Hemodiafiltration in BC Current Status and Obstacles Myriam Farah, MD, FRCPC

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1 2015 emodiafiltration in BC Current Status and Obstacles Myriam Farah, MD, FRCPC

2 OUTLINE What Why ow Why Not What Now No financial disclosures.

3 DF = D and igh volume ULTRAFILTRATION to achieve convective clearance A T Total ultrafiltrate + spent dialysate Dialysate Replacement (post-dilution) Limit Filtration Fraction to <25% (ie. Total UF rate <25% of blood flow rate) (eg. at 400ml/min = 100ml/min = 24L of UF) ADVANTAGES OF POST-DILUTION Does not dilute concentration gradients, so does not decrease clearance efficiency DISADVANTAGES OF POST-DILUTION Leads to hemoconcentration within filter (risk of filter clotting) May change heparin requirements

use 2x amount of post-dilution replacement fluid ADVANTAGES Lower risk of filter clotting

4 DF = D and igh volume ULTRAFILTRATION to achieve convective clearance A T Total ultrafiltrate + spent dialysate Dialysate Replacement (pre-dilution) To compensate, need to use 2x amount of post-dilution replacement fluid ADVANTAGES Lower risk of filter clotting DISADVANTAGES Dilution of blood pre-filter reduces concentration gradients for clearance Increases filter TMP

5 DF CIRCUIT A T Blood Ultrapure Dialysis Fluid Weight loss 10 ml/min Replacement 80 ml/min Total UF rate 90 ml/min In 4 hour run Weight loss 2.4L Vrep 19.2L Total UF (conv) 21.6L FILTER 2 Substitution (replacement) Fluid FILTER 1 standard dialysate

6 Challenges with removal of NON-small solutes on D W Added convective clearance Increased middle / large molecule removal ope that this lessens these burdens: Cardiovascular Inflammatory Uremic By extension, hope that decreases: Morbidity Mortality

7 CURRENT STATE OF AFFAIRS There is no conclusive evidence that prescribing DF for any patient will make them live longer There are potential benefits of DF therapy These benefits may be confounded by Use of ultra-pure dialysate Avoidance of intradialytic compromise Patient selection bias These benefits are likely dose dependent Implementation of DF has logistic challenges

INTRADIALTIC STABILIT Major RCT: Italian Convective Study 2010 146 prevalent D patients

hypotension Systematic review AJKD 2014 6 trials using DF Overall risk reduction for ID 0.

8 INTRADIALTIC STABILIT Major RCT: Italian Convective Study prevalent D patients randomized to Ongoing D F or DF 2 year follow-up DF significantly reduced intradialytic hypotension Systematic review AJKD trials using DF Overall risk reduction for ID 0.49 ( ) emodynamic stablization presumed due to thermal cooling and mild sodium load

UREMIA AND INFLAMMATION MAN observational studies demonstrate better middle molecule clearance Inflammatory markers Phosphate Protein-bound solutes Conflicting results regarding direct clinical

9 UREMIA AND INFLAMMATION MAN observational studies demonstrate better middle molecule clearance Inflammatory markers Phosphate Protein-bound solutes Conflicting results regarding direct clinical outcomes Anemia Phosphate control Clinically assessed inflammation Nutritional status No good data on impact on dialysis related symptomatology and QoL Unclear whether middle molecule clearance translates to direct clinical outcomes

10 MORTALIT Observational Data DOPPS RISCAVID (Italy) EuCLID (Chech R, ungary, Italy, UK) UK STUD Very promising 3 Major RCTs CONTRAST (Netherlands + Montreal) TURKIS-DF (Turkey) ESOL (Spain) Mixed results Lots of focus on post-hoc analysis

11 MAJOR OBSERVATIONAL DATA: MORTALIT STUD PATIENTS STUD DESIGN DF MODE F/U MORTALIT OUTCOMES DOPPS (2006) EuCLID (2006) 2165 prevalent D 2564 prevalent D Retrospective igh (15-25L) vs low (5-15L) 3 r 35% reduction Retrospective Online-DF 3r 35% reduction RISCAVID (2008) 757 prevalent D Prospective Bag-DF (~14L) vs Online-DF (~23L) 3r Mortality RR 0.78 (also lower IL-6 levels) UK STUD (2009) 858 incident D Retrospective DF (~15L) 18r Mortality R 0.45 (also less ID and lower inflammatory markers) Signal that igh volume DF did better

