Prevention of Renal Damage in Primary Hyperoxaluria

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DESCRIPTION (provided by applicant): Primary hyperoxaluria (PH) is a rare autosomal recessive disorder (estimated incidence 1:120,000 births). While most patients experience nephrocalcinosis and/or repeated episodes of urolithiasis in childhood, some develop renal failure as early as infancy while others first present as adults with urolithiasis only. The reasons for such disparity are largely unknown. However, the majority, if not all, PH patients eventually lose renal function and require renal transplantation with liver transplantation also needed in most. There is an urgent need for identification of factors responsible for severe disease expression, and for effective treatments. Progress in understanding the pathophysiology of hyperoxaluria and associated renal injury and in development of effective treatments, has been slowed by the rarity of this condition. The overall objective of this grant is to pool patient experience in order to identify factors associated with disease progression in PH, modify them using specific treatment strategies in patients at risk, and demonstrate reduction in renal injury. We have assembled a unique group of physicians and scientists with longstanding interest in PH. Recently we developed a secure, web-based registry as a key tool to facilitate this work. Our goal is to improve diagnosis, treatment, and quality of life for these patients by the following SPECIFIC AIMS: 1) Develop and expand an international disease registry for patients with PH; 2) Define an expanded metabolic phenotype of PH patients; 3) Employ innovative imaging modalities to more accurately detect and quantify disease progression; 4) Determine if urinary levels of retinol binding protein, a- 1 microglobulin, transforming growth factor (TGF)(31, and v-Glutamyltransferase (GGT) are sensitive markers of ongoing renal damage, can serve as surrogate markers of disease progression, and are reduced by angiotensin blockade; and 5) Application of pharmacogenomics to guide PH treatment. The Registry will allow development of consensus, evidence-based diagnosis and management guidelines. Clinical data, samples, and research protocols completed via the Registry will allow rapid testing of hypotheses and promote worldwide collaboration to advance the care of PH patients.