Discovery may aid search for kidney disease treatment and prevent recurrence after transplant.
A protein known as suPAR has been identified in recent years as both a reliable marker for chronic kidney disease and a pathogen of the often deadly condition. Its place of origin in the human body, however, has been a mystery — until now. In study results published Dec. 12 in the journal Nature Medicine, a research team announced they have identified a type of immature myeloid cell, located in the bone marrow, as the source of abnormal levels of suPAR.

"These immature myeloid cells appear as a main source of circulating suPAR," says Jochen Reiser, MD, PhD, principal investigator and senior author of the study presented in Nature Medicine, who has been working on solving the mysteries of suPAR for more than a decade. Reiser is Ralph C. Brown, MD, Professor and chairperson of the Department of Internal Medicine at Rush University Medical Center.

Researchers had deduced that circulating suPAR likely originates from outside the kidneys because clinicians see high levels of the molecule in patients that have received a new kidney after their own kidneys have been damaged by FSGS disease. Recurrence of FSGS can be as high as 30 percent in adults and even higher in children.

Not everyone develops kidney disease – not in the course of a life, nor after the receipt of a transplanted organ. In both cases, Reiser says, "The question was, what triggers the changes in the cells?" suPAR provides an answer and serves as the first identified bona fide circulating factor.

Reiser's team used a "humanized" mouse model that utilizes patients’ peripheral blood stem cells to communicate signals to mouse bone marrow immature myeloid cells. These genetically modified animals serve as a transfer study system of human kidney disease and thus as a study aid to investigate the production and action of suPAR.

Early discoveries led researchers to home in on the hematopoietic system, the organs that produce the two kinds of blood cells, lymphoid and myeloid cells. Using mice bred to lack some types of lymphoid cells, among other features, researchers were able to show that those mice still had high levels of suPAR and proteinuria, indicating that lymphoid cells were not the perpetrators of kidney disease. At that point, the team began to focus on the myeloid cells, leading to their new findings.

Further research will be necessary to establish solid connections between the suPAR production site in mice and the human cell types, Reiser says. It also might be possible to establish a genetic link to the process that unleashes suPAR on a person's system. FSGS rates are high in the black population, for example, Hahm adds.

As for treatments, the paper states, "Stem cell transplantation may prove to be a viable approach to treat diseases such as suPAR–associated kidney disease."

As to those immature myeloid cells that arise in bone marrow, they are more developed than stem cells, but have not grown into their final function as, for example, neutrophil white blood cells. The specific type of cells the researchers in the new Nature Medicine paper looked at, and identified as giving rise to suPAR, are bone marrow GR–1lo, Sca1+ immature myeloid cells.

In the Nature Medicine journal paper, "Bone marrow–derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease," the suPAR researchers suggested that their discovery and their investigative approach owed much to the work of other investigators and might prove useful for researchers investigating other diseases that appear to arise spontaneously in certain individuals for no discernible reason.