1300-1430_Dialyzer how to have there gone_ศ.นพ.ขจร ตีรณธนากุล

Novel Dialyzers: Novel Dialyzers How Far Have They Gone? • Hemodialyzer Innovation ศ.นพ.ขจร ตีรณธนากลุ • Polymer and biomaterial • Biocompatibility ภาควิชาอายุรศาสตร์ คณะแพทยศาสตร์ • Membrane permeability and performances โรงพยาบาลจฬุ าลงกรณ์ และ จฬุ าลงกรณ์มหาวิทยาลยั • High-flux dialyzer online HDF Dialysis Weekend 2023: “Moving Forward in Dialysis Care” • Super high-flux/Medium-cutoff dialyzer 17th February 2023 • Low BFR Hemodialysis • High BFR Hemodialysis: Expanded HD (HDx) • HDx vs. High-flux HD • HDx vs. Online HDF • Albumin loss but stable long-term serum albumin • Conclusion Hemodialyzer Innovation Hemodialyzer Innovation: Membrane polymers • Advances in polymer and biomaterial • Cellulose : Unsubstituted cellulose vs. Substituted cellulose • Membrane polymers • Synthetic polymers • Potting polymers • Caps and Housing • Polysulfone (PSu) family (PSu, PES, PEPA, Blends form) • Polyacrylonitrile (PAN) family • Advances in biocompatibility • Polymethylmethacrylate (PMMA) family and variants • Ethylene vinyl alcohol (EVAL) copolymer family • Advances in permeability and dialysis performances Advancement - Blending with copolymer additive to increase hydrophilicity, biocompatibility, better solute permeability - Advanced in nanocontrolled spinning process - BPA free membrane Hemodialyzer Innovation: Membrane polymers Hemodialyzer Innovation: Membrane and BPA Advancement • BPA (Bisphenol A) plasticizer - Advanced in nanocontrolled spinning process • common component of synthetic polycarbonate plastics and many membrane polymer • endocrine disruptor with adverse health effects : thyroid and hepatic dysfunction, obesity, DM, HT, inflammation, reproductive toxicity, carcinogenesis, and CV event. • BPA in serum : General population 3.25 (0.59-14.89) ng/ml, Dialysis patient 7.5 ± 3.5 ng/mL • International campaigns for reduction the BPA content in commonly used products, especially products for babies or children 1

Hemodialyzer Innovation: Membrane and BPA Hemodialyzer Innovation: Membrane and BPA • BPA is found in housing (polycarbonate) and membrane Bosch-Panadero E, et al. JASN 2015 • Polycarbonate 47.2 ug/g • Polysulfone (PSu) 8-24.5 ug/g • Polyamide • Polyester polymer alloy (PEPA) 12.2 ug/g • Polymethylmethacrylate (PMMA) 0.008 ug/g • Cellulose triacetate • Cellulose 0.008 ug/g 0.016 ug/g • Polyethersulfone (Polynephron) BPA-free Hemodialyzer Innovation: Potting polymers Hemodialyzer Innovation: Cap and Housing • Polyurethanes: most common used • Polycarbonate: most common used • formed by reacting di-isocyanate or • Bisphenol A (BPA) plasticizer : endocrine disruptor with poly-isocyanate with a polyol • Isocyanate may release and contribute to adverse health effects type I sensitization (IgE Ab) Advancement Advancement - Some research is devoted to improve this issue. - New polymers such as polypropylene (such as Elisio-H , Elisio- HX series, and Fresenius FX series) and polystyrene were introduced and could prevent of bisphenol A (BPA) - Substitution of BPA by bisphenol S Hemodialyzer Innovation: Cap and Housing Novel Dialyzers • Dialyzer design • Hemodialyzer Innovation • Polymer and biomaterial • Biocompatibility • Membrane permeability and performances • High-flux dialyzer online HDF • Super high-flux/Medium-cutoff dialyzer • Low BFR Hemodialysis • High BFR Hemodialysis: Expanded HD (HDx) • HDx vs. High-flux HD • HDx vs. Online HDF • Albumin loss but stable long-term serum albumin • Conclusion 2

