D.A.Y. and A.K. received an unrestricted research grant from Astellas Pharma Canada (Markham, Ontario, Canada), which supported the development of novel magnetic resonance imaging sequences for kidney fibrosis.

Acknowledgments

This work was supported in part by an unrestricted research grant from Astellas Pharma Canada, a Collaborative Health Research Project Grant, a Physician’s Services Incorporated Foundation grant, a Kidney Research Scientist Core Education and National Training (KRESCENT) program Infrastructure Grant, and funding from the St. Michael’s Hospital Foundation.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Received July 25, 2016.
  • Accepted December 19, 2016.

References

  1. ↵
    1. Nath KA
    : Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 20: 1–17, 1992
    OpenUrlCrossRefPubMed
  2. ↵
    1. Kang DH,
    2. Kanellis J,
    3. Hugo C,
    4. Truong L,
    5. Anderson S,
    6. Kerjaschki D,
    7. Schreiner GF,
    8. Johnson RJ
    : Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 13: 806–816, 2002
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Fine LG,
    2. Norman JT
    : Chronic hypoxia as a mechanism of progression of chronic kidney diseases: From hypothesis to novel therapeutics. Kidney Int 74: 867–872, 2008
    OpenUrlCrossRefPubMed
  4. ↵
    1. Georges PC,
    2. Hui JJ,
    3. Gombos Z,
    4. McCormick ME,
    5. Wang AY,
    6. Uemura M,
    7. Mick R,
    8. Janmey PA,
    9. Furth EE,
    10. Wells RG
    : Increased stiffness of the rat liver precedes matrix deposition: Implications for fibrosis. Am J Physiol Gastrointest Liver Physiol 293: G1147–G1154, 2007
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Szeto SG,
    2. Narimatsu M,
    3. Lu M,
    4. He X,
    5. Sidiqi AM,
    6. Tolosa MF,
    7. Chan L,
    8. De Freitas K,
    9. Bialik JF,
    10. Majumder S,
    11. Boo S,
    12. Hinz B,
    13. Dan Q,
    14. Advani A,
    15. John R,
    16. Wrana JL,
    17. Kapus A,
    18. Yuen DA
    : YAP/TAZ are mechanoregulators of TGF-β-smad signaling and renal fibrogenesis JASN 27: 3117–3128, 2016.
  6. ↵
    1. Iles L,
    2. Pfluger H,
    3. Phrommintikul A,
    4. Cherayath J,
    5. Aksit P,
    6. Gupta SN,
    7. Kaye DM,
    8. Taylor AJ
    : Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol 52: 1574–1580, 2008
    OpenUrlFREE Full Text
  7. ↵
    1. Grenier N,
    2. Merville P,
    3. Combe C
    : Radiologic imaging of the renal parenchyma structure and function. Nat Rev Nephrol 12: 348–359, 2016
    OpenUrl
  8. ↵
    1. Thoeny HC,
    2. Grenier N
    : Science to practice: Can diffusion-weighted MR imaging findings be used as biomarkers to monitor the progression of renal fibrosis? Radiology 255: 667–668, 2010
    OpenUrlCrossRefPubMed
  9. ↵
    1. Ebrahimi B,
    2. Textor SC,
    3. Lerman LO
    : Renal relevant radiology: Renal functional magnetic resonance imaging. Clin J Am Soc Nephrol 9: 395–405, 2014
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Togao O,
    2. Doi S,
    3. Kuro-o M,
    4. Masaki T,
    5. Yorioka N,
    6. Takahashi M
    : Assessment of renal fibrosis with diffusion-weighted MR imaging: Study with murine model of unilateral ureteral obstruction. Radiology 255: 772–780, 2010
