A human 'tubuloid' model captures the slow progression of chronic kidney disease (CKD), addressing key limitations of animal and stem-cell models. Researchers from Institute of Science Tokyo grew 3D tubuloid structures from adult patient kidney cells and exposed them to the chemotherapy drug cisplatin to replicate key features of CKD: DNA damage, cellular senescence, inflammation, and fibrosis. This realistic platform provides a new way to develop and test treatments for a condition affecting millions globally.
Chronic kidney disease (CKD) is a progressive condition that begins with tissue damage and gradually leads to loss of kidney function. The condition, which affects about 10% of the global population, is difficult to study because it develops slowly over time and is closely linked to aging and cellular senescence. Most kidney models used today, fall short of capturing these aging-related processes. Mouse models, for example, have short lifespans and cannot replicate diseases that unfold over many years. Similarly, kidney tissues grown from stem cells often resemble immature, fetal tissues rather than the adult tissues where CKD develops.
Against this backdrop, a team of researchers at Institute of Science Tokyo (Science Tokyo), Japan, has developed 'tubuloids' that capture the key steps of CKD development. This model provides a way to study how acute kidney injury transitions into chronic disease. Tubuloids are three-dimensional tubular structures created from adult primary human renal proximal tubular epithelial cells (hRPTECs) taken from surgically removed kidneys. Unlike stem-cell organoids, tubuloids retain age-related traits from the donor, giving researchers a more realistic view of how diseased adult kidney tissue behaves.
The study was led by Adjunct Lecturer Makiko Mori, medical student Yuki Nakao, and Tenure-Track Assistant Professor Yutaro Mori from the Department of Nephrology, Graduate School of Medical and Dental Sciences at Science Tokyo, and was published online in the journal Advanced Healthcare Materials on October 9, 2025.
"CKD is challenging to study because of its complex causes and strong links to aging and cellular senescence. Current animal models, primarily mice, are limited by their short lifespan and genetic uniformity, which do not reflect the decades-long progression or diversity seen in human CKD. This highlights the urgent need for more accurate, human-based disease models," says Dr. Mori.
To build the tubuloids, the team isolated proximal tubular epithelial cells from donor kidneys and embedded them in a basement-membrane gel. After approximately two weeks, the cells organized themselves into multiple small tubuloids that showed genetic profiles characteristic of proximal tubular epithelial cells. These tubuloids developed uniform sizes and hollow, tube-like structures closely resembling native renal tubules.
To explore how the tubuloids could model kidney disease, the researchers exposed them to cisplatin, a chemotherapy drug well known for causing kidney damage. Repeated cisplatin exposure successfully recreated the transition from acute kidney injury to chronic kidney disease.
Cisplatin caused DNA damage within the tubuloid cells. This triggered the cells' repair machinery, but with repeated injury, the cells could no longer recover. Instead, they entered a state of cellular senescence. Senescent cells then develop into a senescence-associated secretory phenotype that releases inflammatory cytokines to trigger chronic inflammation and tissue fibrosis, hallmarks of CKD.
By capturing the step-by-step processes of DNA damage, senescence, inflammation, and fibrosis, the researchers were able to visualize the full pathophysiological chain of CKD. With its ability to potentially reveal how CKD develops, it could be used to test potential therapies offering hope for millions affected by this condition.
"Our study represents a major advancement in kidney disease research. Unlike animal models, our tubuloid model offers greater physiological relevance. It is expected to be used as a toxicity testing system and as a nonclinical evaluation platform for CKD therapeutics," explains Dr. Mori.