Hemodialyzer Innovation: Biocompatibility Hemodialyzer Innovation: Biocompatibility • PVP (polyvinylpyrrolidone) สารที่มีคณุ สมบตั ิ hydrophilic ท่ี มกั ผสมอยใู่ นเยื่อกรอง กลมุ่ PSu,PESu, และอีนๆ และเป็น สารที่พบอาการแพ้ได้บ่อยกวา่ สารที่เป็นส่วนผสมอ่ืนๆ Advancement มกี ารพฒั นาวิธีการแก้ไขใหม่ๆ ได้แก่ - เพ่ิมการยึดเกาะโดยเพ่ิม alpha tocopherol - ใช้สารอ่ืนหรือเทคนิคอื่นในการเพิ่ม hydrophilic แทน Novel Dialyzers Hemodialyzer Innovation: Permeability • Hemodialyzer Innovation Membrane characteristic : sieving coefficients vs. MW range • Molecular weight retention onset (MWRO) : MW at which the SC • Polymer and biomaterial • Biocompatibility value first reach 0.9 (Smaller MW molecules could almost freely pass the • Membrane permeability and performances membrane) • High-flux dialyzer online HDF • Molecular weight cut-off (MWCO) : MW at which the SC value first • Super high-flux/Medium-cutoff dialyzer reaches 0.1 (Larger MW molecules mostly could not pass the membrane) • Low BFR Hemodialysis • High BFR Hemodialysis: Expanded HD (HDx) 0.9 • HDx vs. High-flux HD 0.1 • HDx vs. Online HDF • Albumin loss but stable long-term serum albumin • Conclusion Hemodialyzer Innovation: Permeability Hemodialyzer Innovation: Permeability Membrane characteristic : sieving coefficients vs. MW range Membrane characteristic : sieving coefficients vs. MW range • Molecular weight retention onset (MWRO) : MW at which the SC High-flux value first reach 0.9 (Smaller MW molecules could almost freely pass the Membrane membrane) Low-flux Membrane • Molecular weight cut-off (MWCO) : MW at which the SC value first reaches 0.1 (Larger MW molecules mostly could not pass the membrane) 0.9 0.1 3

Hemodialyzer Innovation: Permeability Uremic toxins: from small to large molecules • Long-term mortality of HD is still high Middle molecules Protein-bounded molecules • with adequate Kt/V Small molecules Small Medium Large • Native Kidney Excretion ✓ ✓ ✓ ✓ • Dialyzer+modality low-flux HD high-flux HD / HDF (high-flux) Novel Dialyzers Online Hemodiafiltration (HDF) • Hemodialyzer Innovation Ultrapure dialysis fluid Sterile fluid < 0.1 CFU/mL < 10-6 CFU/mL • Polymer and biomaterial Ultrafilter 2 • Biocompatibility Ultrafilter 1 • Membrane permeability and performances Replacement • High-flux dialyzer online HDF Standard dialysis fluid A • Super high-flux/Medium-cutoff dialyzer < 100 CFU/mL • Low BFR Hemodialysis Dialysate out Dialysate in B • High BFR Hemodialysis: Expanded HD (HDx) + Convective UF • HDx vs. High-flux HD • HDx vs. Online HDF • Albumin loss but stable long-term serum albumin • Conclusion Dialyzer Choice for Online HDF Survival of high-volume online HDF: RCT Spanish HDF study [ESHOL] Surface Area: Qb 200 ml/min per 1.0 m2 Qb 400 ml/min per 2.0 m2 RCT post-dilution high-volume OL-HDF (n=456) vs. HD (n=450) High permeable membrane: Convective volume SC β2M > 0.6, Kuf > 50 mL/h/mmHg 22.9-23.9 L/session ~ 23L Low internal blood flow resistance: 30% lower all cause mortality (HR 0.7) Fiber diameter > 200 micron, length < 30 cm NNT: Switching 8 patients from HD to OL-HDF may prevent one annual death 33% lower risk of CV mortality (p = 0.06) 55% lower risk of infection-related mortality (p=0.03) 4

