Hussein Chahine Prof of Int Prof. Int. Med.

Med & Nephrology AL Azhar University

UREMIC TOXINS
Molecular Weight
500 Da
Small nitrogenous waste products p Protein bound solutes & Middle molecules

Water soluble No Protein binding

Hydrophobicity Protein binding

Original Middle molecule hypothesis

500 2000 Da

European Uraemic toxins Work Group

500 500 - 60.000 Da

Low-Molecular-weight Peptides & Proteins (LMWPs)

Clark William R.; Winchester James F. 2003 Adv.renal replace. ther. Vol 10 n4 pp.270-278

UREMIA
DIALYSIS
. 5-year survival rates < 35% . Hospitalization . Quality of life often low

Vs

TRANSPLANTATION
Over-all quality of life Enhances specific functions . sleep . sexual function . cognition . exercise capacity . growth
Perl J, et al. 2006. Kidney Int;70;1687-93 Valderrabano F, et al. 2001. Am j Kidney Dis;38:443-64 Griva K, et al. 2006.NDT;21:3275-82 Fine RN. 2002.Pediatr. Transplant;6:47-52

RESIDUAL SYNDROME Partially Partially Treated Uremia Uremia

- Severity of classic uremic symptoms is attenuated - The ill effects of dialysis
. Fluctuation of extracellular fluid volume

. Exposure E t to bioincompatible bi i tibl materials t i l . Residual inorganic ion disturbances

- Effect Eff t of f advancing d i age - Systemic y dis. responsible p for loss of kidney y function - Inadequate removal of organic wastes
Depner TA. 2001 Semin Dial;14:246-51

EUROPEAN URAEMIC TOXIN WORK GROUP

( (2000-2007) )

Protein-bound Protein bound solutes

R. Vanholder, et al. 2003 Kidney Int.;63:1934-43

Middle molecules

R. Vanholder, et al. 2003 Kidney Int.;63:1934-43

Uremic toxins in the LMWP class

Leptin
16 kD, , adipocytes, p y , food intake & metabolic rate

ESRD

plasma leptin or plasma leptin/body fat mass

Widjaja, et al Widjaja al. 2000 NDT;15:846-50

~ Anorexia & weight loss 1/ 1/ Dietary protein intake Nutritional parameters Serum albumin Protein catabolic rate Transferrin Lean body mass
Young, et al.1997 NDT;12:2318-23 NDT;12:2318 23

Johansen, et al.1998 JASN;9:1080-84

1/

Stevinkel, et al.2000 JASN;11:1303-9

Uremia-associated Cachexia
TNF- IL-6
CNS Neurotransmitters

Leptin

Appetite pp & Metabolic rate

- Activate Nuclear Factor- Kappa B - Activate Ubiquitin-mediated proteolytic system decreased protein synthesis increased protein degradation

Mak, et al. 2007 Current opinion in Nephrology & Hypertension;16(1):27-31

Uremic toxins in the LMWP class

Adrenomed llin (ADM) Adrenomedullin

6-kD, pheochromocytoma Potent vasodilator, modulated by Sympathetic nervous activity Body y fluid volume Blood pressure

Elevation . 4 of ADM in chronic HD patients

Washimine, et al. 1995 Clin Nephrol; 44:389-393

Pre-HD mean arterial pressure 1/ plasma ADM Pathophysiologic role in hypotension-prone HD patients
Cases, et al. 2000 Kidney Int.;57:664-670

Uremic toxins in the LMWP class

G Granulocyte l I Inhibitory hibi Proteins P i

- Granulocyte inhibitory protein ( GIP I )
28 kD ~ light chains , inhibits 28-kD,

chemotaxis oxidative metabolism intracellular bacterial killing

Horl, et al. 1990 Proc Natl Acad Sci;87:6353-57

- Granulocyte inhibitory protein ( GIP II )

12 kD ~ 2 M , i 12-kD, inhibits hibit

O- production O d ti glucose uptake

Haag weber, et al Haag-weber al. 1994 NDT;9:382-388

Uremic toxins in the LMWP class

G Granulocyte l t Inhibitory I hibit Proteins P t i

- Degranulation inhibiting protein ( DIP I )
14.4-kD, ~ angiogenin, inhibits PMNL degranulation
Tschesche, et al. 1994 J Biol Chem;269:30274-80

- Degranulation inhibiting protein ( DIP II )

Complement factor D
Balke, et al. 1995 FEBS lett;371:300-2

- Chemotaxis inhibiting protein ( CIP )

8.5-kD, modified form of Ubiquitin
Cohen, et al. 1998 JASN;9:451-56

Middle Molecules

P th id Hormone Parathyroid H
9000 D, secretion > clearance Intracellular Calcium

Bone mineralization Pancreatic response to metabolic & hormonal changes Erythropoiesis Immune system, PMNL deactivation Wenisch, et al. 2000
J Leukoc Biol; 67:4045

C di Cardiac Liver function Neuropathy & Pruritis ??

