At the start of each workday, Friedhelm Hildebrandt sits down at his computer and composes e-mails to patients and their physicians around the world. He writes to request a little blood, which contains the DNA his lab uses to find the genes responsible for chronic kidney diseases.

Hildebrandt's lab has used these blood samples, and a database of 3,000 families that includes his own pediatric patients, to identify and characterize nearly a dozen novel genes involved in chronic kidney diseases. As many as 20 million people in the United States alone have a chronic kidney disease and will eventually require dialysis or a kidney transplant to survive.

As a clinician who treats children with chronic kidney disease, Hildebrandt knows how these conditions can affect the life of a child. “These children are chronically ill, and their quality of life can be seriously eroded. They suffer in their growth and development,” he said.

“Hardly anything is known in pediatric nephrology about origins of kidney diseases. Our concept of how these diseases occur hasn't changed much in 150 years,” he said. “We would like to identify as many primary causes of kidney diseases in children as possible. Then, we finally might be able to do something about the disease itself, and not just treat the symptoms.”

Over the past decade, Hildebrandt and his group began to unravel the mystery one gene at a time, homing in on the causes of pediatric kidney diseases including nephronophthisis, nephrotic syndrome, and urinary tract malformations. Interestingly, many of these conditions are mongenic, meaning a mutation in a single gene is enough to cause disease. But the causes of more than 70 percent of cases of chronic kidney disease remain unknown, he said.

Hildebrandt's group uses a technique known as positional cloning to analyze patients' blood samples, scanning a tract of the genome to look for markers of disease. Once the genetic region is found, researchers can identify and sequence the disease gene and any mutations.

Identifying mutated genes that cause chronic kidney disease, Hildebrandt noted, is a starting point. “Once we find them we can figure out the mechanisms by which proteins interact to give rise to the diseases.” That mechanistic understanding is what researchers need to develop treatments for patients.

On occasion, such work can yield a molecular jackpot—a finding that has implications for understanding the broader manifestations of disease. In 2003, Hildebrandt's group published a seminal paper showing that mutations in genes that are active in cilia, common structures on the surface of many kinds of cells, can give rise to cystic kidney diseases. The discovery of these “ciliopathies” helped explain why some kidney diseases can be associated with disorders outside the kidney, causing blindness, hearing loss, liver disease, or mental retardation. “The involvement of cilia was an absolutely surprising common denominator,” Hildebrandt noted. What's more, the group found that the genes at play are conserved in mice and zebrafish, opening the door to valuable new animal models for a fatal human disease.

Much remains to be discovered to explain these diseases, however. So, with the laboratory tools and patient relationships they have developed, Hildebrandt's lab is taking the quest to the next level.