การดูแลผู้ป่วย ICODEXTRIN

การดูแลผู้ป่ วยล้างไตทางช่องท้องอย่างยงั่ ยืน เพื่อสนับสนุนนโยบายของสานักงานหลกั ประกนั สุขภาพแห่งชาติ A holistic approach to improve PD outcomes 27 June 2019 1

Role of Icodextrin 2

Know about Icodextrin • Glucose-free • Single daily exchange for the • Early PD solution long dwell during CAPD or • Late APD (up to 16 hours) for the • Short term management of CRF • Long term 3

Unmet Needs with PD Solutions • There do remain some residual unmet needs with traditional PD solutions. ➢ Conventional older PD solutions use o Glucose at concentrations (13.6-42.5 g/L) as the osmotic agent, o Be bioincompatible, which may result in structural changes to the peritoneal membrane with long-term therapy and functional alterations o Other undesirable characteristics, including - acidic pH (5.2-5.5) and - hyperosmolarity (360-511 mOsm/kg) These changes may result in a decline in UF rate and a decrease in dialysis efficiency, leading to poor outcomes Baxter Confidential — Do not distribute without prior approval | 4

Conventional PD Solutions Glucose Absorption 5

Drivers of peritoneal changes during PD Exposure to solution Components “Acute Inflammatory Episodes (cumulative effect of severity) Local Inflammatory status Systemic Inflammatory status Mesothelial cell integrity Fibrogenesis (vascular and fibrotic changes) 0 2.5 5 7.5 10 + Time on PD (years) 6

Clinical consequences of long term Peritoneal membrane changes Pediatr Nephrol (2008) 23:19–25 Adapted from :Andreas Fusshoeller. 7

Vicious Cycle

Unmet Needs • Conventional solution – bioincompatible, undesirable characteristics • Symptomatic fluid retention occurs in 25% of all PD patients Baxter Confidential — Do not distribute without prior approval | 9

Role of Icodextrin use in PD Maintain fluid balance CV status Reduced the risk Benefits for Diabetic pts improvement of CHF Reduction in EC water & LV mass 16% lower risk of mortality 24Up to months for maintenance of peritoneal Prolonged time on PD membrane transport characteristics 1.21 years in pts with refractory fluid overload 10

Icodextrin Icodextrin solution is an advanced, glucose-free PD solution • Starch-derived glucose polymer • Mean MW 17,000 dalton • Does not readily diffuse across the peritoneal membrane 11

Icodextrin • Icodextrin (Extraneal) ➢ High molecular weight, cornstarch-derived glucose polymer ➢ Inducing sustained ultrafiltration over prolonged (6-12 hours for CAPD, 14–16 hours for APD) PD dwells Composition DIANEAL® EXTRANEAL® Extraneal PI (Nov 2017) PD2 Dextrose (g/dL) --- Icodextrin (g/dL) 1.5, 2.5, 4.25 7.5 Sodium (mEq/L) --- Chloride (mEq/L) 132.0 Calcium (mEq/L) 132.0 96.0 Magnesium (mEq/L) 96.0 3.5 Lactate (mEq/L) 3.5 0.5 0.5 40.0 40.0 282 Osmolality(mOsm/kg) 346-485 5.2 pH 5.2 12

Metabolism of Icodextrin 13

Icodextrin • Icodextrin (Extraneal) คือน้ำยำลำ้ งไตทำงช่องทอ้ งท่ีเป็ น Glucose-free polymer ทำหนำ้ ที่เป็นสำรที่มีคุณสมบตั ิในกำรดึงน้ำ (ออสโมติก) • มีคุณสมบตั ิช่วยใหเ้ กิดกำรดึงน้ำส่วนเกินออกจำกร่ำงกำย แต่ไม่เพม่ิ ปริมำณกำรไดร้ ับแคลอรี(น้ำตำล ) เม่ือ เทียบกบั กำรใหน้ ้ำยำ 4.25% เดก็ ซ์โทรส ในปริมำตรที่เท่ำกนั Extraneal PI (Nov 2017) 14

