F12 Sorbent Based and Hybrid Therapies for Extracorporeal Support Continuous Hemodiafiltration with Cytokine-Adsorbing Hemofilters (CAH-CHDF)

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1 F12 Sorbent Based and Hybrid Therapies for Extracorporeal Support Continuous Hemodiafiltration with Cytokine-Adsorbing Hemofilters (CAH-CHDF) Hiroyuki Hirasawa, MD, PhD Professor Emeritus, Department of Emergency and Critical Care Medicine Chiba University Graduate School of Medicine, Chiba, Japan Professor, Graduate School of Medicine International University of Health and Welfare, Chiba, Japan (March 7, Wednesday, 2018)

2 Keywords in a New Pathophysiology of Sepsis PRRs (pattern-recognition receptors): A primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify pathogen-associated molecular patterns (PAMPs), and/or damage-associated molecular patterns (DAMPs) or alarmins. PAMPS (pathogen-associated molecular patterns): Molecules associated with groups of pathogens, that are recognized by cells of the innate immune system. DAMPs (damage-associated molecular patters), Alarmins: An array of structurally diverse multifunctional host proteins that are rapidly released during infection or tissue damage, and that have mobilizing and activating effects on receptor-expressing cells engaged in host defense and tissue repair. 2

3 A List of PAMPS and DAMPs / Alarmins PAMPS (Exogenous) Triacyl lipopeptide Peptideglycan Lipoprotein Double-stranded RNA endotoxin Flagellin Diacyl lipopeptide Single-stranded RNA Unmethylated CpG DNA Uropathogenic Echerichia coli Lipoteicoic acid DAMPs / Alarmins (Endogenous) Necrotic tissue HSPs (HSP-60, HSP-70, Gp-96) Biglycan Self-messenger RNA Extra domain A-containing fibronectin Fibrinogen Polysaccharide fragments of heparin sulfate Oligosaccharides of hyaluronic acid Oxidized low-density lipoprotein Surfactant protein A in the lung epithelium 1 Neutrophil elastase Chromatin-IgG complex β-defensin 2 HMGB1 S100s HDGF IL-1a Uric acid Cathelicidins Defensins EDN Galectins Thymosins Nucleolin Annexins

4 Endotoxin Removal in the Treatment of Septic Shock Endotoxin is only one of PAMPs, not a key player in the pathophysiology of septic shock. There are many septic shock patients without endotoxemia. Therefore, the efficacy of the modality solely aiming at the removal of endotoxin in septic shock treatment is questionable.

5 Pathophysiology of Sepsis and Septic Shock Infection Protease activation Endogenous Activators, Alarmin PAMPS PRRs (TLRs, NLRs, RLRs, CLRs) Pro-Inflammatory Cytokines Anti-Inflammatory Cytokine Hypercytokinemia Dysregulation of Host Immune Mechanism Inflammatory Response NETTING Coagulation System Disruption of Tight Junction and Glycocalyx Circulatory Failure Cell Dysfunction / Death necrosis, apoptosis, necroptosis stunning, autophagy Endothelial Hyperpermeability Capillary Leak Syndrome Interstitial Edema Dysoxia Organ Failure (Hirasawa H: Blood Purif 2012;34:164-70)

6 Therapeutic Approach to PAMPs and DAMPs / Alarmins Pathway PAMPs Blockade PRRs Blockade Cytokine Blockade PAMPS Pattern Recognition Receptors (PRRs) Hypercytokinemia Infection Alarmins Damps or Alarmins Blockade

7 Countermeasures against Hypercytokinemia 1) Prevention of Excess Release 2) Immunotherapy 3) Pharmacotherapy 4) Biological Therapy 5) Blood Purification 6) Gene Therapy 7) Immunomodulation 8) Autonomic Nerve Modulation 9) Others

8 Acute Blood Purification Modalities for Removal of Cytokines and Other Humoral Mediators 1) High Filtration Volume Continuous Hemofiltration (CHF) or Continuous Hemodiafiltration (CHDF) 2) Continuous Hemodiafiltration (CHDF) with a Cytokine- Adsorbing Hemofilter 3) On-line Hemodiafiltration 4) Direct Hemoperfusion (DHP) with Endotoxin Adsorbing Polymyxin B Immobilized Column (PMX) 5) Plasma Exchange 6) Coupled Plasma Filtration Adsorption