Smogorzweski, et al. 1997 Kidney Int;52:512-14

Middle Molecules

2-M
Dialysis-related Amyloidosis (DRA)
Carpal p tunnel syndrome y Chronic invalidating arthralgias Multiple bone cysts Bone fractures Spinal cord compression GIT complications Jadoul M. 1998
NDT;13:S61 64 NDT;13:S61-64

AGE-Modified 2-M Pentosidine-/ Carboxymethyllysine-/ Imidazolone- 2M

Monocytic migration Cytokine secretion
Bailey A, Moe S. 1997 JASN;8:227A

Middle Molecules

AGE
Glucose + Reducing sugars Free amino groups
days

reversible Schiff base

weeks

Stable Amadori

AGE

Peptide- linked degradation products, 2000 - 6000 D

AGE

ESRD on HD without ith t DM > N Nonuremic i Di Diabetics b ti

Miyati, et al. 1996 JASN;7:1198-1206

RAGE

moderate uremia
Abel, et al. 1995 NDT;10:1662-67

Cytokines & cellular events associated with

AGE or RAGE activation

VCAM 1 VCAM-1 ICAM-1 eNOS IL-6 TGF- TGF TNF- RAGE VEGF

E d th li l cells Endothelial ll

Mesangial, smooth muscle cells, macrophages

Podocytes, mesangial, endothelial cells

Jurgen M Bohlender. 2005 Am j Physiol renal physiol;289:645-659

Middle Molecules

ALP
Ad Advanced d Lipoxidation Li id ti End E d Products P d t
Malondialdehyde- modified proteins
ESRD
Miyata, et al. 1997 Kidney Int;55:389-99

Carbonyl Carbonyl Stress Stress

Atherosclerosis
Miyata, et al. 2001 Kidney Int;59:S25 Int;59:S25-31 31

Middle Molecules

AOPP
Ad Advanced d oxidation id ti Protein P t i Products P d t Novel class of inflammatory mediators
AOPP

Oxidative stress & Monocyte respiratory burst

monocyte

M Monocyte as target & actor in i i immune d dysregulation l i associated i d with i h uremia i

Veronique Witco Witco-Sarsat, Sarsat, et al.. 1998 Journal of Immunology;161;2524-32

Proteomics
- Identification of proteins in complex protein mixtures - Interrelations between identified proteins - Characterization, quantity, function

Techniques

. Two-dimensional gel elctrophoresis . MALDI-TOF mass spectrometry

Uremic toxins in ultrafiltrate using various HD membranes

Opatrny K Jr. 2004 Vintr lek;50(7):556-63

A better b tt understanding d t di of f uremic i solutes l t and d th their i t toxic i Effects, would place dialysis on a more rational basis And should lead to more effective therapy therapy
Timothy, et al. 2007 New Engl J Med;357:1316-25

Factors influencing uremic toxin removal

- Preserved residual renal function - New generation of Dialyzers - Dialysis modalities - Frequency regimens - Treatment duration

Residual renal function

Removal of Middl molecule Middle l l Uremic toxins

Erythropoeitin A Anemia i

I Inflammation fl ti

Phosphorus removal l

Malnutrition

Cardiac hypertrophy & Heart failure

Atherosclerosis

Vascular calcification

Overall & cardiovascular mortality

Wang & Lai. 2006 Kidney Int;69:1726-32

Strategies for Preserving RRF

Preferential use of PD over HD in patients with RRF

G Greater t hemodynamic h d i stability t bilit

I fl Inflammatory t mediators di t
from extracorporeal circuit

Fewer ischemic insults to kidney y

Nephrotoxic p effect

Misra, et al Misra al. 2001 Kidney Int;59:754-63

Strategies for Preserving RRF Integrative Integrative Care Approach Approach

Start on PD first Transfer to HD

Survival compared to patients

- remained on PD - started on & remained on HD

Van, et al Van al. 2000 JASN;11:116-125

Strategies for Preserving RRF

- HD using modern synthetic membrane - Ultrapure dialysis fluid
Holley, et al. 2001 Perit Dial Int;21:302-5

Schiffl, et al. 2002 NDT;17:1814 18 NDT;17:1814-18

- Avoiding use of contrasts or nephrotoxic agent - Maintaining M i t i i good d BP control t l - Avoidance of overzealous UF & Intradialytic hypotension

Strategies for Preserving RRF

- Blockade of RAS by ACEi or ARBs
- Slow the progression to anuria in stage 5 CKD patients on dialysis
Li, et al. 2003 Ann Intern Med;139:105-112

- Should be continued in all dialysis patients with RRF

Suzuki, et al. 2004 Am J Kidney Dis;43:1056-64

Dialyzers
Flux
Measure of ultrafiltration capacity,
Low flux Kuf < 10 ml/h/mmHg High flux Kuf > 10 ml/h/mmHg

Kuf

Permeability
Measure of the clearance of MM.w mol, ( 2m)
Low permeability, 2m clearance < 10 mL/min High permeability, 2m clearance >20 mL/min