    OpenUrlCrossRefPubMed
  11. ↵
    1. Warach S,
    2. Gaa J,
    3. Siewert B,
    4. Wielopolski P,
    5. Edelman RR
    : Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 37: 231–241, 1995
    OpenUrlCrossRefPubMed
  12. ↵
    1. Li B,
    2. Li Q,
    3. Nie W,
    4. Liu S
    : Diagnostic value of whole-body diffusion-weighted magnetic resonance imaging for detection of primary and metastatic malignancies: A meta-analysis. Eur J Radiol 83: 338–344, 2014
    OpenUrlCrossRefPubMed
  13. ↵
    1. Zhao J,
    2. Wang ZJ,
    3. Liu M,
    4. Zhu J,
    5. Zhang X,
    6. Zhang T,
    7. Li S,
    8. Li Y
    : Assessment of renal fibrosis in chronic kidney disease using diffusion-weighted MRI. Clin Radiol 69: 1117–1122, 2014
    OpenUrlCrossRefPubMed
    1. Thoeny HC,
    2. De Keyzer F,
    3. Oyen RH,
    4. Peeters RR
    : Diffusion-weighted MR imaging of kidneys in healthy volunteers and patients with parenchymal diseases: Initial experience. Radiology 235: 911–917, 2005
    OpenUrlCrossRefPubMed
  15. ↵
    1. Inoue T,
    2. Kozawa E,
    3. Okada H,
    4. Inukai K,
    5. Watanabe S,
    6. Kikuta T,
    7. Watanabe Y,
    8. Takenaka T,
    9. Katayama S,
    10. Tanaka J,
    11. Suzuki H
    : Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging. J Am Soc Nephrol 22: 1429–1434, 2011
    OpenUrlAbstract/FREE Full Text
    1. Namimoto T,
    2. Yamashita Y,
    3. Mitsuzaki K,
    4. Nakayama Y,
    5. Tang Y,
    6. Takahashi M
    : Measurement of the apparent diffusion coefficient in diffuse renal disease by diffusion-weighted echo-planar MR imaging. J Magn Reson Imaging 9: 832–837, 1999
    OpenUrlCrossRefPubMed
  17. ↵
    1. Thoeny HC,
    2. Zumstein D,
    3. Simon-Zoula S,
    4. Eisenberger U,
    5. De Keyzer F,
    6. Hofmann L,
    7. Vock P,
    8. Boesch C,
    9. Frey FJ,
    10. Vermathen P
    : Functional evaluation of transplanted kidneys with diffusion-weighted and BOLD MR imaging: Initial experience. Radiology 241: 812–821, 2006
    OpenUrlCrossRefPubMed
  18. ↵
    1. Hueper K,
    2. Hartung D,
    3. Gutberlet M,
    4. Gueler F,
    5. Sann H,
    6. Husen B,
    7. Wacker F,
    8. Reiche D
    : Magnetic resonance diffusion tensor imaging for evaluation of histopathological changes in a rat model of diabetic nephropathy. Invest Radiol 47: 430–437, 2012
    OpenUrlCrossRefPubMed
    1. Lanzman RS,
    2. Ljimani A,
    3. Pentang G,
    4. Zgoura P,
    5. Zenginli H,
    6. Kröpil P,
    7. Heusch P,
    8. Schek J,
    9. Miese FR,
    10. Blondin D,
    11. Antoch G,
    12. Wittsack HJ
    : Kidney transplant: Functional assessment with diffusion-tensor MR imaging at 3T. Radiology 266: 218–225, 2013
    OpenUrlCrossRefPubMed
  20. ↵
    1. Hueper K,
    2. Khalifa AA,
    3. Bräsen JH,
    4. Vo Chieu VD,
    5. Gutberlet M,
    6. Wintterle S,
    7. Lehner F,
    8. Richter N,
    9. Peperhove M,
    10. Tewes S,
    11. Weber K,
    12. Haller H,
    13. Wacker F,
    14. Gwinner W,
    15. Gueler F,
    16. Hartung D
    : Diffusion-Weighted imaging and diffusion tensor imaging detect delayed graft function and correlate with allograft fibrosis in patients early after kidney transplantation. J Magn Reson Imaging 44: 112–121, 2016
    OpenUrl
  21. ↵
    1. Hueper K,
