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

Abstract

Introduction: Plasma exchange therapy (PEX) was standard treatment for thrombotic microangiopathy before eculizumab was available and is still widely applied. However, most PEX patients still ultimately progress to end-stage renal disease (ESRD). It has been suggested that infusion of plasma that contains active complement may induce additional complement activation with subsequent activation of neutrophils and endothelial cells, leading to exacerbation of organ damage and deterioration of renal function.

Objective: This observational pilot study examines the effect of hemodialysis, eculizumab and PEX before and after treatment in plasma of aHUS patients on complement-, neutrophil and endothelial cell activation.

Methods: Eleven patients were included in this pilot study. Six patients were treated with hemodialysis, 2 patients received regular infusions of eculizumab, and 3 patients were on a regular schedule for PEX. Patients were followed during 3 consecutive treatments. Blood samples were taken before and after patients received their treatment.

Results: Complement activation products increased in plasma of patients after PEX, as opposed to patients treated with hemodialysis or eculizumab. Increased levels of complement activation products were detected in omniplasma used for PEX. Additionally, activation of neutrophils and endothelial cells was observed in patients after hemodialysis and PEX, but not in patients receiving eculizumab treatment.

Conclusion: In this pilot study we observed that PEX induced complement and neutrophil activation, and that omniplasma contains significant amounts of complement activation products. Additionally, we demonstrate that hemodialysis induces activation of neutrophils and endothelial cells. Complement activation with subsequent neutrophil activation may contribute to the deterioration of organ function and may result in ESRD. Further randomized controlled studies are warranted to investigate the effect of PEX on complement- and neutrophil activation in patients with thrombotic microangiopathy.

Keywords: Atypical hemolytic uremic syndrome; Complement; Nucleosomes; Plasma exchange therapy; Solvent detergent-treated plasma.

Fig. 1

Complement activation is elevated in patients after PEX. a C3b/c. b C3a. c C3d. d C4b/c. e C3. Concentrations were measured in patients before and after they received treatment. n = 18 hemodialysis (3 consecutive treatments of 6 patients), n = 6 eculizumab (3 consecutive treatments of 2 patients), n = 8 PEX (3 consecutive treatments of 2 patients and 2 consecutive treatments of 1 patient). **p < 0.01, ****p < 0.0001.

Fig. 2

Omniplasma contains high levels of activated complement products. a C3b/c. b C3a. c C3d. d C4b/c. Concentrations were measured in plasma before and after treatment of 2 patients and in 10 omniplasma units administered to these 2 patients subjected to PEX.

Fig. 3

Endothelial and neutrophil activation were observed after hemodialysis and PEX. a Von Willebrand factor antigen. b Von Willebrand factor propeptide. c Elastase-α₁-antitrypsin complexes. d Lactoferrin. e Nucleosomes. All were measured in patients before and after they received treatment. n = 18 hemodialysis (3 consecutive treatments of 6 patients), n = 6 eculizumab (3 consecutive treatments of 2 patients), n = 8 PEX (3 consecutive treatments of 2 patients and 2 consecutive treatments of 1 patient). The dotted line represents the normal value or range in plasma. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Fig. 4

mtDNA is not affected by treatment in aHUS patients. a mtDNA concentrations were measured in patients before and after they received treatment. n = 18 hemodialysis (3 consecutive treatments of 6 patients), n = 6 eculizumab (3 consecutive treatments of 2 patients), n = 8 PEX (3 consecutive treatments of 2 patients and 2 consecutive treatments of 1 patient). b mtDNA concentrations were measured in plasma before and after treatment of 2 patients and in 10 omniplasma units administered to these 2 patients subjected to PEX.