© 2008 Universitair Ziekenhuis Gent FUTURE OF HEMODIALYSIS R Vanholder, University Hospital, Gent,...

© 2008 Universitair Ziekenhuis Gent

FUTURE OF HEMODIALYSIS

R Vanholder, University Hospital,

Gent, Belgium

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


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

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)


High Salt Normal Salt

OR EVEN MORE SIMPLE: SODIUM

P < 0,001


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


SODIUM PROFILING

Dheenan S, et al; Kidney Int 2001; 59: 1175-1181.

HNa: high sodium; NaM: sodium profiling; UF: ultrefiltration followed by dialysis


SODIUM PROFILING (CONT)

Song J , et al; Am J Kidney Dis 2002; 40: 291-301

TACNa = Time averaged concentration of Na


SODIUM PROFILING

Dheenan S, et al; Kidney Int 2001; 59: 1175-1181.

HNa: high sodium; NaM: sodium profiling; UF: ultrefiltration followed by dialysis


EFFECT OF DIALYSATE TEMPERATURE ON IDH

Selby NM and McIntyre CW, Nephrol Dialys Transplant 2006; 21: 1883-1898

BTM: biofeedback temperaturemonitoringBT


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


ADSORPTION BETA2-MICROGLOBULIN

Abe et al, KI, 64: 1522-1528; 2003


BETA2-M RELATED AMYLOIDOSIS


A.M. Wilson et al, Circulation. 2007;116:1396-1403


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


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


WHAT CAN WE DO WITH THE CURRENTLY AVAILABLE POSSIBILITIES?


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


UREMIC TOXINS WITH VASCULAR IMPACT


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


OSTEOCALCIN AND MYOGLOBIN

Maduell et al, AJKD, 40, 582-589, 2002


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


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


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


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


MPO: KAPLAN-MEIER SURVIVAL ANALYSIS

Locatelli et al, JASN, in press


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


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.


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


OSTEOCALCIN AND MYOGLOBIN

Maduell et al, AJKD, 40, 582-589, 2002


IMPACT ON OUTCOME

Santoro et al, AJKD, 52, 507-518, 2008


STUDY DESIGN

Santoro et al, AJKD, 52, 507-518, 2008


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


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


PERCENTAGE CHANGE VS. 4 HRS

Eloot et al, KI, 73: 765-770


ß2-MICROGLOBULIN2-YEAR EVOLUTION (HF)

Raj et al, NDT, 15, 58-64, 2000


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


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.

© 2008 Universitair Ziekenhuis Gent FUTURE OF HEMODIALYSIS R Vanholder, University Hospital, Gent,...

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Transcript of © 2008 Universitair Ziekenhuis Gent FUTURE OF HEMODIALYSIS R Vanholder, University Hospital, Gent,...