    2. Hensen B,
    3. Gutberlet M,
    4. Chen R,
    5. Hartung D,
    6. Barrmeyer A,
    7. Meier M,
    8. Li W,
    9. Jang MS,
    10. Mengel M,
    11. Wacker F,
    12. Rong S,
    13. Gueler F
    : Kidney transplantation: Multiparametric functional magnetic resonance imaging for assessment of renal allograft pathophysiology in mice. Invest Radiol 51: 58–65, 2016
    OpenUrl
  22. ↵
    1. Cui Y,
    2. Zhang XP,
    3. Sun YS,
    4. Tang L,
    5. Shen L
    : Apparent diffusion coefficient: Potential imaging biomarker for prediction and early detection of response to chemotherapy in hepatic metastases. Radiology 248: 894–900, 2008
    OpenUrlCrossRefPubMed
  23. ↵
    1. Boor P,
    2. Perkuhn M,
    3. Weibrecht M,
    4. Zok S,
    5. Martin IV,
    6. Gieseke J,
    7. Schoth F,
    8. Ostendorf T,
    9. Kuhl C,
    10. Floege J
    : Diffusion-weighted MRI does not reflect kidney fibrosis in a rat model of fibrosis. J Magn Reson Imaging 42: 990–998, 2015
    OpenUrl
  24. ↵
    1. Ries M,
    2. Basseau F,
    3. Tyndal B,
    4. Jones R,
    5. Deminière C,
    6. Catargi B,
    7. Combe C,
    8. Moonen CW,
    9. Grenier N
    : Renal diffusion and BOLD MRI in experimental diabetic nephropathy. Blood oxygen level-dependent. J Magn Reson Imaging 17: 104–113, 2003
    OpenUrlCrossRefPubMed
  25. ↵
    1. Wong EC,
    2. Buxton RB,
    3. Frank LR
    : Implementation of quantitative perfusion imaging techniques for functional brain mapping using pulsed arterial spin labeling. NMR Biomed 10: 237–249, 1997
    OpenUrlCrossRefPubMed
  26. ↵
    1. Artz NS,
    2. Wentland AL,
    3. Sadowski EA,
    4. Djamali A,
    5. Grist TM,
    6. Seo S,
    7. Fain SB
    : Comparing kidney perfusion using noncontrast arterial spin labeling MRI and microsphere methods in an interventional swine model. Invest Radiol 46: 124–131, 2011
    OpenUrlCrossRefPubMed
  27. ↵
    1. Ritt M,
    2. Janka R,
    3. Schneider MP,
    4. Martirosian P,
    5. Hornegger J,
    6. Bautz W,
    7. Uder M,
    8. Schmieder RE
    : Measurement of kidney perfusion by magnetic resonance imaging: Comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome. Nephrol Dial Transplant 25: 1126–1133, 2010
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Heusch P,
    2. Wittsack HJ,
    3. Blondin D,
    4. Ljimani A,
    5. Nguyen-Quang M,
    6. Martirosian P,
    7. Zenginli H,
    8. Bilk P,
    9. Kröpil P,
    10. Heusner TA,
    11. Antoch G,
    12. Lanzman RS
    : Functional evaluation of transplanted kidneys using arterial spin labeling MRI. J Magn Reson Imaging 40: 84–89, 2014
    OpenUrlCrossRefPubMed
    1. Artz NS,
    2. Sadowski EA,
    3. Wentland AL,
    4. Grist TM,
    5. Seo S,
    6. Djamali A,
    7. Fain SB
    : Arterial spin labeling MRI for assessment of perfusion in native and transplanted kidneys. Magn Reson Imaging 29: 74–82, 2011
    OpenUrlCrossRefPubMed
  30. ↵
    1. Rossi C,
    2. Artunc F,
    3. Martirosian P,
    4. Schlemmer HP,
    5. Schick F,
    6. Boss A
    : Histogram analysis of renal arterial spin labeling perfusion data reveals differences between volunteers and patients with mild chronic kidney disease. Invest Radiol 47: 490–496, 2012
    OpenUrlPubMed
  31. ↵
    1. Hueper K,
