Nephrolithiasis and Kidney Failure: the Rare Kidney Stone Consortium

The proposed study will be completed through collaboration with the Rare Kidney Stone Consortium (RKSC). 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 an AGXT gene mutation on chromosome 2q37.3, causing uncontrolled liver oxalate (Ox) production. Ox is a normal metabolic by-product and is excreted from the body but disproportionately high Ox levels are highly toxic to the kidneys, resulting in calcium Ox nephrolithiasis, advancing nephrocalcinosis and loss of kidney function. Due to poor genotype to phenotype correlation, it is simply not known how quickly most PH1 patients will progress to 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, limited therapies with only partial efficacy are available and no real advances in new therapeutics or preventive care have occurred in over 20 years. We will use mass spectrometry to identify and quantitate urine peptides, many of which will be present due to the disease process in the kidneys. For Aim 1, we will identify urine peptide markers of disease (PH1), comparing those findings to samples from their healthy 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 examines the "disease in progress"; using PH1 urine samples collected over 5-8 years by the RKSC, determining relative risk for rapid PH1 progression from detected peptides and their biopathways. 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 will provide important data on PH1 progression in association with known AGXT mutations, allowing for future application of these findings to develop targeted therapeutics towards decreasing overall disease burden and loss of life.