Infection from E. coli O157:H7 and other Shiga toxin-producing serotypes can lead to the severe, life-threatening complication called hemolytic uremic syndrome, or HUS, that can injure the kidneys, pancreas and brain.
Care during the acute phase is mostly just supportive, because there are scant treatment options for HUS, which is the most common cause of renal failure in children. About half the children who suffer HUS require dialysis.
Now two discoveries by University of Toronto researchers are said to hold promise for not only determining which people exposed to harmful E. coli are most likely to develop HUS, but also a possible treatment.
Published this week in The Journal of Clinical Investigation, the study by U of T professor Philip Marsden demonstrates that the toxins produced by E. coli increase a small protein known as SDF-1 (for chemokine stromal-derived factor 1).
When E. coli toxins attach to receptors inside human blood vessel cells, the inflamed cells begin to shred red blood cells as they pass through, which clots and slows blood flow to the kidneys. By definition, HUS is a progressive condition that develops with the destruction of red blood cells, a low platelet count and the loss of the kidneys’ filter function.
Marsden found elevated levels of SDF-1 in plasma samples from E. coli-infected children who went on to develop HUS. His research suggests that looking for excess levels of the protein in people exposed to E. coli could help doctors predict who is most likely to develop HUS.
In studying the cells most affected by HUS, the researchers also found mice with the disease showed improved health and higher survival rates when exposed to the drug plerixafor/AMD3100, which is sold under the brand name Mozobil.
Further research is required, the researchers say, but suggest that Mozobil — a chemokine receptor antagonist — could be a viable way to halt the progression of HUS by blocking proteins that impair kidney function.
Mozobil was granted so-called orphan drug status by the U.S. Food and Drug Administration in 2008 and has been used to treat patients with certain types of cancer who require stem cell transplant. “Orphan drugs” demonstrate promise for treating rare diseases or conditions.
Marsden has been studying E. coli issues since the 2000 outbreak in in Walkerton, Ontario. Seven people died in that epidemic, and 2,300 were sickened, when E. coli O157:H7 and Campylobacter from a small herd of grass-fed cows contaminated the community’s water supply.
Ten years later, researchers have found that the Walkerton survivors continue to be at risk for hypertension, kidney disease and heart disease, indicating that E. coli infection and HUS can cause permanent injury, and underscoring the need for treatment options.
In September, 2011, the FDA approved the use of Soliris (generically eculizumab) to treat atypical hemolytic uremic syndrome (aHUS), which accounts for about 5 to 10 percent of all HUS cases.
Soliris, which also works by blocking proteins that impair kidney function, was used during the E. coli O104:H4 epidemic in Germany to treat a few children suffering from HUS who were not responding to blood plasma exchange.
Three children who doctors feared would die or suffer permanent brain damage were given Soliris, and all regained renal function. One girl improved within 24 hours, and after three days no longer needed dialysis.