300 words Four inborn errors of metabolism lead to high concentrations of insoluble mineral salts in the urine and severe, recurrent nephrolithiasis. Patients with primary hyperoxaluria (PH), cystinuria, APRT deficiency (dihydroxyadeninuria, DMA), and Dent disease experience stones beginning in childhood. Deposition of crystals in kidney tissue and loss of kidney function is observed in all. Disease expression varies widely. Some PH patients, for example, progress to end stage renal failure during infancy, while others maintain kidney function until middle age. This variability is poorly understood. Modifiers of disease expression, if identified, offer promise as potential new treatment strategies. Yet progress toward effective treatment has been slow. Small numbers of widely scattered patients make rigorous characterization and longitudinal assessment of disease expression difficult. The ability to test efficacy of new treatments is limited since few patients are available for clinical trials. To address this problem, we will build on previous, successful work of the International Primary Hyperoxaluria Registry (IPHR) to expand the IPHR and establish secure, web-based registries and tissue banks for cystinuria, DHA, and Dent disease. Longitudinal studies of individual patients conducted in each disease will emphasize generation of testable hypotheses and identification of well characterized cohorts of patients for future clinical trials. All four diseases appear mediated by renal deposition of crystals, and the cellular response, which in turn, appears modulated by urinary protein inhibitors. Therefore, there is great potential for synergy to understand the impact of the urinary proteome and renal cell biology in disease progression. An outstanding consortium of clinical scientists with unique expertise and access to patient with these diagnoses will address this work. Multidisciplinary collaboration will occur through joint activities with the relevant patient support organizations, regular communications among Consortium members, and open sharing of newly developed resources with patients, members of the medical community and scientists.
The Consortium for Hereditary Causes of Nephrolithiasis and Renal Failure is highly suited to accomplish the characterization and longitudinal assessment needed to facilitate discovery of biomarkers of disease risk, disease activity, and response to therapy for four rare diseases that share similar mechanisms and severe disease manifestations. This work will address barriers of rare diseases research through vigorous multidisciplinary cooperation.
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