Applications for Kidney Diseases
Renovascular Diseases
Renal MR angiography has long been established as an accurate, clinically acceptable method for depicting RAS. Because of the high incidence of asymptomatic renal artery stenosis, several methods have been investigated as adjuncts to anatomic imaging to help determine the functional significance of the stenosis, to monitor therapy, and to develop predictive indices to identify patients likely to benefit from revascularization.
To assess the functional significance of the RVD, renal blood flow can be measured using ASL or DCE MRI, using Gd contrast agents or ultrasmall paramagnetic iron-oxide particles that stay in the intravascular space. Using ultrasmall paramagnetic iron-oxide–enhanced imaging, Schoenberg et al. found that with renal artery diameter narrowing <80%, intrarenal cortical perfusion did not change significantly (average 513 ml/100 g/min), whereas artery narrowing >80% caused a fall of more than 200 ml/100 g/min in cortical perfusion. ASL-MRI uses spin-labeled arterial blood as the tracer, thereby avoiding the potential adverse effects of exogenous contrast agents. Its value in RVD remains to be determined.
The management of RVD, often asymmetric in nature, may benefit from the determination of single-kidney GFR using MRR. The detection of hemodynamically significant RAS, often corresponding to >70% decrease in diameter, can be facilitated by the administration of angiotensin-converting enzyme inhibitors. Angiotensin-converting enzyme inhibitor attenuates GFR and thus the magnitude of signal enhancement in the presence of significant RAS, but this attenuation is difficult to determine in subjects with low basal signal enhancement. To overcome this barrier, a multicompartmental modeling method for analyzing dual-injection MRI data has been developed to allow for GFR determinations in human kidneys with significant stenotic renal arteries and has shown that angiotensin-converting enzyme inhibitor caused a significant decrease in GFR averaging ~26% in a group of kidneys with RAS ≥50%.
The effects of RVD on intrarenal hypoxia have been evaluated using BOLD MRI. Although it is relatively preserved in moderate RVD, a decrease in renal oxygenation becomes evident once severe stenosis develops. This is possibly because, in severe vascular occlusion that threatens cortical perfusion, processes of compensating tissue oxygenation become overwhelmed. Histogram-based analysis over large cortical and medullary regions can be used to evaluate the distribution of tissue oxygenation in these regions and reduces sampling error. Moreover, a furosemide challenge enables the study of tubular oxygen–dependent transport, which is blunted in damaged kidneys but enhanced in hyperfiltering kidneys. Hence, BOLD MRI may be useful to assess the functional integrity of the renal medullary tubules.
Other methods have also been explored in RVD. Magnetic resonance elastography utilizes the translocation of mechanical shear waves to estimate elasticity, which may decrease in fibrotic kidneys. Interestingly, in swine with RVD, overall kidney stiffness is unaltered, because a fall in renal blood flow reduces renal turgor and masks decreased elasticity. In contrast, medullary elasticity appears to be less dependent on hemodynamic variables, and may reflect kidney fibrosis.
DWI detects changes in tissue property based on its sensitivity to restriction of free-water diffusion. In patients with RVD, but not hypertension alone, ADC declines and correlates with the extent of RVD, suggesting that significant kidney injury is required to become detectable by DWI.
The noninvasive and versatile nature of MRI positions this modality at the forefront for evaluation of RVD in humans. The rapid progress in this field will hopefully inspire the development of molecular and metabolic probes to assess mechanisms of injury and viability of the poststenotic kidney. These developments would be for identifying the subset of patients with RVD who may benefit from revascularization of stenotic renal arteries. The determination of tissue perfusion and oxygenation may facilitate the decision to perform the revascularization procedure and monitoring of the kidney responses after the procedure.
Diabetic Nephropathy
Recent advances suggest that progressive CKD eventually results in peritubular capillary injury, tubular hypoxia and atrophy, and interstitial fibrosis, independent of the type of underlying primary kidney disease. DN is the most common form of CKD, and functional renal MRI is an attractive opportunity for noninvasive diagnosis and monitoring of potential therapeutic interventions. Most studies have focused on hypoxia using BOLD MRI, fibrosis using DWI, tubular damage using DTI, or a combination of BOLD MRI and DWI. A recent preliminary report applied ASL to show reduced cortical blood flow in patients with CKD.
Studies using BOLD-MRI in rodent models suggest that, at least in the early stages, type 1 and type 2 DN is associated with increased hypoxia. DWI that measures water diffusion in the interstitial space, however, has failed to show any changes in early-stage DN. Part of the reason may be related to the specific parameters of the diffusion MRI method.
