May 29, 2020

New method for mapping kidney disease and drug discovery

Kyoto researchers chart the course of tissue inflammation during kidney disease and treatment

Short-term, or acute, injuries to the kidneys can often turn into life-threatening and long-term, or chronic, diseases. Although over a hundred drugs can stop acute kidney injuries from developing into chronic diseases when tested in mice, none of them has worked in humans. A possible explanation is the young age of the mice in such drug studies, which may not recapitulate AKI pathophysiology, which mainly occur in the elderly.

Because older people have an increased risk for chronic kidney disease progression after acute kidney injury, researchers have shifted their attention to investigating biological differences between different age-groups, in both humans and animals. Indeed, a team from the Institute for the Advanced Study of Human Biology at Kyoto University recently found that kidney injury led to the appearance of immune tissues inside the kidneys of older, but not younger, mice and humans.

The researchers have now also discovered the multiple and variable types of immune tissues in extracted kidneys from patients who had kidney infection. The type of immune tissue present reflected the severity of kidney disease. By charting the extent of immune tissue development in mice, the team found that drug treatment could reverse kidney inflammation.

Motoko Yanagita, leader of the Kyoto University team, says, “We previously noticed that older mouse and human kidneys developed multiple tertiary lymphoid tissues, which seemed to promote inflammation after an acute injury. We were curious to see if these immune tissues in human kidneys could provide some insights for improving diagnosis and designing new therapies.”

Tertiary lymphoid tissues, or TLTs, form from immune cells in inflamed organs. Resembling lymph nodes, these structures act like local factory branches of the immune system. They assemble, nurture, and activate immune cells called T- and B-cells but can have positive or negative health effects depending on local conditions.

First, the team cut thin sections of 16 human kidneys that were inflamed from infection. After the addition of specific molecular tags of various colors, microscopy revealed three types of TLTs, as groups of proliferating T- and B-cells with distinctive features. The team classified the types as stages I, II, and III, in increasing level of maturity and organization. Half of the infected kidneys contained stage I TLTs, whereas the other half contained TLTs at stages II and III, regarded as advanced-stage TLTs.

Next, the researchers looked at cancer-free sections of kidney from 69 older patients. Nearly half of the kidneys contained TLTs, mostly at stage I. Analysis of the 29 kidneys with chronic disease (low filtration rate or high protein level in urine) versus the 40 kidneys without chronic disease revealed an association between the extent of kidney disease and an increased proportion of advanced-stage TLTs.

When compared with TLT-positive kidneys from the older patients, those from the patients with kidney infection showed a higher proportion of advanced-stage TLTs. However, noticing that the immune tissues in kidneys from both patient groups displayed similar compositions and positions, the researchers conclude that TLT formation may be a common feature of disease and thus a potential general biomarker of local inflammation and injury.

Finally, studies in older mice involving a simulated kidney injury confirmed that the proportion of advanced-stage TLTs was linked to the severity of kidney injury. Remarkably, treatment of the mice with dexamethasone — a steroid that is commonly used to treat inflammation and was recently found to help manage COVID-19 symptoms — greatly reduced the amount of advanced-stage TLTs. In another mouse experiment in which kidney damage was chemically induced, dexamethasone caused all TLTs to disappear, partially reversed scarring, and improved kidney function. These results offer promise for future effective treatment and drug discovery for kidney disease in humans.

Yanagita says, “It was surprising to find a variety of tertiary lymphoid tissues in inflamed or injured kidneys of both mouse and human. It will be clinically useful that we can now place the structures into categories that are related to the course of disease. I hope the classification system will guide more accurate diagnosis for sufferers of chronic kidney disease.”

Paper Information

Yuki Sato, Peter Boor, Shingo Fukuma, Barbara M. Klinkhammer, Hironori Haga, Osamu Ogawa, Jürgen Floege and Motoko Yanagita (2020), Developmental stages of tertiary lymphoid tissue reflect local injury and inflammation in mouse and human kidneys, Kidney International, DOI: