Kidneys damage lungs with inflammatory signals

About half of patients with acute kidney problems die because other, undamaged organs suddenly begin to shut down.

A research team from the Hopkins School of Medicine has found that in mice, the damaged kidneys are sending out protein signals that cause inflammation and organ dysfunction in otherwise healthy organs.

Drugs that can target and inactivate these specific proteins may help halt further organ failure in patients with kidney damage.

The research team, led by immunologist Dmitry Grigoryev, focused on the lungs' response to kidney failure. The lungs are often the first organ affected in these cases, and only 20 percent of kidney-damaged patients survive subsequent lung damage.

Grigoryev's team cut off circulation to the kidneys of lab mice for an hour to cause irreversible tissue damage.

A second group had circulation cut off for half an hour and a control group received a sham operation where the blood supply was not restricted.

The research team then analyzed the genetic activity and chemical changes in the mice's lung and kidney tissues. Although blood supply was only cut off to the kidneys, the team found similar tissue damage in the lungs.

The approximately 109 genes that control the inflammatory response for both organs showed heightened activity in the same areas.

The first group showed the greatest lung tissue injury and changes in the greatest number of genes, both persisting even 36 hours after blood flow was restored.

The second group showed changed expression in fewer genes, which were insignificant compared to those in the group receiving the sham operation, and which disappeared 36 hours after restored blood flow.

When the kidneys are injured, these genes are activated to cause inflammation at the damage site. Among other responses, the genes cause the kidney and white blood cells to secret inflammatory proteins called interleukin-6 and interleukin-10 into the bloodstream.

These proteins in turn reach other organs through the circulatory system, provoke an inflammatory response and can cause organ failure.

Lungs are especially susceptible because their large network of capillaries, the smallest blood vessels, exposes them to almost all of the chemicals passing through the bloodstream.

Although the lungs of a patient may have been perfectly healthy, the toxic signals sent out by the kidneys make them behave as if they were also damaged kidney tissue.

This study was the first to examine the genetic changes in both kidneys and distant organs as a result of kidney damage. They identified the two proteins most likely responsible for organ failure after kidney injury out of over 1,000 inflammatory proteins.

They also discovered that there are several proteins that serve as mediators between inflammation at the local site and in distant organs.

Eventually, drugs that specifically disable inflammatory proteins or these mediators can be given to patients with kidney damage to stave off failure of other organs.

Grigoryev and his team plan to study the lungs of mice that have been genetically modified and are unable to manufacture those specific inflammatory proteins, to see if this change can reduce lung damage in kidney failure.