Icodextrin: UF Mechanism Osmosis refers to the movement of water across barrier that is permeable to water but restricts the transport of solutes Osmotic Colloid osmotic crystalloid pressure (glucose) pressure (icodextrin) Small molecular weight molecules High molecular weight molecules Fast and important osmotic pressure at Small osmotic pressure at start – slow start, gradual absorption and decrease of absorption – late UF osmotic gradient over time Molecular size is osmotic driving force Peritoneum Interstitium Peritoneum Interstitium GG G G Ico Ico GG G Ico Osmotic flow Osmotic flow G Peritoneal UF = water movement associated to permeable solutes through the peritoneal membrane Osmotic pressure = depends on the number of osmotic active molecules in the solution Reflection coefficient (RC) = Reflection coefficient of Icodextrin is 0.76 as compared to 0.03 of glucose 15

How Icodextrin Works: Colloid Osmosis 16 • Icodextrin - Slow absorption from the peritoneum - Resulting in an almost linear increase in UF during the long-dwell • Glucose-based solutions - Peak UF after a much shorter dwell time - Fast glucose diffusion across the peritoneum and absorption of fluid - Decrease in UF after the net peak UF Mujais et al. Kidney Int 2002; 62:(Suppl 81):S17-S22

Improving PD patient outcomes with Icodextrin Sustained UF Potential Icodextrin vs Dextrose ✓ Icodextrin จะไม่ทำใหเ้ กิด negative UF ถึงแมว้ ำ่ จะแช่ไวใ้ นช่องทอ้ งเป็ นเวลำนำน 8-16 ชว่ั โมง (long dwell) ในทำงกลบั กนั ยง่ิ แช่ไวใ้ นช่องทอ้ งเป็ นเวลำนำน ยงิ่ ทำให้ UF เพม่ิ มำกข้ึนเรื่อย ๆ Net UF (mL) 1200 Positive UF 1000 800 600 1.5% dextrose 400 2.5% dextrose 200 4.25% dextrose 0 7.5% icodextrin -200 -400 -600 -800 0 2 4 6 8 10 12 14 16 Time (hrs) Mujais S et al. Kidney Int 2002; 62(Suppl 81): S17-S22 17

Water moves through the peritoneal membrane through 3 pores, but one type of pore, the aquaporin (AQP), is too small for sodium to move through along with the water. Glucose exchange Icodextrin exchange A Glucose B Icodextrin Crystalloid osmosis (colloid) osmosis The movement of salt and Half of the movement of fluid is water is almost all through through the aquaporins. small pores (SP). Therefore, Therefore, the movement of Na there is no Na sieving with is low, especially at the start of Icodextrin! a dwell (typically the length of an APD dwell). This phenomenon is called Na sieving. 18

Guideline The use of Icodextrin solution is endorsed by clinical practice guideline for patients with diabetes Woodrow et al. BMC Nephrology (2017) 18:333 19 Angela YM Wang, et al. Peritoneal Dialysis International, 2015; Vol. 35: pp. 379–387

Low glucose therapy with Icodextrin stabilizes peritoneal membrane function Low glucose therapy that includes ICODEXTRIN helps maintain peritoneum membrane function which could help facilitate fluid balance

Icodextrin • Single daily exchange for the long (8-16 hour) dwell during CAPD or APD for the management of CRF ขอ้ บ่งช้ีในกำรใช้ แนะนำใหใ้ ชว้ นั ละหน่ึงคร้ัง สำหรับกำรใชน้ ้ำยำลำ้ งไตทำงช่องทอ้ งชนิดทว่ั ไปที่มีเดก็ ซ์โทรสเป็นองคป์ ระกอบ ซ่ึงอำจเป็ นส่วน หน่ึงของ CAPD หรือเครื่อง automated peritoneal dialysis (APD) สำหรับกำรรักษำภำวะไตวำยเร้ือรัง โดยเฉพำะสำหรับผปู้ ่ วยท่ี ใช้น้ำยำลำ้ งไตทำงช่องทอ้ งชนิดท่ีมีเด็กซ์โทรสแลว้ ไม่สำมำรถดึงน้ำออกจำกร่ำงกำยได้ (ultrafiltration) เนื่องจำก Extraneal สำมำรถช่วยยดื ระยะเวลำกำรรักษำในผปู้ ่ วยกลุ่มน้ีใหน้ ำนข้ึนได้ Extraneal PI (Nov 2017) Baxter Confidential — Do not distribute without prior approval | 21

