Diabetic Kidney Disease: Potential New Therapeutic Target Discovered

Dr. Paolo Fiorina, MD PhD Assistant Professor, Division of Nephrology, Harvard Medical SchoolMedicalResearch.com Interview with:
Dr. Paolo Fiorina, MD PhD
Assistant Professor, Division of Nephrology,
Harvard Medical School

and
Dr. Roberto Bassi Post-doctoral research fellow Nephrology Department at Children's Hospital Boston.
Dr. Roberto Bassi

Post-doctoral research fellow
Nephrology Department at Children’s Hospital Boston.

 

MedicalResearch.com: What are the main findings of the study?

Dr. Fiorina: It is common knowledge that type 2 diabetes is a worldwide epidemic and that diabetic nephropathy has become the leading cause of renal failure in the western world. One of the main drivers and worsening factors for the diabetic kidney disease is proteinuria associated with various degrees of tubular damage, and unfortunately, therapies to halt or prevent this complication are not available so far. Our findings show that B7-1 when expressed on podocytes (a specific subset of renal cells) determines alterations in podocytes function and morphology, predisposing individuals with T2D to the loss of proteins into the urine. We also demonstrate that Abatacept, an immunomodulatory drug currently employed for the treatment of a variety of autoimmune diseases, is able to specifically target this malignant pathway, preventing podocytes cellular alterations in vitro and proteinuria development in two murine models of diabetic nephropathy in vivo.

MedicalResearch.com: Were any of the findings unexpected?

Dr. Bassi: We started off this project aiming to analyze new intracellular pathways of kidney damage during diabetes and eventually, thanks also to our collaboration with the Joslin Diabetes Center led by Dr. Krolewski, we were also able to define a candidate extracellular inducer of podocyte damage: soluble CD28, which immunologically speaking, is an activator of B7-1. According to our results, high concentrations of soluble CD28 in the bloodstream up to 10 years before the onset of the diabetic kidney disease, might render those patients more susceptible to the development of renal failure in the future. On one hand, this is important in the view of a potential screening of patients at high risk for diabetic kidney failure, while on the other hand it will help to define a population of diabetic individuals that would benefit the most from B7-1 therapeutic targeting with Abatacept.

MedicalResearch.com: Should clinicians and patients take away from your report?

Dr. Fiorina: The first important message that the community should take away from our report is that much work and effort are being put in the research of a feasible, safe and possibly definitive cure for diabetic nephropathy and new insights into this complication are being discovered every day. With our work we propose the first targeted therapy against proteinuria, which is a major risk factor for the progression towards end stage renal disease in diabetic patients.

Dr. Bassi: The most important aspect of the whole story is that our study re-invents a potential clinical application for a drug (Abatacept) that is already on the market as an immunomodulatory agent. The fact that Abatacept is FDA approved will most probably make it easier to start soon human studies in patients with type 2 diabetes and diabetic nephropathy.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Fiorina: Our study sheds light on a totally new mechanism of kidney damage in diabetes and importantly defines a non-immunomodulatory role for a drug that was designed to have a specific immunomodulatory action. The results that we propose find their strength in in vitro and murine model experiments but now we need to widen this exciting findings and take them into the clinical world. Much work still has to be done and we envision the application of our results into clinical trials in the near future, to confirm the validity of our study in humans as well, and finally bring our discoveries from the bench to the bedside.

Citation:

Role of Podocyte B7-1 in Diabetic Nephropathy

Paolo Fiorina, Andrea Vergani, Roberto Bassi, Monika A. Niewczas, Mehmet M. Altintas, Marcus G. Pezzolesi, Francesca D’Addio, Melissa Chin, Sara Tezza, Moufida Ben Nasr, Deborah Mattinzoli, Masami Ikehata, Domenico Corradi, Valerie Schumacher, Lisa Buvall, Chih-Chuan Yu, Jer-Ming Chang, Stefano La Rosa, Giovanna Finzi, Anna Solini, Flavio Vincenti, Maria Pia Rastaldi, Jochen Reiser, Andrzej S. Krolewski, Peter H. Mundel, and Mohamed H. Sayegh

JASN ASN.2013050518; published ahead of print March 27, 2014, doi:10.1681/ASN.2013050518