ad e quate adjective \ˈa-di-kwət\

PD Prescriptions and Adequacy Monitoring: The Basics Fundamentals of Dialysis in Children Seattle, Washington February 27th, 2016 Colin White Steve Alexander Brad Warady Alicia Neu Franz Schaefer Bruce Morgenstern Objectives 1. Define and be able to measure/monitor PD Adequacy at the level of the individual patient Specifically in reference to small solute clearances 1. Demonstrate understanding of the major prescriptive components of a comprehensive PD prescription; and be aware of commonly used standards/ guidelines as they apply to children Merriam Webster ad e quate adjective \ˈa-di-kwət\ :good enough :of a quality that is acceptable but not better than acceptable

What is Adequate PD? Adequacy most often refers to the quantity of solute clearance delivered but in a broader sense is often meant to reflect on the quality of the dialysis prescription as a whole Tzamaloukas et al Semin Dialysis 2008 Vol 21, No 3, p250-257 Handbook of Dialysis, 5 th Ed, Chap. 25 Blake and Daugirdas Adequacy as defined by Quantity of Clearance In broad strokes Quantity of Clearance refers to clearance of small easily measureable molecules felt to reflect uremia or toxin accumulation Historically, in PD these quantity of clearance measures were of: UREA reported as Weekly Kt/Vurea CREATININE reported as Weekly Creatinine Clearance Current guidelines and consensus statements favor use of Kt/Vurea as the standard measure to follow and to strive for in order to reach a CLEARANCE TARGET Kt/Vurea Fractional Clearance of Body Urea UNIT-LESS / NON-PHYSIOLOGIC MEASURE/a mathematical construct Developed by Gotch and Sargent to allow comparison of doses of dialysis K is representative of CLEARANCE in the Kt/V formula Kd = clearance of dialysis delivered Kr = clearance of residual renal function t is the time over which that dialysis is delivered In PD calculations t is normally considered 24 hours/ 1 day...ie the calculation is based on full day of dialysate/urine output (then scaled to 1 week) V urea is the volume of distribution for Urea in the patient, which is the patient s Total Body Water (TBW) V is NOT trivial and in fact can be a major source of error

Weekly Dialysis Kt/V 24 Hr D/P Urea x 24-Hr Drained Volume x7 V Daily Renal Urea Clearance Volume of 24-Hr Urine in ml x Urine Urea Nitrogen Conc. 1440 min/day x Blood Urea Nitrogen Concentration Weekly Renal Kt/V ml/min Urea clearance x 1440 min/day x 7 1000 ml x V Total Weekly Kt/V_urea Total Weekly Kt/V_urea = 7 days * { [Day of Renal Clearance + Day of Dialysis Clearance] / Vd_Urea } Renal Clearance = [Uvol x Uurea/Purea]; Uvol is 24 hr urine volume in L Dialysis Clearance = [Dvol x Durea/Purea]; Dvol is 24 hr drained dialysate volume in L Vd_urea is the volume of distribution of urea (the TBW) in L 100 cm 20 kg Male with Vd_urea of 10 L, he voids 200 cc/day & TOTAL dialysate drained for day is 7 L Urine urea 8 mmol/l (22.4 mg/dl), plasma urea 17 mmol/l (47.6 mg/dl), dialysate urea 10 mmol/l (28 mg/dl) Weekly Kt/V = 7*{[0.2L * 8/17] + [7L * 10/17] / 10 L} = 7*{[0.1] +[4.1]/10} = 7*[0.42] Weekly Kt/V_urea = 2.9 It s all about the V Current best practice is to use Gender-Specific Nomograms developed from studies on Pediatric PD patients reported by Morgenstern, et al in 2006. Used Heavy Water Dilution studies to develop and validate TBW Prediction equations in 64 Pediatric PD patients Formulae exist with Ht in cm and Wt in kg MALE TBW = [0.10 * (Ht*Wt) 0.68 ] [0.37 * Wt] FEMALE TBW = [0.14 * (Ht*Wt) 0.64 ] [0.35 * Wt] Note extremes not included here ie very obese or malnourished Anthropometric prediction of total body water in children who are on pediatric peritoneal dialysis. Morgenstern BZ1, Wühl E, Nair KS, Warady BA, Schaefer F. J Am Soc Nephrol. 2006 Jan;17(1):285-93.

