Adequacy Current and future KKU-25Aug2022

Adequacy: Current concept and future perspectives Talerngsak Kanjanabuch, M.D. Professor of Internal Medicine, Chair of Advisory board of PD and Secretory General, Nephrology Society of Thailand Director of CE in Kidney Metabolic Disorders, Chulalongkorn University, Thailand

SCOPES o Urea kinetic model o High-quality PD care o Goal-directed PD o Volume status, monitoring, and trouble shooting o RKF and slow progress, o Balanced electrolyte and acid-base metabolism o Incremental PD o Future trends: Tele

Guidelines for PD Adequacy Guidelines Weekly Kt/Vurea Total weekly UF(L/d) Frequency of ISPD 2006 ≥ 1.7 CCr(L/1.73m2) Euvolemia evaluation (mo) Thai 2018 ≥ 1.7 N/A; 4-6 ≥ 45 in L and LA Euvolemia Re-evaluate when N/A clinically indicated K/DOQI 2006 ≥ 1.7 N/A Euvolemia 4 CSN-Canada 2011 ≥ 1.7 N/A Euvolemia Re-evaluate only if indicated EBPG2005 ≥ 1.7 ≥ 45 for APD 1.0 N/A CARI 2005 Euvolemia 6 ≥ 1.6 ≥ 60 for H&HA; (CAPD&APD) ≥ 50 for L&LA 1. Perit Dial Int. 2006 Sep-Oct;26(5):520-2. 2.Am J Kidney Dis. 2006 Jul;48 Suppl 1:S98-129 3.Perit Dial Int.2011 Mar-Apr;31(2):218-39 4.Nephrol Dial Transplant. 2005 Dec;20 5.Nephrology (Carlton).2005 Oct;10 Suppl 4:S81-107

Moving Beyond UREA Clearance • Uremic Toxin....a) Small water soluble molecules b) Middle molecules ex b2m c) Protein bound (e.g. Indoxyl sulphate, p-cresyl sulphate) • Limitations • V: Accuracy of the estimation, which BW? • toxic by itself or just surrogate markers for declining RKF; inconclusive • Balance between high dose prescription and burdens • HrQoL and adequacy of dialysis • Incremental peritoneal dialysis • Delivering PD for special conditions (multi-morbidities, frail, palliative patient, children, LICs) • Individualization Brown EA, et al. Perit Dial Int 2020 May;40(3)

High-quality PD: Parameters Share-decision Prescription (pt-centric) Goal-directed Brown EA, et al. Perit Dial Int 2020 May;40(3) AJKD 2020 Mar;75(3):404-412

High-quality PD Care Anemia Small Solutes and other uremic toxins Residual Volume and kidney BP control function Patient Nutritional Reported status ex Outcomes ex PEW QoL, social, Biochemical stress, travel markers Credit to Aj. Sarinya Boongird

Euvolemia Metaanalysis 42 cohorts, 60790 cases (Tabinor M, et al. Sci Rep 2018) Overhydration (↑ECW/TBW) - 5% PD - 30-60% overhydrate CHF LVH ↑NT- ↑BP ↑Arterial stiffness - HR of overhydration: 2.3x proBNP Endothelial Dysfunction Malnurtion ↓Techniqu ↑Hospitali Sleep ↑RRF↓ e Survival zation apnea Too Dry : Intravascular volume depletion and hypotension may lead to a loss in RRF Kim YL, et al. Seminars in Nephrology, Vol37,No1, 2017,pp43–53

Residual Kidney Function Uremic toxins or protein-bound BP control Peritonitis ? clearances Volume control Improved Nutritional status Reduced ESA Less systemic requirement inflammation Credit to Aj. Sarinya Boongird

