RESEARCH

Faculty                        division publications 2004 2005 2006 2007 2008                     

NAPRTCS The division has participated over the past two decades as a member of the North American Pediatric Renal Trials Cooperative Study (NAPRTCS).  Robert Wyatt is the center principal investigator for this registry that compiles important clinical data and outcomes for pediatric patients who have a kidney transplant, are on chronic dialysis, or have chronic renal insufficiency but have not yet progressed to dialysis or transplantation.

CKID  The division is presently enrolling eligible subjects in CKID, a prospective cohort study of kidney disease in children.  Deborah Jones is the site principal investigator and a member of the cardiovascular subcommittee for this NIH supported multicenter study (5U01DK066143-03).  The specific aims of this study are 1) to determine risk factors for progression of pediatric chronic kidney disease (CKD), 2) to examine the impact of CKD on neurocognitive development, 3) to examine the impact of CKD on risk factors for cardiovascular  disease, and 4) to examine the impact of CKD on growth.  As of January 1, 2007, seven subjects from the UTHSC are entered in the study.

End Organ Damage in Children with Primary Hypertension On October 1, 2005 Dr. Deborah Jones received a 5-year NIH K23-Mentored Patient Oriented Research Career Development Award, “End organ damage in children with primary hypertension” (K23HL08910-01A2).

Familial IgA Nephropathy: Genetic and Metabolic Studies  Robert J. Wyatt an Investigator for the Clinical Resources and Biostatistical Core of this Program Project Grant (5P01DK061525-04) that began on April 1, 2002 and was funded through January 31, 2007 with a no-cost extension through January 31, 2008.  The University of Tennessee Health Science Center (UTHSC) and the University of Alabama at Birmingham (UAB) were the two sites for recruitment of subjects with additional subjects recruited from eastern and central Kentucky region.  Dr. Bruce Julian, internal medicine nephrologists at UAB, was the other clinician investigator for the PPG.  He and Dr. Wyatt have collaborated on studies on familial IgA nephropathy (IgAN) in Kentucky since the early 1980’s.

Project 1.  Using multiplex pedigrees from eastern Kentucky (first described by Wyatt and Julian) and Italy, Dr. Richard Lifton’s laboratory at Yale University undertook a genome-wide analysis of linkage, genotyping polymorphic markers distributed at 10-cM intervals.   We found linkage of IgAN to chromosome 6q22-23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked.  These findings for the first time indicated a locus, now called IGANI, with a large effect in the development of IgAN, and identified the chromosomal location of this disease gene.   Linked Kentucky and Italian kindreds both showed peak lod scores in the same interval.   The observed penetrance is compatible with an inherited susceptibility whose clinical expression depends on environmental or genetic modifiers.   There was no apparent clinical or demographic feature that distinguished families with positive or negative lod scores at IGANI.   This work was published in Nature Genetics in 2000. Identification of the molecular defect underlying IGANI may provide insight into the pathogenesis, diagnosis, and treatment of renal dysfunction in patients with IgAN.

Project 2. Dr. Mestecky’s group previously demonstrated 1) that galactose deficiency is restricted to O-linked glycans in the hinge region of IgA1 molecules 2) IgA1 with aberrantly glycosylated hinge region is present in circulating immune complexes (CIC) and bound to IgG with anti-glycan activity; 3) Epstein Barr virus (EBV) transformed peripheral blood mononuclear cells from IgAN patients, but not normal controls, produce IgA1 with altered glycosylation and this process can be significantly enhanced with influenza virus infection  or exposure to selected bacterial products.