Male TBW Nomogram Height (cm) 50 54 58 62 66 70 74 78 82 86 90 94 98 102 106 110 114 2 1.6 1.7 1.8 1.9 3 1.9 2.1 2.2 2.4 4 2.2 2.4 2.6 2.8 3.0 5 2.4 2.7 2.9 3.1 3.3 6 2.6 2.9 3.1 3.4 3.6 3.9 4.1 Weight (kg) 7 2.8 3.1 3.4 3.6 3.9 4.2 4.4 4.7 4.9 8 2.9 3.2 3.5 3.9 4.1 4.4 4.7 5.0 5.3 5.5 5.8 9 4.0 4.4 4.7 5.0 5.3 5.6 5.9 6.2 6.5 6.7 10 4.2 4.6 4.9 5.2 5.6 5.9 6.2 6.5 6.8 7.1 7.4 7.7 11 4.4 4.8 5.1 5.5 5.8 6.2 6.5 6.8 7.1 7.5 7.8 8.1 8.4 8.7 12 4.5 4.9 5.3 5.7 6.0 6.4 6.8 7.1 7.5 7.8 8.1 8.5 8.8 9.1 13 6.3 6.6 7.0 7.4 7.8 8.1 8.5 8.8 9.2 9.5 14 6.5 6.9 7.3 7.7 8.0 8.4 8.8 9.2 9.5 9.9 15 6.7 7.1 7.5 7.9 8.3 8.7 9.1 9.5 9.9 10.2 16 6.8 7.3 7.7 8.1 8.6 9.0 3.4 9.8 10.2 10.6 17 8.4 8.8 9.2 9.7 10.1 10.5 10.9 18 8.6 9.0 9.5 9.9 10.4 10.8 11.2 19 8.8 9.3 9.7 10.2 10.6 11.1 11.5 20 9.0 9.4 9.9 10.4 10.9 11.3 11.8 Female TBW Nomogram Height (cm) 50 54 58 62 66 70 74 78 82 86 90 94 98 102 106 110 114 2 2.0 2.1 2.2 2.4 3 2.4 2.6 2.8 2.9 4 2.8 3.0 3.2 3.4 3.6 5 3.1 3.3 3.5 3.8 4.0 6 3.3 3.6 3.8 4.1 4.3 4.6 4.8 Weight (kg) 7 3.5 3.8 4.1 4.4 4.8 4.9 5.2 5.5 5.7 8 3.7 4.0 4.3 4.6 4.9 5.2 5.5 5.8 6.1 6.4 6.6 9 4.9 5.2 5.5 5.8 6.1 6.4 6.7 7.0 7.3 7.6 10 5.1 5.4 5.8 6.1 6.4 6.8 7.1 7.4 7.7 8.0 8.3 8.6 11 5.3 5.6 6.0 6.4 6.7 7.1 7.4 7.7 8.1 8.4 8.7 9.0 9.3 9.6 12 5.4 5.8 6.2 6.6 7.0 7.3 7.7 8.0 8.4 8.7 9.1 9.4 9.7 10.0 13 7.2 7.6 8.0 8.3 8.7 9.1 9.4 9.8 10.1 10.4 14 7.4 7.8 8.2 8.6 9.0 9.4 9.7 10.1 10.5 10.8 15 7.6 8.0 8.5 8.9 9.3 9.7 10.0 10.4 10.8 11.2 16 7.8 8.3 8.7 9.1 9.5 9.9 10.3 10.7 11.1 11.5 17 9.3 9.8 10.2 10.6 11.3 11.4 11.8 18 9.6 10.0 10.5 10.9 11.3 11.7 12.2 19 9.8 10.2 10.7 11.1 11.6 12.0 12.5 20 10.0 10.4 10.9 11.4 11.8 12.3 12.7 How much dialysis is enough?

