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© 2008 Universitair Ziekenhuis Gent
FUTURE OF HEMODIALYSIS
R Vanholder, University Hospital,
Gent, Belgium
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22© 2008 Universitair Ziekenhuis Gent
NOT NECESSARILY EXTRACORPOREAL / ARTIFICIAL ORGANS ONLY
Saline
Captopril 10 µM
*
**
•p<0.05 vs control; ** p<0.05 vs SDMA; n=8Schepers et al, NDT, 2008
No SDMA SDMA
20
10
0
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33© 2008 Universitair Ziekenhuis Gent
RELATIVE RISK
Vanholder et al, NDT, 20, 1048-1056, 2005
y = (0.1262x) + 10.77, r = 0.645, P < 0.001; y = (–0.1018x) + 2.727, r = 0.574, P < 0.004
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44© 2008 Universitair Ziekenhuis Gent Levey, Am J Kidney Dis (2002) S1: S1-S266
CKD(ml/min)
<15
15-29
30-59
60-89
>90
CKD stage
5
4
3
2
1
X10³(%)
300 (0.1)
400 (0.2)
7600 (4.3)
5300 (3.0)
5500 (3.3)
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55© 2008 Universitair Ziekenhuis Gent
High Salt Normal Salt
OR EVEN MORE SIMPLE: SODIUM
P < 0,001
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66© 2008 Universitair Ziekenhuis Gent
RENEWED ATTENTION SALT INTAKE!
The long forgotten salt factor and the benefits of using a 5-g-salt-restricted diet in all ESRD patients
Stanley Shaldon and Joerg Vienken
Nephrol. Dial. Transplant. 2008 23: 2118-2120; doi:10.1093/ndt/gfn175 Dietary sodium: the dark horse amongst cardiovascular
and renal risk factors Albert Mimran and Guilhem du Cailar
Nephrol. Dial. Transplant. 2008 23: 2138-2141; doi:10.1093/ndt/gfn160
Aphrodite, sex and salt—from butterfly to man Bernard M. Moinier and Tilman B. Drüeke
Nephrol. Dial. Transplant. 2008 23: 2154-2161; doi:10.1093/ndt/gfm956
Salt and water: a brief natural historyPedram Fatehi
Kidney Int 74: 3-4; doi:10.1038/ki.2008.239
Evidence-based politics of salt and blood pressureQais Al-Awqati
Kidney Int 69: 1707-1708; doi:10.1038/sj.ki.5001520
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77© 2008 Universitair Ziekenhuis Gent
SODIUM PROFILING
Dheenan S, et al; Kidney Int 2001; 59: 1175-1181.
HNa: high sodium; NaM: sodium profiling; UF: ultrefiltration followed by dialysis
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88© 2008 Universitair Ziekenhuis Gent
SODIUM PROFILING (CONT)
Song J , et al; Am J Kidney Dis 2002; 40: 291-301
TACNa = Time averaged concentration of Na
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99© 2008 Universitair Ziekenhuis Gent
SODIUM PROFILING
Dheenan S, et al; Kidney Int 2001; 59: 1175-1181.
