Towards improving HD efficiency .. HD membranes update - prof. Hesham Elsayed MNDU 8

1. Towards Improving HD
Efficiency
HD Membranes update
HESHAM ELSAYED
PROFESSOR OF NEPHROLOGY
AIN SHAMS UNIVERSITY - ESNT 2018
1

3. HD improvements the
“3” Unknowns
Solid
Knowns
Known
Unknowns
Unknown
Unknowns
Time
Kt/V
UFR
Toxins
Fluxes
RCT
IntegratedApproach
Mortality
+
QOL
3

4. HD improvements the
“3” Unknowns Solid
Knowns
Known
Unknowns
Unknown
Unknowns
Mortality
+
QOL
4
More Proteomics to come to
Known Unknowns

5. Men and Women are equal on St Kt/V Women need More HD Dose with BSA correction
KT/V urea is still the official marker of Adequacy
5

6. Nature Review of Nephrology 2018
6

7. Pushing
Towards A
Better
Dialysis
To Know the
Unknowns
7

8. Measures of HD Adequacy Thirty Years: Lessons Learned in Dialysis
Daugirdas :Semin on Dialysis Jan 2017
Additional Measure
Secondary Measure
Primary Measure
Kt/V
Embraced by the KDOQI adequacy
guidelines
Embraced by the
Caregivers
PAYERS
volume status and
ultrafiltration rate
phosphorus and beta-2-
microglobulin (β2-M) removal
QOL against Renal Tx
8

9. Dying to Feel Better: The Central Role of Dialysis–
Induced Tissue Hypoxia (CJASN April 07, 2016 )
Control of
Uremic
Symptoms
Smooth UFR
Avoid Organs
Stunning
Better
Recovery
time Post HD
Improve
Depression /
dependence
Higher QOL
IMPROVING HD
HD
Different
Techniques
Outcome
9

10. Missing points in clinical practice (Am J Kidney Dis. 2014 Jul;64)
Post HD Recovery Time ( 6000 Patients )
How long does it take you to recover from a dialysis session?
32%
41%
17%
10%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
< 2 Hours 2- 6 Hours 7 - 12 Hours > 12 Hours
% of Patients Recovery Time
Longer recovery times after dialysis is associated with poorer
HRQOL and 20% have greater 50% increase in mortality,> 50 % Have Delayed Recovery
10

11. Recovery Time
Identify patients Have
Poor QOL
High Risk of Dying
11

12. "Optimal" Dialysis Dose prescription Should
Goal
Comfortable HD
Better Control of BP ,
Anemia , CKD-MBD
Better control of Uremic Toxins
and Volume state
Better
Survival
And HRQOL
High
Permeable
membranes
Prolonged Time ?
More
Frequent?
12

13. Therapeutic Approach Kidney International (2014)
13

14. Haemodialysis Therapy: A Never-Ending Journey
•LF Dialysis = Small solute KT/V Sunset of KT/V
• High Flux Dialysis and HDF ?? HD dose prescription
• Medium Cut off Dialysis ?? HD dose prescription
• High Cut off Dialysis ?? HD dose prescription
14

15. ULTRAPURE DIALYSATE
Ultrapure dialysis water obtained
with additional ultrafilter may
reduce inflammation in patients
on hemodialysis.
Journal of Nephrology December 2017, Volume 30
Microbes and ET are
not allowed
15

16. Achieving High Quality water system for Ultrapure Dialysate ( UPD)
Standard Water
Standard
Dialysate
Ultrapure Water
Ultrapure
Dialysate
Sterile Dialysate
Bacterial limits a,
CFU/mL
< 100-200 < 100-200 < 0.1 < 0.1 < 10-6
Endotoxin limits b,
EU/mL
< 0.25-2 < 0.25 < 0.03 < 0.03 < 0.03
MicrobiologicalStandardsforWaterandDialysisFluidPurity
UPW+UPD
16

17. HD Membranes Physiochemical Structures
17

18. Before Riding the Road
18
Blood contact 3 km every
15 sec

19. Membrane for Hemodialysis Less Clotting

20. HD Membranes Physiochemical Structures 20
The Structure
Back Bone and a Hydrophilic Components
The Function
Fluxes and Ultrafiltration
Biocompatibility
As Smooth as an Endothelium

21. HD Membranes Physiochemical Structures SEM of Ps 21
Asymmetrical Structure
Back Bone of PS
Hydrophobic
Internal skin Layer
Sieving Layer