Clinical results of BOLD MRI in DN have been strikingly variable. Consistent with rodent studies, one recent BOLD MRI study of 46 patients with type 2 diabetes using 3.0 T MRI found that the ratios of medullary-to-cortical R2* (MCR) were higher in stages 1 and 2 CKD compared with controls, suggesting a greater than expected medullary tissue hypoxia relative to the cortex. Interestingly, the MCR values were lower at later stages (3–5) of CKD compared with controls. The reason for this paradox is not apparent, but it may provide interesting clues to the understanding of the pathophysiology of DN. Another study of 20 diabetic patients (14 with stages 3–5 CKD) performed using 1.5 T MRI confirmed lower MCR values than healthy subjects. Yet another study of type 2 diabetic patients (CKD stages 1–4) using 3.0 T MRI found no change in MCR compared with controls reported in the literature. As noted above (BOLD section), the apparently contradictory results of BOLD imaging in these patients is likely due to technical challenges such as image artifacts and the oversimplification of interpretation of R2* (or T2*) values.
Diffusion-weighted imaging has also been applied to DN patients. A recent study of CKD patients with (n=43) or without (n=76) diabetes found a statistically significant correlation between ADC and estimated GFR values in both groups of patients. However, this correlation was only seen in the nondiabetic patients and not in the diabetic patients. A recent DTI study suggested changes in fractional anisotropy in the renal medulla with different levels of DN probably related to glomerulosclerosis, interstitial fibrosis, and tubular damage.
Overall, these reports clearly demonstrate the complexities involved in translating results from animal models to humans. In addition to technical challenges inherent in the MR methods, these discrepancies may also be related to differences species, pathogenesis of diabetes, severity of kidney disease, comorbid conditions, use of medications such as renin–angiotensin system blockers, hydration, and other preparations for imaging. Further refinement and validation of these techniques and their applications to larger, well-designed clinical studies may establish their utility in clinical research of DN and routine clinical use.
Renal Transplants
MRI has emerged as an attractive approach for evaluating the function of renal allografts owing to its noninvasiveness and suitability for repeated application. The most promising results have involved near-term allograft complications, of which acute tubular necrosis (ATN) and acute allograft rejection (AR) are the most common. Szolar et al. observed that the first-pass cortical signal enhancement using DCE MRI was markedly reduced in allografts with AR compared with normally functioning kidneys, whereas allografts with ATN showed no difference compared with normal cases. Using a similar approach, Wentland et al. reported lower cortical and medullary blood flow in AR compared with normal kidneys and lower medullary blood flow in AR compared with ATN. Most recently, by applying a multicompartmental tracer kinetic model to DCE MR images, Yamamoto et al. showed that MTTs could differentiate normal allografts from AR or ATN, where AR cases had a higher ratio of vascular MTT over whole-kidney MTT, whereas ATN cases had higher ratio of tubular MTT over whole-kidney MTT.
Several studies have investigated the diagnosis of acute dysfunction using non-contrast techniques such as BOLD MRI. Sadowski et al. and Han et al. performed BOLD MRI in recent kidney transplant recipients and observed significantly lower medullary R2*, or higher oxygenation, in cases of AR compared with ATN. As the authors suggested, this could be due to preferential blood shunting toward the medulla during acute rejection or reduced oxygen consumption rate owing to subclinical medullary tubular injury or both. Taken together, the results consistently show differentiation between ATN and AR based on perfusion and oxygenation parameters; however, robust differentiation of ATN from normally functioning allografts has not been demonstrated. Therefore, Chandarana et al. have proposed a follow-up role for MRI only after acute dysfunction has been implicated by other tests such as elevated serum creatinine.
Studies of long-term allograft function have combined multiple functional MRI techniques, including BOLD, DWI, and ASL MRI. In a cross-sectional BOLD MRI study of healthy volunteers and transplant recipients with chronic allograft nephropathy, Djamali et al. observed significantly reduced cortical and medullary R2*, indicating increased oxygenation, in allografts affected by chronic allograft nephropathy. Long-term longitudinal studies, however, have produced mixed results. Vermathen et al. reported stable DWI parameters and an increase of cortical R2* (decrease in oxygenation) in allografts between 7 and 32 months after transplant. In a small pilot study involving matched donor and recipient pairs, Malvezzi et al. observed a reduction in cortical R2* in both groups and a reduction in medullary R2* (increase in oxygenation) in the transplanted kidney 1 month after transplant. In a recent study of 14 donor and recipient pairs, Niles et al. observed a reduction in both medullary R2* (increase in oxygenation) and ASL-estimated cortical perfusion in transplanted kidneys 3 months after transplant, and this reduction persisted for at least 2 years. The clinical significance of these changes was unclear, as all allografts were functioning well based on conventional clinical biomarkers. Further longitudinal studies with larger sample sizes will be necessary to determine whether long-term changes in MRI measures of allograft function are associated with clinical outcomes.
Renal Tumors
Renal masses are increasingly discovered incidentally, which is largely attributable to the increased use of medical imaging. Because tumors differ in biologic behavior, aggressiveness, and prognosis, their increased detection has led to a management dilemma. Accurate characterization of tumor aggressiveness can guide management. Although CT is most widely used to diagnose renal lesions in clinical practice, advantages of MRI include superior soft tissue contrast, avoidance of ionizing radiation and iodinated contrast media, and most importantly the availability of different techniques such as DCE, DWI, and BOLD MRI to probe different aspects of tumor such as vascularity, microstructure, and oxygenation (6).
