May 04, 2016
Polycystic kidney disease (PKD) is one of the most common inherited diseases—a parent with PKD has a 50 percent chance of passing the disease on to their child.
In PKD patients, dozens of fluid-filled cysts develop within the kidneys. They often become larger, causing high blood pressure, chronic pain and eventual kidney failure.
PKD also shares two important traits with cancer: both involve unregulated cell growth and neither has an effective treatment that will permanently deter the disease.
James Calvet, Ph.D., deputy director of The Kidney Institute at The University of Kansas Medical Center and member of The University of Kansas Cancer Center’s Cancer Biology program, spends the majority of his time researching PKD, and the Kidney Institute has been home to many key basic discoveries on the mechanics of the disease.
He and his team have received a large grant from the National Institutes of Health to create the Kansas PKD Research and Translation Core Center.
The PKD Core Center will focus on gene targeting, epigenetics (how pathways are disrupted in PKD), biomarkers (finding blood or urine biomarkers that would help predict early PKD progression) and clinical research (studies that bridge the gap between pre-clinical studies and early-phase clinical trials).
“Now that the genes are identified we’re hoping we’re able to target them with new therapeutics and treatment,” said Dr. Calvet.
The relationship between PKD and cancer is a major initiative of the PKD Core Center. And because the basic building block of cancer and PKD is the same—cells that don’t know when and how to stop dividing—PKD research could also provide a window into cancer prevention and treatment.
“PKD is a neoplastic disease, meaning it’s an overgrowth of abnormal cells, just like what happens in cancer,” said Dr. Calvet. “So we know there are genes in PKD that we can target for treatment, just like we’ve been able to with cancer.”
Dr. Calvet and many of his colleagues are part of KU Cancer Center’s Cancer Biology Research Program, due to the molecular similarities between the two diseases. Determining what confines PKD to the kidneys instead of spreading, or metastasizing, like cancer is one of the main questions of Dr. Calvet’s research.
“My view is that there is some protector involved that keeps the disease contained to kidneys and not metastasize,” said Dr. Calvet.
The lab recruited an epidemiologist from the National Cancer Institute (NCI) to help them study potential links between PKD and kidney cancer. Kidney cancer is the ninth most common cancer, according to the NCI, with 61,500 estimated new cases in 2015 alone.
Their study examined whether PKD patients who received kidney transplants have a higher incidence of cancer than the general population. They also looked at the cancer incidence between PKD transplant patients and kidney transplant patients without the disease.
PKD is largely a genetic disease, caused by mutations in either the PKD1 or PKD2 genes. People with this mutation see cells that make up cysts multiply out of control in kidney tissue. Previous research has shown that the formation of these cysts is driven by a large amount of proto-oncogenes. In cancer, proto-oncogenes are normal genes that can become an oncogene if they get mutated or increase in number.
Dr. Calvet and his researchers found that cancer incidence in PKD patients who received kidney transplants was 48 percent higher than expected in the general population. The most common cancers were lung, prostate, kidney, Non-Hodgkin lymphoma and melanoma.
But after adjusting for age and other factors, PKD recipients (who were generally older) were actually 16 percent less likely to develop cancer.
Still, the research suggested that while PKD mutations definitely cause cysts to form, it also seems likely that the mutations also trigger the cells to create some kind of protective mechanism that stop the cells from becoming cancerous.
Recent research by Christopher Ward, Ph.D., another faculty member of the Kidney Institute, supports this theory, showing that germline mutations in PKHD1, the gene responsible for the autosomal recessive type of PKD, stopped the formation of colorectal cancer.
Another theory proposed by Dr. Calvet and his colleagues is that PKD patients typically know at an early age that they have the disease and can create a healthy lifestyle for themselves accordingly. This knowledge could reduce some of the risk factors that can cause cancer, such as smoking and obesity.
Because this research only looks at kidney transplant recipients, it is still not known if there is a clear influence between PKD and cancer development. The PKD Core Center will be able to continue its research into the link between cancer and PKD with the support of each of its departments.
“If we can figure out why these cells are metastasizing into cancer, it would be of great interest and help to those in the cancer research field,” said Dr. Calvet.
Funding sources
The project described was supported by grant number P30 DK106912 01 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.Relevant publications
- Wetmore, J. B., Calvet, J. P., Alan, S. L., Lynch, C. F., Wang, C. J., Kasiske, B. L., & Engels, E. A. (2014). Polycystic kidney disease and cancer after renal transplantation. Journal of the American Society of Nephrology, ASN-2013101122.