The kidney, in all its complexity, is captured in a new atlas

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

Only in the past few decades have scientists been able to take advantage of new techniques, like the ever-growing list of “-omics,” to peer deeply into human cells. This week, in a milestone aided by these technologies and preceded by years of work by thousands of researchers, a detailed atlas of the human kidney has been released to the public via an article published in Nature. The researchers involved consider it the most comprehensive model of kidney tissue to date and believe it could be a vital resource in studying how organs go bad and how to stop it.

By overlaying the techniques used to analyze the tissue samples, the scientists were able to find 51 major cell types, 28 cell states of kidney damage and 1.2 million “damage quarters”. This latest discovery may have the greatest potential for uncovering the causes of kidney disease, said Matthias Kretzler, professor of computational medicine and bioinformatics at the University of Michigan Medical School and corresponding author of the paper.

The researchers studied cells from nearly 100 samples from people with healthy kidneys, as well as people with acute kidney injury or chronic kidney disease. Then they compared cells from those samples to those of mice and other humans, to information in other large databases. In doing so, they were able to identify “good” and “bad” cell neighborhoods – the good being the stable areas that were functioning as intended. The bad ones were collapsing, usually due to dysfunctional neighborhood dynamics.

“You have angry neighbors yelling at each other. And we learn exactly what words are being used, ie what genes are being expressed,” Kretzler said. Then they could take that list of cellular swear words and search them in a long-term data pool from the Rare Diseases Clinical Research Network run by the National Center for Advancing Translational Sciences. “Now we ask which of these poor neighborhoods is associated with good and poor long-term outcomes” for these rare disease patients. By doing so, the researchers were able to test their hypotheses about neighborhood wars leading to poor health outcomes. In this way, rare disease research is often helpful in elucidating what happens in common conditions and how they might be treated.

New approaches are needed in kidney disease, one of the leading causes of death in the United States. One in seven adults suffer from chronic kidney disease, according to CDC estimates. But the majority of people don’t know they are sick because symptoms don’t appear until later stages of the disease. Once the organ’s function declines to the point of causing kidney failure, a transplant is the best bet that’s hard to come by – if it works, it can extend a person’s life by more than a decade. Other than that, many patients (especially people of color, who are disproportionately affected) have to rely on dialysis to filter their blood for them. Dialysis is a strenuous form of maintenance that can put people at increased risk of infections while prolonging their life by just a few years.

The hope is that the Kidney Atlas can get scientists on the same page and nudge the field toward breakthroughs after decades of relative stagnation.

“This is a huge step in the right direction,” said Rafael Kramann, a professor of medicine who heads the Kidney and Cardiovascular System Translational Research Laboratory at the Erasmus Medical Center 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 receives very little oxygen or nutrients. These ungrateful workers appeared to be one of the weakest parts of the nephron, which is a building block of the entire organ, Kretzler said. But experts already knew that: Kidney physiologists from the National Institute of Diabetes and Digestive and Kidney Diseases’ Kidney Precision Medicine Project, which funded the project, had studied the phenomenon in the 1980s.

In this way, the Kidney Atlas serves to corroborate what scientists have thought for decades and offer new insights. In the past, researchers would do the equivalent of standing outside a building, trying to figure out what loud noise was radiating through the walls, but never being able to get inside. Now, thanks to next-generation sequencing tools, experts are inside the building, identifying the source of the noise and working 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,” says Anna the Greek, a physician-researcher at the Broad Institute of Harvard and MIT, whose group has contributed to the understanding of cell neighborhoods. Because the International Human Cell Atlas – which strives to track all human cells throughout life – was involved, the Kidney Atlas and accompanying data are public and open source. A websiteatlas.kpmp.org, offers additional information on how the atlas was built and allows anyone to download study guides and data for their own studies.

“It’s important, because we want all scientists around the world to have access to this information,” Greka said.

And there is still a lot to do. The atlas data is at the mRNA level, a step between DNA and proteins that help cells perform their basic functions. Further studies are therefore needed to dig deeper into the protein level and understand how crosstalk between cells affects health and disease, Greka said.

For Kramann, fully mapping the human kidney will require more information and high-resolution spatial data on specific kidney diseases, such as glomerular diseases (from these tiny filters), with clinical follow-up information. These additions would go a long way toward “understanding disease mechanisms to pave the way for urgently needed new therapies,” he said.

While the document itself has 50 authors, the atlas is the culmination of the work of hundreds of researchers. The Human BioMolecular Atlas program, or HuBMAP, was also involved in the project. It creates a platform for scientists around the world to map healthy cells in the human body.

STAT’s coverage of chronic conditions is supported by a grant of Bloomberg Philanthropies. OUR financial support are not involved in decisions about our journalism.