RESEARCH EPICENTER

The ongoing research activities of the Division of Nephrology provide an important focus for potential fellowship research projects and training. The Division of Nephrology has 23 full-time faculty members located at the UW Medical Center, Harborview Medical Center, Veterans Administration Puget Sound Health Care System and the Northwest Kidney Centers, and an additional two adjunct faculty. Faculty research interests vary from basic science to clinical science to translational science and are supported by several million dollars annually in research funding. The Division of Nephrology typically accepts five ACGME fellows into the program annually and seven to nine non-ACGME postdoctoral fellows in basic and clinical sciences annually (not supported by T32 mechanism). There is a large clinical program of patients with varying stages of kidney diseases, many of whom are enrolled in clinical studies, and a large transplant program as well. In addition to a mentor within the Division of Nephrology, each trainee is required to have a mentor from a division or department outside of nephrology. This model has been very successful for our basic and clinical science training programs as it provides the opportunity for a nephrology trainee to branch out into new directions. This will, of course, provide the trainee with opportunity to develop an independent area of study that is different from that of the renal mentor, thereby bringing “new ideas” to renal research. Thus, a major strength of the training program is the collaboration with other basic and clinical schools and departments within the UW.

The Basic and Clinical Science Research Programs are integral to the daily activities in the Division of Nephrology. Moreover, the division’s outstanding established clinical care programs are complemented by asking, “Can we improve patient care through research?” Divisional research programs and training activities are now grouped thematically into four major, overlapping research areas, based on current strengths and interests of divisional members, collaborators at UW, research databases and availability of core research facilities and specialized clinics.

Diabetic kidney disease

Members of the Division and close collaborators are actively engaged in basic and clinical research of diabetic kidney disease, the most common cause of chronic and end stage renal disease in the United States. Basic science research focuses on new discoveries in cellular and molecular mechanisms of proteinuria, inflammation, and fibrosis in diabetic kidney disease, using a cell culture, animal model and human biopsy approach. Several large clinical research projects and trials utilize data from major epidemiology health studies that are headed by faculty at the UW and are currently being used by faculty and trainees in our training program. These include the Epidemiology of Diabetes Intervention and Complications (EDIC) study; the Women’s Health Initiative (WHI); the Multi-Ethnic Study of Atherosclerosis (MESA) to examine diabetes-related dyslipidemia, central obesity related to intensive insulin therapy and the potential role of vitamin D metabolism in the prevention of diabetes; the Diabetes Prevention Program Outcomes Study (DDOPS); the long-term follow up of the Diabetes Prevention Program (DPP) cohort; the Look Ahead (Action for Health in Diabetes) study; and the database for the Japanese-American Community Diabetes Study. Faculty are well funded, with a broad range of research interests to help future trainees launch research careers in diabetic kidney disease.

Diabetic nephropathy continues to be a major clinical interest of the UW. To this end, a multi-disciplinary diabetic kidney disease clinic co-directed by Raimund Pichler, MD, and Irl Hirsch, MD, solidifies collaboration between the Divisions of Nephrology and Endocrinology and provides a large population for participation in clinical and translational research studies. Drs Young and de Boer have diabetic nephropathy clinics at the VA Puget Sound. There are several well-established centers at the UW complementing the diabetic kidney research in the Renal Division. These include the NIDDK-funded Diabetes Endocrinology Research Center (http://depts.washington.edu/diabetes) with core facilities (cellular and molecular imaging, mass spectrometry, molecular genetics and others), the NIH-funded Mouse Metabolic Phenotyping Center that supports diabetes- and obesity-related research (http://depts.washington.edu/mmpc/about/contact.html), and the soon to open Diabetes/Obesity Center of Excellence at UW. Finally, the Northwest Metabolism and Diabetes Research Laboratories provide core support for numerous analyses related to diabetic and lipid metabolism.