Widely used clinically, DCE MRI is one of the most robust techniques for evaluating the aggressiveness of renal tumors. Studies have shown that by imaging at three time points following contrast administration, the low level and homogeneous enhancement of papillary RCC can help distinguish it from clear cell RCC. With a higher temporal resolution of ~30 s per acquisition, a distinct pattern of enhancement was identified for angiomyolipomas: an early enhancement peak followed by lower-level enhancement. Using a two-compartmental model to analyze the high temporal resolution data, Notohamiprodio et al. estimated perfusion and permeability of renal tumors. These parameters could help differentiate tumor subtypes and identify tumor features such as necrosis and vessel invasion.
Cellular renal lesions, such as RCC, restrict water diffusion in interstitial space, which explains the associated lower ADC values in the lesion compared with normal tissue. Kim et al. found significantly lower ADC values in malignant lesions compared with benign lesions (1.75±0.57 vs. 2.50±0.53 × 10 mm/s). Sandrasegaran et al. found similar results. Taouli et al. reported lower ADC values in Bosniak category 3 and 4 lesions compared with category 1 simple cysts, although a statistically significant difference between Bosniak 2F and 3–4 lesions was not detected. Low ADC values have been shown in the papillary subtype of RCC compared with non-papillary subtypes. Wang et al. found that clear-cell RCCs showed a significantly higher mean ADC (1.85 × 10 mm/s) than papillary (1.09 × 10 mm/s) and chromophobe (1.31 × 10 mm/s) RCCs. ADC has also been reported to be significantly lower in high nuclear-grade (III and IV) than low nuclear-grade (I and II) clear-cell RCCs. With advanced DWI methods, Chandarana et al. showed that DWI has potential in assessing renal tumor cellularity, as well as vascularity, and can help discriminate RCC subtypes.
Acute Kidney Injury
AKI, previously termed as acute renal failure, refers to a rapid and reversible decline of GFR within days or weeks and has recently been defined and classified more specifically by the RIFLE (risk, injury, failure, loss, end stage) criteria. Causes of AKI include renal ischemia and renal parenchymal diseases such as contrast-induced nephropathy and ATN. AKI predisposes the patients to CKDs.
Although DCE MRI with low Gd dose is capable of measuring single-kidney GFR with higher accuracy than serum creatinine, it is typically not used for assessing AKI, as lowered GFR in severe AKI patients could potentially increase the risk of NSF. He et al. developed an innovative non-contrast MRI technique for estimating GFR based on ASL. Although not yet validated against any gold standard, this approach showed a promising 28% increase in the estimated GFR after protein loading, as would be expected. In a rat model of ischemic AKI, Zimmer et al. observed that although their ASL-estimated cortical perfusion was ~30% lower than that from DCE MRI, both were able to differentiate between healthy and AKI cases. Prowle et al. used phase-contrast MRI, a non-contrast MRI method to measure blood flow rate through the renal artery, and found that renal blood flow in ischemic AKI patients was significantly lower than that in normal volunteers (335–1137 vs. 791–1750 ml/min).
Tissue oxygenation is another physiologic parameter of interest for AKI. BOLD MRI enables noninvasive mapping of renal tissue oxygenation for human subjects (section 'BOLD MRI'). Assessment of ATN by BOLD is also discussed in section 'Renal Transplants'. Contrast-induced nephropathy is another form of AKI. Using BOLD and a rat model of contrast-induced nephropathy, Li et al. found that BOLD measurements could detect the effects of viscosity and dose of iodinated contrast on subsequent contrast-induced nephropathy.
Pediatric Kidney Imaging
Congenital anomalies of the kidney and urinary tract are frequent in children. Ultrasonography remains the primary imaging modality to image these disorders. An extension of MRR, MR urography (Figure 5), is increasingly used in practice as a complementary tool, as it can combine exquisite anatomic depiction and functional evaluation in a single examination without radiation exposure. Heavily T2-weighted images allow a complete visualization of the urinary tract in a few seconds (with two-dimensional acquisitions) to few minutes (with three-dimensional acquisitions and respiratory synchronization). With three-dimensional isotropic acquisitions, multiplanar and volumetric reconstructions that are easily understandable for urologists have made intravenous urography obsolete. In addition, the renal parenchyma can be studied in detail: corticomedullary differentiation, thickness, cortical scarring, and cysts.
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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.
In pediatric urology, one of the most challenging issues is to identify whether dilated systems have true obstruction and therefore require surgery. True chronic obstruction is defined in practice by a decrease in the split (differential) renal function on serial functional imaging, such as renal scintigraphy, MRR, or MR urography. Using Gd contrast agents and a tracer compartmental model of analysis, the relative filtration of the parenchyma can be calculated for each side with classical scintigraphic-derived estimates such as the integral method and/or the Rutland–Patlak method. These results have to take into account the volume of renal parenchyma on both sides. As with scintigraphy, many estimates have been developed to assess the drainage, such as the shape of the renograms or transit times. These parameters turned out to be of poor value, and the presence of chronic obstruction remains based on an evolving decrease in split (differential) renal function.