From the original DOQI Guidelines: Clinical judgment suggests that the target doses of PD for children should meet or exceed the adult standards However, there are currently no definitive outcome data in pediatric patients to suggest that any measure of dialysis adequacy is predictive of well-being, morbidity, or mortality DOQI 1997 1997 DOQI PD Adequacy Targets Kt/V C cr CAPD 2.0/wk 60 L/wk/ 1.73m 2 NIPD 2.2 66 CCPD 2.1 63 There were problems with the pediatric application of the 1997 DOQI PD adequacy guidelines. Difficult to achieve both Kt/Vurea and Ccr targets in some patients (esp. infants). Unclear which is more important, Kt/Vurea or Ccr. Difficult to reach targets in older anuric patients without daytime exchanges involving significant life-style sacrifices. Difficult to measure residual renal function in incontinent infants and others.

CANUSA Study Showed clear association between total small solute clearance and mortality in adult CAPD patients. For each 0.1 decrease in total Kt/V, there was an associated ~12% increase in mortality risk! Originally thought to suggest that peritoneal and renal small solute clearances had equivalent impacts on outcome. Only later was the dominant role of residual renal function understood Bargman, et al: JASN, 2001 12:2158-82. ADEMEX Study High Dose Low Dose DOQI targets reached ~80% <40% Survival rate 69.3% 68.3% Total Kt/V per wk 2.13 1.62 Total Ccr (L per wk) 63 53 Paniagua R. et al, JASN 2002, 13:1307 PD Prescription Targets Dosing targets in adults derived from studies linking urea removal with morbidity/mortality No large scale, prospective studies in children to define the adequate dose of dialysis What to do when there are no data on which to base a Guideline? EXPERT OPINION!

The minimal delivered dose of total (peritoneal and kidney) small-solute clearance should be a Kt/ V urea of at least 1.8/wk.

For Patients with Residual Kidney Function (urine Kt/V urea >0.1/wk) The minimal "delivered" dose of total (peritoneal and kidney) small-solute clearance should be a Kt/V urea of at least 1.8/week. Total solute clearance should be measured within the first month after initiating dialysis and at least once every 6 months thereafter. If the patient has RKF and the residual kidney clearance is being considered as part of the patient's total weekly solute clearance goal, a 24-hour urine collection for urine volume and solute clearance determinations should be obtained at a minimum of every 3 months. For Patients without Residual Kidney Function (Urine Kt/V_urea <0.1 / week) Minimum DELIVERED dose of Small Solute Clearance (Kd) should be a Kt/V_urea of at least 1.8/ week The peritoneal solute clearance should be measured within the first 30 days after starting dialysis and AT LEAST* once every 6 months thereafter *Caveat: re-measure whenever potential significant change to Peritoneal Membrane Function [post surgery/peritonitis] or change in patient body habitus/ size/ nutrition etc. Meeting Dosing Targets 562 Prevalent Pediatric PD Pts Modality N (%) % w/ weekly Kt/V urea > 1.8 CCPD 435 (77%) 89% CAPD 20 (4%) 80% NIPD 53 (9%) 74% Tidal 54 (10%) 89% Fadrowski J. AJKD 2007 50:958-966

Weekly Kt/V Mean value: 2.9 + 1.2 Patients (%) International Pediatric Peritoneal Dialysis Network (IPPN) Japanese Study Group of Pediatric PD (JSPPD) Recommends a Kt/V > 2.5 General approach Honda. Peritoneal Dialysis Prescription Suitable For Children With Anuria. Perit Dial Int 2008; 28(S3):S153 S158 What do you (need to) consider when writing a PD prescription? Verrina et al OUR MAJOR GOALS FOR PD ARE -SOLUTE CLEARANCE -ULTRAFILTRATION/ EUVOLEMIA -NUTRITION AND GROWTH -QUALITY OF LIFE OPTIMIZED VS IDEALIZED REALISM AND REAL LIFE PATIENT VS PROGRAM INDIVIDUAL EXPERIENCE precision medicine