Survival of high-volume online HDF Uremic toxins: from small to large molecules • Long-term mortality of HD is still high Middle molecules Protein-bounded molecules • with adequate Kt/V Thailand HDF Study Cause of death - CVD 33.3% - Malignancy 26.7% - Infectious 20.0% Small molecules Cumulative survival - Cerebrovascular 13.3% - Respiratory 6.7% 2 years 10 years Small Medium Large Chulalongkorn Hospital Years • Native Kidney Excretion ✓ ✓ ✓ ✓ • Dialyzer+modality low-flux HD high-flux HD / HDF (high-flux) ? (Japan, Europe). Super high-flux or High Performance (Europe, US). High or Medium cut-off or High retension onset Novel Dialyzers Glomerulus filter small amount of albumin • Hemodialyzer Innovation • Large molecule including low molecular weight protein including small amounts of albumin are filtered across the glomerular • Polymer and biomaterial basement membrane (GBM) 3.5 g/day (SCalb = 0.034) • Biocompatibility • Membrane permeability and performances • Albumin was detected in glomerular filtrate in the micropuncture study The filtrated albumin is degraded into amino acids and • High-flux dialyzer online HDF peptides by tubular protease and reabsorbed into the blood • Super high-flux/Medium-cutoff dialyzer (Leber PD, Marsh DJ. Micropuncture study of concentration and fate of albumin • Low BFR Hemodialysis in rat nephron. Am J Physiol 1970;219:358-63) • High BFR Hemodialysis: Expanded HD (HDx) • The loss of filtrated albumin will be replaced by newly • HDx vs. High-flux HD synthesized proteins. • HDx vs. Online HDF • Albumin loss but stable long-term serum albumin • Conclusion High-flux HD Super High-flux/Medium cut-off HD Ultrapure dialysis fluid < 0.1 CFU/mL Ultrafilter 1 Standard dialysis fluid A Standard dialysis fluid A < 100 CFU/mL B < 100 CFU/mL B Dialysate out Dialysate in Dialysate out Dialysate in 5

Super High-Flux (Medium - High cut-off) Dialyzer Medium Cut-off (MCO) Dialyzer Dialyzers KUF ß2M (12 kDa) Albumin (68 kDa) MWRO MWCO - MW cut-off < 65 kDa (< albumin size) (ml/h/ (retension (cut-off) - High MW retension onset > 12 kDa Low-flux (LF) mmHg/m2) Clearance Sieving Loss in Sieving - Sieving curve shows a progressive High-flux (HF) (mL/min) coefficient onset) <65 kDa reduction of the solute sieving coefficient - Classic HF < 12 dialysate (g) coefficient >65 kDa values as the MW increase - Super HF ≥ 14 >12 kDa - SC Albumin < 0.01 15 – 40 < 10 - 00 <12 kDa - Albumin loss in dialysate < 4 g. - Medium cut-off (MCO) > 40 ≥ 20 ≥ 0.5-0.6 - Protein-leaking 40 – 60 Nature Reviews Nephrology 2018;14:394-410. - High cut-off (HCO) > 40 20 - 70 0.5 - 0.8 < 0.5 < 0.01 Kidney GBM 40 - 60 ≥ 70 ↔︎ ↔︎ 2-4 > 80 > 0.9 2-6 < 0.01 0.01 – 0.03 > 80 > 0.9 9 - 23 0.03 – 0.20 0.034 - 1.0 Super High-Flux (Medium - High cut-off) Dialyzer Novel Dialyzers Dialyzers KUF ß2M (12 kDa) Albumin (68 kDa) MWRO MWCO • Hemodialyzer Innovation (ml/h/ (retension (cut-off) Low-flux (LF) mmHg/m2) Clearance Sieving Loss in Sieving • Polymer and biomaterial High-flux (HF) (mL/min) coefficient onset) <65 kDa • Biocompatibility - Classic HF < 12 dialysate (g) coefficient >65 kDa • Membrane permeability and performances - Super HF ≥ 14 >12 kDa 15 – 40 < 10 - 00 <12 kDa • High-flux dialyzer online HDF - Medium cut-off (MCO) > 40 ≥ 20 ≥ 0.5 • Super high-flux/Medium-cutoff dialyzer - Protein-leaking 40 – 60 - High cut-off (HCO) > 40 20 - 70 0.5 - 0.8 < 0.5 < 0.01 • Low BFR Hemodialysis Kidney GBM 40 - 60 ≥ 70 ↔︎ ↔︎ ↔︎ • High BFR Hemodialysis: Expanded HD (HDx) 2-4 > 80 > 0.9 2-6 < 0.01 • HDx vs. High-flux HD 0.01 – 0.03 • HDx vs. Online HDF > 80 > 0.9 9 - 23 0.03 – 0.20 • Albumin loss but stable long-term serum albumin 0.034 - 1.0 • Conclusion SHF HD (low BFR): Clinical outcome (Japan) Novel Dialyzers - 3-year nationwide (Japan) cohort (n=242,467) comparison mortality risk • Hemodialyzer Innovation among 5 dialyzer types (SHF = type V) • Polymer and biomaterial Kaplan-Meiser Survival curve Type V (Super HF) • Biocompatibility Super HF dialyzer dialyzers showed a • Membrane permeability and performances significantly lower 3-year LF dialyzer mortality risk when • High-flux dialyzer online HDF compared with type IV (as • Super high-flux/Medium-cutoff dialyzer the reference) • Low BFR Hemodialysis • High BFR Hemodialysis: Expanded HD (HDx) • HDx vs. High-flux HD • HDx vs. Online HDF • Albumin loss but stable long-term serum albumin • Conclusion 6