    2. Gutberlet M,
    3. Rong S,
    4. Hartung D,
    5. Mengel M,
    6. Lu X,
    7. Haller H,
    8. Wacker F,
    9. Meier M,
    10. Gueler F
    : Acute kidney injury: Arterial spin labeling to monitor renal perfusion impairment in mice-comparison with histopathologic results and renal function. Radiology 270: 117–124, 2014
    OpenUrlCrossRefPubMed
  32. ↵
    1. Ogawa S,
    2. Lee TM,
    3. Kay AR,
    4. Tank DW
    : Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci USA 87: 9868–9872, 1990
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Prasad PV,
    2. Edelman RR,
    3. Epstein FH
    : Noninvasive evaluation of intrarenal oxygenation with BOLD MRI. Circulation 94: 3271–3275, 1996
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Pohlmann A,
    2. Arakelyan K,
    3. Hentschel J,
    4. Cantow K,
    5. Flemming B,
    6. Ladwig M,
    7. Waiczies S,
    8. Seeliger E,
    9. Niendorf T
    : Detailing the relation between renal T2* and renal tissue pO2 using an integrated approach of parametric magnetic resonance imaging and invasive physiological measurements. Invest Radiol 49: 547–560, 2014
    OpenUrlCrossRefPubMed
  35. ↵
    1. Pedersen M,
    2. Dissing TH,
    3. Mørkenborg J,
    4. Stødkilde-Jørgensen H,
    5. Hansen LH,
    6. Pedersen LB,
    7. Grenier N,
    8. Frøkiaer J
    : Validation of quantitative BOLD MRI measurements in kidney: Application to unilateral ureteral obstruction. Kidney Int 67: 2305–2312, 2005
    OpenUrlCrossRefPubMed
  36. ↵
    1. Xin-Long P,
    2. Jing-Xia X,
    3. Jian-Yu L,
    4. Song W,
    5. Xin-Kui T
    : A preliminary study of blood-oxygen-level-dependent MRI in patients with chronic kidney disease. Magn Reson Imaging 30: 330–335, 2012
    OpenUrlCrossRefPubMed
  37. ↵
    1. Ebrahimi B,
    2. Crane JA,
    3. Knudsen BE,
    4. Macura SI,
    5. Grande JP,
    6. Lerman LO
    : Evolution of cardiac and renal impairment detected by high-field cardiovascular magnetic resonance in mice with renal artery stenosis. J Cardiovasc Magn Reson 15: 98, 2013
    OpenUrl
  38. ↵
    1. Gloviczki ML,
    2. Glockner JF,
    3. Lerman LO,
    4. McKusick MA,
    5. Misra S,
    6. Grande JP,
    7. Textor SC
    : Preserved oxygenation despite reduced blood flow in poststenotic kidneys in human atherosclerotic renal artery stenosis. Hypertension 55: 961–966, 2010
    OpenUrlAbstract/FREE Full Text
    1. Michaely HJ,
    2. Metzger L,
    3. Haneder S,
    4. Hansmann J,
    5. Schoenberg SO,
    6. Attenberger UI
    : Renal BOLD-MRI does not reflect renal function in chronic kidney disease. Kidney Int 81: 684–689, 2012
    OpenUrlCrossRefPubMed
  40. ↵
    1. Pruijm M,
    2. Hofmann L,
    3. Piskunowicz M,
    4. Muller ME,
    5. Zweiacker C,
    6. Bassi I,
    7. Vogt B,
    8. Stuber M,
    9. Burnier M
    : Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans. PLoS One 9: e95895, 2014
    OpenUrlCrossRefPubMed
    1. Khatir DS,
    2. Pedersen M,
    3. Jespersen B,
    4. Buus NH
    : Evaluation of renal blood flow and oxygenation in CKD using magnetic resonance imaging. Am J Kidney Dis 66: 402–411, 2015
    OpenUrl
    1. Rognant N,
    2. Guebre-Egziabher F,
    3. Bacchetta J,
    4. Janier M,
    5. Hiba B,
    6. Langlois JB,
    7. Gadet R,
