Post-transplant renal injury is a mechanistically complex process that leads to progressive, chronic renal insufficiency and constitutes a major clinical barrier to the short- and long-term success of all organ transplants. There is a strong need for non-invasive, predictive and diagnostic biomarkers that can inform therapeutic decisions for Chronic Allograft Nephropathy/Interstitial Fibrosis with Tubular Atrophy (CAN/IFTA) in kidney recipients, Acute Rejection (AR) in both kidney and non-renal recipients and Chronic Kidney Disease (CKD) in non-renal recipients. In collaboration with Northwestern University (NW), and The Scripps Research Institute (TSRI), Rules-Based Medicine (RBM) proposes a quantitative proteomics approach, using comprehensive Multi-Analyte Profiles (MAPs), to compare the protein profiles in plasma samples obtained from kidney, liver and heart transplant patients and identify both common and unique biomarker signatures and mechanisms of immunity, drug toxicity and the concomitant medical risk factors that drive renal injury. A number of research groups are performing detailed studies to evaluate the expression of individual biomarkers associated with renal injury for use as an objective clinical tool. However, the standard method for measuring plasma or serum levels of cytokines, chemokines or other biomarkers is to measure them one at a time using Enzyme-Linked Immunosorbent Assay. One-at-a-time assessment of each putative biomarker incurs considerable time, cost and sample volume. Clearly, no single molecular marker, or small group of markers, will be able to accurately classify individuals at highest risk. The ability to systematically identify protein profiles, predict risk of clinical events, evaluate therapeutic response, and define underlying mechanisms is thereby limited severely. RBM has developed MAPs to screen large numbers of biomarkers in parallel, using bead-based multiplex immunoassays. This technology provides a quantitative evaluation of protein expression patterns using very small sample volumes (10-20 5L) with a dynamic range of fg/mL to mg/mL. This technology is well suited for screening large numbers of markers in parallel to identify protein profiles associated with renal injury. Using this approach in a recent preliminary study, RBM, NW and TSRI have discovered a protein profile for AR with a 79% Predictive Accuracy, and a profile for CAN/IFTA (Banff 1,2,3) with a 91% Predictive Accuracy. We have also discovered a kidney injury panel that has a 94% Predictive Accuracy for kidney patients with transplant dysfunction due to CAN/IFTA, 82% with biopsy-proven AR and 82% for liver transplant recipients with renal insufficiency due to CNI toxicity, hypertension and metabolic syndromes. In this Fast-Track program, we propose to test, refine and validate these profiles. The goal will be to improve the long-term outcome of recipients of thoracic and abdominal organ transplants by developing novel biomarker patterns that clinicians can use to predict, diagnose and monitor transplant outcomes.
Public Health Relevance: Post-transplant renal injury is a mechanistically complex process that leads to progressive, chronic renal insufficiency and constitutes a major clinical barrier to the short- and long-term success of all organ transplants. This program is designed to investigate what is common and what is unique in the biomarker signatures and mechanisms of immunity, drug toxicity and the concomitant medical risk factors that drive renal injury in kidney, liver and heart transplant patients. The goal will be to improve the long-term outcome of recipients of thoracic and abdominal organ transplants by developing novel biomarker patterns that clinicians can use to predict, diagnose and monitor transplant outcomes.
Public Health Relevance Statement: Project narrative: Post-transplant renal injury is a mechanistically complex process that leads to progressive, chronic renal insufficiency and constitutes a major clinical barrier to the short- and long-term success of all organ transplants. This program is designed to investigate what is common and what is unique in the biomarker signatures and mechanisms of immunity, drug toxicity and the concomitant medical risk factors that drive renal injury in kidney, liver and heart transplant patients. The goal will be to improve the long-term outcome of recipients of thoracic and abdominal organ transplants by developing novel biomarker patterns that clinicians can use to predict, diagnose and monitor transplant outcomes.
