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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.

New Atlas Of Human Kidney Cells To Help Unlock Kidney Disease Research

In a major breakthrough toward understanding and treating kidney disease, a nationwide research team funded by the National Institutes of Health has created the most comprehensive atlas of the human kidney. Data from the Kidney Tissue Atlas will allow the comparison of healthy kidney cells to those injured by kidney disease, helping investigators understand the factors that contribute to the progression of kidney disease and kidney failure or recovery from injury. The atlas, part of the Kidney Precision Medicine Project (KPMP), was supported by NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), as published in Nature.

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Due to the complexity of the kidney, scientists have struggled to develop kidney models that accurately represent human kidney structures and function. The lack of human kidney models has limited the ability to develop new drugs to treat or prevent kidney disease.

The Kidney Tissue Atlas comprises maps of 51 main kidney cell types that include rare and novel cell populations, 28 kidney cellular states that represent injury or disease, a repository of raw gene data, and interactive 3D models of cells and microenvironment relationships created from 45 healthy donor kidneys and 48 kidney disease biopsies. The atlas thus establishes a critical foundation for KPMP's overall goal to help discover new treatments for chronic kidney disease (CKD) and acute kidney injury (AKI), medical conditions that present a significant global health burden. The publicly available data created by KPMP, including all 3D renderings and analytical tools, can be accessed at atlas.Kpmp.Org.

"KPMP's new atlas represents open, public science at its best," said Dr. Eric Brunskill, KPMP program director in NIDDK's Division of Kidney, Urologic, and Hematologic Diseases. "With the atlas, we've created an interactive, hypothesis-generating resource for kidney disease investigators and clinicians around the world."

While CKD and AKI have historically been described as single, uniform diseases, KPMP builds on growing consensus that kidney disease can have several different root causes and disease pathways leading to subgroups of CKD and AKI. Instead of a "one size fits all" approach to treating kidney disease, precision medicine explores more personalized treatments. KPMP's kidney atlas is intended to help identify disease subgroups within CKD and AKI, leading to the discovery of new, and possibly individualized, ways to treat CKD and AKI.

The study also received support from the Human Cell Atlas initiative, an international research effort to gather information on at least 10 billion human cells, and NIH's Human BioMolecular Atlas Program (HuBMAP). HuBMAP's goal is to develop an open and global platform to map healthy cells in the human body; the KPMP and HuBMAP teams worked closely to align the outputs of this molecular atlas as an example of cross-consortia collaborations.

"KPMP brings together the best of new technology, patient engagement, and partnership, and represents an evolution in the way we think about kidney disease," said NIDDK Director Dr. Griffin P. Rodgers. "We're confident the Kidney Tissue Atlas will help us discover new ways to get the right kidney disease treatment to the right patient at the right time."

Single-cell Atlas Of The Human Kidney Provides New Resources To Study Kidney Disease

What causes certain individuals who experience a sudden decline in kidney function to develop kidney disease while others recover? A new study co-led by bioengineers at the University of California San Diego could provide detailed insight -- at the level of individual cells -- into the underlying factors contributing to these divergent outcomes.

The researchers constructed the largest single-cell atlas of the human kidney to date that maps healthy and diseased cell states across over 90 patients. The atlas is intended to serve as a foundation to better understand the progression of kidney disease after acute kidney injury, a condition in which the kidneys suddenly lose their ability to filter waste from blood.

"We want to understand that progression at the single-cell level," said study co-first author Blue Lake, who conducted this research as a project scientist in the Department of Bioengineering at UC San Diego. "By building an atlas of the different types of cells that make up a healthy kidney, as well as injured and diseased kidneys, we can start to figure out which cell types may be contributing to disease progression. We can get an idea of what changes are happening that cause some injured cell types to repair, and in some cases, transition into a state that can no longer be repaired."

The work, published July 19 in the journal Nature, was jointly led by the lab of former UC San Diego bioengineering professor Kun Zhang, who is now at San Diego Institute of Science, Altos Labs, and researchers at Washington University, Indiana University, and University of Michigan.

To construct their atlas, the researchers analyzed more than 400,000 cells and nuclei from a broad range of kidney samples from individuals with healthy kidneys, acute kidney injury, and chronic kidney disease.

Single-cell and single-nucleus sequencing technologies were used to generate RNA expression and gene expression profiles of the cells. These profiles enabled the researchers to identify 51 different populations of cell types. Using spatial imaging technologies, the researchers were able to map where the different cell types are arranged in the kidney.

"This is the most comprehensive atlas so far of cell types in the human kidney," said Lake.

The researchers also discovered that 28 of these cell types are altered in acute kidney injury.

What normally happens when kidney cells get injured is that they enter a repair state in which they make new copies of themselves, as well as release signals that recruit immune cells and fibroblasts, to heal the injured area. Afterwards, they return to their normal cell state.

But with the altered cell types, a return to the normal state does not happen, the researchers found. Instead, they get stuck in the repair state. As a result, they continue to recruit more immune cells and fibroblasts. This drives inflammation and fibrosis, which in turn leads to progression of disease and irreversible reduction of kidney functions.

"These repair states are normally important for healing but can become maladaptive," said Lake. "If they persist or are constantly being stimulated, that will cause the kidney to continue into a diseased state."

The researchers found that these altered cell types, with the so-called "maladaptive repair state," live in two areas of the nephrons, which are the major filtering units of the kidney. The first area is called the proximal tubule, which has been known from previous studies in mice. This new study reveals that a second area in the nephrons, called the thick ascending limb, also houses these altered cell types.

"We were surprised to see this maladaptive repair state show up in human cells in this other area," said Lake. "We have now identified another area in the kidney that can be associated with disease progression. Hopefully, these insights will lead the way to further developments in the field."

The researchers are constructing the next version of their kidney atlas. Their goal is to include data from a more diverse population of patients.

This work was supported in part by the National Institutes of Health Common Fund Programs; National Heart, Lung and Blood Institute; and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

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