Efficiency
Measure of urea clearance, KoA
Low efficiency, KoA <500mL/min Hi h efficiency, High ffi i K A >600mL/min KoA >600 L/ i

High-Performance Extra-Corporeal Therapies for ESRD

- High efficiency hemodialysis - High flux hemodialysis - Hemofiltration, intermittent - Hemodialfiltration, intermittent

Membranes
Pore size & Chemical nature
High Flux membranes
Middle molecules Middl l l Protein-bound solutes Lipophilic substances

Vienkent, et al. 1995 Artif Organs;19:398-406

Synthetic membranes
Adsorption of lipophilic substances &/or proteins
Clark, et al. 1995 Kidney Int;48:481-8

Polyether sulphone Vs classic polysulphone Samtleben, et al. 2003 > Albumin depuration NDT;18:2382-6

Membranes
Pore size & Chemical nature
High Flux Polysulphone

U Uremic i Dyslipidemia D li id i

Atherogenic Risk
Christoph, et al. 2004 NDT;19:2570-75

Ultrafiltration & Convective clearance

HF & HDF
Low MW
Adsorption Convection 100% Adsorption

High MW

50% Diffusion

Convection

Diffusion 0

Canaud, et al. 1999 NDT;14(3):98-105

Ultrafiltration & Convective clearance

HF HD
2m 11.8 kD Leptin 16 kD Myoglobin 15-25 kD 1-microglobulin >30 kD
68%

Vs

OL OL-HDF HDF
81%
Maduell, et al. 2006 Nefrologia;26(4)

7%

31%
Lepinies, et al Lepinies al. 2000 NDT;15:A220

24.7%

62.8%
Maduell, et al. 2002 Am J Kid Dis;40(3):582-9

Null

20%
Kim, et al. 1996 Nephrology;2(1):S183-6

Dialysate y

Ult Ultrapure dialysate di l t

Highly Hi hl purified ifi d sterile t il infusion i f i

Predialysis y AGE Levels in HF & HDF

Gerdemann, et al. 2002 NDT;17:1045-49

Sorbents
Adsorption
- 3d mechanism of uremic toxin removal

- All dialysis membranes - Dependent on accessible surface area

. Greater surface area . Higher g capacity p y for toxin Size & Hydrophobicity

Courtesy Amicon Corp. Lex. Mass.

Botella, et al. 2000 Kidney Int;52:S66-71

Sorbents
Hydrophobic properties
Charcoal & Non Non-ionic ionic microporous resins

Chemical affinity
Ion exchange resins & Chemiosorbents

Resin type remove large toxins (2m)

Winchester, et al. 2001 Blood Purif; 19:255-59

Sorbents
Dialysate
Hemodiadsorption p Hemolipodialysis Albumin dialysis
Steezko, et al. 2000 Int J Artif Organs;23:375-88 Organs;23:375 88 Wratten, et al. 1999 Blood Purif;17:127-33 ; Stange, Mitzner. 1996 Int J Artif Organs;19:677-91

Ultrafiltrate
Regeneration of ultrafiltrate

Plasma

Marinez, et al. 2000 Kidney Int;58(76);S66-71

Combined with plasma filtration strategies

Tella, et al. 1998 NDT;13:1458-64

Blood

Ronco, et al. 2001 Blood Purif;19:260-3

HD Regimens
Prolonged &/or Frequent Dialysis
- 8h, 8h 3-times weekly HD HD, Tassin, Tassin France - Every y other day y or 4-times weekly y HD, leece, Italy - Short daily HD, Perugia, Italy - Nocturnal HD, Toronto, Canada
Wen. 2002 Acta Nephrologica;16:1-11

HD Regimens
Prolonged &/or Frequent HD
Longer dialysis duration Improve tolerability to treatment Greater removal of uremic toxins (MM)
Saran, et al. 2006 Kidney Int;69:1222-28 Int;69:1222 28

Longer HD sessions could improve outcomes for patients receiving thrice-weekly HD

HD Regimens
P l Prolonged d &/or &/ Frequent F t HD
Kc Intercompartmental mass transfer coefficient
Dialysis Frequency Depuration of big molecules ( low Kc )
Maduell, et al. 2006 Nephrologia;26(4):469-75

NANODIALYSIS

Sorption filter pads - Lightweight (30-100 grams), small sized, disposable sorption filter pad- Removal of uremic toxins by nanostructured sorption materials - Highly efficient in eliminating small and middle molecules - Allowing All i 2x 2 better b tt clearance l rate t and d reduced d d di dialysate l t consumption ti - Allowing small, wearable peritoneal and artificial kidney devices

NANODIALYSIS

Wearable artificial kidney - Direct hemofiltration, blood blood plasma separation - High efficient sorption filter pad to remove small and middle molecule toxins - High clearance rate (4 x hemodialysis) - Continuous operation, no blood peaks - Small sized, wearable unit