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Reduction of complement activation and renal dysfunction with PMMA-based CVVH treatment in sepsis-induced AKI

New relevant findings on the role of polymethylmethacrylate (PMMA)-based continuous venous venous hemofiltration (CVVH) in an animal model of sepsis-induced AKI have been published in Frontiers of Immunology. The results show that PMMA-based CVVH significantly reduces tissue and systemic complement activation limiting renal damage and fibrosis, highlighting the potential role of PMMA membrane as a therapeutic strategy in patients with septic acute kidney injury (AKI).

The article is available as open-access here.

 

Aim of study

To investigate the efficacy of polymethylmethacrylate membrane (PMMA)-based continuous hemofiltration (CVVH) in modulating systemic and tissue immune-activation in a swine model of LPS-induced AKI.

 

Methods

After 3 h from LPS infusion, animals underwent to PMMA-CVVH or polysulfone (PS)-CVVH. Renal deposition of terminal complement mediator C5b-9 and of Pentraxin-3 (PTX3) deposits were evaluated on biopsies whereas systemic complement activation was assessed by ELISA assay. Gene expression profile was performed from isolated peripheral blood mononuclear cells (PBMC) by microarrays and the results validated by real-time PCR.

 

Results

Endotoxemic pigs presented oliguric AKI with increased tubulo-interstitial infiltrate, extensive collagen deposition, and glomerular thrombi; local PTX-3 and C5b-9 renal deposits and increased serum activation of classical and alternative complement pathways were found in endotoxemic animals.

PMMA-CVVH treatment significantly reduced tissue and systemic complement activation limiting renal damage and fibrosis.

Microarray analysis identified 711 and 913 differentially expressed genes with a fold change >2 and a false discovery rate <0.05 in endotoxemic pigs and PMMA-CVVH treated-animals, respectively. The most modulated genes were Granzyme B, Complement Factor B, Complement Component 4 Binding Protein Alpha, IL-12, and SERPINB-1 that were closely related to sepsis-induced immunological process.

 

Conclusions

These data suggest that PMMA-based CVVH can efficiently modulate immunological dysfunction in septic induced AKI. The  results demonstrated that PMMA-CVVH treatment prevented the development of tubulointerstitial fibrosis, tubular damage, and inflammatory process by interfering with the activation of renal resident cells and circulating leucocytes.

Indeed, PMMA showed excellent removal capacity of soluble components involved in inflammation and in immune system and reduced local and systemic Complement activation, recovering the balance between the pro- and anti-inflammatory mediators.

Finally, PMMA based treatment modulated gene expression in circulating leucocytes, thereby controlling complement system and innate immunity and preserving B and T cells response against infection, limiting immunological dysfunction and renal damage. These results highlight for the first time the efficacy of a new PMMA membrane in CVVH modality as a possible future therapeutic strategy with a significant impact on short- and long-term outcomes for patients  with septic acute kidney injury (AKI).