กำรใช้ Icodextrin สำหรับ CAPD & APD Extraneal Extraneal Baxter Confidential — Do not distribute without prior approval | 22

Know about Icodextrin • Glucose-free • Single daily exchange for • Early PD solution the long dwell during • Late CAPD or APD (upto 16 • Short term hours) for the • Long term management of CRF Baxter Confidential — Do not distribute without prior approval | 23

Icodextrin สำมำรถพจิ ำรณำใชไ้ ดห้ ลำยช่วงของระยะเวลำกำรลำ้ งไต ดงั ภำพ Davies SJ, et al. Kidney International 1998; 54: 2207–2217 Baxter Confidential — Do not distribute without prior approval | 24

EARLY: ผปู้ ่ วย ESRD ระยะเริ่มตน้ ที่ยงั มีปัสสำวะอยู่ (early ESRD with RRF) เพอ่ื ชะลอกำรเสื่อมของผนงั ช่องทอ้ งและ ไตใหช้ ่วงกลำงคืน และมีกำรใหน้ ้ำยำที่มี Glucose เพมิ่ ตำมเวลำ (added incrementally over time) ตำม ขอ้ บ่งช้ีทำงคลินิก ซ่ึงขณะน้ีงำนวจิ ยั ยงั มีนอ้ ย Jeloka T, et al. Indian Journal of Nephrology 2013 Baxter Confidential — Do not distribute without prior approval | 25

LATE: • ผปู้ ่ วยที่มีผนงั หนำ้ ทอ้ งเป็น High or High average peritoneal transport1 • ผปู้ ่ วยที่ ultrafiltration failure (UFF) ซ่ึงจะมีปัญหำ failure to achieve at least 400 ml of net ultrafiltration during a 4 h 2L dwell using 4.25% dextrose • แนะนำใหใ้ ชใ้ นผปู้ ่ วย UFF Type I (High Effective Peritoneal Surface Area) ซ่ึงเป็นผลจำกกำร เปล่ียนแปลงของผนงั หนำ้ ทอ้ งจำกหลำยปัจจยั uremic state, prolonged exposure to glucose degradation products (GDPs), และ cumulative effects of episodes of peritonitis ส่งผลใหม้ ีกำรสร้ำง proinflammatory และ angiogenic mediators ตำมมำ2 กำรเปลี่ยนแปลงของ ultrafiltration profile ท่ีสมั พนั ธ์กบั high transport status ที่พบกบั glucose และ icodextrin3 1. Davies SJ, et al. J Am Soc Nephrol. 2003;14:2338-2344 2. Teitelbaum I. Blood Purif 2015;39:70–73. 3. Davies SJ. Kidney International 2006; 70: S76–S83 26

SHORT TERM: • ผปู้ ่ วยลำ้ งไตทำงช่องทอ้ งที่มีภำวะน้ำเกิน (volume overload)1 • ผปู้ ่ วยที่มีปัญหำ negative ultrafiltration หรือเพือ่ ใหก้ ำรควบคุมสำรน้ำของเหลว (fluid control) ทำไดด้ ีข้ึนระหวำ่ งเกิดepisode of peritonitis2 • ผปู้ ่ วยที่ตอ้ งกำร Long dwell เช่น เม่ือนอนโรงพยำบำล ประกอบกบั UF เปล่ียนแปลง, เหตุผลจำกกำร ทำงำน จะเกิดปัญหำหำกมีกำรเพม่ิ ควำมถ่ีของกำรใหน้ ้ำยำจำกน้ำยำพ้ืนฐำนเพ่ือใหไ้ ด้ UF และ Solute clearance ตำมเป้ำหมำย ขอ้ มูลจำกประสบกำรณ์กำรใช้ Range of Ultrafiltration Volume and Sodium Removal across Patient Transport Types โดยปกติ 9 h dwell ของ Icodextrin จะได้ประมาณ 460 ml of ultrafiltration แต่แปรผนั ได้ในแต่ละคนจาก <400 ml ถงึ >1000 ml3 27 1. Johnson DW, et al. BMC Nephrol. 2001; 2:2. 2. Chow KM, et al. Nephrol Dial Transplant. 2014;29:1438-1443. 3. Davies SJ, et al. Nephrol Dial Transplant 2006; 21 (Suppl 2): ii47-50.

