Primary hyperoxaluria, type 1 (PH1) is a rare, monogenic disorder in which a mutation in the AGXT gene leads to overproduction of oxalate by the liver, resulting in widespread deposition of calcium oxalate in the kidneys and other organs. Unfortunately, PH1 disease progression is not understood. Despite identification of the AGTX mutation, there is little genotype-phenotype correlation in these patients, with kidney stone formation and loss of kidney function proceeding in a seemingly haphazard fashion. Many patients may progress to end- stage kidney disease (ESKD), despite current supportive therapy. An objective diagnostic that accurately detects PH1 and identifies individuals at high risk for rapid progression to ESKD is an unmet clinical need. Clearly, no single molecular marker, or small group of markers, will be able to meet this need. Common proteomic technologies, such as Enzyme-Linked Immunosorbent Assay (ELISA), lack the ability to quantify multiple biomarkers simultaneously. One-at-a-time assessment of each putative biomarker incurs considerable time, cost and sample volume. Newer technologies lack sensitivity, precision and automation. The ability to systematically identify protein profiles, predict risk of clinical events, evaluate therapeutic response, and define underlying mechanisms is thereby limited severely. Rules-Based Medicine (RBM) resolved these limitations by developing bead-based, multiplexed immunoassays for identifying disease-specific Multi-Analyte Profiles (MAPs). Exciting preliminary data indicates that MAP technology is well suited for screening large numbers of markers in parallel to identify protein profiles associated with PH1, and may provide insight into the disease course. During Phase I, RBM, and Children's Memorial Hospital (CMH) propose to utilize this quantitative proteomics approach to compare the protein profiles in urine samples obtained from patients diagnosed with PH1 vs. age- and gender-matched control populations. The level and pattern of expression for 201 proteins will be studied. It is expected that the physiological insight obtained from the proposed study may be used to better define the pathological mechanisms associated with PH1. During Phase II, a prospective validation of the MAP identified for PH1 during Phase I efforts will be performed. The sensitivity, specificity,and positive and negative predictive values for each analyte, as well as, the MAP of biomarkers for predicting progression of the disease to ESKD will be determined. In addition, a proposed physiological range of MAP analytes for children and adolescents will be developed based on age, and gender for both the normal and PH1 populations. Such range values, typically used for diagnosis and intervention, can be used as a reference for future studies and for the development of both a diagnostic test and therapeutic algorithms. The identification of novel biomarker patterns of individuals with PH1, as well as, individuals at high risk for rapid progression to ESKD, will allow for improved management of the condition by objective selection of treatment course or dosage, determining treatment effectiveness, and providing a framework for developing and evaluating new treatments.
Public Health Relevance: Primary hyperoxaluria, type 1 (PH1) is a rare, genetic disorder that leads to widespread deposition of calcium oxalate stones in the kidneys and other organs. Unfortunately, PH1 disease progression is not understood, and many patients may progress to end-stage kidney disease, despite therapy. The identification of novel biomarker patterns of individuals with PH1 as well as, individuals at high risk for progression to end-stage kidney disease, will allow for improved management of the condition by objective selection of treatment course, aiding the determination of treatment dosage and/or effectiveness, and providing a framework for developing and evaluating new treatments.
Public Health Relevance Statement: Project narrative: Primary hyperoxaluria, type 1 (PH1) is a rare, genetic disorder that leads to widespread deposition of calcium oxalate stones in the kidneys and other organs. Unfortunately, PH1 disease progression is not understood, and many patients may progress to end-stage kidney disease, despite therapy. The identification of novel biomarker patterns of individuals with PH1 as well as, individuals at high risk for progression to end-stage kidney disease, will allow for improved management of the condition by objective selection of treatment course, aiding the determination of treatment dosage and/or effectiveness, and providing a framework for developing and evaluating new treatments.
NIH Spending Category: Clinical Research; Kidney Disease; Pediatric; Urologic Diseases
Project Terms: 0-11 years old; Adolescent; Adolescent Youth; Age; Algorithms; Archives; Automation; Biliary or Urinary Stones; Calcium Oxalate; Calculi; Causality; Chicago; Child; Child Youth; Childhood; Children (0-21); Citrates; Clinical; Clinical Management; Collaborations; Data; Deposit; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Disorder; ELISA; ESRD; Effectiveness; End stage renal failure; End-Stage Kidney Disease; Ensure; Enzyme-Linked Immunosorbent Assay; Ethanedioic acid, calcium salt; Etiology; Event; Forecast of outcome; Future; Gender; Genes; Genetic Alteration; Genetic Change; Genetic Condition; Genetic Diseases; Genetic defect; Genotype; HOSP; Hereditary Disease; Hospitals; Hour; Human, Child; Hyperoxaluria, Primary; Immunoassay; Individual; Intervention; Intervention Strategies; Kidney; Kidney Calculi; Kidney Stones; Laboratories; Life; Liver; Measures; Medicine; Modeling; Molecular Disease; Mutation; Organ; Oxalates; Patients; Pattern; Phase; Phenotype; Physiologic; Physiological; Population; Population Control; Predictive Value; Primary Hyperoxaluria; Primary Hyperoxalurias; Prognosis; Proteins; Proteomics; Rare Diseases; Rare Disorder; Registries; Relative Risks; Renal Calculi; Renal Disease, End-Stage; Renal Stone; Renal function; Research Specimen; Resource Development; Risk; Sampling; Science of Medicine; Scientist; Screening procedure; Selection for Treatments; Sensitivity and Specificity; Siblings; Specimen; Stone; Supportive Therapy; Supportive care; Technology; Therapeutic; Time; Treatment Effectiveness; Universities; Urinary System, Kidney; Urinary System, Urine; Urine; Validation; Variant; Variation; age effect; aging effect; base; biomarker; body system, hepatic; children; clinical Diagnosis; cohort; cost; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; dosage; gene product; genetic disorder; genome mutation; hereditary disorder; high risk; hypercalcinuria; hypercalciuria; hypercalciuric; improved; insight; interventional strategy; juvenile; juvenile human; kidney function; medical schools; meetings; molecular marker; nephrolith; new technology; novel; organ system, hepatic; outcome forecast; pediatric; pediatric department; prospective; protein expression; protein profiling; public health relevance; renal; response; screening; screenings; time use; validation studies; youngster
