HEMODIAFILTRATION · 2 © 2008 Universitair Ziekenhuis Gent 2 UREMIC SOLUTES LISTED Vanholder et...

© 2008 Universitair Ziekenhuis Gent

HEMODIAFILTRATION

R Vanholder

University Hospital, Gent,

Belgium

2 2 © 2008 Universitair Ziekenhuis Gent

UREMIC SOLUTES LISTED

Vanholder et al, KI, 63:1934-1943; 2003


UREMIC SOLUTES LISTED Small water soluble compounds (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


THE MIDDLE MOLECULES


PRE-DIALYSIS β2-M VS. OUTCOME – HEMO-

STUDY

Cheung et al, JASN, 17: 546-555; 2006


Β2-MICROGLOBULIN MIGHT BE PARTLY INERT

Neirynck et al, J Ren Nutr, 23: 456-463; 2013


Β2-MICROGLOBULIN MIGHT BE PARTLY INERT

Neirynck et al, J Ren Nutr, 23: 456-463; 2013

Figure 3. Effects of hB2M, dB2M, and dialysates

on bursttest after stimulation with (A-C) E. coli

and (D-F) with PMA show that dB2M had no

longer an effect on free radical production

whereas d1 had similar effects as hB2M. PMA,

phorbol myristate acetate; co, control (saline);

LPS 1.5, lipopolysaccharide 1.5 endotoxin units

(EU)/mL; hB2M, human b2 microglobulin

(unpurified); dB2M, dialyzed (purified) b2-

microglobulin; 10, 10 mg/L; 50, 50 mg/L; d1,

dialysate collection after 30 minutes (0-30 min);

d2: dialysate at end (10h30-11h30), * P , 0.05, **

P , 0.01, *** P , 0.001 vs.co,P , 0.05,P , 0.01,P ,

0.001 vs LPS, # P , 0.05, ### P , 0.001 vs

dB2M10, 1 P , 0.05, 111 P , 0.001 vs dB2M50, §

P , 0.05, §§§ P , 0.001 vs d2; Kruskall-Wallis 1

pairwise comparisons.

hB2M: unpurified

dBM: dialysed

D: dialysate


Background—Peripheral arterial disease (PAD) is common but commonly unrecognized.

Improved recognition of PAD is needed. We used high-throughput proteomic profiling to find

PAD-associated biomarkers.

Methods and Results—Plasma was collected from PAD patients (ankle brachial index of 0.90;

n45) and subjects with risk factors but without PAD (n43). Plasma was analyzed with surface-

enhanced laser desorption/ionization

time-of-flight mass spectrometry to quantify 1619 protein peaks. The peak intensity of a 12-kDa

protein was higher in PAD patients. Western blot analyses and immunoaffinity studies confirmed

that this protein was 2-microglobulin (B2M). In a validation study, B2M was measured by ELISA

in plasma in age- and gender-matched PAD (n20) and non-PAD (n20) subjects. Finally, we

studied a larger cohort of subjects (n237) referred for coronary angiography but without known

PAD. Plasma B2M levels were higher in PAD patients than in non-PAD patients with coronary

artery disease. Plasma B2M correlated with ankle brachial index and functional capacity.

Independent predictors of PAD were diabetes mellitus, age, and the combination of B2M and C-

reactive protein level.

Conclusions—In PAD patients, circulating B2M is elevated and correlates with the severity of

disease independent of other risk factors. These findings might provide a needed biomarker for

PAD and new insight into its pathophysiology. Further studies in other populations are needed to

confirm the utility of measuring B2M in cardiovascular disease risk assessment.

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 patients

Ferreira 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 mice

Menaa et al, KI, 2008


IL-6 AND MORTALITY IN CKD

Barreto et al, KI, 77: 550-556; 2010

(a) Kaplan–Meyer estimates of overall mortality for all patients (n=125) as a function of median plasma IL-6 levels. (b) Kaplan–Meyer

estimates of cardiovascular mortality for all patients (n=125) as a function of median plasma IL-6 levels.


FGF-23: PATHO-PHYSIOLOGIC ROLE

Larsson, NDT, 25: 1376-1381; 2010


PROGRESSION CKD VS. FGF-23

Fliser et al, JASN, 18: 2601-2608; 2007

Kaplan-Meier curves of renal end points in patients with below and

above optimal cutoff of plasma c-terminal (A) FGF23 concentrations

and for intact (B) FGF23 concentrations below and above the

median


PROGRESSION CKD VS. FGF-23

Fliser et al, JASN, 18: 2601-2608; 2007

a Data are means ± SD and 25th, 50th (median), and 75th percentiles for skewed variables where appropriate.


ODDS OF DEATH VS. FGF-23 QUARTILES

Guttierrez et al, NEJM, 359: 584-592; 2008


FGF-23 AND LEFT VENTRICULAR DYSFUNCTION

Seiler et al, Eur Heart J, 32:2688-2696; 2011

Figure 2 Fibroblast growth factor

23 levels after stratifying for the

ejection fraction and for presence

of left-ventricular hypertrophy in

individuals in the total study

cohort. Data are presented as

mean ± SEM.


