Powerful tool supports advances in diagnosis,
prognosis and treatment
PHILADELPHIA, July 24,
2024 /PRNewswire/ -- Researchers at Children's
Hospital of Philadelphia (CHOP)
and the Perelman School of Medicine at the University of Pennsylvania revealed the most
extensive single cell atlas of the human kidney, capturing the
complexity of healthy and diseased kidneys at an unprecedented
level and predicting chronic kidney disease (CKD) progression
earlier in its course. The findings were published today in the
journal Nature Genetics.
CKD affects more than 1 in 7 U.S. adults – an estimated 37
million Americans, according to the National Institutes of Health
(NIH). The risk is even higher for Americans with diabetes or
high blood pressure – the two most common causes of CKD.
"CKD is rare in children, but for those affected, it can be a
very serious life-altering condition," said Jonathan Levisohn," MD, PhD, one of the first
authors and a pediatric nephrology fellow in the Division of
Nephrology at CHOP. "It is also clear that while CKD most commonly
affects older individuals, the risk for developing the disease
starts to accrue much earlier, starting during gestation and
childhood."
Senior study author Katalin Susztak, MD, PhD, emphasized that
the findings fill a critical knowledge gap by presenting the first
ever roadmap of the human kidneys that includes the analysis of
spatial relationship of the cells.
"Human kidneys are intricate three-dimensional structures in the
body, but until this research, the spatial and molecular principles
of kidney health and disease were not well understood," said
Susztak, Co-Leader of the Penn-CHOP Kidney Innovation Center, a
research collaboration between CHOP and Penn-Medicine focused on
transforming patient care through early detection, prevention and
treatment of kidney disease and its complications across the
lifespan. "We now have a powerful tool for prognosis, outperforming
traditional histopathological analysis especially in early-stage
kidney disease."
In the study, Susztak and her team analyzed more than 700,000
cells from 81 kidney samples in patients from ages 24 to 90. The
researchers used machine learning to develop the high-resolution
atlas, allowing them to integrate multi-omics data, map cellular
and spatial information, identify tissue microenvironments and
develop predictive models for kidney disease progression.
Key findings include identification of 44 main and 114 distinct
cell sub-types or states in both healthy and CKD-affected human
kidneys. The researchers identified four distinct spatial
microenvironments based on gene expression: glomerular, immune,
tubule and fibrotic.
Fibrosis is a common manifestation across all forms of
progressive CKD with most prior studies focusing on its predictive
ability in severe cases. Glomerular filtration rate (GFR) and
albuminuria predict kidney function decline reasonably well in
advanced CKD, but prognosis is challenging in earlier disease
stages. In this study, however, data revealed a gene signature in
the fibrotic microenvironment (FME-GS), that can classify kidney
samples and predict future kidney function decline.
The team plans to further define the fibrotic microenvironment,
validate its predictive power in additional cohorts and understand
the underlying mechanisms. They aim to explore therapeutic targets
within the fibrotic microenvironment, potentially paving the way
for new treatments to halt or reverse kidney fibrosis.
"Although foundational, we envision the clinical implications of
this study to be potentially profound, as this new understanding
can lead to better diagnostics and precision treatments for
patients with chronic kidney disease," said Susztak, who is also a
Professor of Medicine at Penn.
Work in the Susztak Lab is supported by the National Institutes
of Health grants P50DK114786, DK076077, DK087635, DK132630 and
DK105821. The study is also supported by GSK, Regeneron, Boehringer
Ingelheim and Novo Nordisk. The funders have no influence
on the reported results. Additional support for this work was
provided by the Ben Lipps Fellowship. the Deutsche
Forschungsgemeinschaft German Research Foundation grant DU
2449/1-1, the MOLMED Ph.D. program at the Medical University of
Graz, a Marietta-Blau Grant and an Austrian Marshall
Plan Foundation scholarship.
Abedini and Levinsohn et al. "Single-cell multi-omic and spatial
profiling of human kidneys implicates the fibrotic microenvironment
in kidney disease progression." Online July
24, 2024. Nature Genetics. DOI:
10.1038/s41588-024-01802-x.
About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of
Philadelphia was founded in 1855
as the nation's first pediatric hospital. Through its long-standing
commitment to providing exceptional patient care, training new
generations of pediatric healthcare professionals, and pioneering
major research initiatives, the hospital has fostered many
discoveries that have benefited children worldwide. Its pediatric
research program is among the largest in the country. The
institution has a well-established history of providing advanced
pediatric care close to home through its CHOP Care Network, which
includes more than 50 primary care practices, specialty care and
surgical centers, urgent care centers, and community hospital
alliances throughout Pennsylvania
and New Jersey, as well as the
Middleman Family Pavilion and its dedicated pediatric
emergency department in King of
Prussia. In addition, its unique family-centered care and
public service programs have brought Children's Hospital of
Philadelphia recognition as a
leading advocate for children and adolescents. For more
information, visit https://www.chop.edu.
Contact: Jennifer Lee
Children's Hospital of Philadelphia
(267) 426-6084
leej41@chop.edu
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SOURCE Children's Hospital of Philadelphia