Project Terms: 4H-Imidazol-4-one, 2-amino-1,5-dihydro-1-methyl-; Abdomen; Abdominal; Acute; Address; Age; Antirejection Therapy; Atrophic; Atrophy; Benchmarking; Best Practice Analysis; Biopsy; Blood; Blood Plasma; Blood Pressure, High; Blood Proteins; Blood Serum; Body Tissues; CREA; Calcineurin antagonist; Calcineurin inhibitor; Causality; Cell Communication and Signaling; Cell Signaling; Cells; Chest; Chronic; Chronic Allograft Nephropathy; Chronic Kidney Failure; Chronic Kidney Insufficiency; Chronic Renal Disease; Chronic rejection of renal transplant; Clinical; Clinical, Transplantation, Organ; Collaborations; Complex; Complication; Creatinine; Cytokines, Chemotactic; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Drug toxicity; Drugs; Dysfunction; ELISA; Early Diagnosis; Ensure; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Evolution; Face; Fibrosis; Functional disorder; Gender; Goals; Grafting Procedure; Grafting, Heart; Grafting, Kidney; Grafting, Liver; Heart Transplantation; Homologous Chemotactic Cytokines; Hypertension; INFLM; Immune; Immune Targeting; Immunity; Immunoassay; Immunosuppressants; Immunosuppression Effect; Immunosuppressions (Physiology); Immunosuppressive Agents; Immunosuppressive Effect; Immunosuppressive Therapy; Individual; Inflammation; Inflammatory; Infrastructure; Injury; Intercrines; Intracellular Communication and Signaling; Ischemia; Kidney; Kidney Failure; Kidney Failure, Chronic; Kidney Insufficiency; Kidney Transplantation; Kidney Transplants; Laboratories; Literature; Liver; Liver Transplant; Measures; Mediating; Medical; Medication; Medicine; Metabolic syndrome; Methods; Metric; Modeling; Monitor; Natural immunosuppression; Nephrotoxic; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; Outcome; Pain; Painful; Patients; Pattern; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Physiopathology; Plasma; Plasma Proteins; Population Study; Prediabetes; Prediabetes syndrome; Prediabetic State; Predictive Value; Process; Programs (PT); Programs [Publication Type]; Proteins; Proteomics; Protocol; Protocols documentation; Quantitative Evaluations; Renal Failure; Renal Failure, Chronic; Renal Insufficiency; Renal Insufficiency, Chronic; Renal Transplantation; Renal Transplants; Renal function; Reperfusion Therapy; Research; Research Infrastructure; Research Institute; Reticuloendothelial System, Blood; Reticuloendothelial System, Serum, Plasma; Risk; Risk Factors; Running; SBIR; SBIRS (R43/44); SIS cytokines; Safety; Sampling; Science of Medicine; Screening procedure; Sensitivity and Specificity; Serum; Serum, Plasma; Signal Transduction; Signal Transduction Systems; Signaling; Small Business Innovation Research; Small Business Innovation Research Grant; Staging; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic immunosuppression; Therapy, Anti-Rejection; Thorace; Thoracic; Thorax; Time; Tissues; Toxic effect; Toxicities; Transplant Recipients; Transplantation; Transplantation Surgery; Transplantation of liver; Transplantation, Cardiac; Transplantation, Hepatic; Tubular; Tubular formation; Universities; Urinary System, Kidney; Validation; Variant; Variation; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Work; artificial immunosuppression; base; biological signal transduction; biomarker; body system, hepatic; cardiac graft; chemoattractant cytokine; chemokine; chronic kidney disease; cost; cytokine; design; designing; diabetes; disease causation; disease etiology; disease/disorder etiology; disorder etiology; drug/agent; early detection; facial; gene product; heart transplant; high risk; hyperpiesia; hyperpiesis; hypertensive disease; immunosuppression; immunosuppressive; improved; injury prevention; interstitial; intervention therapy; kidney development; kidney function; liver transplantation; minimally invasive; molecular marker; nephrogenesis; nephrotoxicity; novel; organ allograft; organ graft; organ system, hepatic; organ xenograft; pathophysiology; prevent; preventing; programs; prospective; protein expression; protein profiling; public health relevance; renal; reperfusion; response; risk sharing; screening; screenings; success; syndrome x; time use; tool; transplant; transplant patient; validation studies