22. HD Membranes Physiochemical Structures 22
PS Polymer in the
39 um Thickness
Internal skin Layer
Sieving Layer 1 um
Define the Molecule that
can Pass
Should be smooth as an
Endothelium
Only Area of Blood contact

23. HD Membranes Physiochemical Structures
23

24. 24

25. PVP Based PS Hydrogel Formation
Smooth as an Endothelium
25

26. Computer Simulation of Flow Design
26
Flow Design
Blood / Dialysate
Match
Clearance and Ko
Blood Entry

27. 27
Clearance and Ko
Diffusive Permeability

28. Thrombogenicity
28
Blood Contact with Membrane
Front. Immunol., 25 January 2018

29. Thrombogenicity
29
Blood cells
Activations
Front. Immunol., 25 January 2018

30. Thrombogenicity
30
Nature Reviews Nephrology
volume 13, 285–296 (2017)
Contact with surface Protein changes Activation
recruits platelets and
catalyses fibrin formation
Ab, antibody; Bb, activated factor B; C5aR, C5a anaphylatoxin chemotactic receptor 1; FcγR, Fcγ receptor; HK, high molecular weight kininogen; PAR1/4,
proteinase-activated receptor 1/4; P2Y1/12, P2Y purinoceptor 1/12.

31. Model of innate immunity
activation as a cause of
cardiovascular disease during
dialysis
31
Contact Activation Augmentation
Thrombosis
transfer of
inflammation to EC
EC Atheroma Calcifications

32. How to Choose a Dialyzers ?
32
Fibers • Material and Flux
Size • Surface area in m2
Dialyzer • Biocompatibility
Steriliz
• Steam – Gamma –
Ebeam EO
clotting • Better Rhology
Performance • Clearance values
Micro-undulation ?

33. HD membranes in clinical uses
Clinical uses Determine the outcome
33

34. Man Power / Equipment / patients
Dialysis unit in a convenient mode
High Quality HD machines
High Quality Disposables
Adequate HD ??
HD safety

35. Blood speed in the
middle and the
periphery

36. Improving clearance by better Blood & dialysate
flow geometry
Blood in
Blood out
Hollow fiber
Casing or jacket
Dialysate
Header
Blood to Dialysate matching
to increase the clearance
1.9 cm/sec
1.3 cm/sec

37. Blood Flow speed is higher in the
center
Dialysate Flow is higher in the
periphery

38. Towards Better Dialysis current achievements
Membranes
Higher SC
Removing MM
More Porous
Membranes
Higher Convection
TTT
Amplified Clearance
HE-HDF
Extended and
Frequent Sessions
Improve compartmental
Removal
More Physiological
Expanded HD
HDx
Removal of bigger
molecule
Than HFD
Adsorption
Remove Bigger molecules
Protein Bound Toxins
Line of improvements
Towards Larger
Molecules Removal
Towards Higher Fluxes
38

39. FLUX AND SOLUTE PERMEABILITY
cut off = SC 0.1
LF MF HF
Super
Flux
MCO HCO
Plasma
Filter
5000 8000 20000 3000 45000 65000 2 M
Cut off
MW
D
Higher MW Uremic Toxins
Beyond B2m
39

40. Small
MM
PB Toxins
40

41. “STUDY OF THE EFFECTS OF HEMODIAFILTRATION VERSUS
HEMODIALYSIS ON DNA METHYLATION AND INDOXYL SULFATE
REMOVAL Elsayed H , etal 2018
Indirect correlation (r= -0.922, P < 0.001)
Cytokine Reduction with HF Dialysis
Elsayed H , etal 2017
0.45
0.28
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
Myoglobin SC
Dialyzer 1 Dialyzer 2
27.10%
10%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
IL-1 B RR
Dialyzer 1 Dialyzer 2

42. Dialyzer
membrane
“Pore
diameter”
Medium
Cut Off
42

43. Targeting Beyond B2m in MW
43

44. Medium cut-off membranes - closer to the natural
kidney removal function ( MCO )
44

45. Medium cut off Membrane MCO
Bigger pore
Radius
M
M
Albumin
BM
45

46. MCO
Higher Membrane
Permeability
HDF
Membrane Permeability
+
TMP dragging
Quantification is
needed
Quantification is
calculated
More RCT is needed RCT on longterm
benefits
46

47. HD Backfiltration internal HDF
Pressure Drop
Back filtration volume is risky for
Pyrogen transfer `… volume ??
47

48. HDF and dose optimization 48

49. HDF Dose
Depends on :
 1-Blood volume
processed.
 2- UF and substitution
volume
Volume of
processed Blood
Volume of
convection
volume
Filtration Fraction in
the Safe Limits
between 25 – 30 %
FF = UFR / QB
49