    8. Laville M,
    9. Juillard L
    : Evolution of renal oxygen content measured by BOLD MRI downstream a chronic renal artery stenosis. Nephrol Dial Transplant 26: 1205–1210, 2011
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Textor SC,
    2. Glockner JF,
    3. Lerman LO,
    4. Misra S,
    5. McKusick MA,
    6. Riederer SJ,
    7. Grande JP,
    8. Gomez SI,
    9. Romero JC
    : The use of magnetic resonance to evaluate tissue oxygenation in renal artery stenosis. J Am Soc Nephrol 19: 780–788, 2008
    OpenUrlAbstract/FREE Full Text
  44. ↵
    1. Djamali A,
    2. Sadowski EA,
    3. Muehrer RJ,
    4. Reese S,
    5. Smavatkul C,
    6. Vidyasagar A,
    7. Fain SB,
    8. Lipscomb RC,
    9. Hullett DH,
    10. Samaniego-Picota M,
    11. Grist TM,
    12. Becker BN
    : BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction. Am J Physiol Renal Physiol 292: F513–F522, 2007
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Wang ZJ,
    2. Kumar R,
    3. Banerjee S,
    4. Hsu CY
    : Blood oxygen level-dependent (BOLD) MRI of diabetic nephropathy: Preliminary experience. J Magn Reson Imaging 33: 655–660, 2011
    OpenUrlCrossRefPubMed
  46. ↵
    1. Siddiqi L,
    2. Hoogduin H,
    3. Visser F,
    4. Leiner T,
    5. Mali WP,
    6. Blankestijn PJ
    : Inhibition of the renin-angiotensin system affects kidney tissue oxygenation evaluated by magnetic resonance imaging in patients with chronic kidney disease. J Clin Hypertens (Greenwich) 16: 214–218, 2014
    OpenUrlCrossRefPubMed
  47. ↵
    1. Epstein FH,
    2. Prasad P
    : Effects of furosemide on medullary oxygenation in younger and older subjects. Kidney Int 57: 2080–2083, 2000
    OpenUrlCrossRefPubMed
  48. ↵
    1. Prasad PV,
    2. Epstein FH
    : Changes in renal medullary pO2 during water diuresis as evaluated by blood oxygenation level-dependent magnetic resonance imaging: Effects of aging and cyclooxygenase inhibition. Kidney Int 55: 294–298, 1999
    OpenUrlCrossRefPubMed
  49. ↵
    1. Muthupillai R,
    2. Lomas DJ,
    3. Rossman PJ,
    4. Greenleaf JF,
    5. Manduca A,
    6. Ehman RL
    : Magnetic resonance elastography by direct visualization of propagating acoustic strain waves. Science 269: 1854–1857, 1995
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Wang Y,
    2. Ganger DR,
    3. Levitsky J,
    4. Sternick LA,
    5. McCarthy RJ,
    6. Chen ZE,
    7. Fasanati CW,
    8. Bolster B,
    9. Shah S,
    10. Zuehlsdorff S,
    11. Omary RA,
    12. Ehman RL,
    13. Miller FH
    : Assessment of chronic hepatitis and fibrosis: Comparison of MR elastography and diffusion-weighted imaging. AJR Am J Roentgenol 196: 553–561, 2011
    OpenUrlCrossRefPubMed
  51. ↵
    1. Yin M,
    2. Woollard J,
    3. Wang X,
    4. Torres VE,
    5. Harris PC,
    6. Ward CJ,
    7. Glaser KJ,
    8. Manduca A,
    9. Ehman RL
    : Quantitative assessment of hepatic fibrosis in an animal model with magnetic resonance elastography. Magn Reson Med 58: 346–353, 2007
    OpenUrlCrossRefPubMed
  52. ↵
    1. Kirpalani A,
    2. Jiang N,
    3. Burute N,
    4. Leung G,
    5. Yuen DA
    : Magnetic resonance elastography of the transplant kidney: A feasibility study. European Congress of Radiology, Vienna, 2014.