Project 3. Drs. Novak and Tomana have previously demonstrated 1) the presence of IgA1 proteins with Gal-deficient O-linked glycans in CIC of IgAN patients 2) IgA1 and IgA1-containing CIC bind to cultured human mesangial cells (MCs) through a receptor other than ASGP-R or CD89R; 3) Gal-deficient IgA1 containing-CIC from patients activate MCs in vitro; 4) IgAN-CIC induce changes in tyrosine phoshorylation; 5) IgAN-CIC induces differential gene/protein expression in cultured human MCs

CLINICAL FEATURES AND OUTCOME OF PEDIATRIC IgA NEPHROPATHY

For virtually his entire academic career Robert Wyatt has documented clinical features and outcome of pediatric patients with IgA nephropathy. In 1984 he published the first kidney survival data (time to progression to end stage renal disease) for adults in the United States with IgA nephropathy (Wyatt et al: Am J Kidney Dis 4: 192-200, 1984). This study incuded data for 24 pediatric patients, none of whom had progressed to end stage renal disease at the time of the report. Dr. Wyatt was an author on the 1994 report from the Southwest Pediatric Nephrology Study Group of 218 pediatric patients with IgA nephropathy that documented progression to end stage renal disease for 12. This study showed that as in adults, the degree of proteinuria at biopsy and findings of glomerular sclerosis on biopsy were associated with poor outcome. This link is to kidney survival data for the 97 pediatric patients diagnosed in Memphis from 1974 through 2004 (link).

Fellow            go to Fellowship Program page

Student                   

Since 1980 the UT College of Medicine has maintained a successful NIH-funded medical student research program with Dr. Solomon Solomon as the PI (2T35DK007405-21).  This grant has recently been extended through May 2010.  The T35 award supports stipends for 24 students per year.  In 2001 the UTHSC General Clinical Research Center (GCRC) began supporting 4 additional students per year.  The GCRC Medical Student Research Program is designed to enable medical students to engage in individualized research projects under the supervision of faculty investigators at the GCRC.  This program introduces medical students to the possibility of a career in research.  Awardees devote full-time effort to their research activity during a 3-month period.  In addition to the faculty preceptor, students also participate in a special seminar series that include:  (1) Principles of Scientific Investigation, (2) Working with Human Subjects, (3) Molecular Biology in Human Disease, (4) Research Ethics, and (5) Evaluation of Scientific Data.  This program is available to all undergraduate students enrolled in the College of Medicine.  Students participate during the summer option period (June-August).

In the summer of 2004, two students, Kim McGlothan and Quinisha Logan, undertook clinical research projects in the division of pediatric nephrology as part of the GCRC Medical Student Research Program.  Drs. Bruce Alpert and Jones mentored Ms. Logan’s project, “Measurement of vascular compliance in children with hypertension.” Drs. Deborah Jones and Robert Wyatt mentored Ms. McGlothan’s project, “Ambulatory blood pressure monitoring in children after renal transplantation.”  This study has resulted in a poster presentation at the 2005 meeting of the Pediatric Academic Societies/American Society of Pediatric Nephrology (ASPN) in Washington, D.C.  Ms. McGlothan was awarded a travel grant from the ASPN to attend the meeting. The study also resulted in the manuscript - McGlothan KR, Wyatt RJ, Ault BH, Hastings MC, Rogers T, DiSessa T, Jones DP: Predominance of nocturnal hypertension in pediatric renal allograft recipients. Pediatric Transplantation 10: 655-667, 2006

In the summer of 2005, Kerry Sharpe was supported by the GCRC Medical Student Research Program for her project, “Extension of pedigrees of patient with IgA nephropathy from Clay County, Kentucky.”  This work was a part of the multi-center IgA nephropathy program project, Familial IgA Nephropathy: Genetic and Metabolic Studies.  Ms. Sharpe participated in a field trip to Manchester, Kentucky to interview patients and family members who were having blood drawn for the larger NIH-supported project.  Investigators at Yale School of Medicine, University of Alabama at Birmingham and Columbia University who are trying to establish a genetic basis for the disease will use her work. An abstract based upon this work has been accepted for poster presentation at the 39th annual meeting of the American Society of Nephrology[Sharpe K, Gharavi A, Julian BA, Woodford SY, Wyatt RJ: Familial IgA nephropathy (IgAN) in southeastern Kentucky].