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Healthy versus damaged podocytes: An electron microscopy image shows the difference in a healthy kidney (right), with filtering cells called podocytes that have distinct, finger-like structures. In minimal change disease (left), these structures flatten out. This change is only visible at very high magnification.
Image Credit: Eri Koshi-Ito, Nagoya University
Scientific Frontline: Extended "At a Glance" Summary: Rituximab and T Cells in Kidney Disease
The Core Concept: Rituximab (RTX), an intravenous drug primarily known for depleting B cells, has been found to also trigger positive metabolic changes in T cells, specifically improving energy production and lowering cellular stress in patients with nephrotic syndrome who respond favorably to the treatment.
Key Distinction/Mechanism: While RTX's established mechanism is the elimination of B cells, its effectiveness in treating minimal change disease (MCD) is now linked to downstream effects on T cells. In responders, the depletion of B cells reduces T-cell exhaustion, enhances mitochondrial energy metabolism, and lowers reactive oxygen species (ROS) levels, a sequence of events largely absent in non-responders.
Origin/History: RTX has been utilized to treat steroid-dependent nephrotic syndrome, but its mechanism beyond B-cell depletion remained unclear. In Japan, RTX was recently approved for adult health insurance coverage in June 2026, following off-label use and clinical observations conducted at Nagoya University between 2018 and 2022.
Major Frameworks/Components:
- Minimal Change Disease (MCD): A form of nephrotic syndrome where immune system dysregulation damages specialized kidney filtering cells, called podocytes, without causing structural damage visible under standard microscopic examination.
- B-Cell and T-Cell Crosstalk: The fundamental communication pathway between these two immune cell types, which becomes abnormal in MCD and is subsequently modulated by RTX treatment.
- Oxidative Stress Reduction: The mechanism by which RTX lowers elevated levels of reactive oxygen species (ROS) in T cells, preventing the molecular damage and functional degradation associated with cellular exhaustion.
- CD4⁺ Cytotoxic T Cells: A specific subset of T cells that demonstrates significantly reduced exhaustion and improved energy metabolism following successful RTX treatment.
Branch of Science: Immunology, Nephrology, and Cellular Biology.
Future Application: The early changes observed in T-cell metabolism and ROS levels could serve as predictive biomarkers to identify which patients will respond to RTX. This would allow clinicians to avoid unnecessary repeated infusions, minimize infection risks, and optimize personalized treatment protocols for steroid-dependent patients.
Why It Matters: Because long-term steroid use causes severe side effects and some patients relapse upon dose reduction, understanding RTX's dual effect on B and T cells offers a crucial pathway to reliable, targeted remission in difficult-to-treat forms of nephrotic syndrome.
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| After rituximab removes B cells, T cells demonstrate reduced cell exhaustion and improved energy metabolism in patients who respond to the treatment, especially within a subset called CD4⁺ cytotoxic T cells. Credit: Koshi-Ito et al., 2026, iScience (CC BY-NC 4.0) |
Nephrotic syndrome occurs when the filtering system in the kidneys is damaged, allowing large amounts of protein to leak into the urine. It is usually treated with steroids; however, in some cases, steroids alone are insufficient, and long-term steroid use has serious side effects. Some patients develop a difficult-to-treat form of the disease that returns when the steroid dose is reduced.
For these patients, the intravenous drug rituximab (RTX) has proven effective. RTX removes B cells—a type of immune cell thought to contribute to the disease—from the blood. Now, researchers from Nagoya University in Japan have found that the drug does more than eliminate B cells; it also triggers a reaction in another type of immune cell, T cells. This reaction increases the T cells' energy production and lowers cell stress in patients who respond to RTX treatment. These changes were largely absent in nonresponders.
The findings, published in iScience, identify a previously unknown link between B cells and T cells that could help predict how a patient with nephrotic syndrome will respond to RTX.
One Drug, Two Cell Types, Different Responses
The most common cause of nephrotic syndrome is minimal change disease (MCD). In most cases, it is thought to occur when the immune system damages specialized filtering cells in the kidney called podocytes. However, the exact mechanism is unknown. Even in severe cases, the kidney shows no visible structural damage under standard examination. The damage only becomes visible under high magnification, hence the name “minimal change.”
“B cells and T cells communicate with each other to regulate the immune system. Normally, B cells help fight infections by producing antibodies, but in minimal change disease, they are thought to play a role in causing it,” said lead author Eri Koshi-Ito, an assistant professor at the Graduate School of Medicine at Nagoya University.