What can you control when writing a PD prescription? Verrina et al WE CONTROL THE PD -DWELL VOLUMES -TEMPO/ TIMING - REGIMEN - EXCHANGES - DWELL TIME - SOLUTION COMPOSITION AND IF WE ARE LUCKY WE CAN FIND WAYS TO SLOW LOSS OF RESIDUAL RENAL FUNCTION Anatomic and Physiologic Facts that Drive the PD Prescription Peritoneal membrane surface area is proportional to body surface area independent of patient age Scaling peritoneal dialysis exchange volume to body surface area (and not to weight) allows optimal exposure of peritoneal membrane to dialysate PD Prescription- Fill Volume Recommended target: 1000-1200 ml/ m2 Infants <2 yrs: 600-800 ml/m2 1,000-1,200 ml/m2 is just too much for infants to tolerate! 3 kg infant: BSA = 0.22m2 1000 x 0.22 = 220mL = >70mL/kg!

What can you control when writing a PD prescription- Dwell Volume Primary Goal - Clearance The Rules Maximize exposure of peritoneal membrane/blood supply to dialysate! Generally the easiest/cheapest ($$ and time) modification OFTEN IS & SHOULD BE FIRST OPTION JASN 13: 584-591, 2002 What can you control when writing a PD prescription- Dwell Volume Excess Volumes may lead to -Raised Intraperitoneal Pressures - Loss of UF [ Lymphatics ] - Pain - Risk of hernia - Risk of hydrothorax - Risk of breathing problems -Position matters! -Supine<Stand<Sit Maximum ~ 15-18 cmh20 Fischbach et al Ped Nephrol 18: 976-980 2003

What can you control when writing a PD prescription- Dwell Volume and Ultrafiltration Heinrich s P&P Dialysis 4 th Ed Chapter 14 Fig 14.7 NET Ultrafiltration achieved is complex interplay of Dextrose Concentration and Dwell Volume but also... -Dwell Times and the effects Lymphatic Absorbtion When controlling for Osmotic Strength... In general more FLUID IN means more UF OUT Normal Lymphatic Absorbtion rates on PET tests: Adults 1-2 ml/min Or >/=240 cc/4 hour exchange What can you control when writing a PD prescription- Tempo/ Timing Each patient has a UNIQUE membrane... To maximize the patients membrane function and best clearance at the least metabolic cost you need to know what is under the hood! Peritoneal Equilibration Test PET Handbook of Dialysis, Daugirdas, Blake and Ing, 4 th Ed, Chapt 22, Fig 22-1 Classic PET Test Methodology(1) Long overnight SINGLE exchange of usual volume and solution FULL drain and very fast instillation of 1000-1100 ml/m2 of 2.5% Dianeal 4 hour test time with PD fluid samples drawn at Time Zero/ 120 and 240 minutes [Urea/ Creatinine/ Glucose + Na or PO4] Blood sample drawn at Time 120 minutes [Urea/ Creatinine/Glucose + Na or PO4]

Classic PET Test Methodology(2) From the Dialysate and Serum Values one can calculate a fractional amount of solute that appeared over a period of time in the dialysate So call D/P ratio or Dialysate/Plasma Concentration Generally interested in D/P Urea and D/P Creatinine as markers of clearance characteristics of membrane Interested in D/D0 Glucose as a marker of metabolic cost of doing business (i.e. how much glucose absorbed in a period of time; 0-240 minutes) D/P Na and PO4 have value and are standard in some programs though not part of Classic PET... PET Equations D/P RATIO: dialysate urea concentration serum urea concentration D/DO RATIO: dialysate glucose concentration dialysate glucose concentration at time 0

