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8/8/2019 Renal Failure Socioeconomic Challenge
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CHRONIC KIDNEY DISEASE: A
MAJOR SOCIO-ECONOMIC,MEDICAL AND SCIENTIFIC
CHALLENGER Vanholder
University Hospital, Gent
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MECHANISMS KIDNEY
FAILURE Healthy kidneys purify the blood from waste
products by excreting them in the urine
Normally, 120 mL of blood are purified perminute (GFR)
In kidney failure this blood purifying processis blunted: waste products are accumulatedin the body
This induces a progressive process of
intoxication, which affects all organ systems,leading to an accelerated death, even ifdialysis is performed (worse than cancer)
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K/DOQI stages of renal failure (1)
Stage Characteristics Creatinine Clearance(~GFR, ml/min/1,73m)
Metabolic consequences
1 Normal or
increased GFR
> 90
2 Early renal failure 60 89* Concentration PTH increased
3 Moderate renal
failure
30 59 Decrease Ca absorption
Lipoprotein activity decreasedMalnutrition
Left ventricular hypertrophyAnemia
4 Pronounced renalfailure
(pre-end stagerenal failure)
15 29 TG concentration increasesHyperphosphatemia
Metabolic acidosisTrend towards hyperkalemia
5 Terminal renalfailure(ESRD)
< 15 and/or RRT Azotemia
1: Parmar, BMJ, 2002, 325: 85-90
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PRE-DIALYSE VS DIALYSE
VERDIKKING CAROTIDEN
Shoji et al, KI, 61, 2187-2192, 2002
40-49 50-59 60-69 70-79 Total
#
**
**** **
*
****
**
60 26 71 123 30 125 80 27 97 39 27 52 302 110 345
Age, years
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
CA-IMT,mm
Control
Pre-dialysis
Dialysis
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CLINICAL EVIDENCE OF AN
ASSOCIATION BETWEEN RENALFAILURE AND VASCULAR
DISEASE PRE-DIALYSIS
85 studies (1986-2003) 552,258 patients
71 with correction for traditional risk factors
Sharpest threshold Screa: 0,90 mg/dL
GFR: 90 mL/min
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RELATIEF RISICO
Vanholder et al, NDT, 20, 1048-1056, 2005
0 25 50 75 100 125 150
GFR (ml/minute)
15
10
5
0
RR_mortality
(foldincrease)
y = -0.1262 x + 10.77
r = 0.645; p< 0.001
y = -0.0180 x + 2.727
r = 0.574; p < 0.004
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GFR & CVD (> 65 y)
Manjunath et al, KI, 63, 1121-1129, 2003
Log-rank Pvalue < 0.001
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
ProportionfreeofCVD
0 500 1000 1500 2000
Time since baseline, days
15 GFR 59, mL/min/1.73 m
60 GFR 89, mL/min/1.73 m
90 GFR 130, mL/min/1.73 m
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AHA Scientific Statement
Kidney Disease as a Risk Factor for Development of
Cardiovascular Disease
A Statement From the American Heart Association Councils on Kidney in
Cardiovascular Disease, High Blood Pressure Research, Clinical
Cardiology, and Epidemiology and Prevention
Mark J. Sarnak, MD, Cochair; Andrew S. Levey, MD, Cochair;
Anton C. Schoolwerth, MD, Cochair; Josef Coresh, MD, PhD; Bruce Culleton, MD;
L. Lee Hamm, MD; Peter A. McCullough, MD, MPH; Bertram L. Kasiske, MD; Ellie
Kelepouris, MD; Michael J. Klag, MD, MPH; Patrick Parfrey, MD;Marc Pfeffer, MD, PhD; Leopoldo Raij, MD;
David J. Spinosa, MD; Peter W. Wilson, MD
Sarnak et al, Circulation, 108, 2154-2169, 2003;
Hypertension, 42, 1050-1065, 2003
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NHANES III / AUSDIAB
Prevalence renal failure
Third National Health and NutritionExamination Survey > 15,000 subjects
(USA)
GFR < 60 mL/min ( 50%): 4.7% GFR < 90 mL/min ( 25%): 35.9%
AusDiab
11,247 subjects (Australia) GFR < 60 mL/min ( 50%): 10.9%
45-64 j old: 2.5%
65 j old: 53.1%
Coresh et al, AJKD, 41, 1-12, 2003; Chadban et al,JASN, 14, S131-S138, 2003
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POPULATIONS AT RISK
Worldwide in dialysis or transplanted:
2,000,000 persons Worldwide with GFR < 60 mL/min:
6,000,000,000 x 0.05 = 300,000,000 This problem has similar epidemic
proportions as diabetes mellitus, but is
unfortunately strongly underestimated
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Cost of HD
.00 1.00 2.00
PERIOD
0
20000
40000
60000
80000
Mean
3590
53432 51929
2676
10382
6506
10869
6557
4660
4218
6719
4407
COSTDIALMEDRIZ
HOSPRIZ
TECHRIZ
Type:
0 = PD
1 = HD
2 = TX
Period:
0 = 1th hospital
1 = Year 1
2 = Year X
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Rise of cost
100
120
140
160
180
200
1 2 3 4 5 6 7 8 9 10
Patients
+ 8 %
Economies
+ 2 %
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FUTURE AIMS
Correct and timely estimation kidneyfunction, especially in risk groups: diabetes,hypertension, familial renal failure, > 60j,nephrotoxic medication, proteinuria
If GFR < 60 mL/min
secundary prevention:life style, smoking stop, correction tension,treatment diabetes, angiotensin blockers,correction lipid disturbances,hypercoagulability blood, inflammation
Prevention of both the early complicationsand the progression towards dialysis
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MORTALITY
Age CO HD HD/CO
25-34 0.008 3 375.0
35-44 0.03 4.5 150.0
45-54 0.1 6 60.0
55-64 0.3 8 26.7
65-74 0.9 10 11.175-84 3 15 5.0
Foley et al, AJKD, S3, S112-S119, 1998
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COX-PROPORTIONAL
ANALYSIS*Coeff P-value
LDL-cholesterol -0.002 NSTriglycerides -0.003 NS
Predialysis MAP -0.110 NSBMI -0.066 NS
Hypertension -0.57 NS
Smoking 0.04 NS
*: adjusted for age, gender and race (n=453);Fleischmann et al, Clin Nephrol, 56, 221-230, 2001
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ATHEROSCLEROTIC CARDIOVASCULARE
RISK IN CHRONIC HEMODIALYSISPATIENTS
Alfred K. Cheung et al, Kidney International, 58: 353-5362; 2000
Some of the traditional coronary factors in the general population
appear to be also applicable to the hemodialysis population, while
other factors did not correlate with atherosclerotic cardiovascular
disease in this cross-sectional study. Nontraditional risk factors,including the uremic milieu and perhaps the hemodialysis
procedure itself, are likely to be contributory. Further studies are
necessary to define the cardiovascular risk factors in order to
devise preventive and interventional strategies for the chronichemodialysis population.