Medium Cut-off HD: Expanded HD (HDx) Medium Cut-off HD: Expanded HD (HDx) BFR ≥ 300 mL/min The internal convective volume of HDx with BFR ≥ 300 and DFR ≥ 500 mL/min DFR ≥ 500 mL/min with β2M SC 0.9 is comparable to OL- HDF convective volume 23 L/session (β2M SC 0.5) MCO HD vs HF HD: RCT for 6-month MCO HD vs HF HD - Decrease inflammation - Improve anemia management - Lower infection and inflammation Novel Dialyzers MCO HD/HDx (high BFR) vs HDF • Hemodialyzer Innovation MCO dialyzer HF dialyzer • Polymer and biomaterial • Biocompatibility • Membrane permeability and performances • High-flux dialyzer online HDF • Super high-flux/Medium-cutoff dialyzer • Low BFR Hemodialysis • High BFR Hemodialysis: Expanded HD (HDx) • HDx vs. High-flux HD • HDx vs. Online HDF • Albumin loss but stable long-term serum albumin • Conclusion 7

MCO HD/HDx (high BFR) vs HDF MCO HD/HDx (high BFR) vs Mixed dilution HDF MCO dialyzer HF dialyzer Albumin removal (g) 3.2 (range 1.9-3.9). 4.9 (1.1-7.2) 0.2 (0.2-0.3) 0.4 (0.3-0.8) Chulalongkorn Hospital Eiamcharoenying J, Tiranathanagul K. et al. Blood Purif. 2022 MCO HD/HDx (high BFR) vs Mixed dilution HDF MCO HD/HDx (high BFR) vs Online HDF (12 kD) (22 kD) (33 kD) (45 kD) (0.06 kD) (0.21 kD + Protein) - 1-year RCT MCO HD (n=43) vs. Online HDF (n=37) - The changes in baPWV and ⊢ Middle molecules ⊣ ⊢ Large molecules ⊣ ⊢Small molecule⊣⊢Protein-bound⊣ echocardiographic parameters did not differ - The CAC scores was an increasing trend Chulalongkorn Hospital only in the HDx group (P = 0.012). Eiamcharoenying J, Tiranathanagul K. et al. Blood Purif. 2022 - Other endpoints, including cardiovascular and all‐cause mortalities, were similar between the two groups. CARTOON study Super High-Flux HD (high BFR) vs HDF Novel Dialyzers High-BFR super high-flux HD vs. • Hemodialyzer Innovation High-volume post-dilution online HDF • Polymer and biomaterial - Small, Middle (B2M; 12,000 Da), • Biocompatibility • Membrane permeability and performances Protein-bound solute removal did not significant difference • High-flux dialyzer online HDF - Higher large solute (alpha1 • Super high-flux/Medium-cutoff dialyzer macroglobulin; 33,00 Da) removal • Low BFR Hemodialysis - Higher albumin loss (4.5 vs. 0.5 • High BFR Hemodialysis: Expanded HD (HDx) g/session) but similar stable long-term albumin levels • HDx vs. High-flux HD • HDx vs. Online HDF Chulalongkorn Hospital • Albumin loss but stable long-term serum albumin Ther Apher Dial. 2021 Feb;25(1):73-81. • Conclusion 8

