1. Adequacy of RRT in the Critically Ill: Membrane and Filter related factors Claudio Ronco, MD Department of Nephrology, St. Bortolo Hospital, International Renal Research Institute Vicenza - Italy

2. For long time there has been very little improvement in mortality. This may be explained by changing demographics: age and comorbidity of patients with AKI continued to rise, possibly obscuring any increased survival related to improved critical care or amelioration in technology. AKI: Changing Pattern Vicenza Database 1995 – 2000 Total number of incident cases = 525 Vicenza Database 1974 – 1979 Total number of incident cases = 48 Mortality 54 %Mortality 53 %

3. CRRT-Associated Mortality in Major RCTs Clinical Trial APACHE II Endpoint Mortality Ronco et al (2000) 22 15-day 59% Mehta et al (2001) 25.5 Hospital 66% Augustine et al (2004) - Hospital 68% Saudan et al (2006) 25 90-day 66% Vinsonneau et al (2006) 25 60-day 68% Lins et al (2008) 27 Hospital 58% Tolwani et al (2008) 26 Hospital 60% ATN Trial (2008) 26.3 60-day 52.5% RENAL Trial (2010) 26 90-day 45%

4. 1996 2000 2001 2005 2006 2010 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Adjusted OR (95% CI) Mortality Dialysis Dependence

5. 1)Improvement in ICU practice in general 2)Improvement in patient identification and risk assessment 3)Early and effective institution of organ support/replacement 4)Improvement in RRT modality and technology a)Expanded use of Continuous Renal Replacement Therapy b)Correct prescription (Dose and Fluid balance) c)Personalized Modality and Schedule d)Accurate Monitoring and Delivery (Machines) e)Efficient Membranes and Filters for CRRT

6. CRRT in Critically Ill Patients Advantages Excellent Clinical Tolerance Optimal Fluid Control Optimal uremic Control Excellent Homeostatic Control Continuous Clearance Limitations Long term exposure to EC Continuous anticoagulation Cost and work load

7. 0.2.4.6.8 1 020406080100 IRRT CRRT days Modality-related recovery from dialysis dependence Recovery from dialysis dependence Hypotension: IRRT: 24.0% CRRT: 11.1% Ucino et Al Int. J Artif Organs 2007

8. RRT dependent on day 90 Almost exclusively CRRT utilization

9. 0 Hours of observation 612182430364248 +20 +10 0 -10 -20 -30 110 100 90 80 70 60 Mean 50 40 Art. Press. (mmHg) Blood Volume Variation (%) CVVH Uf = 3050 ml HD Uf = 3030 ml Potential Kidney Injury

10. n. 345 n. 564 19982004

11. Ronco et Al, The Lancet 356, 1, 26-30, 2000 Tolwani et Al, JASN 2008 Palewsky et Al, NEJM 2008 Dose of Dialysis (ml/Kg/hr) AKI and CRRT S u r v i v a l Bellomo et Al, NEJM 2009 Saudan et Al, KI 2006 Presence of Sepsis Early Intervention Honoré et Al. CCM, 2002 1020304050607080 Stork M, et Al. The Lancet 1991;337:452-455.

12. CRRT Prescription vs Delivery Venkataraman et al, J Crit Care, 2002 24.5  6.7 16.6  5.4 16.1  3.5 68% of prescribed dose 67% of total hours in day

13. DoReMi Database (N=865) Median prescribed = 34 mL/kg/h Median delivered = 27 mL/kg/h Ronco et al, 2009 Dose of CRRT (mL/kg/h) Patients (%)

14. 14 Delivered dose of CRRT in 2016 ( Crit. Care,In press) CVVHD CVVHDF CVVH ml/kg/h 25 40 32 Adjusted for 24 hrs DoReMiFa database

16. Flow-Pressure Monitoring System Flow and Pressure conditions are continuously monitored in the access, effluent, return lines, and in different compartment of the filter.

17. DELIVERED AND PRESCRIBED CLEARANCE Factors affecting discrepancy Blood flow rate lower than that displayed by the dialysis machine Inadequate vascular access Dialysate/ Filtrate flow lower than that displayed by the dialysis machine. Excessive filtration fraction Inadequate performance of the Filter/Membrane Incorrect priming procedures Loss of surface area (clotting, air) Loss of permeability (clogging of the membrane) High blood viscosity and hematocrit Excessive filtration fraction

18. Unplanned interruptions of CRRT

19. Blood In Blood Out Dial. InUF or Effluent Diffusable Solutes membrane Non diffusable solutes Proteins Cells

20. Jd = D T A (  c/  x ) D = Diffusion Coefficient T = Temperature A = Surf. Area  c = C. Gradient  x = Distance DIFFUSION Hollow fiber Blood Small solutes Colloids Cells Jd = Diffusion flow Jc = Qf [uf]/[p] Qf = Ultrafiltration rate [uf] = Solute concentration in the ultrafiltrate  p  = Solute concentration in plasma water CONVECTION Hollow fiber Small solutes Colloids Cells Jc = Convection Flow Solutes transported by solvent drag UF ULTRAFILTRATION Blood TMP = P -  = (Pb - Pd) -  Ultrafiltration Rate (ml/h) Transmembrane Pressure (mmHg) Kf = 18 ml / h / mmHg x m 2 (mid flux) Pb Pd HYDROSTATIC ONCOTIC  Hollow fiber UF Blood Qf = Kf TMP High Flux (Kf=30) Low Flux (Kf=6) 20406080100 0 500 1000 1500 2000 2500 Hollow fiber Blood S = 1 -  = [uf]/[p] Membrane Sieving Molecular Weight (Daltons) 10 2345 High Flux (Kf=30) Low Flux (Kf=6) 0 0.2 0.4 0.6 0.8 1.0 S [p] [uf] Human Glomerulus S = [uf]/  p  Sieving Coefficient A D C B