RKF on mortality Reference (year) Study design N, characteristic KRF Measurement RR/OR of mortality per increase of KRF (CI or p value) Maiorca et al,1995 3 y prospective single-centre Prevalent 68 CAPD and 34 HD GFR 10 L/wk/1.73 m2 Diaz-Buxo et al, 1999 1 y prospective single-centre Prevalent 2686 CAPD or CCPD 0.4 (p<0.001) Rocco et al, 2000 7 mo prospective multi-centre Prevalent 1446 CAPD or CCPD Szeto et al, 2000 3 y prospective single-centre Prevalent 270 CAPD Renal CrCl 10 L/wk/1.73 m2 0.89 (p=0.003) Bargman et al, 2001 2 y prospective multi-centre Prevalent 680 CAPD Incident 965 CAPD Renal CrCl 10 L/wk/1.73 m2 0.6 (0.4-0.8) Paniagua et al, 2002 2 y multi-centre RCT 0.65 (0.45-0.94) Incident 413 CAPD GFR 1 mL/min/1.73m2 Termorshuizen et al, 2003 3 y prospective multi-centre Incident 117 CAPD 0.88 (0.83-0.94) Incident 2434 CAPD or APD GFR 5 L/wk/1.73m2 0.64 (0.51-0.8) Urine volume > 250 mL/day 0.89 (p=0.01) Renal CrCl 10 L/wk/1.73 m2 0.94 (p=0.01) Renal Kt/V 0.1 unit (not primary outcomes) 0.88 (0.79-0.99) GFR 1 mL/min/1.73m2 Chung et al, 2003 2 y retrospective GFR 1 mL/min/1.73m2 0.79 (0.62-0.99) Rumpsfeld et al, 2009 3 y retrospective GFR 10 L/wk/1.73m2 0.93 (p=0.01) Nongnuch et al. Clin Kidney J. 2015 Apr;8(2):

Strategies to preserve RKF • PD prescription: no clear consensus on the effect of PD modality (APD vs. CAPD) on RKF, including incremental PD • PD solution types: Neutral-pH low GDP, ICO vs. Conventional PD bag • RAAS blockage (1A) • Diuretics • Euvolemia • Avoid Nephrotoxic agents: aminoglycoside and contrast media (2B)

Balance of electrolyte, acid-base metabolism Proposed clinical and biochemical targets for high-quality PD Delivering High-Quality Peritoneal Dialysis What Really Matters?. CJASN. 2020: 15: 1663–1665.

PD patient characteristics in PDOPPS Characteristic A/NZ Canada Japan Thailand UK US Age, years Diabetes 64.3 61.5 64.4 56.0 62.8 57.2 APD, % 45% 47% 40% 52% 28% 53% 66% 72% 37% 68% 83% Caregiver(s) involvinga, % 17% 16% 13% 5% 24% 17% Potassium, mEq/L 4.4 4.2 4.2 56% 4.4 4.2 Albumin, g/dL 3.3 3.5 3.3 3.7 3.4 3.5 11.2 11.0 10.9 11.2 11.0 Hb, g/dL 0.72 0.82 0.84 3.1 1.41 0.77 24-Hr Uvol, L/1.73 m2 7.66 7.84 5.87 10.2 7.14 8.46 Prescribed total V, L 0.58 8.67 Confirm late initiation & No incremental dialysis Boudville N, et al. NDT 2018 Wong AYM, et al. PDI 2020 Kanjanabuch T, et al. PDI 2021

Low Serum K Levels and Clinical Outcomes in PD All-cause mortality PD-related peritonitis Davies SJ, et al. Kidney Int Rep (2021) 6, 313–324

Effectiveness of K Supplement in Hypokalemic PD Patients: A Stratified Randomized Controlled Trial Pichitporn W, et al. Am J Kidney Dis. 2022 May 18:S0272-6386(22)00627-8.

Lopes MB,…, Kanjanabuch T,…, et al. NDT 2022 Aug (E-Pub)

Multi-variate regression analysis of factors associated with calcification Superficial Femoral Artery Below Knee Artery Factors R P-values Factors R P-values Age 0.333 0.0003 Age 0.285 0.0024 DM 0.308 0.0004 DM 0.371 <0.0001 CAD 0.229 0.009 CAD 0.330 0.0003 Ohtake T. J Vasc Surg. 2011 Mar;53(3):676-83

PTH and serum calcium control in PD Distribution of serum calcium levels Distribution of serum iPTH levels Nitta K,…, Kanjanabuch T, … et al. Manuscript in Prep

