Proteomics of Primary Hyperoxaluria Type I: A Rare Calcium Oxalate Stone Disease

The proposed pilot study will be completed through the collaboration of the Rare Kidney Stone Consortium (RKSC), providing de-identified data and urine samples. The goal of this research is to provide insight into little known pathologic mechanisms of a rare autosomal recessive disorder, primary hyperoxaluria type 1 (PH1). This orphan disease results from a mutation of the AGXT gene on chromosome 2q37.3 with consequences of uncontrolled liver oxalate (Ox) production. Although Ox is a normal metabolic by-product and excreted from the body, disproportionately high Ox levels yield highly toxic effects on the kidneys, resulting in calcium Ox nephrolithiasis, advancing nephrocalcinosis and loss of kidney function. As there is poor genotype to phenotype correlation, it is simply not known how quickly most PH1 patients will progress to fulminant kidney failure and systemic oxalosis, depositing calcium Ox crystals throughout the body's organs, causing other end organ damage. With incomplete understanding of its mechanisms, there are limited therapies with only partial efficacy and no real advances in new therapeutics or preventive care have been developed in over 20 years. We will use mass spectrometry to identify and quantitate urine peptides, many of which will be present due to the ongoing disease process in the kidneys. For Aim 1, we will identify urine peptide markers of disease (PH1) and compare those findings to samples from their healthy intra-familial (sibling) controls. To best distinguish differences between the diseased and healthy state, we will control for AGXT mutations, kidney filtering function, urine and plasma Ox levels, medications, and vitamin supplements. Aim 2 will extend our findings, examining the "disease in progress" using PH1 urine samples collected by the RKSC over 5-8 years, determining relative risk for rapid PH1 progression from detected peptides and biopathway patterns. Aim 3’s extensive statistical analyses focuses on peptide patterns, targeting when loss of protective mechanisms of tissue healing and recovery occur as PH1 progresses. Identification, quantitation and classification of peptides and their pathologic mechanisms will provide significant data on PH1 progression in association with known AGXT mutations, allowing for future application of these findings to development of targeted therapeutics to decrease overall disease burden and loss of life.