The kidney, in all its complexity, is captured in an atlas that could aid disease research

The kidneys are some of the most architecturally complex organs in the human body — intricate in a way that becomes frustrating when, for millions of people each year, they lose function. 

It’s only in recent decades that scientists have been able to leverage new techniques, like the ever-growing list of “-omics,” to peer deep inside human cells. This week, in a major milestone aided by those technologies and preceded by years of work by thousands of researchers, a detailed atlas of the human kidney was unveiled to the public via a paper published in Nature. Researchers involved consider it the most comprehensive kidney tissue model to date, and think it could be a vital resource in the study of how the organs go awry, and how to stop it. 

By layering techniques used to analyze tissue samples, scientists were able to find 51 main cell types, 28 kidney injury cellular states, and 1.2 million “injury neighborhoods.” The latter finding might have the most potential for uncovering the causes of kidney disease, said Matthias Kretzler, a professor of computational medicine and bioinformatics at the University of Michigan Medical School, and a corresponding author on the paper. 

Researchers studied cells from nearly 100 samples from people with healthy kidneys, as well as those with acute kidney injury or chronic kidney disease. Then, they compared the cells in those samples to those from mice and other humans, to information in other large databases. In doing so, they could identify “good” and “bad” neighborhoods of cells — the good being stable areas that were working as intended. The bad were falling apart, usually due to dysfunctional neighborly dynamics. 

“You have unhappy neighbors shouting at each other. And we learn exactly what words are used, meaning what genes are expressed,” Kretzler said. Then, they could take that list of cellular cuss words and search for them in a pool of long-term data from the Rare Diseases Clinical Research Network led by the National Center for Advancing Translational Sciences. “Now we ask which of these unhappy neighborhoods is associated with good and bad long term outcomes” for those rare disease patients. By doing so, the researchers could test their hypotheses about which neighbor wars led to bad health outcomes. In that way, rare disease research is often helpful to elucidate what’s happening in common conditions, and how they might be treated.

New approaches are sorely needed in kidney diseases, a leading cause of death in the U.S. One in every seven adults has chronic kidney disease, the CDC estimates. But the majority of people don’t know they’re ill because symptoms don’t show up until later stages of disease. Once the organ’s function declines to the point of kidney failure, a transplant is the hard-to-get best bet — if it works, it can extend a person’s life by over a decade. Short of that, many patients (especially people of color, who are disproportionately affected) must rely on dialysis to filter their blood for them. Dialysis is a taxing form of maintenance that can put people at greater risk of infections while extending their lives by only a few years. 

The hope is that the kidney atlas can get scientists on the same page and push the field toward some breakthroughs after decades of relative stagnation. 

“This is a tremendous step into the right direction,” said Rafael Kramann, a professor of medicine who directs the Laboratory of Translational Kidney and Cardiovascular Research at Erasmus Medical Centre in the Netherlands. Kramann published his own kidney atlas in 2022, but was not an author on the latest iteration. 

One of the most alarming neighborhoods was a cell subtype that works hard to filter — one of the kidney’s essential functions — but gets very little oxygen or nutrients. These thankless workers appeared to be one of the weakest parts of the nephron, which is a building block of the whole organ, Kretzler said. But experts already knew that: Renal physiologists from the Kidney Precision Medicine Project of the National Institute of Diabetes and Digestive and Kidney Diseases, which funded the project, had studied the phenomenon in the 1980s. 

In that way, the kidney atlas serves to corroborate what scientists have thought for decades, and to offer new insights. In the past, researchers were doing the equivalent of standing outside of a building, trying to figure out what the loud noise is that’s radiating through the walls, but never able to get inside. Now, with next-gen sequencing tools, experts are inside the building, identifying the source of the noise and investigating how to silence it. 

One of the great benefits of having an organ atlas is that it “can serve as a common reference for everyone in the field,” said Anna Greka, a physician-scientist at the Broad Institute of Harvard and MIT, whose group contributed to the understanding of cell neighborhoods. Since the international Human Cell Atlas — which is working to track all human cells across the lifespan — was involved, the kidney atlas and accompanying data is public and open source. A website, atlas.kpmp.org, offers additional information on how the atlas was built, and lets anyone download instructional guides and data for their own studies. 

“This is important, because we want all scientists all around the planet to have access to this information,” Greka said. 

And there is still a lot to do. The atlas data is on the mRNA level, a step between DNA and the proteins that help cells perform their basic functions. So more study is needed to drill down to the protein level and understand how cross-talk between cells affects health and disease, Greka said. 

To Kramann, fully mapping the human kidney will require more high-resolution spatial information and data on specific kidney diseases, such as glomerular diseases (of those tiny filters), with clinical follow-up information. Those additions would greatly help “understand disease mechanisms to pave the way for urgently needed novel therapies,” he said. 

While the paper itself has 50 authors, the atlas is a culmination of work by hundreds of researchers. Also involved in the project was the Human BioMolecular Atlas Program, or HuBMAP, which is creating a platform for scientists around the world to map healthy cells in the human body.

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.