  53. ↵
    1. Lee CU,
    2. Glockner JF,
    3. Glaser KJ,
    4. Yin M,
    5. Chen J,
    6. Kawashima A,
    7. Kim B,
    8. Kremers WK,
    9. Ehman RL,
    10. Gloor JM
    : MR elastography in renal transplant patients and correlation with renal allograft biopsy: A feasibility study. Acad Radiol 19: 834–841, 2012
    OpenUrlCrossRefPubMed
  54. ↵
    1. Shah NS,
    2. Kruse SA,
    3. Lager DJ,
    4. Farell-Baril G,
    5. Lieske JC,
    6. King BF,
    7. Ehman RL
    : Evaluation of renal parenchymal disease in a rat model with magnetic resonance elastography. Magn Reson Med 52: 56–64, 2004
    OpenUrlCrossRefPubMed
  55. ↵
    1. Warner L,
    2. Yin M,
    3. Glaser KJ,
    4. Woollard JA,
    5. Carrascal CA,
    6. Korsmo MJ,
    7. Crane JA,
    8. Ehman RL,
    9. Lerman LO
    : Noninvasive in vivo assessment of renal tissue elasticity during graded renal ischemia using MR elastography. Invest Radiol 46: 509–514, 2011
    OpenUrlCrossRefPubMed
  56. ↵
    1. Korsmo MJ,
    2. Ebrahimi B,
    3. Eirin A,
    4. Woollard JR,
    5. Krier JD,
    6. Crane JA,
    7. Warner L,
    8. Glaser K,
    9. Grimm R,
    10. Ehman RL,
    11. Lerman LO
    : Magnetic resonance elastography noninvasively detects in vivo renal medullary fibrosis secondary to swine renal artery stenosis. Invest Radiol 48: 61–68, 2013
    OpenUrlCrossRefPubMed
  57. ↵
    1. Swift J,
    2. Ivanovska IL,
    3. Buxboim A,
    4. Harada T,
    5. Dingal PC,
    6. Pinter J,
    7. Pajerowski JD,
    8. Spinler KR,
    9. Shin JW,
    10. Tewari M,
    11. Rehfeldt F,
    12. Speicher DW,
    13. Discher DE
    : Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341: 1240104, 2013
    OpenUrlAbstract/FREE Full Text
  58. ↵
    1. Bull S,
    2. White SK,
    3. Piechnik SK,
    4. Flett AS,
    5. Ferreira VM,
    6. Loudon M,
    7. Francis JM,
    8. Karamitsos TD,
    9. Prendergast BD,
    10. Robson MD,
    11. Neubauer S,
    12. Moon JC,
    13. Myerson SG
    : Human non-contrast T1 values and correlation with histology in diffuse fibrosis. Heart 99: 932–937, 2013
    OpenUrlAbstract/FREE Full Text
  59. ↵
    1. Jiang K,
    2. Ferguson CM,
    3. Ebrahimi B,
    4. Tang H,
    5. Kline TL,
    6. Burningham TA,
    7. Mishra PK,
    8. Grande JP,
    9. Macura SI,
    10. Lerman LO
    : Noninvasive assessment of renal fibrosis with magnetization transfer MR imaging: Validation and evaluation in murine renal artery stenosis [published online ahead of print October 3, 2016]. Radiology doi:10.1148/radiol.2016160566
  60. ↵
    1. Caravan P,
    2. Das B,
    3. Dumas S,
    4. Epstein FH,
    5. Helm PA,
    6. Jacques V,
    7. Koerner S,
    8. Kolodziej A,
    9. Shen L,
    10. Sun WC,
    11. Zhang Z
    : Collagen-targeted MRI contrast agent for molecular imaging of fibrosis. Angew Chem Int Ed Engl 46: 8171–8173, 2007
    OpenUrlCrossRefPubMed
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