By Elodie Vaz | Published on April 27,
2026 | 3 min read
Chronic kidney disease
(CKD) affects more than 10% of the global population, representing nearly 850
million people. It is characterized by a progressive and irreversible decline
in kidney function, which may ultimately require dialysis or transplantation.
While its risk factors—such as diabetes, hypertension, obesity, and
inflammation—are well established, one particularly concerning feature remains:
even when the initial cause is treated, the disease almost always continues to
progress. This self-sustaining nature, long poorly understood, represents a
major challenge in clinical management.
In this context, two
research teams from the Necker-Enfants Malades Institute
(Inserm/CNRS/Université Paris Cité), led by Dr. Marco Pontoglio and Dr. Fabiola
Terzi, sought to identify the mechanisms responsible for this relentless
progression. Their work focused on HNF1B, a protein known for its key role in
kidney embryonic development and in regulating numerous genes.
A multi-model
experimental approach
The researchers combined
human data with mouse models to investigate the consequences of reduced HNF1B
activity in the adult kidney. They relied on advanced gene expression analysis
techniques, as well as the study of more than 900 kidney biopsies covering
various stages and causes of chronic kidney disease. This integrated approach
aimed to link early molecular changes with functional alterations.
A molecular vicious
cycle
The findings show that
decreased HNF1B activity leads to rapid and severe kidney dysfunction,
associated with fibrosis and tissue atrophy. Tubular cells, which are normally
differentiated and stable, lose their identity, begin to proliferate
abnormally, and eventually enter senescence or undergo apoptosis, contributing
to tissue deterioration.
The researchers also
identified a specific gene expression signature regulated by HNF1B, which is
altered very early in disease models—sometimes even before visible lesions
appear. This alteration is associated with impaired tissue repair.
Moreover, the study
highlights a self-perpetuating mechanism: pathological factors such as
inflammation or the presence of albumin in urine reduce HNF1B activity. “Our
results reveal the existence of a true vicious cycle that explains the
self-sustaining nature of kidney diseases: reduced HNF1B activity promotes
kidney disease, and in turn, kidney disease progressively suppresses HNF1B
activity, further aggravating kidney damage,” explained Dr. Marco Pontoglio in
an Inserm press release.
Analysis of human
biopsies confirms the robustness of this mechanism: the molecular signature of
HNF1B loss of function is consistently observed, with intensity correlating
with disease severity. “This study establishes HNF1B as a true guardian of
kidney function. Its loss of activity, for the first time, links rare genetic
kidney diseases and common forms of chronic kidney disease through a single
mechanism,” emphasized Dr. Fabiola Terzi.
Therapeutic perspectives
By identifying a unifying
mechanism that explains continuous disease progression, these findings open up
promising therapeutic avenues. “Finding a way to restore HNF1B activity could
help slow down, or even modify, the course of chronic kidney disease,” concluded
Dr. Fabiola Terzi.
Beyond the kidney, this
discovery also invites further investigation into whether similar mechanisms of
loss of cellular identity and harmful feedback loops may exist in other chronic
diseases, potentially opening new directions in translational medicine.
Read next: sFas:
a new warning signal in kidney disease?
About the Author – Elodie Vaz
Health journalist, CFPJ graduate (2023).
Élodie explores the marks diseases leave on bodies and, more broadly, on
human life. A registered nurse since 2010, she spent twelve years at patients’
bedsides before exchanging her stethoscope for a notebook. She now investigates
the links between environment and health, convinced that the vitality of life
cannot 
