Renal transplantation is the most desirable and cost effective treatment for end stage renal disease, but 20- 30% of allografts fail in living recipient by 10 years, and prolonging graft health is one of the major unmet needs for transplant patients. Although graft health is extended by preemptive treatments that prevent irreversi- ble damage, intervention is inadequately motivated by current transplant monitoring methods. Noninvasive methods, including changes in serial serum creatinine levels, lack sensitivity and specificity. In the absence of reliable noninvasive biomarkers, invasive biopsy remains the standard for assessing transplant health, but sur- veillance or protocol biopsies are associated with morbidity and cost and are therefore controversial in stable, unsensitized patients. The lack of a demonstrated, noninvasive biomarker for allograft health - one that identi- fies early graft degeneration with sufficient sensitivity and specificity to motivate appropriate biopsy and enable timely intervention - represents a major gap in renal transplant management. To fill this gap, the proposed re- search aims to demonstrate Viscoelastic Response (VisR) ultrasound, a novel acoustic radiation force (ARF)- based technology that noninvasively interrogates the viscoelastic properties of tissue, for monitoring renal allo- graft health. Alternative mechanical ultrasound approaches have shown correlation between renal fibrosis and measured stiffness, but these approaches are inhibited by the heterogeneity and anisotropy of the kidney as well as renal perfusion and urinary pressure. Unlike these methods, VisR estimates viscoelastic property by observing ARF-induced displacements in only the ARF region of excitation, so the disturbing mechanical force is focally distributed, and shear wave disturbances from heterogeneity are not confounding. Further, our pre- liminary data show that a symmetric ARF focal configuration obviates the angle dependence of VisR outcomes in anisotropic tissue. Our preliminary data also demonstrate that VisR delineates fibrosis and inflammation, the presence of which one-year post transplantation has been shown to predict later decline in kidney function and graft failure. Finally, we have demonstrated VisR's potential to impact renal transplant monitoring in a pilot clini- cal feasibility study, which illustrates that VisR distinguishes glomerular disease, moderate-to-severe vascular disease, and chronic allograft nephropathy (CAN) in renal transplant patients undergoing clinically indicated biopsy for suspected graft dysfunction versus control renal transplant recipients not undergoing biopsy. Our body of preliminary data suggests that VisR has strong potential to improve noninvasive monitoring of renal transplant health. We hypothesize that in vivo VisR ultrasound delineates renal allograft dysfunction earlier and with greater sensitivity and specificity than serum creatinine concentration in renal allograft recipients. To test this hypothesis, we will pursue the following specific aims: 1) Demonstrate which VisR outcome metrics are independent of renal pressure and tissue orientation in normal, inflamed and fibrotic pig kidneys; 2) Deter- mine which VisR outcome metrics detect renal allograft dysfunction clinically; and 3) Compare serial VisR and serum creatinine outcomes in terms of ability to detect renal allograft dysfunction and the timeliness of detec- tion. We anticipate that this approach will allow the individual parts of the project to be synergistic withut being interdependent. At the completion of this project, VisR imaging will be poised for a follow-on, larger-scale clini- cal trial to substantiate its usefulness for monitoring renal transplants.
Ten percent of American adults, more than 20 million people, have chronic kidney disease, which in the advanced state of end stage renal disease is most desirably and cost-effectively treated by kidney transplantation. However, 20-30% of transplanted kidneys fail in living recipients by 10 years, owing largely to insufficient monitorin methods. The goal of the proposed research is to improve noninvasive kidney transplant monitoring using a new ultrasound-based imaging method called Viscoelastic Response (VisR) ultrasound.
|Moore, Christopher J; Caughey, Melissa C; Meyer, Diane O et al. (2018) In Vivo Viscoelastic Response (VisR) Ultrasound for Characterizing Mechanical Anisotropy in Lower-Limb Skeletal Muscles of Boys with and without Duchenne Muscular Dystrophy. Ultrasound Med Biol 44:2519-2530|
|Hossain, Md Murad; Levy, Benjamin E; Thapa, Diwash et al. (2018) Blind Source Separation-Based Motion Detector for Imaging Super-Paramagnetic Iron Oxide (SPIO) Particles in Magnetomotive Ultrasound Imaging. IEEE Trans Med Imaging 37:2356-2366|
|Hossain, Md Murad; Selzo, Mallory R; Hinson, Robert M et al. (2018) Evaluating Renal Transplant Status Using Viscoelastic Response (VisR) Ultrasound. Ultrasound Med Biol 44:1573-1584|
|Zhang, Yuqi; Yu, Jicheng; Wang, Jinqiang et al. (2017) Thrombin-Responsive Transcutaneous Patch for Auto-Anticoagulant Regulation. Adv Mater 29:|
|Czernuszewicz, Tomasz J; Homeister, Jonathon W; Caughey, Melissa C et al. (2017) Performance of acoustic radiation force impulse ultrasound imaging for carotid plaque characterization with histologic validation. J Vasc Surg 66:1749-1757.e3|
|Czernuszewicz, Tomasz J; Gallippi, Caterina M (2016) On the Feasibility of Quantifying Fibrous Cap Thickness With Acoustic Radiation Force Impulse (ARFI) Ultrasound. IEEE Trans Ultrason Ferroelectr Freq Control 63:1262-75|
|Geist, Rebecca E; DuBois, Chase H; Nichols, Timothy C et al. (2016) Experimental Validation of ARFI Surveillance of Subcutaneous Hemorrhage (ASSH) Using Calibrated Infusions in a Tissue-Mimicking Model and Dogs. Ultrason Imaging 38:346-58|
|Hossain, Md Murad; Thapa, Diwash; Sierchio, Justin et al. (2016) Blind Source Separation - Based Motion Detector for Sub-Micrometer, Periodic Displacement in Ultrasonic Imaging. IEEE Int Ultrason Symp 2016:|
|Selzo, Mallory R; Moore, Christopher J; Hossain, Md Murad et al. (2016) On the Quantitative Potential of Viscoelastic Response (VisR) Ultrasound Using the One-Dimensional Mass-Spring-Damper Model. IEEE Trans Ultrason Ferroelectr Freq Control 63:1276-87|
|Wang, Zhuochen; Li, Sibo; Czernuszewicz, Tomasz J et al. (2016) Design, Fabrication, and Characterization of a Bifrequency Colinear Array. IEEE Trans Ultrason Ferroelectr Freq Control 63:266-74|