By Lauren Malecki

Katalin Susztak, MD, PhD

Katalin Susztak, MD, PhD, a professor of Internal Medicine, Nephrology and Genetics at the Perelman School of Medicine at the University of Pennsylvania, never envisaged she would one day pioneer groundbreaking advancements in kidney disease treatment. Yet, an unforeseen twist during her postgraduate training, set her on a path of exploration to unravel the intricacies of the kidney and revolutionize the way kidney disease is identified, prevented, and managed.

It was during medical school in Hungary, where she was born and raised, that Susztak discovered her fascination with research to understand how organs and the human body works. She started doing research in medical school focused on ion channels and transporter molecules that transport electrolytes in and out of white blood cells. After earning her MD and PhD from Semmelweis University in Budapest, she moved to New York City to train in internal medicine and later in nephrology.

A chance meeting leads to nephrology

Her interest in kidney disease was sparked during her intern year when she saw a patient whose illness was caused by defects in the exact same transporter protein she had studied in graduate school. She was beyond excited about the possibility of taking her discoveries at the bench to the bedside of such patients. Erwin P Bottinger, MD, then professor of Nephrology and presently CEO of the Wyss Center for Bio- and Neuroengineering, was so impressed by her molecular understanding of the patient’s kidney problem, he invited her to visit his renal lab and work there. She instantly fell in love with the work and decided to become a nephrologist.

According to Susztak, few new approaches had worked to treat or cure kidney disease over two decades, between 2000-2019, when she embarked on her career in this field and the understanding of how the kidney helps the body get rid of waste remains incomplete. As she began developing her own research lab as a principal investigator, Susztak and her team looked at how more than one million people worldwide die of kidney failure each year — despite existing therapies that include drugs, dialysis and transplants and said, “We have to change that.”

It was the early 2000s, when scientists were just starting to study gene expression changes in a genome wide level, not just one gene at a time, which was immediately appealing for Susztak. She decided to analyze biopsy samples collected from patients with kidney disease using these genomics tools to take an open-ended or unbiased look at all the genes expressed in the samples. The goal was to identify new genes and molecular pathways for the development of diabetic kidney disease, the most common cause of renal failure in patients.

Bringing award-winning work to Penn Medicine

Some of the first discoveries the team has made using these unbiased methods include defining the role of developmental pathways in chronic progressive kidney disease. For this early work, Susztak received the Young Investigator Award from the American Society of Nephrology and the American Heart Associations in 2011.   

Susztak moved to Penn Medicine the following year with the mission of working toward defining the pathomechanism of diabetic and hypertensive kidney disease.

Her team doubled down to tackle kidney disease using a variety of approaches. First, they started to focus on characterizing the genetic underpinning. Kidney function has a strong heritable component, meaning it tends to run in families, so by collecting genetic and kidney function data for more than 1.5 million people, her team was able to generate a genetic map of where the likely causal genes reside in the genome. Second, Susztak’s team expanded the use of tools for analyzing kidney tissue not only just how the expression of genes change (genomic) but also how genes are organized and regulated ( epigenetics ) as well as studying kidney proteins and metabolites at global scale.

Breakthrough pinpoints problematic kidney cells

A critical limitation of prior work has been that the kidney is a very complex organ made of more than 30 different cell types. Nearly five years ago, Susztak’s lab made a major advancement for kidney disease when a single-cell tool—the first of its kind at Penn Medicine—became available for their use to pinpoint which kidney cells were responsible for different disease types at a cellular and molecular level. “It was transformative and accelerated our research and we were able to connect different subtypes of kidney disease to different cell types in the kidney,” said Susztak.

Now, thanks to the combination of human genetic information and variety of single-cell tools, her team has identified hundreds of genes likely contributing to kidney dysfunction. From this long list, Susztak’s lab has already characterized the role of nearly half a dozen specific genes to better understand why people develop kidney disease and how the diseases progress. Furthermore, Susztak has made her comprehensive datasets available to the public, via generating and maintaining a website where other scientists can look up and analyze her results and discover new genes.

One of her favorite genes is apoliprotein L1 (APOL1). She was the first to demonstrate the causal role of APOL1 risk variants, explaining the higher risk of kidney disease, sepsis, and COVID-19 severity specifically in Black people. She delineated cellular pathways of APOL1 toxicity, enabling the development of targeted therapeutics to address these significant health disparities.

Susztak works alongside Michelle Denburg, MD, MSCE, associate professor of Pediatrics and Epidemiology at Children’s Hospital of Philadelphia (CHOP), as a co-leader of the Penn-CHOP Kidney Innovation Center, establishing a large research collaboration on Penn‘s campus focused on transforming patient care by early detection, prevention, and treatment of kidney disease and its complications across the life course.

In addition, she is the founder and principal investigator of the Transformative Research In Diabetic Nephropathy (TRIDENT) study, a unique academic/industry partnership working to identify and test novel therapies that can improve the lives of those with diabetes and kidney disease.

Each of these advancements is in service toward a larger goal, she said: “We need to bring basic discoveries back to the clinic and to our patients, we need new disease classification, diagnostics and therapeutics. The goal should be to eliminate kidney disease during the next 20 years.” 

 

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