Research Highlights
The Cincinnati Children's Division of Nephrology and Hypertension faculty contains a variety of research interests. Here are basic summaries of their research.
Louise M. Williams Professor of Pediatrics and Developmental Biology
Director of Nephrology & Hypertension
Basic Science
Dr. Devarajan's major research interest is the cell and molecular biology of acute renal failure (ARF). This is an exceptionally important area of investigation in Nephrology. ARF from ischemia-reperfusion injury continues to represent a very significant and potentially devastating problem in clinical medicine. The incidence of ARF varies from 5% of hospitalized patients to 50% of patients in intensive care units. Despite significant technical advances in therapeutics, the mortality and morbidity associated with ARF remain dismally high (up to 80% in the ICU patient with multi-organ damage), and have not appreciably improved during the last four decades. An improved understanding of the underlying pathophysiology and endogenous repair mechanisms will be critical for innovative and effective therapy.
While pioneering studies over several decades have paved the way for successful therapeutic approaches in animal models, translational research efforts in humans have yielded disappointing results. The reasons for this include a lack of early markers for ARF (and hence a delay in initiating therapy), and the multi-factorial nature of the disease. Attempts to unravel the molecular basis of these myriad mechanisms have been significantly facilitated by recent advances in functional genomics that have yielded new tools for genome-wide analysis of complex biologic processes.
These transcriptome inquiry approaches have recently been utilized to analyze the renal response to ischemia both in vitro and in animal models. We have identified several players that appear to be predominant arbiters of cell death and cell survival in renal ischemia-reperfusion injury. A systematic analysis of candidate genes and proteins including loss of function and gain of function studies in a variety of animal, human and in vitro models is a major goal of our present and future research endeavors.
Overall, these targeted studies will provide a comprehensive understanding of the molecular pathophysiology underlying ARF, and will reveal critical clues for our long-term goals, namely the identification of novel early biomarkers and the rational design of innovative and effective interventions aimed at ameliorating renal cell damage and/or accelerating the recovery process.
The laboratory includes full-time technicians, post-doctoral fellows, and PhD research associates, and is funded by several grants from the NIH and other agencies.
Clark D. West Chair of Nephrology
Director of Fellowship Training Program
Associate Professor of Pediatrics
Basic Research
Dr. Bissler is interested in the molecular mechanisms of somatic mutagenesis resulting in autosomal dominant polycystic kidney disease and tuberous sclerosis complex. These two diseases have closely adjacent genes located on chromosome 16p13.3, PKD1 and TSC2 that are mutated in majority of their patients exhibiting disease. These autosomal dominant diseases require a somatic mutation in the allele inherited from the unaffected parent to manifest the phenotype. Dr. Bissler has identified alternative DNA secondary structures in the TSC2 and PKD1 genes that arrest human replication fork progression and therefore are hypothesized to facilitate the "second hit" leading ultimately to disease.
Dr. Bissler is also interested in intelligent control of Hemofiltration and hemodialysis. Dr. Bissler has earned multiple patents on improved hemofiltration technologies. He is currently applying for funding to further his goal of developing a robust intelligent control architecture implemented for both dialysis and hemofiltration that adapts therapy to the patient's physiologic condition.
Clinical Research
Dr. Bissler cares for children who have polycystic kidney disease. He attends the tuberous sclerosis clinic and has pioneered an improved strategy to deal with renal angiomyolipomas associated with this disease.
Dr. Bissler also attends the Tuberous Sclerosis Clinic in Cincinnati. This clinic has over 300 patients, making it one of the largest TS clinics in the world. Dr. Bissler cares for the renal component of this disease process. Furthermore, in conjunction with Dr. David Franz, Director of the Tuberous Sclerosis Clinic and Dr. Frank McCormack, Pulmonologist who specializes in the lymphangioleiomyomatosis, Dr. Bissler is conducting a clinical trial in hopes to discover a pharmacological treatment for the renal lesion of TS.
Research Instructor of Pediatrics
Basic Research
Dr. Dixon's primary research focus is microenvironmental influences on damage to and repair of DNA. These interests involve the effect of high concentrations of substances such as sodium chloride and urea on the integrity of DNA in various biological systems such as the inner portion of the kidney and the urinary bladder. The clinical applications of this research are somatic mutation and genetic renal diseases, as well as the correction of complex urological anomalies by bladder reconstruction, or augmentation cystoplasty. One of the long-term complications of such reconstruction is malignancy of the reconstructed bladder, the causative mechanisms of which are largely unknown. Using both cell culture and animal models, Dr. Dixon is seeking to understand these mechanisms so that preventative strategies may be developed for these patients.
Associate Professor of Pediatrics; Medical Director of Kidney Transplantation
Associate Professor of Pediatrics
Basic Research
Dr. Goebel is interested in T lymphocytes, the immune cells predominantly driving transplant rejection. He specifically studies lipid rafts, which are designated areas on the cell surface containing clusters of molecules critical for the function and life cycle of T lymphocytes and other cells. The receptor for interleukin-2, a cytokine critical for the regulation of T lymphocyte activation and survival, is partially located within lipid rafts and thus another focus of his work.