FGF-23: MORE THAN A SIMPLE MARKER

Faul et al, J Clin Invest, 121: 4393-4408; 2011


EFFECT OF SPECIFIC AGEs ON LEUKOCYTE

CL-RESPONSE

Glorieux et al, KI, 66: 1873-1880; 2004


LEPTIN INDUCES TISSUE FACTOR ACTIVATION

Napoleone et al J Thromb Haemost , 5: 1462-1468; 2007


MM WITH BIOLOGICAL POTENTIAL

Adrenomedullin

AGE

Angiogenin

AOPP

Atrial natriuretic peptide

Cholecystokin

Clara cell protein

Complement factor D

Cystatin C

Cytokines

Delta sleep inducing protein

Endothelin

-Endorphin

Ghrelin

Glomerulopressin

GIP I

GIP II

Leptin

-Lipotropin

Macrophage-colony-stimulating

factor

Methionine-enkephalin

ß2-Microglobulin

Neuropeptide Y

Orexin A

Retinol binding protein

Red: pro-inflammatory


MM WITH BIOLOGICAL POTENTIAL

Adrenomedullin

Adiponectin

AGE

Angiogenin

AOPP

Atrial natriuretic peptide

Cholecystokin

Clara cell protein

Cholecystokinin

Complement factor D

Cystatin C

Cytokines

Delta sleep inducing protein

Endothelin

-Endorphin

Ghrelin

Glomerulopressin

GIP I

GIP II

Leptin

-Lipotropin

Macrophage-colony-stimulating factor

Methionine-enkephalin

ß2-Microglobulin

Neuropeptide Y

Orexin A

Pentraxin-3

Peptide YY

Prolactin

Resistin

Retinol binding protein

Visfatin

Red: pro-inflamatory or anorexic Carrero et al,Sem Nephrol,

Green: new in press


PROTEIN BOUND UREMIC TOXINS

R Vanholder

University Hospital, Gent,

Belgium


PROTEIN BOUND UREMIC TOXINS

Indoxylsulfate

P-cresylsulfate

Indoxylglucuronide

P-cresylglucuronide

Phenylacetic acid

Hippuric acid

P-OHhippuric acid

Homocysteine

…


AN INCREASING NUMBER OF PUBLICATIONS

Neirynck et al, Int Urol Nephrol, 45:139-150; 2013


1st Author, year, ref Country Cell/organ system toxin concentration albumin

1) In vitro, albumin

Dou, 2004 {207} France Endothelium IS 25-250 mg/L 4 g/L

Odamaki, 2004 {205} Japan Hepatocytes IS 50-100 mg/L 4 g/L

Faure, 2006 {194} France Endothelium IS 256 mg/L 4 g/L

Yamamoto, 2006 {191} Japan Smooth muscle cells IS 250-500 µM 4 g/L

Dou, 2007 {170} France Endothelium IS 125-250 mg/L 4 g/L

Schepers, 2007 {183} Belgium Leukocytes PCS 121.0 mg/L Whole blood

Itoh, 2012 {12} Japan Endothelium IS 29.9-57.2 mg/L 4 g/L

Chitalia, 2013 {394} USA Smooth Muscle Cells IS 25 mg/L 4 g/L

2) In vitro, low

Tsujimoto, 2010 {91} Japan Liver Microsomes IS 30 µM -

Lekawanvijit, 2010 {113} Australia Cardiac Fibroblasts / Myocytes IS > 1µM -

Yu, 2011 {86} S-Korea Endothelium IS 1.25-125 mg/L - (no m)

Sun NDT, 2012 {5} Taiwan Proximal Tubular Cells IS, PCS 1 & 5 mg/L -

Sun Plos1, 2012 {10} Taiwan Proximal Tubular Cells IS, PCS > 1 mg/L -

Sun, 2012 {17} Taiwan Proximal Tubular Cells IS, PCS IPCS & IS 1&5

mg/L

- (no m)