Super High-Flux HD (high BFR) vs HDF MCO HD/HDx (high BFR): Stable serum albumin No long term albumin loss: REMOVE study High-BFR super high-flux HD vs. REMOVE study High-volume post-dilution online HDF p < 0.05 - Small, Middle (B2M; 12,000 Da), Protein-bNoSund solute removal did not significant difference - Higher large solute (alpha1 macroglobulin; 33,00 Da) removal - Higher albumin loss (4.5 vs. 0.5 g/session) but similar stable long-term albumin levels Chulalongkorn Hospital Ther Apher Dial. 2021 Feb;25(1):73-81. MCO HD/HDx (high BFR): Stable serum albumin Super High-Flux HD/ HDx : Reused COREXH registry Membrane Polyethersulfone Effective surface area (m2) 2.1 KUF (ml/hr/mmHg) 82 Clearance (ml/min) 358 Urea 334 Creatinine 314 Phosphate 240 Vitamin B12 148 Myoglobin β2M Clearance A-port and V-port at 60 min Reduction ratio Pre- and post-dialysis Dialysate albumin Dialysate fluid Comparing the Efficacy of Hemodialysis Chulalongkorn Hospital with Super high-flux Dialyzer between Prapunwatana P, Tiranathanagul K, et al. (Manuscript preparation) First use and Repeated use Super High-Flux HD/ HDx : Reused Super High-Flux HD/ HDx : Reused λ-free light chain 45 kDa (large-middle molecule) *no statistically significant change P < 0.001 P < 0.001 100.0 32.2 β2microglobulin reduction ratio (%) 86.2 P < 0.001 P < 0.001 λ-FLC reduction ratio (%) 85.5 85.2 83.7 82.5 60.0 50.4 90.0 50.0 40.0 46.0 80.0 40.0 32.8 70.0 30.0 60.0 20.0 50.0 10.0 40.0 2nd use 5th use 10th use 15th use 0.0 2nd use 5th use 10th use 15th use First use First use Used times Used times Comparing the Efficacy of Hemodialysis Chulalongkorn Hospital Comparing the Efficacy of Hemodialysis Chulalongkorn Hospital with Super high-flux Dialyzer between Prapunwatana P, Tiranathanagul K, et al. (Manuscript preparation) with Super high-flux Dialyzer between Prapunwatana P, Tiranathanagul K, et al. (Manuscript preparation) First use and Repeated use First use and Repeated use 9

Super High-Flux HD/ HDx : Reused Novel Dialyzers λ-free light chain 45 kDa • Hemodialyzer Innovation (large-middle molecule) • Polymer and biomaterial *statistically significant change • Biocompatibility • Membrane permeability and performances 1.20 0.90 P 0.001 P 0.001 P 0.001 • High-flux dialyzer online HDF Dialysate albumin per dialysis session 1.00 • Super high-flux/Medium-cutoff dialyzer (gram) 0.80 • Low BFR Hemodialysis • High BFR Hemodialysis: Expanded HD (HDx) 0.60 0.23 • HDx vs. High-flux HD 0.40 0.08 0.00 0.00 • HDx vs. Online HDF 0.20 • Albumin loss but stable long-term serum albumin 15th use 0.00 2nd use 5th use 10th use • Conclusion Used times First use -0.20 Comparing the Efficacy of Hemodialysis Chulalongkorn Hospital with Super high-flux Dialyzer between Prapunwatana P, Tiranathanagul K, et al. (Manuscript preparation) First use and Repeated use Summary and Conclusion For Your Attention • Hemodialyzer innovation included biomaterial, biocompatibility, www.themegallery.com and membrane performance improvement. • High-flux online HDF with high volume of convection improved long-term survival, reduced CV death. • Super high-flux/MCO dialyzer is a new class of dialyzer that enhance large uremic toxin removal via diffusion and internal convection • High BFR super HF/MCO HD (HDx) using standard HD machine provide large molecule removal not inferior to high-volume OL HDF • Weekly albumin loss ≤ 12 g is safe but ≥ 20 g is unsafe • Many clearance studies and prospective studies demonstrate benefits of SHF/MCO HD over HF HD. Waiting for large RCT. www.themegallery.com 10