NIH (NIDDK) P20 Funded Center Grant Renewed: Optimizing Kidney Stone Management Using Metallomics and Metabolomics

Presently, stone analysis has little impact in directing clinical decision making; it remains rudimentary, unreliable, and unreproducible. Traditional 24-hour urine testing does not correctly predict future stone events and thus has limited utility in preventing stone recurrence.

 

In this proposal renewal we plan to validate novel metallomic and metabolomics profiling on human stones and urine at our Analytic Core Facilities found during our previously funded P20 efforts. These combined results will facilitate identification of core metal and small molecule biomarkers to develop practical diagnostic and therapeutic tools. Our work will create a much-needed modern resource for the broader urology community and provide the necessary scientific foundation to launch future intervention studies in patients with recurrent kidney stone disease.

Our P20 Center will expand our hub of interdisciplinary research, leveraging our ongoing collaborations with the Buck Institute for Research on Aging, the Children’s Hospital of Oakland Research Institute, the Dentistry Department at UCSF, the Veterinary School of Medicine at UC Davis, the Materials Science and Mechanical Engineering Departments at UC Berkeley, the National Center of Electron Microscopy at the Lawrence Berkeley National Laboratory, and the O’Brien Urology Research Center at the Mayo Clinic. These collaborations will continue to shed new insights in the pathogenesis of biomineralization.

We believe our work will provoke new lines of research in the scientific community. We hope you find our discoveries exciting and look forward to future correspondence.

Stone disease accounted for more than $2 billion in 2000 in annual medical expenditures and affects up to 12% of Americans over the course of their lifetime. Over half of these people will require surgery to treat their stone, and worldwide, stone disease is a leading cause of death in the developing world.

The establishment of a P20 Center at UCSF created a new hub of interdisciplinary research in urinary stone disease, leveraging our ongoing collaborations with the O’Brien Urology Research Center at the Mayo Clinic, the Buck Institute for Research on Aging, the Children’s Hospital of Oakland Research Institute, and the Lawrence Berkeley National Laboratory. Our Center characterizes the role of non-calcium metals in human and fly stones by a combination of genetic and pharmacologic approaches. Investigating the use of commonly available chelators like aspirin in the Drosophila model. This should identify potential targets for drug development that over time will lead to the production of new medications and the novel application of established, FDA-approved medications for the treatment and prevention of human urinary stones. Our continuing goal is to advance our ability to treat patients with new medical therapies to decrease stone recurrence and limit the need for surgical intervention.

The mineralization process underlying stone disease is likely shared across a spectrum of disorders including atherosclerosis and vessel calcification, obesity, the metabolic syndrome, loss of bone mineral density. As such, the proposed program center will seek to bring together perspectives from multiple disciplines including genetics, clinical urologic, imaging, and metal analysis to advance our understanding of the stone formation process. As the center matures, we envision an infrastructure that will provide an outstanding opportunity for translational research involving basic research, clinical and epidemiologic studies, and drug development. The Center will continue to leverage the strengths of the University of California, San Francisco (UCSF) and the Buck Institute for Research on Aging and expand collaborations to include the neighboring Children’s Hospital of Oakland Research Institute, the Advanced Light Source at the Lawrence Berkeley National Laboratory, and the O’Brien Center at the Mayo Clinic in Rochester.

While significant advances in surgical treatments for stone disease have been made over the last 50 years, there has been little forward progress in the development of medical and preventative treatments for stones. Many questions regarding how stone are formed, whether and how they are inherited, and what the risk factors for forming a stone are either unanswered or poorly understood. The proposed educational program for this program center would bring together a community of researchers from both within and outside of urology to create a cross-disciplinary dialogue on improving our understanding of urinary stone disease.

UCSF and the Buck Institute for Research on Aging are uniquely positioned to develop a research center focused on answering many of these questions regarding the fundamental disease processes underlying stone formation and develop new medical treatments for stone disease. These two institutions, leaders in the field of stone disease, diet, aging, and metabolism hold the potential for bringing a multidisciplinary approach to the field of stone disease that can link the realms of basic science and clinical work to accomplish our mission. Such a center would not only represent a novel means of understanding and treating disease, it would represent the first such center in California and one of the few such centers in the United States.

Our Vision:
The pathophysiologic mechanisms underlying stone formation have been implicated in calcium and protein metabolism, inflammation, and genetics, processes that link diseases across multiple fields, including aging, cardiovascular disease, bone health, bone fracture, and obesity. In developing an environment designed to foster advances in stone research and treatment on an epidemiologic, genetic, basic science, clinical, and educational front, our vision is that this multidisciplinary approach to understanding and treating stone disease embodied in a single center will revolutionize the way we think about stone disease and ultimately direct appropriate prophylactic measures and as needed treat patients.