Emily H. Chang

Self-reported gadolinium toxicity: A survey of patients with chronic symptoms

PURPOSE This study aims to describe the self-reporting symptoms experienced by individuals with self-reported normal renal function after gadolinium based contrast agent (GBCA) administration. MATERIALS AND METHODS This HIPAA-compliant, IRB-approved study consisted of an anonymous online survey of patients who believe that they suffer from gadolinium toxicity. 50 respondents completed the nine-question survey. RESULTS Fifty (100%) of the subjects ascribed their complaints to gadolinium exposure. Thirty-three (66%) described the onset immediately following GBCA administration and 16 (32%) within 6weeks. The most common symptoms included bone/joint pain and head/neck symptoms including headache, vision change, and hearing change (77.6% each). Other symptoms occurred with lesser incidence. CONCLUSIONS This survey represents an initial description of patients with normal renal function who self-described toxicity related to GBCA administration. Bone and joint complaints and skin changes are two of the most common complaints.

Management of Indeterminate Cystic Kidney Lesions: Review of Contrast-enhanced Ultrasound as a Diagnostic Tool

Indeterminate cystic kidney lesions found incidentally are an increasingly prevalent diagnostic challenge. Standard workup includes Bosniak classification with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). However, these tests are costly and not without risks. Contrast-enhanced ultrasound (CEUS) is a relatively new technique with lower risk of adverse events than iodine-containing contrast or gadolinium. In our review of the evidence for characterization of cystic kidney lesions with CEUS, CEUS displayed sensitivity (89%-100%) and negative predictive value (86%-100%) comparable to contrast-enhanced CT or MRI, with no decrease in specificity compared with CT and only a slight decrease compared with MRI.

Palladin expression is a conserved characteristic of the desmoplastic tumor microenvironment and contributes to altered gene expression

The stroma surrounding solid tumors contributes in complex ways to tumor progression. Cancer‐associated fibroblasts (CAFs) are the predominant cell type in the tumor stroma. Previous studies have shown that the actin‐binding protein palladin is highly expressed in the stroma of pancreas tumors, but the interpretation of these results is complicated by the fact that palladin exists as multiple isoforms. In the current study, the expression and localization of palladin isoform 4 was examined in normal specimens and adenocarcinomas of human pancreas, lung, colon, and stomach samples. Immunohistochemistry with isoform‐selective antibodies revealed that expression of palladin isoform 4 was higher in adenocarcinomas versus normal tissues, and highest in CAFs. Immunohistochemistry staining revealed that palladin was present in both the cytoplasm and the nucleus of CAFs, and this was confirmed using immunofluorescence staining and subcellular fractionation of a pancreatic CAF cell line. To investigate the functional significance of nuclear palladin, RNA Seq analysis of palladin knockdown CAFs versus control CAFs was performed, and the results showed that palladin regulates the expression of genes involved in the biosynthesis and assembly of collagen, and organization of the extracellular matrix. These results suggested that palladin isoform 4 may play a conserved role in establishing the phenotype of CAFs in multiple tumor types.

A Pilot Clinical Study in Characterization of Malignant Renal-cell Carcinoma Subtype with Contrast-enhanced Ultrasound

Malignant renal cell carcinoma (RCC) is a diverse set of diseases, which are independently difficult to characterize using conventional MRI and CT protocols due to low temporal resolution to study perfusion characteristics. Because different disease subtypes have different prognoses and involve varying treatment regimens, the ability to determine RCC subtype non-invasively is a clinical need. Contrast-enhanced ultrasound (CEUS) has been assessed as a tool to characterize kidney lesions based on qualitative and quantitative assessment of perfusion patterns, and we hypothesize that this technique might help differentiate disease subtypes. Twelve patients with RCC confirmed pathologically were imaged using contrast-enhanced ultrasound. Time intensity curves were generated and analyzed quantitatively using 10 characteristic metrics. Results showed that peak intensity (p = 0.001) and time-to-80% on wash-out (p = 0.004) provided significant differences between clear cell, papillary, and chromophobe RCC subtypes. These results suggest that CEUS may be a feasible test for characterizing RCC subtypes.

