Research

The principal goal of the Division of Nephrology is to excel in research, education and patient care related to diverse kidney disease. The current topics below illustrate the list of faculty members and their clinical, research and educational activities including publications and sponsored research performed during the past three years.

For questions about the current clinical studies please contact Char Klis at (414) 805-9075.

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  Acute Kidney Injury

The primary goal of Kevin R. Regner, MD, MS, FASN is to investigate the cellular, molecular, and genetic mechanisms involved in ischemic acute kidney injury (AKI) and kidney repair. Current projects include:

1) Activator of G Protein Signaling 3 in Ischemic Renal Injury. The objective of this study is to characterize the role of Activator of G protein signaling 3 (AGS3), a novel non-receptor regulator of G-protein function, in renal tubular regeneration following ischemic AKI.

2) Genetic mapping and gene identification for acute kidney injury in outbred rats. The objective of this study is to identify novel genes that modulate susceptibility or resistance to AKI using a novel genetic resource, heterogeneous stock rats.

Michael Yeboah, MD, PhD, has two ongoing projects one of which include:

1) Biomarkers in Hepatorenal Syndrome. Our goal here is to identify novel biomarkers that will help to determine patients at risk of developing the hepatorenal syndrome. The approach involves both animal models and patient level clinical studies.

  Mechanism of Chronic Renal Injury

The primary goal of Michael Yeboah, MD, PhD, is to investigate the cellular, molecular, and physiologic mechanisms of chronic renal injury.

1) Mechanisms of Renal Fibrosis. Here we are using different animal models of chronic kidney disease (CKD) to understand the cellular and molecular mechanisms of renal fibrosis. The long-term goal is to help to develop therapeutic agents to prevent the progression of CKD.

  Renal Cell Biology and Signaling

The laboratory of Andrey Sorokin, PhD, is interested in multiple projects with focus on cell signaling as related to pathobiology of kidney disease.

Research is primarily focused on characterizing the molecular mechanisms underlying the activation and termination of signaling pathways, as well as defining the cellular consequences of specific stimulation of these cascades in systems relevant for the signaling from G-protein coupled receptors.

By combining of molecular biological, biochemical and cellular biological approaches the defining the alterations in signal transduction which lead to pathological phenotype can be obtained.

  • Studies are being performed to explore molecular mechanisms responsible for manifestation of short-and long-term effects of Endothelin-1 (ET-1) in kidney cells. ET-1 exerts vasoconstrictor, hypertrophic and mitogenic actions on the renal vasculature and glomerular messangial cells. In particular, laboratory is interested in 1.) identifying mechanisms involved in regulation or signaling via guanine nucleotide exchange factors Pix and C3G; 2.) evaluation of the role of cytoplasmic tyrosine kinase Pyk2; 3.) elucidation of the negative regulation of endothelin signaling on the level of intracellular MAPK cascades by dual specificity phosphatases.
     
  • Studies are being performed to define the role of adaptor proteins Crk and p66 Shc in regulation of distinct intracellular signaling cascades in renal cells. This laboratory has cloned a novel and biologically distinct member of the Crk family that has been termed CrkIII. Adaptor protein p66 Shc controls oxidative stress apoptotic responses and regulates life span in mammals. The ability of p66 Shc to control oxidative cell response apoptosis and animal longevity is unequivocally dependent on Ser phosphorylation of p66 Shc. It is likely that longevity is unequivocally dependent on Ser phosphorylation of p66 Shc. It is likely that signaling via Crk and p66 Shc is extremely important agents and is affected during the progression of kidney disease.
     
  • The role of COX-2 in the cell has been the focus of intense investigation since discovery of this enzyme. This lab has demonstrated the anti-apoptotic effect of COX-2 in a number of cell systems and provided evidence that COX-2 promotes cell survival by a mechanism linking increased expression of pro-survival genes coupled to inhibition of NO- and superoxide-mediated apoptosis. We have also proved the existence of a casual link between COX-2 and P-gp (MDR1) activity, which would have implications for kidney function and multidrug resistance in tumors where COX-2 is over expressed. Apoptosis is important for reparative glomerular remodeling in glomerulonephritis.
  Clinical Research on Diabetic Nephropathy and Chronic Kidney Disease (CKD) and ESRD

For the nephrology population we have:

Kadmon KD019-101 - The purpose of this study is to find out if the experimental drug, KD019, is safe as a possible treatment of ADPKD at various doses.  Phase 1 was to determine the safety of the drug and to determine the maximum tolerated dose.  Phase 2 will use the selected best dose to see how effective KD019 is at treating ADPKD.

MENTOR - This study will determine whether rituximab is non inferior to cyclosporine in inducing long-term remission of proteinurea in patients with idiopathic membranous nephropathy with less side effects.

  Clinical Studies on Renal Transplantation: Newer Immunosuppressive Therapy and Prevention

Liliana Osadchuk, MD and Tepsiri Chongkrairatanakul, MD have been involved in the following transplant population studies:

BMS IM103116 - This is a 24 month randomized trial. Subjects will be randomized to continue their current CNI or converted to Belatacept. Previous studies have shown that subjects could be converted from CNI to belatacept without an increased risk of death or graft loss. These subjects showed improvement in renal function through Month 36 post randomization, there was no evidence of proteinuria or increased infections and they experienced less side effects.

ENLiST Registry - Studied population in this registry will consist of adult de novo patients treated with belatacept for a kidney transplant in routine clinical practice in the US as determined by treating clinicians.

CMX001–307 - A Phase 3 study with the primary objectives of

  • To compare the efficacy of brincidofovir (BCV) to valganciclovir (vGCV) for the prevention of CMV disease in kidney transplant allograft recipients who are CMV-seropositive pre transplant and received antilymphocyte induction therapy.
  • To compare the safety and tolerability of BCV to vGCV in kidney transplant recipients who received antilymphocyte induction therapy

CMX001–303 - A Phase 3 study with the primary objectives of:

  • To compare the efficacy of brincidofovir (BCV) to valganciclovir (vGCV) for the prevention of cytomegalovirus (CMV) disease in kidney transplant allograft recipients who are high-risk for CMV disease (CMV-seronegative pre-transplant and received a kidney from a CMV-seropositive donor)
  • To compare the safety and tolerability of BCV to vGCV in high-risk kidney transplant allograft recipients
  Kidney Stone Research

The kidney stone research group at MCW consists of three full-time faculty, two physician scientists, Jack G. Kleinman, MD, and Jeffrey A. Wesson, MD, PhD, and one PhD investigator.

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. Neil Mandel, PhD, focuses his research activities on five specific research programs:

  1. 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.
     
  2. 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.
     
  3. 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.
     
  4. 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.
     
  5. 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 G. 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 five 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:

  • 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.
     
  • 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.
     
  • Studies on the use of artificial homopolymers to inhibit calcium oxalate and other crystal retention in animal models of stone disease.
     
  • 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.
     
  • Studies on the determinants of vascular calcification in animal models of chronic kidney disease.
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