HNa: high sodium; NaM: sodium profiling; UF: ultrefiltration followed by dialysis
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1010© 2008 Universitair Ziekenhuis Gent
EFFECT OF DIALYSATE TEMPERATURE ON IDH
Selby NM and McIntyre CW, Nephrol Dialys Transplant 2006; 21: 1883-1898
BTM: biofeedback temperaturemonitoringBT
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1111© 2008 Universitair Ziekenhuis Gent
EXTRACORPOREAL: NOT NECESSARILY DIFFUSION / CONVECTION
Effect of 2-microglobulin adsorption column on dialysis-related amyloidosis
Takaya Abe, Kazuhiro Uchita, Hikari Orita, Motohiro Kamimura, Minoru Oda, Hirohito Hasegawa, Hirotsugu Kobata, Masaaki Fukunishi, Masami Shimazaki, Tomiya Abe, Tadao Akizawa and Suhail Ahmad
Center of Blood Purification Therapy, Wakayama Medical University, Wakayama, Japan; Scribner Kidney Center, University of Washington, Seattle, Washington; and Medical Devices Division, Kaneka Corporation, Osaka, Japan
Abe et al, KI, 64: 1522-1528; 2003
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1212© 2008 Universitair Ziekenhuis Gent
ADSORPTION BETA2-MICROGLOBULIN
Abe et al, KI, 64: 1522-1528; 2003
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© 2008 Universitair Ziekenhuis Gent
BETA2-M RELATED AMYLOIDOSIS
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1414© 2008 Universitair Ziekenhuis Gent
A.M. Wilson et al, Circulation. 2007;116:1396-1403
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1515© 2008 Universitair Ziekenhuis Gent
AND ALSO
Association with arterial stiffness in the general population
Sajio, Hypertens Res, 2005
Association with bone turnover in hemodialysis patientsFerreira et al, NDT, 1995
Association with bone resorption in non-CKD post-menopausal women
Ripoll et al, Eur J Clin Invest, 1996
Enhancement of bone resorption in miceMenaa et al, KI, 2008
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1616© 2008 Universitair Ziekenhuis Gent
FUTURE?
RemovalFiltration through extremely large pores
Adsorption (blood)
Adsorption x convection
PrometheusRAdsorption x diffusion
Lipodialysis
Albumin dialysis (MARS®)
x PD
DrugsNeutralizing toxic effects
Reaches a much larger target population than removal
Several options already in use (e.g. aspirin)
Potential targets
Ca-influx (ACEi)
NFκB
Vanholder et al, JASN, 19, 863-870, 2008
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© 2008 Universitair Ziekenhuis Gent
WHAT CAN WE DO WITH THE CURRENTLY AVAILABLE POSSIBILITIES?
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1818© 2008 Universitair Ziekenhuis Gent
UREMIC SOLUTES LISTED
Vanholder et al, KI, 63, 1934-1943, 2003
Small water soluble compounds (<500D): 1-Methyladenosine, 1-Methylguanosine, 1-Methylinosine, ADMA, -Keto-guanidinovaleric acid, -N-acetylarginine, Arab(in)itol, Argininic acid, Benzylalcohol, ß-guanidinopropionic acid, Creatine, Creatinine, Cytidine, Dimethylglycine, Erythritol, - guanidinobutyric acid, Guanidine, Guanidinoacetic acid, Guanidonosuccinic acid, Hypoxanthine, Mannitol, Methylguanidine, Myoinositol, N4-acetylcytidine, N6-methyladenosine, Orotic acid, Orotidine, Oxalate, Phenylacetylglutamine, Pseudouridine, SDMA, Sorbitol, Taurocyamine, Threitol, Thymine, Uracil, Urea, Uric acid, Uridine, Xanthine, Xanthosine Protein-bound molecules: 2-Methoxyresorcinol, 3-deoxyglucosone, CMPF, Dimethylguanosine, Fructoselysine, Glyoxal, Hippuric acid, Homocysteine, Hydroquinone, Indole-3-acetic acid, Indoxyl sulfate, Interleukin 1ß, Interleukin 6, Kinurenine, Kynurenic acid, Leptin, Melatonin, Methylglyoxal, N-(carboxylmethyl)lysine, P-cresol, Pentosidine, Phenol, Phenylacetic acid, Phenylethylamine, P-OHhippuric acid, Putrescine, Quinolinic acid, Retinol binding protein, S-nitrosothiol, Spermidine, Spermine, Thiocyanate, Tumor Necrosis Factor Middle molecules (>500D): Adrenomedullin, Atrial natriuretic peptide, ß2-microglobulin, ß-endorphin, Cholecystokinin, Clara cell protein, Complement factor D, Cystatin C, Degranulation inhibiting protein I, Delta-sleep inducing peptide, Endothelin (ng/L), Ghrelin, Hyaluronic Acid, Interleukin 1ß, Interleukin 6, Interleukin-18, -Ig light chain, -Ig light chain, Leptin, MC-SF, Methionine-enkephalin, Neuropeptide Y, Orexin A, Parathyroid hormone, Retinol binding protein, Tumor Necrosis Factor
