Merits of Plasma Exchange Called Into Question in Small aHUS Study

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Plasma exchange may be doing more harm than good for people with atypical hemolytic uremic syndrome (aHUS), a small study suggests.

Specifically, the treatment was found to increase the activation of the complement system — a part of the immune system that is already overly active in aHUS patients. However, the study found that Soliris (eculizumab) or hemodialysis did not have this effect.

Plasma exchange products were found to have high levels of complement activation molecules, which may explain why many treated aHUS patients still progress to kidney failure, the researchers noted.

Larger studies are needed to confirm these findings, they wrote.

The study, “Plasma Exchange Therapy Using Solvent Detergent-Treated Plasma: An Observational Pilot Study on Complement, Neutrophil and Endothelial Cell Activation in a Case Series of Patients Suffering from Atypical Hemolytic Uremic Syndrome,” was published in the journal Transfusion Medicine and Hemotherapy.

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aHUS is a rare disorder characterized by the destruction of red blood cells, low platelet levels, and the formation of blood clots in small blood vessels, which can lead to organ damage, particularly in the kidneys.

It is caused by the abnormal activation of the complement system, a set of more than 30 blood proteins that form part of the body’s immune defenses. This leads to the activation and damage of endothelial cells — those lining blood vessels — which lose their anti-blood-clotting properties, thereby promoting the formation of blood clots.

Before the approval of Alexion Pharmaceuticals’ Soliris — a complement-suppressing therapy shown to effectively prevent kidney failure — plasma exchange was the mainstay treatment for aHUS. It is “still applied as emergency treatment upon presentation and in case complement inhibitors are not available,” the researchers wrote.

Plasma exchange involves removing and replacing a person’s plasma — the liquid portion of blood that contains water, salts, and proteins — which in the case of aHUS is used to substitute defective or deficient complement control proteins.

However, healthy plasma used in this approach can contain several complement-activating proteins, which may result in a sustained activation of the complement system and subsequent organ damage in people with aHUS.

While about two-thirds of aHUS patients “initially show a positive response to PEX [plasma exchange] with preservation of [kidney] function for multiple years, most patients still finally progress to [kidney failure],” the researchers wrote.

With this in mind, a team of researchers in the Netherlands and Switzerland evaluated the effects of plasma exchange, hemodialysis, and Soliris on the activation of the complement system, endothelial cells, and neutrophils in 11 aHUS patients.

Hemodialysis, a standard treatment for aHUS patients who have kidney problems, involves using a machine that filters waste products, salts, and fluid from the blood when the kidneys can no longer do it. Neutrophils are a type of immune cell whose activation is thought to be involved in aHUS.

Six patients were treated with hemodialysis (three times a week), three with plasma exchange (once or twice a week), and two with Soliris (every other week) at the Amsterdam University Medical Centre. They were followed for three consecutive treatments, and blood samples were collected 30 minutes before and after each treatment.

Patients in the hemodialysis group were older (median of 50 years) than those treated with plasma exchange (median of 18 years) or Soliris (median of 26 years). Both patients on Soliris and one patient given plasma exchange had received a kidney transplant, and two patients in the hemodialysis group and one in the plasma exchange group had high blood pressure.

Results showed the levels of several molecules indicative of complement activation — C3b/c, C3a, C3d, and C4b/c — were significantly increased after treatment with plasma exchange, but not after hemodialysis or Soliris.

The team found that OctaplasLG, the plasma used for plasma exchange in these patients, contained high levels of complement activation products. These levels were similar or higher than those found in the blood of aHUS patients after plasma exchange.

In addition, plasma exchange and hemodialysis both resulted in a significant increase in the levels of neutrophil activation markers, while endothelial cell activation was significantly boosted only after hemodialysis. Soliris had no effect on these processes.

Markers of neutrophil activation were also detected in OctaplasLG.

These findings highlight that plasma exchange promotes complement and neutrophil activation, which “may contribute to the deterioration of organ function and may result in [kidney failure],” the team wrote.

The data also “identified the complement activation products in [OctaplasLG] as a potential source of the complement activation products observed in patients after PEX,” the researchers wrote.

“By introducing complement activation products in the patient’s circulation, PEX may theoretically not cease but rather maintain the ongoing complement activation,” and giving plasma “that already contains complement activation products may therefore cause more harm than benefit,” they wrote.

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“It remains surprising that … PEX, a therapy used to treat complement-mediated diseases, in fact seems to increase the amount of complement activation products in patients,” and that “the products used for this procedure contain complement activation products,” the team wrote.

Previous studies have suggested that the separation and filtration steps in plasma preparation may promote complement activation.

Larger studies are needed to confirm these findings and better understand the relevance of this plasma exchange-induced complement and neutrophil activation.