Qadri SI1, Koratala A.: Clin Case Rep. 2017;5(8):1418-1419. Fernández M1, Morales E. Nefrologia. 2017;37(5):501-507 Halasz CL. J Am Acad Dermatol. 2017;77(2):241-246.e3 Aihara S and Tsuruya K.: Intern Med. 2016;55(14):1899-905

Hb and serum ferritin in PD

ADenteamil fioaraCnAdPDPaPtrieesnctriSputirovnival Manuscript in preparation

Assisted PD performed by caregivers and outcomes Most of the caregivers were family % Assisted PD by caregivers increased members (98%), while the rest with age and FS impairment were non-family paid caregivers (2%). Puapatanakul P, et al. PDI 2022

Compared with self-PD, assisted PD was significantly associated with an increased risk of all-cause mortality

PATIENT LEVEL: Psychosocial QoL: SF-13 CES-D10 FS score Employment status

Peritonitis Death Poor oral health status was common among PD patients and was independently associated with a higher risk of peritonitis and death but not HDT and may be a proxy of poor overall personal hygiene.

Distribution of total weekly Kt/V (urea clearance) for APD and CAPD patients

Detail for CAPD Prescription

Incremental Dialysis Peritoneal Residual renal Clearance clearance/volume Less than standard “full-dose” PD…..in people initiating PD so that the combination of RKF and peritonePaelrcitloenaeraalnce achieved pisaslulifafticivieenotrUtofriinnaeacnhcieiavlecionndsitvriadiunatlized clearance goals…..≠ Credit to Aj. Sarinya Boongird

prospective open-label RCT ✓ Limitation: single-center design; no formal sample-size calculations CAPD patients with GFRs (renal urea and creatinine clearance from a 24-hour urine ✓ Small-sized patient(BMI 21); Asian with significant urine collection) ≥ 2 mL/min and urine volume ≥ 500 volume (1400-1600 ml at baseline) mL/d BMI • 3-exchange group (n=70) 3-exchange: 21.4 ± 3.0 • 4-exchange group (n=69) 4-exchange: 21.9 ± 3.2 glucose-based PD fluid Daily exchanges would be increased if total Kt/V No statistically difference in GFR, urine volume, time to anuria, < 1.7 with uremia or fluid overload (failed patient survival and technique survival medication) Peritonitis • Primary outcome: GFR, urine volume, and anuria-free survival at 24 months • Longer peritonitis-free survival time in 3-exchange group (log-rank test statistic = 3.811; P = 0.05) • Secondary outcomes included peritonitis, patient survival, and technique survival • Nominally lower in the 3- exchange group versus the 4-exchange group (13% vs 26%), but not statistically significant (P = 0.06).

Single-center retrospective cohort BMI 3-exchange: 21.4 ± 3.0 Incident PD patients 4-exchange: 21.9 ± 3.2 Exclude: total duration PD < 6 months, urine volume < 200 mL/day, previous HD, age<16 years • Full dose PD: 3 or more exchanges/d, 7 days Time to anuria a week (n=171) • 50 (28%) patients in the incremental PD group and 87 (51%) in the • Incremental PD: 1-2 dwells/day on CAPD, 7 full-dose PD group developed anuria. Median follow up time 5.9 yrs days a week, weekly pKt/V <1.7 but total Kt/V 1.7 (n=176) No significant difference in patient survival, technique survival, and peritonitis-free survival • Primary outcome: time to anuria (urine <100 mL/day) Limitations: Retrospective-bias, confounders, differed clinical profile at baseline between the treatment groups. • Secondary outcomes included peritonitis, technique failure, and all-cause mortality

Incremental PD Approach to incremental PD Incremental • Monitor clinical well-being Full dose PD PD • Urine volume, serum Cr, urea, phosphate ± β2- microglobulin • Review PD prescription at least every 3 months and more frequently if the person has new or unexplained symptoms • Regular measurement of both peritoneal and renal clearance Incremental peritoneal dialysis. Perit Dial Int. 2020 May;40(3):320-326.