21. Rb Rm Rd Bulk Flow Stagnant Layer Boundary Layer MEMBRANE Stagnant Layer Transition layer Bulk Flow Proteins SOLUTE TRANSPORT Urea Creatinine  2  Albumin Observed Sieving Curve Membrane A 2 V At Wall: = -------- = -------------- = -------- Sh w 4 Q 4 V  r 4 V 2  r 3 3 r V max V = 0 V = 1/2 V max r dv dr = Shear Rate (Sh) T = -  ---- dv dr Shear Stress r    Shear Rate (Sh) Hollow fiber High Shear Rate S = 1 -  Low Shear Rate S = 1 -   Blood Hollow fiber Concentration Polarization B C D

22. Blood layer thickness Reduced Blood Speed (Visc) Possible Turbulence Stagnation Areas Blood Flow Distributor

23.   V max Blood Compartment C. Ronco 2001  Potting Surface and fiber density Conic Spiral

24. Flusso Normale Senza RicircoloPresenza di Parziale Ricircolo

25. Filter after 24h with optimal anticoagulation Filter at 24h with minimal anticoagulation Filter after 48h with optimal anticoagulation Filter after 48h with minimal anticoagulation

26. Pre-pump Pressure (Access) (1) Pre-filter Pressure (Blood in) (2) Post-filter Pressure (Venous) (3) Clotting 123

27. The coagulation of CRRT circuit depends on Clinical Therapeutic COAGULATION causes Blood factors (hematocrit, platelets, proteins, clotting factors) Septic factors Contraindication to anticoaugulant use (heparin or citrate)

28. Factors: Clinical Therapeutic Organizational Operating procedures COAGULATION causes Anticoagulation therapy Flows: Q B, Q UF, Q replacement, Filtration Fraction Check:, TMP, P pre-filter, P ret and Drop pressure

29. COAGULATION adequate prescription check: visual inspection filter/lines pressures monitoring monitoring clinical parameters (coagulation time) Flush for clearing out a circuit Eventual improving organizational, managerial, procedural factors. prevention resolution

30. Rb Rm Rd Bulk Flow Stagnant Layer Boundary Layer MEMBRANE Stagnant Layer Transition layer Bulk Flow Proteins

31. 2 V At Wall: = -------- = -------------- = -------- Sh w 4 Q 4 V  r 4 V 2 ê r  r r r r  r r r r 3 3 r V max V = 0 V = 1/2 V max r dv dr = Shear Rate (Sh) = -  ---- dv dr Shear Stress r    Shear Rate (Sh)

32. High Shear Rate S = 1 -  Low Shear Rate S = 1 -   Blood Blood Shear Dependent Protein Layer and Polarization

33. The concept of Filtration Fraction FF = Qf / Qp The fractional amount of ultrafiltrate produced in relation to the amount of plasma flowing in the hemofilter per unit of time. Optimal Ranges = 15 - 20 % OPTIMIZATION OF TREATMENT PARAMETERS

34. Sieving Ccoefficient 0.00 SOLUTES SIEVING COEFFICIENTS as a function of Filtration Fraction Molecular Weight (Daltons) 1010101010 2345 1.00 0.80 0.60 0.40 0.20 FF = 20% FF = 30 % FF = 40 %

35. Extended blood-membrane interaction (chemical and physical) may produce significant fouling and reduction in sieving properties and hydraulic permeability SEM micrographs showing the inner selective layer

36. Surface Roughness Analysis & Protein Deposition Atomic Force Microscopy ® Helixone ® ® Fresenius Polysulfone ® New membrane Used membrane (24 h)

37. 0 100 200 300 400 500 ULTRAFILTRATION (ml/min) Transmembrane Pressure (mmHg) 100 80 60 40 20 0 180 160 140 120 Kf = ml / h / mmHg x m 2 Boundary layer limitation Protein Layer Formation Uf

38. Reduction of RRT efficiency The performance characteristics of the membrane decrease by : Clotting/clogging Increasing hematocrit (due to NetUF) Concentration polarization phenomenon Increasing proteins concentration Protein cake layer in the inner surface Increasing proteins concentration Pores plugging

39. Reduction of RRT efficiency The performance characteristics affected are: Ultrafiltration coefficient Sieving coefficient (in convective modalities) Membrane permeability (Clerance, in diffusive modalities) Sakurai ACYaK: Dialysis Membranes — Physicochemical Structures and Features. In: Updates in Hemodialysis. Edited by Suzuki H; 2015.

40. Timing of filter clotting in CRRT

41. ULTRAFILTRATION BEHAVIOUR OVER TIME 40 36 32 28 24 20 16 12 8 4 0 0 4 81620244872 12 Hours of Treatment ( ml / min )

42. Creatinine Sieving Coefficient over time

43. CONCLUSIONS Effective treatment delivery in CRRT can be very different from prescription Membrane permeability decreases over time reaching critical values after 24 hours of use Filter clotting occurs in high percentage of cases after the first 24 hours leading to blood loss High anticoagulant dose is required to maintain filter patency beyond 24 hours In a randomized trial, 90% of prescription target was achieved by changing the filter every 24 hours The cost/benefit ratio of changing the filter at 24 hours in CRRT seems to be in favor of this policy.

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