50. 50
HDF
Requirements for Sterile
Dialysate infusion
2
Barriers • Using 2 ERF
3
Barriers • Using 3 ERF
ELITE NEPHROLOGISTS SCHOOL (ENES) 2018

51. HDF benefit over High Flux HD
Elsayed H in press 2018
82 82.2
76
67.4
0
10
20
30
40
50
60
70
80
90
URR % B2M RR%
RR %
HDF HFHD
51

52. EFFECT OF OL-HDF on DNA methylation
Elsayed H, Elsharkawey M etal 2018 in press
ct correlation (r= -0.922, P < 0.001)
DNA methylation
r P
Substitution volume -0.922 <0.001**
**; High Statistical Significant difference
DNA Methylation
Correlation coefficient p value
Indoxyl
sulfate
HFHD -0.156 0.510
HDF 0.004 0.987
52

53. Hemodiafiltration Reduces All-Cause and
Cardiovascular Mortality in Incident Hemodialysis
Patients: A Propensity-Matched Cohort Study
October 2017, Vol.46, No. 4
study cohort comprised 3,075 incident dialysis patients treated
Compared with patients on high-flux HD, those on online hemodiafiltration
received a median replacement volume of 23.45 L/session
Median follow-up period was 2.54 (1.09–4.46) years
53

54. Manifested 24 and 33% reductions in all-
cause and cardiovascular mortality
54

55. October 2017, Vol.46, No. 4
HDF Dose
dependent
HR
Crude model: The univariate analysis, only
including the convective volume;
The crude model adding the Td and the QB
Adjusted analysis all the variables recorded for the study
55

56. Improving Erythropoiesis Stimulating Agent
Hyporesponsiveness in Hemodialysis Patients: The
Role of Hepcidin and Hemodiafiltration Online
2018, Vol.45, No. 1-3
56

57. HDF latest 11 October 2017
Mortality risk in patients on hemodiafiltration versus hemodialysis:
a ‘real-world’ comparison from the DOPPS
52%
13%
23%
0%
10%
20%
30%
40%
50%
60%
% of Patients on HDF
SWEEDEN GERMANY OVERALL
16%
27%
50%
7%
0%
10%
20%
30%
40%
50%
60%
% of patients Subst volumes
4-15 L 15-20 L > 20 L Missing
57

58. From: Mortality risk in patients on hemodiafiltration versus hemodialysis: a ‘real-world’ comparison from
the DOPPS NDT 2017
58

59. Nephrologists’ perception on clinical indications for HDF use
DRA PN
Hemodynamic
instab
> 10 years on HD > 5 years on HD CHF DM Elderly
% of Patients 84% 77% 75% 63% 58% 58% 51% 28%
84%
77% 75%
63%
58% 58%
51%
28%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
% of Patients
59

60. Role of dialysis in amyloidogenesis (DRA)
Retention
Longer duration
of HD
Overproduction
inflammation
60
Dialysate
Impurities
Type of
Dialyzers
LF – HF
Elevated
levels of
cytokines
B2M
Deposition

61. 2293 patients with a minimum of 2 years of follow-up were analysed
61

62. Kidney Int. 2015 Nov;
Parameter Value
Treatment time per session (min;
mean±s.d.)
241.5±14.0
Patients on thrice weekly treatments (%) 96
Effective blood flow (ml/min; mean±s.d.) 404.9±69.4
Dialyzer surface (m2; mean±s.d.) 1.54±0.20
Post-dilution HDF (%) 100%
Effective dialysate flow (ml/min;
mean±s.d.)
506.1±53.6
Substitution flow (ml/min; mean±s.d.) 91.4±13.6
Substitution flow normalized to BSA
(ml/min/m2, mean±s.d.)
52.2±11.4
62

63. MCO MEMBRANE
Expanded HD ( Expanded than HF removal )
ERA-EDTA 2017 MADRID
they allow for removal of an
expanded range of uremic
toxins compared to
conventional high-flux
membranes.
63

64. Potential Benefits of MCO membranes
Expanded
HD
Greater clearance of
λFLC (45 kDa in size
limited effect on
protein-bound toxins
downregulate the expression of
both IL-6 and tumor necrosis
factor-α mRNA
removal of soluble
mediators is enhanced
Transcription of pro-
inflammatory cytokines in
peripheral leukocytes is
markedly reduced
Higher Albumin loss 2.9
– 7 gm
Albumin Loss in
conventional HF
is below 0.4 gm
64

