Stimulating your own recovery power may prevent chronic kidney damage

In sepsis, your immune system reacts so violently to infection with a pathogen that your organs suffer damage, including the kidneys. Half of sepsis patients already have acute kidney damage when they enter the hospital. “One in five people with sepsis do not survive,” says internist-acute medicine and pharmacologist Prof. Dr. Hjalmar Bouma of UMCG in Groningen. Of the people who do survive, one in five will have chronic kidney damage a few years after sepsis. And with that: an increased risk of high blood pressure and death from cardiovascular disease and kidney failure. Bouma: “We suspect that broken energy factories in the kidney cells are involved.”

Hope to prevent suffering
Bouma has now devised a way to repair acute kidney damage caused by sepsis. This not only reduces the risk of death during sepsis, but probably also prevents people from developing chronic kidney damage after recovery from sepsis. “If we succeed, we can prevent a lot of suffering.”

Stimulate your own recovery power
What Bouma wants to do is get the energy factories in the kidney cells (so-called mitochondria) working again. Sepsis ensures that these are thwarted, causing kidney cells to die rapidly. “People who recover from sepsis without permanent kidney damage manage to repair their mitochondria themselves. If we find out how, we may be able to stimulate our own recovery power in others.” He will receive a Kolff+ grant from the Kidney Foundation for his idea and the innovative way in which he wants to do it.

Less repair in sepsis
It was Bouma himself who discovered that the energy factories are involved in kidney damage during sepsis. “You see much fewer mitochondria and more damaged mitochondria in sepsis kidney cells. And in the blood of sepsis patients you see more damaged mitochondrial DNA.” Mitochondria carry their own DNA because of their important job: providing the cell with energy. It is normal for this DNA to regularly sustain damage. In healthy people the cell repairs this. This happens less during sepsis. Bouma: “There is a strong relationship between the amount of broken mitochondrial DNA in the blood and the chance that you will die.”

Push button not yet known
Repairing the energy factories in kidney cells has never been done. Mitochondria repair is a new field of expertise. “But we know that you can stimulate mitochondria to repair. This has been demonstrated in laboratory research with different types of cells.” Only the push button which allows you to restore kidney cells Onmove, unknown. “Several processes are probably involved. And there are several proteins that regulate this.” Those are the push buttons that Bouma is going to look for. He also examines which means you can use to push them in in a controlled manner.

Compare thousands of proteins
To do this, Bouma will first look at proteins in mouse kidney cells. And specifically to signaling proteins. They pass on certain substances within the cell, for example, or cut other proteins and thus influence a specific cell process. Bouma will compare, among other things: how many of which signaling proteins are present in healthy kidney cells, in kidney cells with sepsis and in kidney cells that recover from sepsis? Bouma: “Then the painstaking work starts, because this will generate a lot of data.” A cell always contains thousands of proteins. If you discover a protein that fewer occurs in kidney cells that die from sepsis but well in surviving kidney cells, this does not prove that this protein caused the mitochondria to recover. “Smart computer programs help us find out which proteins are probably the push buttons.”

Human kidney cells
But is Bouma sure that the findings he will make in mice also apply to humans? To check this, he will culture human kidney cells, induce sepsis in them and look at the signaling proteins again. Does he see the same proteins and processes involved in sepsis recovery in mice? Then follows another double check. “We then culture human kidney cells that are no longer able to produce those specific signaling proteins. Then we induce sepsis. Will energy factories indeed not be restored? Then we have the right push buttons.”

Green light
Then you have to wait for the green light. Literal. Bouma will select substances from a database that are likely to react with the signaling proteins he has found. He will test these drugs on cultured human kidney cells. This can be done automatically, with hundreds of resources at the same time. “We then adapt the cells in such a way that they emit a fluorescent light when the protein that forms the push button for mitochondria repair is activated. Is it caused by the drug? Then the cells light up green.”

Quickly to possible treatments
Since no one yet knows how to restore kidney mitochondria, Bouma’s research is fundamental. But the aim of this Kolff+ research is to quickly translate it into possible treatments.
“Working at the boundaries of knowledge and applying it immediately is exactly what I like about it,” says Bouma. One day he works in the hospital as an internist in the emergency room, the next he is in the lab and spars with fellow researchers. “It starts with questions that arise when I talk to people affected by sepsis and acute kidney injury. The research provides answers. This will allow us to offer patients better care in the future. That’s what we do this for.”