“We tracked changes in gene expression in individual T cells and conducted oxidative stress measurements for these cells in a separate group of patients. All individuals were adults with MCD who had been steroid-dependent for about 10 years.”
Blood samples were collected from patients before their first RTX treatment and one month later. Samples from 14 patients were obtained: six for gene expression analysis and eight for oxidative stress measurements. Patients were classified into “responders,” who were able to stop steroids and stay in remission after treatment, and “nonresponders,” who could not stop steroids or who relapsed within six months of treatment.
Gene expression analysis of T cells showed that genes involved in mitochondrial energy production were more active in responders after treatment. The patient group assessed for oxidative stress showed elevated levels of reactive oxygen species (ROS) in T cells before treatment, which dropped afterward; in contrast, nonresponders showed the opposite trend.
Oxidative stress occurs when a cell accumulates too many ROS. These are unstable molecules produced as a byproduct of the cell’s energy-producing processes. In small amounts, ROS help the cell function normally; however, when they build up faster than the cell can neutralize them, they can damage cell proteins, DNA, and other components and wear down the cell.
“In both responders and nonresponders, RTX depleted B cells as expected, but only in responders did this trigger significant downstream changes in T cells, including a reduction in the number of exhausted T cells weakened by prolonged stimulation. In nonresponders, T cells showed comparatively little change,” said senior author Professor Hiroshi Suzuki of the Graduate School of Medicine. “Our findings suggest that the effectiveness of RTX is linked to improved cell metabolism and reduced cell stress soon after treatment begins.”
Using public data on children with nephrotic syndrome, the researchers also found that T cells rely on a less efficient method of producing energy and that disease-related B cells and T cells exhibit abnormal communication with each other.
Toward a Predictive Test
B cells nearly disappear after RTX treatment and typically return within six months. Some patients stay in remission well after the cells return, while others relapse even when no B cells are present. Therefore, B-cell removal alone cannot explain how RTX works, and no reliable method exists to predict who will respond.
In Japan, RTX has been covered by health insurance for adults only since June 2026. For this study, RTX was administered to patients at Nagoya University between 2018 and 2022 under an approved ethical protocol for off-label use. At the time, the drug was used more cautiously, often administered months apart, making it possible to clearly distinguish responders from nonresponders. Now that early, repeated RTX use is more common, this distinction is harder to make.
With adults now gaining wider access, determining who should receive RTX and when remains a key question. Early identification of likely responders could lead to earlier remission and fewer complications. It could also prevent unnecessary repeat infusions and the associated infection risks for likely nonresponders.
The researchers believe the early changes they have identified in T-cell metabolism and ROS levels can serve as biomarkers to address these issues and help optimize treatment for this difficult-to-treat form of nephrotic syndrome. They note that larger trials are needed to confirm their results and determine if these changes can predict how a patient will respond.
Funding: This work was supported by grants from the Japan Agency for Medical Research and Development (AMED) (JP24ek0109753, JP22ama221111, JP23kk0305026, JP23tk0124003, JP24ck0106875, JP25nk0101727, JP25ck0106019, JP25ak0101291, JP23ck0106791, and JP25kk0305028); the YOKOYAMA Foundation for Clinical Pharmacology (YRY-2412); an Aichi Kidney Foundation Grant; a JSPS Grant-in-Aid for Research Activity Start-up (JP24K23431); a JSPS Grant-in-Aid for Early-Career Scientists (JP25K19485, JP25K19486); a JSPS Grant-in-Aid for Scientific Research (A) (JP24H00614); JSPS Home-Returning Researcher Development Research (JP19K24694); the Takeda Science Foundation; the Toray Science Foundation (22-6304); the Inamori Research Institute for Science (InaRIS); and a JSPS Fellowship for Young Scientists.
Published in journal: iScience
Authors: Eri Koshi-Ito, Yu Watanabe, Chikao Onogi, Asuka Horinouchi, Koichi Ogami, Seiko Yoshino, Yohei Sugimoto, Shintaro Komatsu, Akihito Tanaka, Kazuhiro Furuhashi, Shoichi Maruyama, and Hiroshi I. Suzuki
Source/Credit: Nagoya University
Edited by: Scientific Frontline
Reference Number: imgy090926_01