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1919© 2008 Universitair Ziekenhuis Gent
UREMIC TOXINS WITH VASCULAR IMPACT
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2020© 2008 Universitair Ziekenhuis Gent
MM WITH BIOLOGICAL POTENTIAL
AdrenomedullinAGEAngiogeninAOPP Atrial natriuretic peptideCholecystokinClara cell proteinComplement factor DCystatin CCytokinesDelta sleep inducing proteinEndothelin-Endorphin
GhrelinGlomerulopressinGIP IGIP IILeptin-LipotropinMacrophage-colony-stimulating factor Methionine-enkephalin
ß2-Microglobulin Neuropeptide Y Orexin ARetinol binding protein
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2121© 2008 Universitair Ziekenhuis Gent
OSTEOCALCIN AND MYOGLOBIN
Maduell et al, AJKD, 40, 582-589, 2002
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2222© 2008 Universitair Ziekenhuis Gent
HIGH FLUX TREATMENTS AND RISK OF MORTALITY
Design Convective treatment
Sample size
% reduction in risk of death
P value
Hornberger et al. 1992
Retrospective HF-HD 253 76 <0.001
Koda et al. 1997
Retrospective HF-HD 819 39 <0.05
Locatelli et al. 1999
Historical, prospective
HDF or HF 6,444 10 NS
Leypold et al. 1999
Retrospective HF-HD 1,771 5 <0.0001
Woods et al. 1999
Retrospective HF-HD 715 42 <0.01
Port et al.2001
Retrospective HF-HD 12,791 19 0.04
Eknoyan et al. 2003
Prospective, randomised
HF-HD 1,846 8 NS
Cheauveau et al. 2005
Prospective, observational
HF-HD 650 38 0.01
adapted from Locatelli et al. J Nephrol 17: 87-95, 2004
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2323© 2008 Universitair Ziekenhuis Gent
ADDITIONAL SINCE 2005
Delmez et al, AJKD, 47, 131-138, 2006: HF>LFCheung et al, JASN, 17, 546-555, 2005: inverse correlation β2-M and mortalityKrane et al, AJKD, 49, 267-275, 2007: HF>LFCheung et al, cJASN, 3, 69-77, 2008: inverse correlation β2-M and infectious mortality
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2424© 2008 Universitair Ziekenhuis Gent
MPO: KAPLAN-MEIER SURVIVAL ANALYSIS
Locatelli et al, JASN, in press
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2525© 2008 Universitair Ziekenhuis Gent
PROTEIN-BOUND COMPOUNDS: FUNCTIONAL IMPACT
AGEs: inflammation, vascular disease
CMPF: PB drugs, detoxification, neuropathy, anemia
Cytokines: inflammation, malnutrition, anemia
Dimethylguanidine: inhibition Ca2+ ATP-ase
Hippuric acid: PB drugs, glucose intolerance
Homocysteine: vessel disease, detoxification
Indole-3-acetic acid: PB drugs, neuropathy, cytotoxicity
Indoxyl sulfate: decline renal function, thyroid function, PB drugs, detoxification, endothelial function and repair
Kinurenine: neuropathy
Leptin: malnutrition
Phenols: immune function, neuropathy
Phenylacetic acid: nitric oxide synthesis
Quinolinic acid: neuropathy
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2626© 2008 Universitair Ziekenhuis Gent
PAI-1 AS AN INDICATOR OF OXIDATIVE STRESS IN RENAL TUBULAR CELLS
Motojima et al, KI, 63, 1671-1680, 2003
Effects of uremic toxins on the expression of immunoreactive plasminogen activator inhibitor-1 (PAI-1) antigen in human renal proximal tubular cells (HK-2). HK-2 were seeded in 24-well tissue culture plates at a cell density of 2 104 cells/well. The cells were incubated with indicated amount of uremic toxins for 24 hours. The amount of immunoreactive PAI-1 antigen in medium was determined by the PAI-1 enzyme-linked immunosorbent assay (ELISA). Values are mean SD (N = 4). (A) Effect of indoxyl sulfate. (B) Effect of indoleacetic acid. *P < 0.05 vs. nontreated control.