Palladin is Upregulated in Kidney Disease and Contributes to Epithelial Cell Migration After Injury

Recovery from acute kidney injury involving tubular epithelial cells requires proliferation and migration of healthy cells to the area of injury. In this study, we show that palladin, a previously characterized cytoskeletal protein, is upregulated in injured tubules and suggest that one of its functions during repair is to facilitate migration of remaining cells to the affected site. In a mouse model of anti-neutrophilic cytoplasmic antibody involving both tubular and glomerular disease, palladin is upregulated in injured tubular cells, crescents and capillary cells with angiitis. In human biopsies of kidneys from patients with other kidney diseases, palladin is also upregulated in crescents and injured tubules. In LLC-PK1 cells, a porcine proximal tubule cell line, stress induced by transforming growth factor-β1 (TGF-β1) leads to palladin upregulation. Knockdown of palladin in LLC-PK1 does not disrupt cell morphology but does lead to a defect in cell migration. Furthermore, TGF-β1 induced increase in the 75 kDa palladin isoform occurs in both the nucleus and the cytoplasm. These data suggest that palladin expression is induced in injured cells and contributes to proper migration of cells in proximal tubules, possibly by regulation of gene expression as part of the healing process after acute injury.

Diagnostic accuracy of contrast-enhanced ultrasound for characterization of kidney lesions in patients with and without chronic kidney disease

BackgroundPatients with chronic kidney disease are at increased risk of cystic kidney disease that requires imaging monitoring in many cases. However, these same patients often have contraindications to contrast-enhanced computed tomography and magnetic resonance imaging. This study evaluates the accuracy of contrast-enhanced ultrasound (CEUS), which is safe for patients with chronic kidney disease, for the characterization of kidney lesions in patients with and without chronic kidney disease.MethodsWe performed CEUS on 44 patients, both with and without chronic kidney disease, with indeterminate or suspicious kidney lesions (both cystic and solid). Two masked radiologists categorized lesions using CEUS images according to contrast-enhanced ultrasound adapted criteria. CEUS designation was compared to histology or follow-up imaging in cases without available tissue in all patients and the subset with chronic kidney disease to determine sensitivity, specificity and overall accuracy.ResultsAcross all patients, CEUS had a sensitivity of 96% (95% CI: 84%, 99%) and specificity of 50% (95% CI: 32%, 68%) for detecting malignancy. Among patients with chronic kidney disease, CEUS sensitivity was 90% (95% CI: 56%, 98%), and specificity was 55% (95% CI: 36%, 73%).ConclusionsCEUS has high sensitivity for identifying malignancy of kidney lesions. However, because specificity is low, modifications to the classification scheme for contrast-enhanced ultrasound could be considered as a way to improve contrast-enhanced ultrasound specificity and thus overall performance. Due to its sensitivity, among patients with chronic kidney disease or other contrast contraindications, CEUS has potential as an imaging test to rule out malignancy.Trial registrationThis trial was registered in clinicaltrials.gov, NCT01751529.

In vivo mechanical anisotropy assessment in renal cortex using ARFI peak displacement

