Robert J. Wyatt, M.S., M.D.
Division Chief and Fellowship Program Director

Dr. Robert J. Wyatt has been a member of the division of pediatric nephrology at the UTHSC since 1984. He has been chief of the division of pediatric nephrology since 1999. Dr. Wyatt received his pediatric nephrology training at the University of Kentucky under Dr. Nancy H. Holland from 1975 to 1976 and Cincinnati Children’s Hospital from 1976 until 1979. Dr. Clark D. West was Dr. Wyatt’s research mentor for work related to complement regulatory proteins in glomerular diseases. Dr. Wyatt maintained an active complement laboratory from 1979 to 1984 at the University of Kentucky Medical Center in Lexington and was supported from 1981 to 1984 by a Clinical Investigator Award from the N.I.D.D.K.D for studies on the role of complement regulatory proteins in glomerulonephritis. He moved to the UTHSC in 1984 and maintained a laboratory research program in the field of complement from 1984 through 1991.

In 1998 Dr. Wyatt was one of 8 students in the initial class of the Master’s of Science in epidemiology program at the University of Tennessee College of Graduate Health Sciences. In 1995, during his tenure as President of the College of Medicine Faculty Organization, Dr. Wyatt chaired the committee that examined the need and feasibility for establishing this degree program at the UTHSC. Dr. Wyatt remained in the program as a part-time student and in 2001 received his M.S. degree in epidemiology.

Since 1980 Dr. Wyatt has maintained an active research program related to IgA nephropathy. With Dr. Bruce Julian he described kindred of patients from eastern Kentucky (Julian et al: NEJM 312: 202-208, 1985). This work led to collaboration with Drs. Richard Lifton and Ali Gharavi who were the first to find a locus linked to the disease (Nature Genetics). Dr. Wyatt has published long-term outcome data for pediatric IgA nephropathy and the only population-based incidence data from the United States for adult and pediatric IgA nephropathy.

Dr. Wyatt was previously funded by the N.I.D.D.K.D. (4/1/2002-1/31/2008) as an investigator for the clinical core of the program project grant: Familial IgA Nephropathy: Genetic and Metabolic Studies Program Director: Jiri Mestecky, University of Alabama Birmingham (5P01DK65125-01). The overall objective of this Program Project was to determine the genetic and molecular basis of this common disease through integrated studies of patients with IgA nephropathy or Henoch-Schonlein purpura. The Program Project consists of three component research project and two core facilities: Project 1: Genetic Studies of IgA Nephropathy Project 2: Biosynthesis and Glycosylation of IgA1 Molecules in IgA Nephropathy Project 3: Immune Complexes and Mesangial Cells in IgA Nephropathy Core A: Clinical Resources and Biostatistics Core B: Administrative. The results generated through extensive collaboration among the participating investigators provided information concerning the genetic and molecular defects characteristic of IgAN, identified mechanisms of the pathogenesis of this disease, and may ultimately provide a basis to develop rational therapeutic approaches. Over the six years of the study patients and their family members are enrolled at three sites. The Memphis site was the major site of enrollment of patients with Henoch-Schonlein purpura (HSP) and children with IgA nephropathy during and after episodes of macroscopic hematuria. There were opportunities for investigators in Dr. Wyatt’s group to collaborate with investigators in the core laboratories on studies specifically geared to pediatric issues in these diseases.

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

Dr. Wyatt has extensive experience with clinical trials in both glomerular diseases and pediatric kidney transplantation. He was a member of the planning and scientific advisory committees for the recently completed study, “Pilot Trial in Young Patients with IgA Nephropathy” (5R01DK049368-06). He contributed to the protocol for the second trial of the North American IgA nephropathy study “A Randomized Controlled Trial of Mycophenelate Mofetil in Patients with IgA nephropathy” that is funded by Roche Laboratories and began in the spring of 2003.

Dr. Wyatt is the site principal investigator for the LBCMC and UTHSC for the North American Renal Transplant Co-operative Study and was the site principal investigator for “Co-operative Trials in Pediatric Transplantation, A double blind, randomized trial of steroid withdrawal in sirolimus and cyclosporine treated primary transplant recipients” (5U01AI046134-04).

Dr. Wyatt has served as mentor for the following clinical research projects of 9 pediatric nephrology fellows and the laboratory research project of one post-doctoral fellow:
1) C4 and Bf phenotypes in black and white pediatric patients with insulin-dependent diabetes mellitus. Can Wang, M.D., Visiting Scholar from Bejing, People's Republic of China, 1986-1987.
2) Complement phenotypes in children with Henoch-Schonlein purpura. Bettina H. Ault, M.D., Pediatric Nephrology Fellow, 1988-1990.
3) Antineutrophil cytoplasmic autoantibody and fibronectin/IgA complexes in patients with IgA nephropathies. Lou Anne Baldree, M.D., Pediatric Nephrology Fellow, 1989-1991.
4) Terminal complement complexes in glomerulonephritis. Douglas G. Matsell, M.D., Pediatric Nephrology Fellow, 1989-1992.
5) Outcome of pediatric renal transplants. Donald L. Batisky, M.D., Pediatric Nephrology Fellow, 1990-1993
6) IgA nephropathy in African-American children and adolescents. Azra Sehic, M.D., Pediatric Nephrology Fellow, 1992-1995.
7) Induction therapy in African-American pediatric renal transplant patients. Mohammed Ilyas, M.D., Pediatric Nephrology Fellow, 1994-1997.
8) Angiotensin-coverting enzyme genotype and prognosis in IgA nephropathy. Noel Delos Santos, M.D., Pediatric Nephrology Fellow, 2000 – 2003
9) Clinical features at presentation and outcome of pediatric IgA nephropathy since 1990 for Caucasians and African-Americans. Keith K. Lau, M.D., Pediatric Nephrology Fellow, 2004-2007
10) The role of surveillance renal allograft biopsies in high-risk recipients, M. Colleen Hastings, M.D., Pediatric Nephrology Fellow, 2005-2008