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2727© 2008 Universitair Ziekenhuis Gent
LONG-TERM EVOLUTION OF PRE-TREATMENT CONCENTRATION: 9 WEEKS POST-DILUTION HDF
*p<0.05 vs baselineAll concentrations are expressed in mg/100ml, except β2-microglobulin in mg/L
Meert et al, in progress
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2828© 2008 Universitair Ziekenhuis Gent
OSTEOCALCIN AND MYOGLOBIN
Maduell et al, AJKD, 40, 582-589, 2002
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2929© 2008 Universitair Ziekenhuis Gent Santoro et al, AJKD, 52, 507-518, 2008
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3030© 2008 Universitair Ziekenhuis Gent
IMPACT ON OUTCOME
Santoro et al, AJKD, 52, 507-518, 2008
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3131© 2008 Universitair Ziekenhuis Gent
STUDY DESIGN
Santoro et al, AJKD, 52, 507-518, 2008
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3232© 2008 Universitair Ziekenhuis Gent
ONLINE HDF: REDUCED MORTALITY
Adjusted for age, sex, race, country, time on dialysis,
14 comorbities, catheters, weight, Kt/V
p=0.01
Canaud et al, KI, 69, 2087-2093, 2006
Risk of Mortality for HDF Patients
0.65
0.940.99 1
0
0,2
0,4
0,6
0,8
1
1,2
High EfficiencyHDF 15-25 Liters
Low EfficiencyHDF 5-14 Liters
High Flux HD
Low Flux HD
35 % LowerRisk of Death
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3333© 2008 Universitair Ziekenhuis Gent
RESPONSE OF DIALYSIS FLUID SAMPLES WITH DIFFERENT PURITY GRADE IN THE LAL-TEST COMPARED TO THE THP-1 ASSAY (IL-1ß).
Dialysates(n=269)
EU/ml IL-1ß (measured)
IL-1ß (expected)
P-value
EU/ml
<0.03 Ultrapure [n=230;21 (9.1%) IL-1ß positive]
0.008 ± 0.01 17.78 ± 53.21 6.87 ± 0.14 <0.0001
<0.25 Pure[n=260; 27 (10.3%) IL-1ß positive]
0.11 ± 0.07 35.23 ± 89.11 7.91 ± 0.76 0.039
>0.25 Impure (n=9) 1.38 ± 2.37 72.49 ± 86.27 21.71 ± 25.65 0.0004
Glorieux et al, NDT, 24, 548-554, 2009
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3434© 2008 Universitair Ziekenhuis Gent
PERCENTAGE CHANGE VS. 4 HRS
Eloot et al, KI, 73: 765-770
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3535© 2008 Universitair Ziekenhuis Gent
ß2-MICROGLOBULIN2-YEAR EVOLUTION (HF)
Raj et al, NDT, 15, 58-64, 2000
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3636© 2008 Universitair Ziekenhuis Gent
CONCLUSIONS (1)
ESRD treatment should not be limited to extracorporeal blood purification
Drug treatment in function of disturbed pathways should be considered
Future developments in the area of adsorption might result in breakthroughs
For the time being HF hemodialysis very likely offers a survival advantage
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3737© 2008 Universitair Ziekenhuis Gent
CONCLUSIONS (2)
Extra benefit might be obtained by adding convection
Among convective strategies, post-dilution HDF offers the most effective removal
In case of convection, measures should be taken to guarantee dialysate purity
Prolonging dialysis per se also increases removal capacity
Both dialysis with positive sodium balance and dialysis with cool dialysate prevent hypertension. Positive sodium balance however induces water retention.