Clinical Research
Dr. Goebel's clinical research revolves around cardiovascular and metabolic issues especially as related to the long-term outcome of pediatric kidney transplant recipients. It includes efforts to design and modify immunosuppressive protocols for these patients and to improve their overall long-term management to minimize the significant late complications this population is experiencing increasingly. Of note, attempts are ongoing to link these clinical research efforts with more basic work in a truly translational, "bench-to-bedside-and-back" sense.
Associate Professor of Nephrology
Basic Research
Dr. Elizabeth Jackson's research lies in the area of bladder dysfunction. She is participating in a study sponsored by the Kidney Foundation of Cincinnati to evaluate the effectiveness of gentamicin bladder irrigation to prevent urinary tract infections in children who are on an intermittent catheterization program for bladder drainage. The Astellas Company is sponsoring a trial of alpha blockers to reduce the leak point pressure in children with neurogenic bladders. CCHMC will be participating in this multicenter trial with a goal of reducing bladder pressures as documented by urodynamics.
Clinical Research
Dr. Jackson will be investigating the contribution of dietary renal solute load to nocturnal polyuria in children with nocturnal enuresis as an aid to future therapy for this common childhood problem.
Emeritus Professor of Pediatrics
Clinical Research
Dr. McEnery is associated with Children's Hospital Medical Center of Cincinnati Division of Nephrology in an emeritus status, yet still works actively in the areas of the outcome of membranoproliferative glomerulonephritis, as well as transplant outcomes.
Attending Physician
Associate Professor
Clinical Research
Dr. Mitsnefes is interested in the epidemiology of cardiovascular disease in children with chronic renal disease. The target is identification of possible risk factors for cardiac morbidity and mortality in children with ESRD, primarily evaluation of left ventricular hypertrophy (LVH) in children on chronic dialysis or with renal transplants. His studies have showed that LVH is prevalent and frequently severe in chronically dialyzed children, it is frequently present at the initiation of chronic dialysis therapy and progresses during long-term dialysis and after renal transplantation. The future focus is a prospective evaluation of cardiovascular abnormalities in children and adolescents with mild-to-moderate chronic renal insufficiency (CRI). The hypothesis underlying this proposal is that cardiovascular changes occur in children and adolescents with relatively mild CRI, and progress as end-stage disease approaches. An additional hypothesis is that in addition to LV abnormalities, pediatric patients with chronic renal disease have a high prevalence of vascular abnormalities (increased carotid intima-media thickness and endothelial dysfunction), which occur in children with relatively mild renal failure, progress as end-stage disease approaches, and persist after renal transplantation.
Research Assistant Professor of Pediatrics
Basic Research
Dr. Patterson's research interest is the molecular control of renal development. Molecular mechanisms controlling reciprocal inductive interactions between the mesenchyme and the ureteric bud have been an area of great interest in developmental biology. Much progress has been made in this area, but there remain many other areas that have not received the same degree of attention and are equally important. Current projects address the developmental control of the anterior-posterior axis of the intermediate mesoderm and the mechanism that controls determination of the metanephric mesenchyme, the tissue from which the mature kidney develops. In addition, studies address the mechanism of proximal-distal nephron patterning and collecting duct patterning and differentiation. Transgenic mice, organ culture, and tissue separation/recombination experiments are being used to study these events.
Director of Clinical Services, Director of the Dialysis Unit
Professor of Pediatrics
Clinical Research
Dr. Strife is interested in improving dialysis of children with end-stage renal disease. He works with a number of clinical research projects related to this patient population. Dr Strife is also interested in the long-term outcome of children with membranoproliferative glomerulonephritis. He participates as center Project Investigator in a number of multi-center studies involving growth hormone, hemolytic uremic syndrome, transplant immunosuppression, anti-hypertensive therapy and others.
Research Assistant Professor
Basic Research
Dr. Zahedi is interested in the regulation of C1 inhibitor gene. The promoter region of C1inhibitor has been examined and a number of potentially important regulatory elements have been identified. He is currently in the process of identifying the transcription factors that regulate the activity of the C1inhibitor promoter. He have also examined and characterized the interferon responsive elements upstream of the C1 inhibitor gene. These studies indicate that interferon responsive elements are present in the 5' upstream region and the first intron of the C1 inhibitor gene. Characterization of the 5' region indicates that a single gamma interferon activated sequence (GAS) in this region mediates the induction of C1 inhibitor gene in response to g-interferon (g-IFN). This element is capable of binding to activated Stat1. Current studies in this area are focused on characterizing the intronic interferon response elements and identifying the phosphatases that regulate the half life of activated Stat1.
Dr. Zahedi is also interested in the biological role of Skb1. Skb1 is a highly conserved protein methyl transferase which expression increases during tubule formation in vitro. The objective of this research is to determine the role of Skb1 in cell growth and differentiation by identifying its partner proteins, determining their methylation status and the effect of methylation on their subcellular localization and interactions with other proteins.