ผลกำรรักษำจำกกำรใช้ Icodextrin (ขอ้ มูลในประเทศ) โรครว่ มของผปู้ ่ วย ประสบการณ์การใช้ Icodextrin ในเวชปฏบิ ตั *ิ (real situation) เป็นตามขอ้ บง่ ชด้ี งั เชน่ ; เบาหวาน , 9, 33% • uncontrollable fluid overload, • long dwell to improve UF in fast transport membrane type HT, 18, • better to control sugar in poor UF 67% *จากขอ้ มลู ผปู้ ่วย 28 รายทม่ี กี ารตดิ ตามผลการใช้ Icodextrin 1-3 เดอื น ระหวา่ งสงิ หาคม2560 - มกราคม2561 spb 2,500 100 120 140 160 180 200 อาการทว่ั ไปของผปู ้ ่ วย 2,000 UF 12 11 10 8 net_uf 1,000 1,500 6 4 12 2 0 ออ่ นเพลยี ปวดตามขอ้ คนั 500 0 baseline visit 1 visit 2 baseline visit 1 visit 2 ความดนั โลหติ (SBP) Mean (sd) 675.9 (523.44) 1,150 (506.95) p<0.001 Baseline Icodextrin use 28

LONG TERM: • High or high average peritoneal transport patients ซ่ึงจะมีกำรใช้ 4.25% dextrose 1 ถุงหรือมำกกวำ่ เป็นประจำเพือ่ ท่ีจะใหเ้ กิด fluid balance พบวำ่ จำกกำรศึกษำเม่ือใหผ้ ปู้ ่ วยท่ี experiencing symptomatic fluid overload ดว้ ย 3.86% glucose มีกำร switched เป็น Extraneal แลว้ time on PD ถูกขยำยเป็น 1.21 ปี อีกท้งั ผปู้ ่ วยท่ีมีปัญหำ ultrafiltration failure พบวำ่ time on PD ถูกขยำยเป็น 1.70 ปี 1 • ผปู้ ่ วยเบำหวำนที่ตอ้ งกำรคุมระดบั น้ำตำลใหด้ ีเมื่อเทียบกบั น้ำยำท่ีมี glucose2-4 • กำรใชร้ ะยะยำวติดตำมยำวกวำ่ 2 ปี จำกกำรศึกษำในผปู้ ่ วยเบำหวำนและกำรศึกษำในผปู้ ่ วย anuric APD5 พบผปู้ ่ วย จำนวนหน่ึงที่ยงั คงใช้ Icodextrin ต่อเป็นเวลำ 5 ปี หลงั จบกำรศึกษำไปแลว้ และผลกำรรักษำเป็นที่น่ำพอใจ6 1. Johnson DW, et al. Adv Perit Dial. 2003;19:81-85. 2. Paniagua R, et al. Perit Dial Int. 2009;29:422-432. 29 3. Li PKT, et al. J Am Soc Nephrol. 2013; 24:1889-1900. 4. Babazono T, et al. Am J Nephrol. 2007;27: 409-415. 5. Davies SJ, et al. Kidney Int 2005; 67: 1609–1615. 6. Peers E and Gokal R. Peritoneal Dialysis International 1997; 17: 22-26

ขอ้ ดีของ Icodextrin ท่ีเหนือกวำ่ 4.25% dextrose ใน PD Pecoits-Filho R, et al. Kidney International 2002; 62 (Suppl 81): S80–S87 Baxter Confidential — Do not distribute without prior approval | 30

Summary Icodextrin Use of Icodextrin • All long Dwell • UFF associated with high transport • During acute peritonitis • Maintenance of volume even without UFF • Difficult to control glucose Baxter Confidential — Do not distribute without prior approval | 31