9 Continuous Hemodiafiltration with Cytokine-Adsorbing Hemofilter (CAH-CHDF) 1) CAH-CHDF is the blood purification employing all three mechanism of blood purification, diffusion, convection and adsorption, and is really a hybrid blood purification modality. 2) CAH-CHDF can remove variety of cytokines from blood stream and effectively lower. Furthermore, CAH-CHDF is also effective as CRRT. 3) The removal of cytokines with CAH-CHDF is mainly through the adsorption of cytokines to hemofilter membrane and such adsorption capacity varies among hemofilter membranes. Therefore, membrane material is crucial when CHDF is applied as a cytokine modulator. 4) Among many kind of hemofilter membrane materials, only PMMA (polymethyl methacrylate) membrane and AN69ST membrane have powerful adsorption capacity of cytokines as far as we know.

10 Non-Renal Indication of Cytokine-Adsorbing Hemofilter CHDF (CAH-CHDF) 1) Sepsis, Septic Shock 2) Acute Respiratory Distress Syndrome (ARDS) 3) Postoperative Status with Persistent Hypercytokinemia 4) Severe Acute Pancreatitis 5) Congestive Heart Failure, Cardiogenic Shock 6) Hematological Disorders, Malignant Tumor 7) Thrombotic Microangiopathy 8) Trauma, Hemorrhagic Shock 9) Post-Cardiac Arrest Syndrome (PCAS) 10) Others

11 100 survival (%) Predicted Survival and Observed 28 Day Survival of Septic Shock Patients Treated with AN69ST CHDF APACHEⅡ score 32.7±9.8 (mean±s.d.) All patients (n =34 ) APACHEⅡ 25 (n = 9 ) APACHEⅡ 30 (n = 6 ) :Predicted survival (predicted with APACHEⅡ score) :Observed 28-day survival (AN69ST-CHDF trial) APACHEⅡ 35 (n = 6 ) APACHEⅡ (n = 13 ) (Hirasawa H, et al: Blood Purif 2012;34:164-70)

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13 Comparison of Survival of Patients with Severe Sepsis and Septic Shock Treated According to SSCG mean±sd Author Shapiro Shorr Ferrer Castellanos Ortega Levy Chiba PMMA- CHDF Japan AN69ST- CHDF Country US US Spain Spain (SSC database) Japan Japan Year of Publication Number of Cases , , Age (years) 68.0± ± ± ±15.1 unavailable 63.5± ±12.1 APACHE II (predicted survival) 22.6±8.8 (57.6%) 23.3±9.6 (54.0%) 21.3±7.8 (61.1%) 23.2±7.8 (54.0%) unavailable 27.0±7.7 (39.5%) 32.5±10.2 (22.7%) Survival 79.7% 70.0% 68.9% 62.5) 65.2% 82.4% 73.5% Ratio to Predicted Survival

14 Reported Survival with Various Blood Purification Modalities aiming at the Removal of Causative Humoral Mediators in Septic Shock Patients Author HVHF Honore et al Piccinni P et al Cornejo R et al Boussekey N et al Year of publication Number of patients APACHE II 31.5 ± ± ± ±4.1 Predicted survival 26.7% 39.5% 43.1% 29.7% Observed 28d survival 55.0% 55.0% 60.0% 66.7% Observed/ predicted survival ratio PMX-DHP Vincent JL et al Kojika M et al Nakamura T et al Cruz DN et al ± ± ± (19-23) 73.8% 73.8% 57.6% 61.1% 70.6% 87.5% 70.0% 67.7% CAH-CHDF (Chiba Group) PMMA-CHDF 2008 AN69ST-CHDF ± ± % 20.3% 79.1% 73.5% HVHF: high volume hemofiltration, PMX-DHP direct hemoperfusion with an endotoxin-adsorbing column CAH-CHDF: continuous hemodiafiltration using cytokine-adsorbing membrane hemofilter, PMMA: polymethyl-methacrylate

15 Summary 1) CAH-CHDF (Continuous Hemodiafiltration with Cytokine-Adsorbing Hemofilter) is the blood purification employing all three mechanisms of blood purification (diffusion, convection and adsorption), and is really a hybrid blood purification modality. 2) CAH-CHDF can remove pro- and anti-inflammatory cytokines from blood stream non-selectively and effectively, and thus is very effective in the treatment of critical illness where hypercytokinemia plays a pivotal role in pathophysiology. 3) Furthermore, CAH-CHDF is also very effective as CRRT.