Incremental PD: Concerns • Lack of standardized protocols • No clear hard outcomes benefits • More workload for health care professionals ?? • Reluctant to increased PD regimen when RKF reduce • Close monitor clinical symptoms and biochemical changes • Malnutrition?? • Measure RKF: more often?? • Save cost?? • Eligibility of ICO • PD solutions package

Hazard ratio of PD discontinuation, compared to US Models were adjusted for age, sex, BMI, US black race, heart disease, diabetes, psychiatric disorder, prior HD experience, urine volume, albumin, caregiver involvement, transplant waitlist referred, and accounting for facility clustering. Lambie M, et al. CJASN (Revision)

Variation in Peritoneal Dialysis Time on Therapy by Country TH UK A/NZ US Encourage KT, Need to issue guideline to STOP & MODALITY SWITCH

PD in low and low middle-income countries ✓ The initial PD prescription ……….consider incremental PD ✓ Preserve RKF and PM function…….without the need to intensify PD prescription ✓To utilize low-cost adjunctive management strategies in LIC and LMIC, such as dietary and life-style modification……. ✓PET and weekly Kt/V should be encouraged if the cost of these tests do not compromise the affordability of PD treatment in LLMICs ✓ PD programs should monitor the outcomes of these clinical interventions, focusing on inexpensive clinical indicators, and biochemical indicators Perit Dial Int. 2020 May;40(3):341-348.

PD for the multimorbid, frail and palliative patient ✓Peritoneal dialysis (PD) is only one component of overall care ✓Management should focus on QoL and symptom control ✓Goals of care should be determined by shared decision-making with the patient and family ✓Residual kidney function enables PD prescription to be reduced….Incremental or Decremental PD ✓Target is unknown??? Perit Dial Int. 2020 May;40(3):341-348.

Peritonitis Prevention is important - Aware of nail, oral, personal hygienes, - Changing cloths after outdoor exposure, - Regular reassess vision, fine coordination - Caregiver





Take Home Message 1. PD should be prescribed using shared decision-making between the patients/their caregivers and the care team with the goals to maintain QoL and minimize treatment burden. 2. A number of assessments should be used to help ensure delivery of high-quality PD care. (a) HRQoL: patient’s perception of his/her well-being. (b) Volume status: BP and clinical examination to ensure euvolemia. (c) Nutrition status: Evaluation of patient’s appetite, clinical examination, BW, and biochemical parameters (i.e., K, HCO3, PO4, albumin). (d) Small solute clearance: No specific target that guarantees sufficient dialysis for an individual. If symptoms, nutrition, and volume are all controlled, no PD prescription adjustment is needed for the sole purpose of achieving an arbitrary clearance target. 3. RKF should be determined for all patients and management should focus on its preservation. 4. Elderly, frail, or with limited life expectancy, there might be a QoL benefit of reduced dialysis prescription to minimize the burden of treatment. 5. The principles of prescribing and assessing delivery of high-quality PD to children are the same as for adults. SG-RC55-210046(V1.0)

Thailand-Peritoneal Dialysis Outcomes and Practice Patterns Study (Thailand-P-DOPPS)

SG-RC55-210046(V1.0)



Serum Phosphorus in PD: Results from the International PDOPPS Exposures N ACM MACE -4P+HF 6-Month mean P (mg/dL) 365 (6%) 0.90 (0.68,1.20) 0.65 (0.41,1.01) P < 3.5 1442 (25%) 1 (ref) 1 (ref) P ≥ 3.5 to ≤4.5 2115 (36%) P > 4.5 to <5.5 1196 (20%) 1.12 (0.93,1.35) 1.12 (0.87,1.42) P ≥ 5.5 to <6.5 729 (12%) 1.42 (1.10,1.82) 1.64 (1.23,2.18) P ≥ 6.5 1.81 (1.33,2.47) 1.85 (1.29,2.66) Months above P target (>4.5 mg/dL) 0 months 789 (13%) 1 (ref) 1 (ref) 1 month 438 (7%) 1.21(0.87,1.69) 1.36 (0.96,1.93) 2 to 3 months 1037 (18%) 1.13 (0.86,1.47) 1.42 (1.03,1.98) 4 to 5 months 1594 (27%) 1.28 (0.99,1.65) 1.43 (1.03,1.98) 6 months 1989 (34%) 1.57 (1.19,2.06) 2.04 (1.47,2.83) Baseline serum P was 4.2 mg/dL for Thailand. Higher serum P was associated with higher mortality & cardiac events. Lopes MB,…, Kanjanabuch T,…, et al. NDT 2022 Aug (E-Pub)