Peritoneal Membrane Characteristics Membrane % Patients 4-Hr Type Characteristics Very efficient membrane Transports solutes quickly 16% High Increased glucose absorption May have difficulty achieving ultrafiltration At risk for low serum albumin High Efficient 35% Average Transports membrane solutes well Ultrafilters well 32% Inefficient membrane Transports solutes slowly 17% Low Difficult to obtain target total Kt/V when no residual renal function Ultrafilters very well Low Less efficient membrane Average Transports solutes somewhat slowly Ultrafilters well CMS ESRD CPM Project 2006 Annual Report Slide by Dr A Neu Membrane % Patients Peritoneal Membrane Characteristics 4-Hr Type Favored Dialysis Prescription 16% High 35% High Average 32% Low Average 17% Low Automated PD NIPD/ CCPD Short Cycles with good clearance Not enough time to absorb much glucose Day dwell likely best with Icodextrin Any major dialysis regimen Likely to benefit in general from minimizing glucose exposure APD with fewer Cycles CAPD +/- Extra Night Dwell = 4-5 cycles/d Requires lower Glucose strengths CAPD and will require prolonged dwell time so maximum 5 exchanges and need to be well spaced Low Glucose exposure Low Protein losses CMS ESRD CPM Project 2006 Annual Report Slide Modified by Dr C White PD Modalities CCPD NIPD CAPD

Major Determinants of PD Modality Choice Financial Center preference Geography Lifestyle Transport characteristics of the individual patient s peritoneal membrane What can you control when writing a PD prescription- Solution Composition Primary Goals Ultrafiltration Minimize Metabolic Effects [Biocompatibility] Balance of Electrolytes Acid Base Glucose Degradation Products Peritoneal Environment Small Solute Clearance What can you control when writing a PD prescription- Solution Composition Dialysate Concentration NEGATIVE UF

What can you control when writing a PD prescription- Solution Composition Biocompatibility -Potential impact on - Residual Kidney Function - Ultrafiltration - Membrane Lifespan - Small Solute Clearance Garcia Lopez Nature Review 2012 What can you control when writing a PD prescription- Solution Composition 36 Studies - Adult and kids - RCT or quasi RCT - 2719 Pts - Poor design - Allocation bias - Lost to Follow up 0-85% - Based on the best available evidence, the use of these 'biocompatible' PD solutions resulted in clinically relevant benefits without added risks of harm. Biocompatible dialysis fluids for peritoneal dialysis Cho, Yeoungjee; Johnson, David W; Craig, Jonathan C; Strippoli, FM Giovanni; Badve, Sunil V; Wiggins, Kathryn J Cochrane Database of Systematic Reviews. Issue 3, 2014. Neutral ph/ Lactate or Bicarbonate/ low GDP vs. Conventional Soln. Low GDP Soln WAS associated with better Urine Output up to 3 years - 7 studies, 520 pts, MD 126 cc/day [95% CI 27-225] Low GDP Soln WAS associated with improved preservation of RRF if >12 months F/U - 6 studies, 360 pts, SMD 0.31 [95% CI 0.10-0.52] Low GDP Soln WAS NOT associated with peritonitis, technique failure or adverse events Glucose Polymer (Icodextrin ) vs. Conventional Soln. Glucose Polymer Soln WAS associated with significant reduction in fluid overload episodes - 2 studies, 100 pts, RR 0.30 [95% CI 0.15-0.59] Glucose Polymer Soln WAS associated with improved ultrafiltration - 4 studies, 102 pts, MD 448.5 cc [95% CI 289-608] Glucose Polymer Soln DID NOT compromise residual renal function - 4 Studies, 114 pts, SMD 0.12 [95% CI (-)0.26 0.49] Glucose Polymer Soln DID NOT compromise urine output - 3 studies, 69 pts, MD (-) 89 cc/day [95% CI (-)357 179] Glucose Polymer Soln HAD SIMILAR incidence of Adverse Events - 4 studies Useful Resources Warady et al Optimal Care of the Infant, Child and Adolescent on Dialysis: 2014 Update. AJKD 2014 July, 64(1); 128-142. Pediatric Dialysis, 2 nd Edition. Warady, Schaefer, Alexander. Chapter 11 Technical Aspects of Prescription of Peritoneal Dialysis in Children p169-203 Handbook of Dialysis, 5 th Edition. Daugirdas, Blake and Ing. Chapter 25 Adequacy of Peritoneal Dialysis p464-482 Chapter 26 Volume Status and Fluid Overload in Peritoneal Dialysis p483-489 Chapter 37 Dialysis in Infants and Children p693-712 KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 2006 Updates. Hemodialysis Adequacy, Peritoneal Dialysis Adequacy and Vascular Access. Am J Kidney Dis. 2006;28(suppl 1):S1

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