65. Performance of hemodialysis
depends of membrane and
technique
Nephrol Dial Transplant (2017)
32 (1): 165-172
65

66. Performance of
hemodialysis
depends of
membrane and
technique
Nephrol Dial
Transplant (2017)
32 (1): 165-172
66

67. HDX versus HD RR % ERA-EDTA 2017 MADRID
Adequacy update :Targeting Beyond B2m in MW
67

68. Dose of removal depends on HD Membrane
international journal of artificial organVol. 40 Issue 7 | Jul 2017 | pp. 313 - 366
Dialyzer type Water
permeability
(mL/(m2*h*mmH
g))
Sieving coefficient
ß2-
Microglobulin
Albumin Loss
Grams
Low-flux 10-20 - zero
High-flux 200-400 0.7-0.8 0.2 0.4 HD
1-4 HDF
Medium cut-off 600-850 1.0 3-7
High cut-off 1100 1.0 > 7 HD
68
Higher SC = Higher Albumin Loss

69. Molecule Rh [nm] Comments
β2 microglobulin 1.7
calculated from the diffusion
coefficient in free solution
Tumor necrosis factor (TNFα) 1.9 − 2.3
depending on its aggregation
state, influenced by
concentration and pH
Free light chains (FLC)
monomeric state (mostly κ-
FLC)
2.3
Stokes’ radius determined by
chromatography
Free light chains (FLC)
dimeric form (mostly λ-FLC)
2.8
Stokes’ radius determined by
chromatography
Albumin 3.51
69
Maximum Pore Radius

70. Performance of hemodialysis with MCO dialyzers
NDT Volume 32, Issue 1, 1 January 2017
Complement
factor D
63.0 (1.73)* 66.7 (1.73)* 32.9 (1.73) 46.3 (1.73)
Myoglobin 67.9 (2.34)* 71.6 (2.34)* 37.2 (2.34) 59.3 (2.37)
β2-
microglobulin
78.5 (1.32)**,**** 78.9 (1.32)** 73.5 (1.32) 80.6 (1.33)
Creatinine 73.5 (1.45) 73.2 (1.45) 71.7 (1.45) 73.7 (1.45)
Phosphate 52.8 (2.13) 48.8 (2.13) 48.4 (2.13) 51.0 (2.13)
Urea 80.7 (1.33)***** 80.3 (1.33)**** 79.4 (1.33) 81.6 (1.33
MCO AA HD MCO BB HD High-flux HD HDF
70

71. 71

72. Medium Cut-Off (MCO) Membranes
Reduce Inflammation in Chronic Dialysis
Patients—A Randomized Controlled
Clinical Trial
 The randomized crossover trial in 48 patients compared
MCO-Ci dialysis to High-flux dialysis of 4 weeks duration
each plus 8 weeks extension phase
PLoS One. 2017; 12(1):
72

73. High-flux MCO
p MCO vs HF
T = 0 T = 4 weeks T = 0 T = 4 weeks
Primary
endpoint
TNF-α mRNA 1.19 ± 0.57 1.02 ± 0.49* 0.92 ± 0.34 0.75 ± 0.31** < 0.001
IL-6 mRNA 0.86 ± 0.68 0.83 ± 0.67 0.78 ± 0.80 0.60 ± 0.43** 0.001
PLoS One. 2017; 12(1):
73

74. High-flux MCO p MCO vs HF
T = 0 T = 4 weeks T = 0 T = 4 weeks
Albumin g/l 36.6 ± 3.2 37.5 ± 2.7 37.0 ± 3.6 35.3 ± 3.7** < 0.001
CRP mg/l 13.4 ± 25.5 9.6 ± 15.7 15.3 ± 30.0 9.3 ± 14.5 n.s
IL-6 pg/ml 9.8 ± 20.5 5.5 ± 4.5* 9.0 ± 13.2 6.0 ± 5.9** n.s.
PLoS One. 2017; 12(1):
74

75. Comparison of hemodialysis with medium
cut-off dialyzer and on-line
hemodiafiltration on the removal of small
and middle-sized molecules
 10 patients treated first with ol-HDF who were
thereafter switched to MCO-HD over a 1-year
period
Clin Nephrol. 2017 Aug 30
75

76. Comparison of hemodialysis with medium cut-off
dialyzer and on-line hemodiafiltration on the removal
of small and middle-sized molecules
Clin Nephrol. 2017 Aug 30
81.5
60
81.6
61
0
10
20
30
40
50
60
70
80
90
B2m RR % Myoglobin RR %
MCO- HD HDF
76