Techniques for Volume Status Assessment Technique What is Estimated Advantages Limitations Dilution tracers ECV, TBW Gold standard method Invasive, not for everyday IVC clinical practice Lung ultrasound Intravascular filling -BV Correlation with cardiac Experienced cardiologist Biomarkers Intravascular filling-BV function, Non-invasive No estimation of TBW, ECV Bioimpedance Noninvasive, easy Little experience in PD Intravascular filling-BV Noninvasive Wide variability ECV, ICV, TBW Good correlation with Influenced by cardiac volume status dysfunction proBNP > BNP > ANP No standardization Easy, noninvasive, fluid Influenced by volume in liters hypoalbuminemia and muscle wasting adapted from Am J Nephrol 202S0G-;R5C515-:251080946–(V61.01) 2

How to assess volume status in PD patients? SG-RC55-210046(V1.0)

Body Fluid Compartments TBW ICW 25% 66% Non-circulating volume: interstitial 33% fluid+ transcellular fluids ECW Circulating volume 8% TBW = total body water ICW = Intracellular water SG-RC55-210046(V1.0) ECW = Extracellular water

Principles of Bioimpedance and Bioimpedance Spectroscopy Infinite frequency: intracellular paths Low frequency: only extracellular paths Resistance: amount of fluid Capacitance: proportional to the cell mass Yong-Lim Kim et al. Seminars in Nephrology, Vol37,No1, 2SG0-R1C755,-p21p040436(–V15.03)

Types of BIA techniques by the type of frequency Frequencies Basic assumption Estimated Advantages Limitations parameter Single (50 Free Fat Weight 73.2% ECW Accurate measurement of Best accuracy in kHz) ICW ICW and TBW normally hydrated hydrated ICW and ECW in HD populations subjects normally distributed (comparison with TBW is the sum of dilution methods) ECW and ICW Multiple (5, Impedance at a low ECW In HD populations, Less accuracy for ICW frequency, ideally 0 kHz, TBW accurate 50, 100, will be inversely related to ICW (in multiple measurement in HD ECW, while frequencies is the of ECW (comparison with populations 200, and impedance at infinite difference singlefrequency/ 500) frequency will be closely between TBW and dilution methods) reltaed to TBW ECW) BIS (5–1,000 Am J Nephrol 2020;51:589–612 kHz) SG-RC55-210046(V1.0)

Table 1. Summary of randomized controlled trials assessing adequacy in peritoneal dialysis Trial Population Intervention Comparison Outcome ADEMEX (RCT) Enrolled 965 incident Peritoneal creatinine Preexisting PD No difference in and prevalent PD clearance of 60 L/wk per prescriptions (this is mortality at 2 years patients 1.73 m2 about 45 L/wk or 4 daily 2-L exchanges) Hong Kong Study Enrolled 320 incident Kt/V 1.7–2.0 or Kt/V Kt/V 1.5–1.7 No difference in (RCT) mortality at 2 years, CAPD patients >2.0 more uremia and volume overload in group with Kt/V of 1.5–1.7 Abbreviations: ADEMEX = ADEquacy of PD in MEXico; CAPD = continuous ambulatory peritoneal dialysis; PD = peritoneal dialysis; RCT = randomized controlled trial. SG-RC55-210046(V1.0)

Multidimensional Assessment Potential Dialytic Goals of ESRD Care Of Optimal Dialysis: Potential Strategies Measures To Achieve Evidence • Patient reported • Treatment • Maximize Outcomes Duration Quality of Life • Small solute removal • Treatment • Maximize • Residual Kidney Function Frequency Survival • Left Ventricular Geometry • Ultrafiltration Rate and • Incremental Dialysis Extracellular Fluid Volume Management • Preservation of Residual • Higher weight range Kidney Function middle molecule removal • Phosphorus • HR and BP Variability • Serum Potassium Control • Consideration SG-RC55-210046(V1.0) of Home Dialysis Abbreviations: HD-hemodialysis, HR-heart rate, BP-Blood Pressure Figure 1. | Multidimensional Measure of Dialysis. HR, heart rate.