Improving PD patient outcomes with APD & RPM 32

Improving PD patients outcome APD: Automated Peritoneal Dialysis Automated Peritoneal dialysis “The better social functioning of APD patients might be related to the fact that daytime for these patients is free • Designed to from treatment, thus facilitating a normal social life.” minimize the burden of frequent de Wit GA, et al. PDI 2001;21:p311. exchanges of dialysate bags • Allow individualized prescription of PD Residual renal function High glucose exposure Fluid overload Solute clearance FOR INTERNAL USE ONLY | Not to be distributed to HCPs

Based on these results, we conclude that; ✓RM-APD has an important role in home dialysis care over time ✓RM permits a tailoring of dialysis treatments and a saving time and costs both for PD patients and PD team

Introduction • PD offers greater patient independence and autonomy compared to in-center HD, with improved quality of life. • However, patient’s adherence to physician’s prescription at home is fundamental for the success of PD • In the home environment, patients may experience a sense of freedom sense of freedom and safety, but they must actively monitor their therapy with daily recording of weight, blood pressure, and fluid removal Milan Manani S, Rosner M, Maria Virzi G, et al. Nephron DOI: 10.1159/000496182 FOR INTERNAL USE ONLY | Not to be distributed to HCPs

Definition of Remote Monitoring There are multiple definitions of remote monitoring. • Falls under the umbrella term of “telehealth” or “telemedicine” Telehealth Telemedicine Telecare Patient Remote Teleconsultations Other Monitoring (PRM) (through video conferencing) • Tele-laboratory Telemonitoring • Tele-diagnostics • Clinician to patient • Tele-education Remote Monitoring • Clinician to clinician (RM) Remote monitoring (RM) : technology/ software in the home setting that collects a patient’s clinical data and transmits it to a hospital, physician’s office, clinic, telehealth vendor, or another party who monitors and analyzes the data received. • The RM data may enable clinician to intervene early in the disease management

• Telemedicine (TM) is an innovative tool to provide remote transmission, interpretation, and storage of clinical parameters and useful diagnostic images • Remote monitoring (RM) is a subset of TM where physiological variables or images can be sent to a central monitoring center for review and intervention of the care team. • TM and RM may have important reflections on prognosis, outcomes, and QoL Heart failure, diabetes, and hypertension

RM of patients on APD with this platform offers; • the potential benefits of accurate monitoring of the therapy, • improved patient safety through surveillance of critical stages of the treatment, • early detection of problems, or limited compliance to prescription + the 2-way communication system with interactive interface allows; • a fast trouble shooting: the physicians can change the prescription using the remote connection, • reducing the need for frequent in person visits to the PD center

APD & RPM Platform Upgrade Connectivity Platform ▪ Display : Larger display with 2 lines text, OLED ▪ An innovative, secure, cloud based connectivity platform ▪ Compliant : comply with RoHS, medical device Class II ▪ A two-way, web-based connection between the Homechoice Claria ▪ Memory : keep 90 treatment records in the machine ▪ Language : Add Thai language cycler and the clinic. ▪ Collects and transmits treatment data from the home dialysis device to the clinic ▪ Location AWS secure data servers : Frankfurt For Healthcare Professionals only | 39

• Connectivity platform – no installation required • Treatment data from Homechoice Claria is sent automatically to Sharesource, after the dialysis session • Clinicians can view treatment data and be alerted of problems through programmable flags • Clinicians can change device settings to adjust parameters of next dialysis session • Technical service support (backend) • Provide confidence through complete therapy AWS Secure Data Storage Clinical Portal: visibility by their clinician • More confidence placing and • Conversations with clinician more fruitful, as patient treatment data is accessible through keeping patients on home Clinical portal therapies • Intuitive dashboard with flagged alarms highlighting issues • Potential earlier detection of clinical issues • Access to patient’s historical treatment files • Remote change of device dialysis settings for next therapy sessions For Healthcare Professionals only | 40

Connectivity platform: External Infrastructure Requirements Setting Infrastructure Required Reason/Explanation Clinic/Hospital • Access to the internet Sharesource is a cloud-based Patient’s Home platform, so no additional servers are required at the clinic/hospital. There is no software to install on computers. • Cellular signal/connection Sharesource sends data via a • Cellular modem (provided as a cellular signal (like your mobile phone) so access to the internet/wi- component of the device) fi is NOT required. The modem is also only enabled to send data between Sharesource and the device (i.e. the patient is restricted from using this modem to connect to the internet, etc.)

