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Principal Investigator: Caterina M Gallippi
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $656,400
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
For the 786,000 people in the United States living with end stage renal disease (ESRD), the treatment of
choice is kidney transplantation. While transplant life has subtly increased over the last 15 years, ten-year graft
survival rates are only 28% for deceased-donor and 46% for living-donor grafts. The primary cause of graft
failure after the first year is antibody-mediated rejection (AMR), the detrimental impacts of which are
compounded by concurrent fibrosis. Thus, there is an urgent yet unmet need to prolong graft life by
remediating AMR prior to extensive fibrotic changes and other severe, irreversible graft damage. Therapeutic
interventions to remediate AMR are not FDA approved or clinically standardized due to their inconsistent and
often suboptimal performances. Promising treatment protocols are in development, but their translation to
clinical trials will require frequent monitoring of AMR response that cannot be supported by the current
evaluation standard, invasive biopsy, due to its associated safety risks. A safer alternative involves tracking
surrogate serum and urine biomarkers, but these markers are nonspecific with unclear diagnostic thresholds,
and measurable fluctuations in their values may occur well after underlying pathological changes to the
allograft. Another safe alternative to biopsy is imaging, most often ultrasound, which also indicates AMR
nonspecifically. The lack of a noninvasive and specific method for detecting AMR and routinely monitoring its
response to treatment in renal transplant patients represents a major gap in prolonging graft life. To fill this
gap, our group has spent the first five-year cycle of this grant award developing noninvasive Viscoelastic
Response (VisR) ultrasound for monitoring renal transplant status. Our research has demonstrated that in vivo
VisR assessments of elastic and viscous differences across the medulla and cortex, as well as medullary and
cortical elastic and viscous anisotropy, delineate renal inflammation and fibrosis in a pig model. Further, in a
pilot clinical feasibility study, our research has shown that in vivo VisR differentiates biopsy-confirmed
tubulointerstitial fibrosis in the allografts of human patients imaged serially from time of implantation. The
success of our investigations thus far motivates further advancement of VisR technology and its extension to
noninvasively detecting and monitoring AMR. Specifically, we will augment the VisR methods developed in the
first funding cycle with a new approach to anisotropy measurement (angle interpolation) and a new imaging
method (Double Profile Intersection (DoPIo) ultrasound) to improve the sensitivity and specificity of detecting
inflammation, a hallmark of AMR. We will apply the advanced VisR and DoPIo methods to identifying AMR and
monitoring its response to treatment in human renal transplant patients. We hypothesize that advanced VisR
and DoPIo ultrasound delineate biopsy-confirmed inflammation associated with AMR in human renal transplant
patients, in vivo, which is relevant to noninvasively monitoring response to AMR treatment.
Terms: <Allografting><Anisotropy><Antibodies><Award><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Biological Markers><Biopsy><Blood Serum><Blood Vessels><Chronic><Clinical><Clinical Trials><Creatinine><Detection><Development><Diagnostic><ESRD><Early Diagnosis><Echography><Echotomography><Elasticity><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Evaluation><Feasibility Studies><Fibrosis><Food and Drug Administration><Funding><Goals><Graft Survival><Grant><Human><IGIV><IV Immunoglobulins><IVIG><Image><Immune globulin IV><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Inflammation><Intervention><Intervention Strategies><Intravenous Antibodies><Intravenous IG><Intravenous Immune Globulin><Intravenous Immunoglobulins><Investigation><Kidney><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><Leanness><Life><Living Donors><Measurable><Measurement><Measures><Mechanics><Mediating><Medical Ultrasound><Methods><Modern Man><Monitor><Non-Invasive Detection><Noninvasive Detection><Operative Procedures><Operative Surgical Procedures><Outcome><Pathologic><Patient imaging><Performance><Persons><Physiologic pulse><Plasmapheresis><Proteinuria><Protocol><Protocols documentation><Public Health><Pulse><Renal Grafting><Renal Transplantation><Renal Transplants><Research><Research Design><Resistance><Risk><Risk Factors><Safety><Sampling><Sensitivity and Specificity><Serum><Standardization><Steroid Compound><Steroids><Study Type><Surgical><Surgical Interventions><Surgical Procedure><Surrogate Markers><Survival Rate><T-Cells><T-Lymphocyte><Technology><Therapeutic Intervention><Therapeutic Plasma Exchange><Therapeutic Plasmapheresis><Thinness><Time><Translations><Transplant Recipients><Transplantation><Treatment Protocols><Treatment Regimen><Treatment Schedule><USFDA><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><United States><United States Food and Drug Administration><Urine><Variant><Variation><Viscosity><Work><antibody based detection><antibody detection><antibody rejection><antibody-mediated rejection><bio-markers><biologic marker><biomarker><detect antibodies><detection method><detection procedure><detection technique><developmental><diagnostic ultrasound><donor antibodies><donor-specific antibody><early detection><graft dysfunction><graft failure><image-based method><imaging><imaging method><imaging modality><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><implantation><improved><in vivo><in vivo Model><indexing><intervention therapy><interventional strategy><kidney tx><longitudinal imaging><mechanic><mechanical><new approaches><non-invasive monitor><noninvasive monitor><novel approaches><novel strategies><novel strategy><pig model><piglet model><porcine model><remediation><renal><resistant><response><response to therapy><response to treatment><serial imaging><sonogram><sonography><sound measurement><study design><success><surgery><surrogate bio-markers><surrogate biomarkers><swine model><therapeutic response><therapy response><thymus derived lymphocyte><translation><transplant><transplant patient><treatment choice><treatment response><treatment responsiveness><ultrasound><ultrasound imaging><ultrasound scanning><vascular><viscoelasticity>