Research on rare diseases took a big step forward in 2001 when Congress established the Office of Rare Disease Research within the National Institutes of Health. The goal was to create a system of research networks that would bring scientists, clinicians and patients with rare diseases together under one central umbrella. Since then, NIH has established 19 research networks. One of them, the Nephrotic Syndrome Study Network or NEPTUNE, is directed by Matthias Kretzler, M.D., a professor of internal medicine.
Kretzler studies rare diseases that affect the kidney and cause a condition called nephrotic syndrome. These diseases can be deadly, especially the most severe form called focal segmental glomerulosclerosis, or FSGS.
“FSGS is a disease that progresses rapidly,” Kretzler explains. “It’s devastating for patients, because adults and children with FSGS can reach end-stage kidney disease — meaning total loss of kidney function — after only one or two years.”
Except for a few rare genetic diseases, researchers don’t know exactly what causes FSGS or other nephrotic syndrome diseases, but Kretzler says they all involve damage to octopus-shaped filtration cells called podocytes, which line millions of tiny blood vessels called glomeruli in human kidneys.
“Podocytes are very sensitive to genetic mutations or environmental challenges from toxins, hormones, diabetes or hypertension,” says Kretzler. “When podocytes are damaged, proteins like albumin start to appear in urine — one of the earliest warning signs of kidney disease.”
When Kretzler joined the U-M Medical School in 2005, his first goal was to establish a multi-institutional clinical research network for the study of nephrotic syndrome similar to a network he had created in Europe. “Michigan had a strong program in basic scientific research and a long-standing association with a private, patient-interest group called the NephCure Foundation to facilitate this research,” he says.
But clinical research was a different story, Kretzler discovered. Because nephrotic syndrome diseases are so rare, it was difficult for any single institution to find enough patients for a clinical research study. Research programs were scattered across multiple institutions, and each investigator had a different research protocol. Patient records and tissue samples from one study weren’t available to other researchers. There was no established research infrastructure available to support scientists working to find causes and develop treatments for these diseases.
So a team of investigators in nephrology set about creating an infrastructure at Michigan. Combining funding from the Medical School, NephCure, the U-M Office of the Vice President for Research and a fund Shayman established to support rare disease research, Kretzler started a small, multi-center translational research study of nephrotic syndrome diseases. Data from this pilot study helped the Michigan team receive, in 2009, a $6.25 million grant from the NIH Office of Rare Disease Research to establish NEPTUNE.
Today, NEPTUNE has trained researchers at 15 participating institutions across North America. Since October 2010, 52 patients have enrolled in the clinical cohort study. More than 750 patients with nephrotic syndrome have signed up for a patient registry maintained by the NIH Office of Rare Disease Research.
“This collaborative network allows us to address one of the key challenges of rare disease research — the difficulty of identifying patients for studies,” says Kretzler.
Biopsied kidney tissue, blood and urine samples from patients enrolled in NEPTUNE are stored in a central biobank. Researchers at one institution complete genomic analyses of all tissue samples. Another institution analyzes proteins present in the samples. Detailed clinical information on patients is collected at each study visit and entered in a central database. Statisticians analyze all this information for clues that could help researchers discover what causes the cell damage and scarring associated with nephrotic syndrome diseases.
“While the specific diseases leading to FSGS are rare, the basic mechanism leading to loss of podocytes and scarring are probably the same between FSGS and other glomerular kidney diseases,” says Kretzler. “So if we can understand FSGS, there’s a real chance we could help patients with all glomerular diseases.”
Kretzler and Shayman are just two of the many U-M investigators whose research is making it possible for more people to live with rare diseases, instead of dying from them. With millions of patients still waiting for an effective treatment, however, much work remains to be done.