RENAL FIBROSIS in Ultrasound Elastography

Extracted from

Theranostics. 2017 Mar 7;7(5):1303-1329. doi: 10.7150/thno.18650. eCollection 2017. Ultrasound Elastography: Review of Techniques and Clinical Applications

Renal Fibrosis

Chronic kidney disease (CKD) in native kidneys and interstitial fibrosis in allograft kidneys are the two major kidney fibrotic pathologies where USE may be clinically useful. Both these conditions can lead to extensive morbidity, mortality, and high health care costs. CKD is a prevalent pathology affecting approximately 14% of the population [98] and it can progress to end-stage renal disease requiring dialysis or renal transplant. Allograft renal interstitial disease can lead to renal transplant failure. Currently, biopsy is the standard method for renal fibrosis staging. Ultrasound elastography methods of strain imaging and SWI can potentially be useful to noninvasively detect, stage and monitor renal fibrosis, reducing the need for renal biopsy [99]. The superficial location of allograft kidneys allows assessment by strain imaging. Orlacchio et al. evaluated 50 patients with allograft kidneys by SE (Philips) and compared USE results with the degree of histopathologic fibrosis (F1=mild, F2=moderate, F3=severe). SE was shown to be useful for predicting fibrosis in renal transplant patients, mainly for F2-F3 cases, with overall accuracy of 95%. Sensitivity, specificity, PPV and NPV were 85.7%, 95.5%, 96% and 84% respectively (using a tissue mean elasticity cut-off value of 46 a.u. – arbitrary units) to diagnose F2-F3 [100]. Strain imaging has also been used to assess native kidneys, although the difficulty of applying external compression to the native kidney in the retroperitoneal location can limit the accuracy of strain elastograms [99]. Menzilcioglu et al. used SE to compare native kidneys in patients with and without CKD. They found the mean strain index value of renal parenchyma in CKD patients (1.81±0.88) was significantly higher than in healthy individuals (0.42±0.30) (p under 0.001). However, SE was not able to distinguish between different stages of CKD (Table 4, [101]). SWI is advantageous to strain imaging in evaluating kidney fibrosis in both allograft and native kidneys since it does not depend on external compression [99]. The majority of studies using SWI to evaluate CKD (Table 4, [102-105]) have shown that the shear wave velocity of the renal parenchyma of CKD patients was significantly lower than in normal patients. Furthermore, studies have shown significant correlations between shear wave velocity and biochemical parameters of CKD. For example, Guo et al used VTQ/ARFI to show that shear wave velocity correlated significantly with estimated glomerular filtration rate, urea nitrogen and serum creatinine (Table 4,[105]), and Hu et al concluded that shear wave velocity correlated significantly with serum creatinine and glomerular filtration rate (Table 4, [103]). In contrast to the above promising results, Wang et al. used VTQ/ARFI to assess 45 patients with CKD referred for renal biopsy and concluded that shear wave velocity measurements did not correlate with any histologic indicators of fibrosis (glomerular sclerosis index, tubular atrophy, interstitial fibrosis) and could not distinguish between CKD stages (Table 4, [106]). Interestingly in SWI of kidney fibrosis, a negative correlation has been reported between shear wave velocity and the progression of CKD. For example, Bob et al. showed that the shear wave velocity decreased with increasing CKD stage (Table 4, [104]). This is supported by other studies that found significantly decreased shear wave velocity in CKD compared to normal kidneys (Table 4 [103, 105]). These findings are opposite to SWI findings in liver fibrosis, where increasing liver fibrosis corresponds to increasing shear wave velocity. The reason for this difference remains unclear. Asano et al. hypothesized that the decreased renal blood flow in patients with CKD reduces kidney stiffness, resulting in decreased shear wave velocities [107].

Limitations of Renal Ultrasound Elastography

The kidney has many unique properties that limit use of USE:
- The retroperitoneal position of native kidneys impairs the application of external compression.
- The kidney’s complex architecture and high tissue anisotropy can influence shear wave velocity. Anatomically, the renal cortex is not organized in linear structures since glomeruli are spherical and proximal/distal tubes have convoluted shape. The medulla consists of the loops of Henle, the vasa recta and the collecting ducts, which have a parallel orientation spanning from the renal capsule to the papilla. When the ARFI pulses are sent parallel to these anatomic structures, shear waves propagate perpendicular to them, creating various tubular and vascular interfaces, decreasing the shear wave velocity, thus, lowering elasticity values. Conversely, when the ARFI pulse is sent perpendicular to these structures, shear waves propagate parallel to them, without any interfaces, increasing their velocities and resulting in higher elasticity values [114]. As shown by Ries et al in a MR imaging-diffusion experiment, anisotropy is 40% in the medulla and 22% in the cortex [115], since the cortex anatomy is not organized in linear structures. Another study used in vivo SWI and also demonstrated higher anisotropy in the medulla than in the inner and outer cortex: 31.8%,29.7% and 10.5% respectively [116]. This suggests SWS measurements are more reliable in the cortex than the medulla.
- The kidney has an outer fibrous covering,  similar to the liver’s Glisson’s capsule, making any stiffness measurements sensitive to blood and urinary pressure [99]. The effects of blood flow on kidney stiffness was demonstrated by an in vivo study where ligation of the renal artery produced a decrease in renal elasticity, conversely, the ligation of the renal vein increased renal elasticity [116]. In this same study, urinary pressure was found to have a strong effect on elasticity measurements in the kidneys.

In summary, USE in both allograft and native kidneys has shown encouraging results in the detection of fibrosis, potentially providing a low-cost, non-invasive imaging alternative to renal biopsy. However, USE has not been reliable in differentiating between stages of CKD [101, 105] or grading fibrosis in transplanted kidneys [117]. Also, the reported negative correlation between shear wave velocity and the progression of CKD is poorly understood. Further work is needed with larger numbers of patients to evaluate renal fibrosis staging and to understand the relationship between the progression of fibrosis and kidney shear wave velocity. Also, only a few studies have used USE to characterize focal renal masses (primarily AML vs RCC) with controversial results so far using existing technology.