77. Combined Therapy with Expanded HD
Expanded HD and HDF ?
Expanded HD and Extended HD ?
Expanded HD and Frequent sessions ?
Expanded HD and Incremental HD ?
77

78. Expanded HD membrane in HDF technique ?
The MCO Membrane should NOT be used in HDF
High TMP
Increase
Albumin loss
Loss of Free Hb
will induce
Blood leak
alarm
Innovative Clinical Approach in Dialysis. Contrib Nephrol. Basel, Karger, 2017, vol 191,
78

79. Albumin Leakage during HD :
is it worth or Beneficial ?
Implications of Albumin Leakage for Survival in
Maintenance Hemodialysis Patients: A 7-year
Observational Study 740 patients follow up
Data is toward accepted 3 gm loss / session
More RCTS is still needed
27 April 2017
79

80. Haemodialysis Prescription for Incident Patients:
Twice Seems Nice, But Is It Incremental?
American Journal of Kidney Diseases 2016
WE ALL DO INCRIMENTAL HD BEFORE THE TERMINOLOGY IS BORN
80

81. Nephrol Dial Transplant (2015) 30 (10):
Evaluate
Monthly
Augmented HD
Frequency
Duration
Flux
HDF
3 Phases Approach for
HD Dose presription
81

82. Incremental
hemodialysis
prescription with
adjustment of
hemodialysis dose
based on Residual
kidney function
Nephrol Dial Transplant (2015) 30 (10):
82
Expanded
orHDF

83. The progressive approach to HD
Progressive HD should be
considered a bridge between
conservative therapy and full
renal replacement therapy
(RRT).
83

84. A user-friendly tool for incremental
haemodialysis prescription ( 05 January 2018 )
‘SPEEDY’, by using the acronym of
its whole definition: Spreadsheet
for the Prescription of incrEmental
haEmoDalYsis.
SPEEDY
KRUn
eKt/V
Session Length
Td
QB and Dialyzer
KoA
nPCR
Native kidney normalized
urea clearance
84

85. 85

86. The finding of two frequency peaks of
sudden death, immediately before and after
the first weekly haemodialysis session,
suggests that daily haemodialysis, or at
least the abolition of the long interdialytic
interval during the weekend, could be
helpful in reducing this kind of mortality.
HD Frequency
HD Time
86

87. Adverse Effects of Conventional Thrice-Weekly Hemodialysis: Is It Time
to Avoid 3-Day Interdialytic Intervals?
Am J Nephrol 2015;41:400-408
87

88. 88

89. Hemodialysis Treatment Time: As Important as it Seems?
16 January 2017
largely avoid
ultrashort dialysis
HD > 4 hours Parking Time
89

90. Dialysis Frequency versus Time : That is the Question 90

91. Extended-hours hemodialysis is associated with lower mortality risk in
patients with end-stage renal disease Kidney international December 2016Volume 90,
compare mortality risk among 1206
individuals undergoing thrice weekly
extended-hours hemodialysis or 111,707
patients receiving conventional
hemodialysis treatments
The crude mortality rate with extended-hours
hemodialysis was 6.4 deaths per 100 patient-
years compared with 14.7 deaths per 100 patient-
years for conventional hemodialysis
extended-hours hemodialysis had a
33% lower adjusted risk of death
the follow-up period for each patient was
divided into successive 91-day periods from the
date of first dialysis; follow-up was available for
up to 20 periods
Better compartmental
dialysis
91

92. LIMITATIONS OF Frequent HD
More frequent hemodialysis does not effectively clear protein-bound azotemic solutes
derived from gut microbiome metabolism Kidney international May 2017Volume 91
Relative protein binding
Azotemic compound
Relative protein binding
(%)
p-Cresol glucuronide < 40
Hippuric acid 40–50
Phenylacetylglutamine 40–50
Indoxyl glucuronide 50–60
Phenylacetic acid 60–70
Indole acetic acid 90–95
p-Cresol sulfate 90–95
Indoxyl sulfate > 95
3-carboxy-4-methyl-5-
propyl-2-furanpropanoic
acid
> 95
92

93. May 2017 Volume 91, Issue 5,
93

94. 94

95. In conclusion
Secondary Measures of Dialysis Adequacy
Additional Measure
QOL
Secondary
Measure
B2m – UFR – etc
Kt/V
Additional Measure
QOL
Secondary Measure
B2m – UFR – etc
Primary Measure
Kt/V
95

96. Pushing Towards
A Better Dialysis
To Know the Unknowns
96
Thank you