Tsujimoto, 2012 {396} Japan Intestinal Cells (hepatic no effect) IS 20 µmol -

Vanholder et al, JASN, in press


1st Author, year, ref Country Cell/organ system toxin concentration albumin

3) Animal

Adijang, 2008 {159} Japan Aorta, kidney IS 23.1 mg/L rat

Ito, 2010 {83} Japan Endolium/leukocyte interaction IS 15.7 mg/L mouse

Adijang, 2010 {94} Japan Aorta IS 15-20 mg/L rat

Bolati, 2011 {44} Japan Proximal Tubular Cells IS 9.4-18.9 mg/L rat

Sun Plos1, 2012 {10} Taiwan Proximal Tubular Cells IS, PCS ? No

concentration

mouse

Watanabe, 2012 {392} Japan Renal Tubular Cells PCS 32.6 mg/L rat

Sun, 2012 {17} Taiwan Proximal Tubular Cells IS, PCS IS 8.5, PCS 5.6

mg/L

mouse

Shimizu, 2012 {14} Japan Proximal Tubular Cells IS 9.4-18.9 mg/L rat

Vanholder et al, JASN, in press


P-CRESYLSULFATE INDUCES INSULIN RESISTANCE

Koppe et al, JASN, 24: 88-99; 2013


Koppe et al, JASN, 24: 88-99; 2013



Pletinck et al, JASN, doi: 10.1681/ASN.2012030281


LEUKOCYTE RECRUITMENT IS ENHANCED IN

RESPONSE TO LPS (1), IS (2) , pCS and pCSpCG (3)

Pletinck et al, JASN, 24, 1981-1994, 2013


RED BLOOD CELL VELOCITY IS HAMPERED IN

INDOXYLSULFATE TREATED RATS



INTRAVITAL MICROCOPY



INTRAVITAL MICROCOPY

CONTROL INDOXYLSULFATE



INDOXYL SULFATE + P-CRESYL

SULFATE: OUTCOME



SULFATE: OUTCOME



SULFATE: OUTCOME

Rev Diabet stud, 7: 275-284; 2010



SULFATE: OUTCOME

Rev Diabet stud, 7: 275-284; 2010

Clin J Am Soc Nephrol 4: 1551–1558; 2009


Kaplan-Meyer estimates of overall mortality for patients as a

function of tertiles for serum IS levels

INDOXYL SULFATE AND SURVIVAL

Barreto et al, CJASN, 4: 1551-1558; 2009

Number of patients at risk


REMOVAL


OSTEOCALCIN AND MYOGLOBIN

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


POST-DILUTION HEMODIAFILTRATION IS SUPERIOR TO PREDILUTION

HEMODIAFILTRATION AND HIGH FLUX DIALYSIS FOR REMOVAL OF MIDDLE

MOLECULES

Meert et al, NDT, 26: 2624-2630; 2011


EVOLUTION OF 2-M OVER TIME

Locatelli et al, KI, 50: 1293-1302; 1996


ß2-MICROGLOBULIN IS LOWER WITH HIGH-FLUX

0

5

10

15

20

25

30

35

40

45

0 6 12 18 24 30 36

Month

mg

/L

High-flux Low-flux

*Changes vs. month 0 are significantly different (p


Eloot et al, KI, 73: 765-770; 2007

4 hrs 6 hrs 8 hrs P

QB and QD 72L 72L 72L NS

Kt/V 1.4 0.3 1.6 0.6 1.5 0.5 NS

INCREASING LENGTH OF DIALYSIS WITHOUT CHANGING

ANY OTHER PARAMETER IMPROVES REMOVAL

Percentage change vs. 4 hrs


HEMODIAFILTRATION (POST AND PRE) IS SUPERIOR

TO PREDILUTION HEMOFILTRATION AND HIGH FLUX

DIALYSIS FOR REMOVAL OF PROTEIN BOUND TOXINS

Meert et al, NDT, 24: 562-570; 2008


OUTCOME STUDIES


Convective treatments and risk of mortality

adapted from Pozzoni et al. J Nephrol 17 Suppl, 8:S87-S95; 2004


censored

failed

Figure 7 : Survival time - whole study time - Albumin


Kaplan Meier Survival Analysis

Subgroup Analysis – Diabetics (Alb ≤ 4 g/dl)


% Patients with Serum Albumin < 4 g/dl

Data from the DOPPS Study


Increasing incidence of Diabetes mellitus as PRD – Data

from 10 European registries

Van Dijk et al. Kidney Int 67: 1489-1499; 2005


HEMODIAFILTRATION:

SURVIVAL ADVANTAGE VS. HEMODIALYSIS

Death: 22.8%

HR: 0.7 [0.53-0.92]

Substitution volume: 20.8- 21.8L

Maduell et al, JASN, 24, 487-497, 2013

ESHOL- trial


CONCLUSIONS

Several of the larger middle molecules and of the protein bound

molecules have the potential for biological (toxic) effects, especially on

the cardiovascular system.


CONCLUSIONS




Larger middle molecules are better removed by increasing dialyzer

pore size (high-flux).


CONCLUSIONS






Removal of those molecules is further enhanced by using the same

dialyzers in a convective mode and/or by increasing dialysis length.


CONCLUSIONS








Also protein bound uremic solutes are better removed in a convective

mode, be it less spectacularly than the middle molecules.


CONCLUSIONS








Also protein bound uremic solutes are better removed in a convective

mode, be it less spectacularly than the middle molecules.

Clinical outcome studies suggest that increasing dialyzer pore and

adding convection might improve outcomes.

HEMODIAFILTRATION · 2 © 2008 Universitair Ziekenhuis Gent 2 UREMIC SOLUTES LISTED Vanholder et...

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