The kidney is an anisotropic organ, with higher elasticity along versus across nephrons. The degree of elastic anisotropy in kidney may be diagnostically relevant if properly exploited; however, if improperly controlled, anisotropy may confound stiffness measurements. The purpose of this study is to demonstrate a novel method for selectively exploiting or obviating elastic anisotropy in kidney using Acoustic Radiation Force Impulse (ARFI)-induced peak displacement (PD). The kidneys of three pigs were imaged in vivo at baseline, with venous ligation, and with arterial ligation, and then kidneys were extracted and imaged ex vivo. Imaging was performed with ARF excitation impulses having F/1.5 or F/5.0 focal configurations, and data were acquired with the transducer oriented along and across nephrons alignment in the renal cortex. In addition to ARFI PD, shear wave velocity was measured along and across nephrons to estimate longitudinal and transverse shear elastic moduli. Elastic anisotropy was then assessed as the ratio of PD across versus along nephrons, and as the ratio of shear moduli along versus across nephrons. PD ratio using the F/1.5 ARF linearly correlated with shear moduli ratio (R2 = 0.95). However, PD ratio using the F/5.0 ARF was approximately 1.0 and had weak correlation to shear moduli ratio (R2= 0.56). Further, the average difference in PD measured along versus across nephrons was 2.91 μm for the F/1.5 ARF but was 0.2 μm for the F/5.0 ARF. These results suggest that the F/1.5 ARF excitation exploited elastic anisotropy in the renal cortex, while the F/5.0 ARF excitation obviated it.

In vivo mechanical anisotropy assessment in renal parenchyma using ARFI peak displacement

Renal parenchyma is strongly anisotropic; mechanical properties differ along versus across nephron alignment. In this work, the feasibility of interrogating such directional differences in mechanical property using ARFI is investigated. We hypothesize that: 1) the ratio of ARFI peak displacements (PDs) achieved with the long axis of an asymmetrical ARF PSF oriented along versus across nephron alignment reflects the mechanical degree of anisotropy (DoA); and 2) directional differences in parenchymal mechanical property are detected when using an asymmetrical ARF PSF but obviated when using a symmetrical ARF PSF.

Contrast-enhanced ultrasound (CEUS) in patients with chronic kidney disease (CKD)

Microbubble based contrast-enhanced ultrasound (CEUS) enables the visualization of vascularity given the tendency of microbubbles to function as a blood pooling agent. Using contrast specific ultrasound (US) imaging, it is possible to quantify the kinetics of these agents and derive various perfusion metrics. In this ongoing clinical study, we evaluate the feasibility of using these microbubble based contrast agents (CA) to develop qualitative and quantitative measures of perfusion in patients with chronic kidney disease (CKD). CEUS imaging may provide information about kidney perfusion that will aid in early diagnosis, disease progression and response to therapy. Patients (n = 63) with CKD and 3 healthy controls were imaged using CEUS. Imaging was performed on a Sequoia 512 (Siemens Healthcare) by trained sonographers using a 4C1 transducer (1–4 MHz). Definity (Lantheus Medical Imaging) was administered to the patient as a continuous IV infusion based on recommended dosage guidelines. Multiple sequences of microbubble flash-replenishment were used to generate signal intensity versus time (TIC) curves for specific regions of interest (ROIs). Maximum intensity projections (MIPs) and perfusion maps were also generated based on flash-replenishment cine sequences. Flow rate (β) based on the slope of the TIC was compared with CKD staging to study the correlation between the metrics. Preliminary evaluation of the perfusion maps showed a marked difference between the healthy controls and CKD patients. Significant correlations (r2=0.20, p=0.03) and (r2=0.16, p<0.01) were found between β and CKD stage by selecting ROIs defined by the whole kidney and in the parenchyma respectively. In this preliminary study, CEUS of CKD patients is shown to be feasible and is able to generate quantitative metrics of perfusion. The diagnostic accuracy of these metrics is yet to be determined.

In vivo bioeffects from phase change and microbubble contrast agents in the rodent kidney: Short term and long-term effects after excitation with a range of mechanical indices

Both microbubble (MB) and phase-change nanodroplet (ND) contrast technology has the potential to enhance ultrasound imaging. However, prior studies have indicated the potential of hemorrhagic bioeffects immediately after sonicating contrast-infused tissue with the low-frequency, high amplitude acoustic energy. To date, little has been reported for NDs or regarding long-term bioeffects of either agent. In this study, we performed short-term experiments to look for bioeffects from MB destruction and ND activation events. We also extended our examination to two weeks post-sonication to explore recovery from cavitation induced bioeffects.