S l 2 DC di l t ith F70 b
S l 1 DC di l t ith F10 b
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0 14 28 42 56 70
Retention Time (Min)
0
1.2E+5
0
10
20
30
40
50
60
70
80
90
100
%I
ntensity
TICTotal Ion Chromatogram
MosaiquesVisu 3D plot
Sample 2: DC dialysate with F70 membrane
0 14 28 42 56 70
Retention Time (Min)
0
1.6E+5
0
10
20
30
40
50
60
70
80
90
100
%I
ntensity
TICTotal Ion Chromatogram
MosaiquesVisu 3D plot
Sample 1: DC dialysate with F10 membrane
7 kD
6 kD5 kD
4 kD
3 kD
2 kD
1 kD
Protein display, DC, F10 Protein display, DC, F70
ma
ss/charge(KD/z
CE-retention time (min) CE-retention time (min)
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ADDITIVE RISK FOR HYPERTENSION, DIABETES AND
RENAL FAILURE
TOD: GFR 90-60 mL/min; ACC: GFR < 60 mL/min
MIA h h i
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MIA hypothesisPro-inflammatory cytokines are the common link
between
Malnutrition, Inflammation and
AtherosclerosisCytokines
(IL-1, IL-6, TNF-)Cytokines
(IL-1, IL-6, TNF-)AtherosclerosisAtherosclerosis InflammationInflammation
MalnutritionMalnutrition
Stenvinkel et al. Nephrol Dial Transplant2000; 15: 95360
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DEAD VS ALIVE AT 34 MTHS
DEAD (41) ALIVE (50)
CRP (g/mL) 10.1 3.4**
Alb (g/dL) 3.7 3.8*
BUN (mg/dL) 5315 6418*
Crea (mg/dL) 9.03.0 11.13.2*
PCRn (g/kg.d) 0.930.19 1.06.21*
*: p
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ATHEROMATOSIS
Ross New Engl J Med 340 (2) : 115, 1999
Endothelial
permeabilityLeukocyte
permeability
Endothelial
adhesionLeukocyte
adhesion
Smooth-muscle
migration
Foam-cell
formation
T-cell
activation
Adherence andaggregation of
platelets
Adherenceand entry
of leukocyt
UREMIC TOXINS WITH
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UREMIC TOXINS WITH
VASCULAR IMPACT
ll
i r
Vanholder et al, IJAO, 24, 695-725, 2001
Endothelial Cells
Advanced glycation products
Advanced oxidation protein
products
2-microglobulinCytokines
Homocysteine
Leptin
Oxalic Acid
Oxidized LDL
Polymorphnuclear Neutrophils
Advanced glycation products
Advanced oxidation protein products
Angiogenin (DIP I)
Complement factor D (DIP II)
Cytokines
Ig Light chains
Leptin
Monophages/Macrophages
Advanced glycation products
Advanced oxidation protein products
AGE-2-microglobulin
2-microglobulin
Cytokines
Homocysteine
Leptin
Platelets
CytokinesLeptin
NeutrophilsMonocytes
Platelets
Vascular LesionMigrationDifferentiation
Adhesion
MPOAOPP
Endothelial Cells
Resident
Macrophage
2-microglobulin
Homocysteine
Smooth muscle cells
Foam Cells
CytokinesROS
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FUTURE AIMS
Detection of the factors which are specific
for renal failure to cause vascular damage(genome, proteome, secretome)
Since renal failure is an accelerated model of
atheromatosis, these factors should thenalso be checked in the non-renal failure
population, where they may as yet have
remained unrecognized
EUROPEAN UREMIC TOXIN
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EUROPEAN UREMIC TOXIN
WORK GROUP (EUTox) A Argiles (F)
P Brunet (F)
G Cohen (A)
PP De Deyn (B)
T Dreke (F)
S Herget-Rosenthal (G)
W Hrl (A)
J Jankowski (G)
A Jrres (G)
ZA Massy (F) H Mischak (G)
A Perna (I)
M Rodriguez (Sp)
G Spasovski (Mac)
B Stegmayr (Sw)
P Stenvinkel (Sw) P Thornalley (UK)
R Vanholder (B)
C Wanner (G)
A Wiecek (P)
W Zidek (G)
Amgen
Baxter Healthcare
Fresenius Medical Care
Gambro
Genzyme
Membrana Roche