Glomerular injury and proteinuric renal disease

A longstanding strength of the Renal Division has been the study of molecular and cellular mechanisms of glomerular injury and how this translates to proteinuria and kidney scarring. Dr. Shankland currently holds three R01 grants to study this topic and holds the prestigious position of Established Investigator of the American Heart Association. Dr. Raghu Durvasula’s K08 and recent R03 awards focus specifically on podocyte injury in vitro and in a variety of animal models of disease, with an emphasis on SPARC. Dr. Vaughan’s K08 award examines podocyte injury and proteinuria. Dr. Caroline Marshall received a Robert Wood Johnson grant to examine how DNA damage of podocytes leads to proteinuria and glomerulosclerosis. Dr. Charles Alpers is well funded to study animal models of glomerular injury and podocyte diseases. Available to trainees are several cores and resources, including the Center for Expression Arrays (http://ra.microslu.washington.edu), proteomics and FACS analysis. On the clinical side, Dr. Ashley Jefferson is co-PI of the Focal Segmental Glomerulosclerosis NIH-funded grant (PI is Sandra Watkins, MD, Pediatric Nephrology, UW), and Dr. Ian de Boer, in collaboration with Dr. Michael Vaughan, is engaging in a clinical trial to test the hypothesis that ATRA enhances kidney survival in proteinuric patients as we have shown in experimental models. Dr. Pichler has a particular research interest in glomerular disease in patients with liver disease and  has collected the largest-known kidney biopsy repository in these patients for study. Dr. Connie Davis is actively studying recurrence of glomerular disease in transplanted patients, with a current emphasis on the association of rapamycin therapy with de novo FSGS.

Vascular pathology and cardiovascular disease

Basic science research in vascular biology includes the labs of Drs. Nicosia and Giachelli. Dr. Nicosia’s NIH-funded research examines key mechanisms of angiogenesis, including angiopoietins and vascular endothelial growth factors, using animal models. Dr. Giachelli, a world expert in in-vitro calcification models, was the first to demonstrate a direct mineralizing role for serum phosphate on vascular smooth muscle cells and serves as a model for future translational research. Dr. Schwartz is an expert in vascular biology, and Kim Muczynski, MD PhD (Nephrology), studies anti-endothelial cell antibodies in disease. Dr. Kestenbaum studies dystrophic vascular calcification in CKD. He recently completed a large ancillary study to the NHLBI-funded MESA study to examine the association of serum mineral metabolism markers with longitudinal changes in coronary calcium in MESA participants with CKD. His R01 project studies whether mineral metabolism markers are associated with vascular stiffness and clinical heart failure among participants in the Cardiovascular Health Study. In collaboration with Dr. Giachelli, Dr. Kestenbaum is currently conducting translational research aimed at developing a novel serum assay for quantifying calcification risk in CKD patients. Drs. Kestenbaum and de Boer work closely with Dr. Siscovick, an internationally known cardiovascular epidemiologist and senior investigator in MESA, CHS, and the Coronary Artery Risk Development in Young Adults (CARDIA) study. Together, they serve as members of a number of collaborative working groups within these studies, including those for renal, diabetes, and mineral metabolism. Dr. de Boer collaborates closely with Dr. Probstfield, professor of cardiology, a major leader in hypertension clinical trials, including ALLHAT and HOPE. Dr. Ahmad, nephrology professor, is an active participant in clinical hypertension trials in patients with normal and abnormal kidney function, including dialysis patients. Finally, the NIDDK-funded Clinical Nutrition Research Unit includes 80 investigators with research interests in lipids, atherosclerosis and diabetes (http://depts.washington.edu/uwcnru). It is utilized by members of the Renal Division, such as Dr. de Boer.

Complications of chronic kidney disease and transplantation

Chronic Kidney Disease (CKD) leads to devastating clinical complications including cardiovascular disease, anemia and bone disease. The UW Division of Nephrology has had a storied history of excellence in the study of CKD complications. For example, Drs. Sherrard and Andress pioneered the study of metabolic bone disease in dialysis patients, and the late Dr. Eschbach was responsible for the clinical introduction of recombinant human erythropoietin. Excellence in the study of CKD complications continues within the division. Dr. O’Hare is a leader in the epidemiology of peripheral vascular disease (PVD) complications of CKD.  Recently she examined cystatin C, an alternative marker of kidney function, as an early indicator of PVD.  Dr. Kestenbaum has published several articles describing cardiovascular and fracture outcomes following surgical parathyroidectomy. Dr. de Boer has published important new data describing early changes in serum lipids, measured by MRI in CKD patients. He is currently studying vitamin D and ATRA therapies as potential novel means to reduce proteinuria and slow progression of CKD. Together, Drs. Young, O’Hare and Rodriguez have published extensively on the role of race in cardiovascular complications of CKD. Central to moving forward in the field of clinical CKD research is the collection of prospective data. To this end, Dr. Kestenbaum established the Seattle Kidney Study (SKS) in 2004 and has already enrolled more than 350 CKD patients from clinical sites within UW. SKS participants provide serum, urine and DNA samples and undergo detailed annual physical and cognitive functional exams. SKS serves as a shared resource for clinical and translational studies within the division. Renal transplant patients represent an important and understudied CKD population. Dr. Davis and Dr. Ajit Limaye (Laboratory Medicine) are leaders in the study of BK Nephropathy, an important cause of graft failure, and Dr. Leca is currently investigating the complications of treatment of BK nephropathy with leflunomide.

Faculty and Research Activities