Summary Remote monitoring Non-compliance Communication Cognitive Anxiety Barriers • Even though optimizing outcomes and adherence from RPM in home dialysis has yet to be proven, evolving the data and case demonstrations support the possibilities that uptake and outcomes of home dialysis can be improved with these technologies • Remote patient management has exciting potential to improve home dialysis patient care and home modalities uptake, to improve quality of life, and to reduce cost Krishna, EL, et al. Adv Chronic Kidney Dis 2017;24(1):12-16 Wallace EL, et al. Kidney Int Rep 2017; 2: 1009–1017

Improving PD patient outcomes with Quality program / CQI initiatives 43

Results of Thailand PD-First Policy Substantially Improved Access to RRT Yearly Incidence and Prevalence of RRT in Thailand Over Time 1200 Incidence Prevalence 1073 1000 907 Per Million Population (PMP) 800 776 667 600 579 528 409 181 227 221 249 24,000+ 100 123 400 200 68 0 2008 2009 2010 2011 2012 2013 2007 Key: PD – peritoneal dialysis, RRT – renal replacement therapy, PMP – per million population. 2. สปสช ประชำสมั พนั ธ์ 22 มิถนุ ำยน 2561 https://www.nhso.go.th/frontend/NewsInformationDetail.aspx?newsid=MjM1Nw 1. Chuengsaman, et al. Semin Nephrol. 2017; 37(3): 287-295. 44 GLBL/MG2/18-0010b 10/18

Peritoneal dialysis Stay in PD First Policy Drop out Scholten N, et al. BMJ Open 2019;9:e025451 Campos et al. Port J Nephrol Hypert 2015; 29(4) 45 Mujais S, Story K. Kidney Int. 2006;70(suppl 103):S21-S26.

Strategies to prevent PD drop-out Modality related • Peritonitis prophylaxis and treatment • Membrane preservation: Use of Glucose polymers/ACEI • Adjust dialysis prescription according to RRF • Correction of catheter malfunction Strategies to prevent PD Patient drop-out related System related • Social support • Psychological counseling (as needed) • Better infrastructure to support PD • Assisted PD • Patient education/training • Physician and nursing education • Larger PD centers Chaudhary K. International Journal of Nephrology; Vol 2011, Article ID 434608, 7 pages, 46

Components of successful PD program • The reimbursement policy • Adequate CKD education programs • Standard training for nephrologists and nurses • Initial management and continuous quality improvement • Appropriate support systems Yu X, Mehrotra R, Yang X. Semin Nephrol 2017; 37:10-16

Common issues Peritonitis Malnutrition Fluid retention 48

Peritoneal dialysis under the PD First Policy Patient survival Technique survival • 1- to 5-year patient survival rates were 82.6, 71.8, 64.0, 58.5, and 54.0%, respectively. 49 • The first-year technique survival rate was 94.8%. The patient and technique survival rates during 2013 – 2016 were better than those seen during 2008 – 2012. Changsirikulchai S, et al. PDI 2018

Quality / CQI intiatives CQI ( Continuous Quality Improvement) คือ การพฒั นาคณุ ภาพอยา่ งตอ่ เน่ือง การใชก้ ระบวนการทางวทิ ยาศาสตร์ และความคดิ สรา้ งสรรค์ ในการปรบั ปรงุ ระบบงานเพอ่ื ตอบสนองความตอ้ งการของ ผรู้ บั ผลงานอยา่ งไมห่ ยดุ ยงั้ โดย มงุ่ สคู่ วามเป็นเลศิ CONTINUOUS QUALITY IMPROVEMENT 50 • We recommend each PD center have a continuous quality improvement (CQI) program in place to reduce peritonitis rates (1C). • We suggest that multidisciplinary teams running CQI programs in PD centers meet and review their units’ performance metrics regularly (2C) Li PKT, et al. ISPD PERITONITIS RECOMMENDATIONS: 2016 UPDATE ON PREVENTION AND TREATMENT. Perit Dial Int 2016; 36(5): 481-508