Kidney Stone Research
The kidney stone research group at MCW consists of five full-time faculty, two physician scientists, Dr. Jack Kleinman and Dr. Jeff Wesson, and three Ph.D. investigators, listed below.
The investigative team conducts peer reviewed funded studies on a number of critical aspects on the pathophysiologic mechanisms mediating the initiation and progression of urinary tract kidney stone disease. Drs. Neil Mandel, John Wiessner, and Gretchen Mandel focus their research activities on five specific research programs.
i. Studies on the epidemiological patterns of stone disease within the Department of Veterans Affairs are directed at defining the prevalence and demographics of the disease. The study focuses on the influence of age, sex, ethnicity, stone composition, and stone recurrence on the necessity for and impact of medical and surgical management of stone disease. The influences of co-morbid diseases such as hypertension are also incorporated in the data analysis, establishing the basis for a defined human study on the genetic predisposition for calcium oxalate stone disease.
ii. Our long-standing research program on the mechanisms of stone initiation, focusing on the role of injury as a necessary event for effective crystal retention, has produced specific mechanisms that prime urinary epithelium for crystal attachment. Investigations on the role of urinary macromolecules in crystal nucleation and growth in the crystal attachment mechanism are also included in this research program.
iii. The clinical observation of the co-morbidity of stone disease, especially calcium oxalate stone disease, with hypertension has allowed us to utilize a genetically controlled rat model for studies on the genetic linkages in these two diseases. The focus is on the genetic basis of recurrent calcium oxalate stone disease as well as on the genetic linkages between that disease and hypertension.
iv. The development of a new animal model of calcium oxalate stone disease focuses on the use of a SPF, Oxalobacter formigenese free, pig colony and the development of calcium oxalate crystalluria and calcium oxalate stone disease with oral oxalate ingestion. This model has successfully utilized dietary oxalate levels similar to that observed in idiopathic stone patients to produce recurrent episodes of calcium oxalate crystalluria and occasional calcium oxalate papillary plague.
v. The stone analysis laboratory continues to provide a valuable database for the analysis of stone composition variations in recurrent stone patients. This database also allows for the identification of potential patients for human genetic studies on stone predisposition and stone recurrence associated with ethnicity, sex, age, and geographic locality as an environmental influence.
Drs. Jack Kleinman and Jeffrey Wesson conduct targeted research on the physical, chemical and physiologic mechanisms of crystal nucleation, growth, and aggregation of crystals that form within the nephron and in related vascular tissue. Drs. Kleinman and Wesson have at least 5 research programs focused on these important mechanistic events. Also included in their research portfolio are investigations that ultimately will lead to translational studies on the inhibitory potential of selected cell derived or synthetic urinary molecules to inhibit crystal nucleation, growth, and potentially the attachment of the crystals to urothelium.
These projects are:
i. Studies on the interaction of artificial and naturally occurring urinary macromolecules with the surface of stone constituent crystals to define the potential influence of various functional groups to alter or arrest the processes of crystal aggregation and attachment to cell surfaces.
ii. Studies to define the cell-associated molecule or molecules that are responsible for the attachment to inner medullary collecting duct cells of stone constituent crystals.
iii. Studies on the use of artificial homopolymers to inhibit calcium oxalate and other crystal retention in animal models of stone disease.
iv. Clinical studies on familial calcium oxalate stone disease are designed to study the urinary aspects that may be associated with stone predisposition and stone recurrence. These studies also serve as the definition of a selected patient database that can be used for translational research investigations.
v. Studies on the determinants of vascular calcification in animal models of chronic kidney disease.