New Model, New Hope #ExpBio

Mar 30 2015 Published by under EB 2015

I have written many times about my arch nemesis, hemolytic uremic syndrome (HUS). This disorder is what we medical docs call a thrombotic microangiopathy. Something damages the lining of small (micro) blood vessels (angio), causing platelets to clump (thrombotic) and form webs across the tiny capillaries. For some reason, organs hit by this damage include the kidney, brain, pancreas, and then pretty much anything else at random.

You can download a handout on HUS for parents here, or watch this video for the material we teach residents about HUS.

We see two forms of HUS in childhood. Atypical forms result from mutations in the complement system, a series of immune system proteins that respond rapidly to threats. This system is pretty complex, as shown in the diagram below from a great article; click the picture for the full reference. This system is always "on" and is regulated by proteins that dampen it. In atypical HUS, these regulatory proteins are deficient, allowing complement to rampage at will. The critical component is the Membrane Attack Complex (MAC) which destroys cells, be they foreign or host.


Click for source and review article.



Currently we can treat atypical HUS with eculizumab, an antibody to complement component C5, a protein just before the MAC. Antibody at c5 prevents formation of the MAC and provides miraculous results for patients with atypical HUS.

The most common form of HUS follows an episode of bloody diarrhea due to a bacteria that produces shiga toxin, most commonly E. coli. We will call this eHUS today. This toxin provides the damage to the blood vessels that triggers the thrombotic microangiopathy. Once the toxin clears, the patient usually recovers but with a high risk of kidney failure many years down the road.

In really bad cases of eHUS we have used eculizumab to help patients (desperate times and desperate measures, you know). It seems to turn off the thrombotic microangiopathy rapidly, suggesting that complement may be involved in these patients as well.

Human Mannose-Binding Lectin (MBL2) Inhibitor Prevents Renal Injury in a Novel Animal Model of Enteropathic Hemolytic Uremic Syndrome M Ozaki et al

This group, led by Gregory Stahl, took mice that lacked the mouse form of mannose-binding lectin (MBL2) and gave them the gene for the human form of this molecule. In the complement diagram above, MBL2 is a component of the Lectin activation pathway for the complement system. They then treated these mice with shiga toxin with or without an antibody to MBL2.

Shiga toxin damaged the cells lining blood vessels, releasing MBL2. This then turned on the complement system,and these mice got thrombotic microangiopathy with kidney damage. Those that received the antibody to MBL2 with the shiga toxin had far less damage from the toxin. Giving the antibody up to a day later also provided some protection from HUS.

This study is so exciting! First, it provides a mouse model of eHUS that we can use to examine the complement pathways in more detail and to develop new drug targets. Second, their anti-MBL2 antibody may be used as a treatment someday. #Winning!

Atypical HUS without treatment almost always results in kidney failure, and the disease more often than not destroys transplanted kidneys as well. Patients with eHUS recover and come off of dialysis in 90% of cases; however, they generally have 2-4 weeks of hospitalization with multiple surgeries. A treatment that could rapidly reverse kidney failure would provide substantial reductions in costs and make patients much happier. They also face an increased lifetime risk of kidney failure, depending on the level of damage at the time of the illness. New treatments beyond supportive care with dialysis may reduce this issue as well.

As a pediatric kidney doc, this study makes me very, very happy!

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