12 RCTs: Prevalent D pts randomized to D vs DF STUD PTS F/U DF V rep TARGET DF V rep ACIEVED CONTRAST r 20L Only 1/3 reached 20L Range 13-23L TURKIS DF OUTCOMES No difference mortality Post-hoc: mortality benefit if V rep >21.95L 782 2r 15L Mean 17.4L No difference mortality No difference ID, hosp rates Post-hoc: mortality benefit if V rep >17.4L ESOL 906 2r 18L Mean 24L 30% reduction in mortality Post-hoc analysis: 40% RR if V rep >22L 45% RR if V rep >25L

13 RCT: ESOL PRIMAR OUTCOME: MORTALIT Mortality benefit largely driven by infection and stroke

14 RCT: ESOL OTER OUTCOMES: OSPITALIZATIONS AND INTRA-DIALSIS SMPTOMS 1. Most hospitalization in D group due to vascular access issues 2. Intradialytic benefits seem believable and supported by other studies

15 RCT: ESOL TABLE 1: BASELINE DEMOGRAPICS D group disadvantaged from the get-go!

16 CURRENT STATE OF AFFAIRS Well-established belief that DF should be better for patients Current attempts to prove this are now focused on DF dosing Recent study suggests fixed dosing, or dosing per TBW or BSA, not body weight Expert opinion recommends Vrep >20-24L (post-dilution) No basis for patient selection criteria No RCT in incident dialysis patients No good data on dialysis-related QoL

17 DF GOAL: Vrep >20-24L, FF <25% LIMITATIONS: BLOOD FLOW RATE AND DURATION OF TERAP O W Bedside Solutions: 1. Increase Qb 2. Increase duration 3. Increase anticoagulation 4. Accept higher FF

18 O W DF GOAL: Vrep >20-24L, FF <25% Qb (ml/min) Desired Vrep (L) Target conv UF (ml/min) Desired weight loss (L) Target UF for weight loss (ml/min) Total UF (conv + weight loss) (ml/min) Effective Filtration fraction (%) Adjusted conv UF (ml/min) to limit FF <25% Adjusted Vrep (L) Bedside Solutions: 1.Consider weight loss UF as part of total UF and lower conv UF (and therefore Vrep)

WATER REQUIREMENTS FOR DF Municipal water O W Pre-treatment Product Water Purification RO

25 EU/ml Acid and Base Concentrate Test for ultrapure dialysate This we can do but felt

5 EU/ml Filter 1 Test for substitution fluid SAL 6 sterility assurance level 6 means: 1 in

19 WATER REQUIREMENTS FOR DF Municipal water O W Pre-treatment Product Water Purification RO Dialysis Fluid < 100 CFU/ml < 0.25 EU/ml Acid and Base Concentrate Test for ultrapure dialysate This we can do but felt unnecessary Standard Dialysate < 100 CFU/ml < 0.5 EU/ml Filter 1 Test for substitution fluid SAL 6 sterility assurance level 6 means: 1 in 1,000,000 chance of contamination No test is this sensitive Testing of substitution fluid therefore futile Ultrapure Dialysate < 0.1 CFU/ml < 0.03 EU/ml Filter 2 Substitution Fluid SAL x 6 < 0.03 EU/ml

20 N O T COST OF NEW TERAP POTENTIAL ADDITIONAL COST POTENTIAL COST SAVINGS UNKNOWNS Medications heparin Water Additional testing (if we do it) Additional dialysate use (depends on Rx) Impact on system Machine disinfection time scheduling Disposables Tubing Filters Medications EPO, phosphate binders, BP meds ospitalization rates Impact on system duration / frequency of runs Disposables on-lime priming vs NS bags Quality of Life Quantity of Life Cost Utility Analysis Studies from CONTRAST cohort suggest favourable cost-utility ratio (adjusted to QAL) Direct cost comparison to D likely a wash (depending on disposable costs for machine

21 A T N O CURRENT STATE Very good likelihood that increased convective clearance could have short-term and long-term clinical benefits oping for mortality reduction may be an unrealistic expectation, especially in prevalent dialysis patients Lack of robust RCT evidence for mortality should not deter reasonable clinical application FUTURE DIRECTIONS DF implementation can be exciting and informative, IF we establish: 1. Patient selection criteria 2. Target DF prescription 3. Logistics of water testing 4. Prospective data collection (Cost, Dialysis related symptoms, QoL) W

22 DISCUSSION 2015

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