An overactive immune response can damage the kidneys but also presents a promising target for treatments to slow or prevent disease progression.

When harmful bacteria or other microorganisms invade the body, neutrophils, a type of white blood cell, are one of the first immune cells to respond. They release powerful weapons to trap and kill these threats, one of the most important being neutrophil extracellular traps, or NETs. These are web-like structures made from DNA and proteins that act like sticky nets, trapping microbes and preventing them from spreading.

While NETs play an important role in fighting infections, scientists have discovered that they can also cause serious harm if produced in the wrong place or at the wrong time. This is especially true in the kidneys, where too many NETs or poor clearance of these webs can trigger inflammation and cause tissue damage.

A new review published in the journal Nature Reviews Nephrology by a team of researchers led by Professor Akihiro Ishizu at the Faculty of Health Sciences, Hokkaido University, highlights the role neutrophils and NETs play in a wide range of kidney diseases. When the immune system fails to properly regulate these structures, the resulting inflammation can injure the delicate blood vessels and filtration systems in the kidneys. Over time, this can contribute to the development of several serious conditions, including ANCA-associated vasculitis, lupus nephritis, thrombotic microangiopathy, diabetic kidney disease, and crystal-induced kidney injury.

“Neutrophils are usually there to protect us, but in these diseases, they seem to be part of what is causing the problem,” says Ishizu, the review’s corresponding author. “We’ve known for years that inflammation is an important part of kidney disease, but what we’re now seeing is that neutrophils and NETs are more than just passive participants. They are actively making the damage worse, and this gives us new ways to think about treatment.”

Researchers are exploring several different strategies to prevent neutrophils from causing harm. One approach focuses on blocking the chemical signals that activate neutrophils in the first place. One of these signals is a molecule called C5a, which can cause inflammation. Drugs like avacopan, which block the receptor for C5a, have already shown promising results in clinical trials for vasculitis and are expected to become more widely used.

Another strategy involves stopping NETs from forming. Scientists are developing drugs that block the enzymes and proteins inside neutrophils responsible for building these DNA webs. The hope is that preventing NET formation will stop the cycle of inflammation and injury that leads to kidney failure.

Researchers are also working on ways to help the body clear away NETs more efficiently. Enzymes like DNase I and DNase1L3 can break down the sticky DNA webs, but NETs that are altered by disease can be more difficult to degrade. Understanding how to overcome this problem is an active area of research.

The review suggests that targeting neutrophils and NETs could lead to a major shift in how kidney diseases are treated. Until now, doctors have mostly relied on general immune-suppressing drugs, which can leave patients vulnerable to infections and other complications.

“The exciting part is that by going after the specific pathways that cause NETs and tissue damage, we might be able to give patients better treatment with fewer side effects,” says Daigo Nakazawa of the Department of Rheumatology, Endocrinology and Nephrology at Hokkaido University and first author of the review. “We’re hopeful that as more clinical trials move forward, therapies that target neutrophils will help slow or even stop the progression of kidney disease.”

Review Article:

Daigo Nakazawa, et al. Neutrophils and NETs in kidney disease. Nature Reviews Nephrology. March 18, 2025.
DOI: 10.1038/s41581-025-00944-3

Funding:

Publication of this work was supported by the Ministry of Health, Labour and Welfare of Japan via the JPVAS (23FC1019).

Contacts:

Professor Akihiro Ishizu
Faculty of Health Sciences
Hokkaido University
Tel: +81-11-706-3385
Email: aishizu[at]med.hokudai.ac.jp

Naoki Namba
Public Relations & Communications Division
Office of Public Relations and Social Collaboration
Hokkaido University
Tel: +81-11-706-2185
Email: en-press[at]general.hokudai.ac.jp