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Cardiovascular Disease In CKD: Is It for Children Gérard M. London Hopital Manhes Fleury-Mérogis France.

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Presentation on theme: "Cardiovascular Disease In CKD: Is It for Children Gérard M. London Hopital Manhes Fleury-Mérogis France."— Presentation transcript:


2 Cardiovascular Disease In CKD: Is It for Children Gérard M. London Hopital Manhes Fleury-Mérogis France

3 Cardiovascular Disease Mortality General Population vs ESRD Dialysis Patients Foley RN, et al. Am J Kidney Dis. 1998;32:S112-S119. GP: General Population. Dialysis Female Dialysis Black Dialysis White Age (years) Annual CVD Mortality (%)

4 –44 years Rate: 95 deaths/10 3 patient years 45–64 years Rate: 173 deaths/10 3 patient years +65 years Rate: 341 deaths/10 3 patient years USRDS. AJKD, 1998 Distribution (%) of causes of death for all dialysis patients by age (1994–96) Cardiac arrest Acute MI Other cardiac Cerebrovascular Non-cardiac

5 The causes of Cardiovascular Diseases in CKD Arteriosclerosis Atherosclerosis Ischemic Heart Disease Volume * Overload Systolic BP; Diastolic BP Adaptive LVH Maladaptive LVH Systolic/diastolic dysfunction Cardiac Failure Sudden Death Cerebrovascular and Peripheral artery disease * Hgb; AVF; Na+ (Decreased coronary reserve) (Decreased coronary perfusion)

6 Foley et al. AJKD, Renal transplant recipients 7540Peritoneal dialysis (PD) 7540Hemodialysis (HD) 25–50N/aChronic renal failure 205–12General population Left ventricular hypertrophy (%) Coronary artery disease(%) Approximate prevalence of CVD by target population

7 > <25 * p<0.001; Ccr <25 vs all others * Levin et al. AJKD, 1999 Baseline prevalence of LVH by degree of renal function Cr clearance (ml/min) % patients

8 Silberberg et al. J Kidney Int, 1989 <125 g/m 2 >125 g/m 2 n=91 Survival rate (%) Time (years) Impact of LVH on survival rates

9 Correlation in ESRD patients between the stroke work index and LVMI r = 0.62 p < Stroke work index (g.m/m 2 ) LVMI (g/m 2 ) London et al. Seminar Dial 1999

10 LV volume-pressure relationship during cardiac cycle Ventricular volume Ventricular pressure Area under the curve represents the stroke work

11 Fibrosis Myocyte hypertrophy normal abnormal overload pressurevolume GH T4 Load+ RAAS Local factors Infammation ischemia stimuli remodeling Function and stiffness Stimuli to myocardial remodelig and their impact on stiffness and function Adapted from Weber et al Blood Press 1991

12 Determinants of LV mass in ESRD patients Independent variables t value p RMS error Stroke volume (ml/beat)7.52< Age (years)5.18< Body height (cm)4.52< Mean aortic systolic4.51< pressure (mmHg ) Gender (1 M; 2 F) Dependent variable: LV mass (g) r 2 =0.65; p<0.0001

13 A-V fistula Na+/H 2 0 retention Chronic anemia – increased stroke volume – increased heart rate Hypertension Arteriosclerosis Aortic stenosis Hemodynamic factors of LV hypertrophy Volume overloadPressure overload

14 interdialytic weight changes (kg) left ventricular mass (g) R=0.29 p<0.01 Correlation between left ventricular mass and interdialytic body weight changes in ESRD patients on hemodialysis London et al advanc.Nephrol 1991

15 Arterio-venous shunt flow (ml) Left ventricular mass (g) Correlation between arteriovenous shunts flow and left ventricular mass in ESRD patients R=0.537 p<0.015 London et al advanc.Nephrol 1991

16 Hematocri t (%) LV mass index (g/m²) Correlation between hematocrit and left ventricular mass index in ESRD patients r= p<0.001 London et al Kidney Int 1987

17 r h r/h<0.45 r h r h r/h>0.45 NormalllEccentric LVHConcentric LVH r-radiush-wall thicknessr/h- relative wall thickness Geometric characteristics of left ventricular hypertropy

18 Echocardiographic measurements Measurement ESRD Controls (n=210) (n=150) LV end-diastolic diameter (mm)54±450±3 ** Posterior wall thickness (mm)11±1.88.5±1.6** Interventricular septal thickness (mm)12.5±2.09.6±1.8** LV mass index (g/m 2 )197±48110±30 ** London et al. Advances in Nephrol 1991; 20: ** p < 0.001

19 Incidence of Cardiovascular Disease in Pediatric Dialysis Patients Herzog Ch Kidney Int


21 Distribution of Left Ventricular Mass Index and Relative wall thickness According the Stage of CKD in Pediatric Patients

22 Echocardiographic findings in pediatric patients with CKD and healthy controls

23 LVH regression after use of EPO in ESRD (hemodialysis) Multifactorial origin (partial treatment) Partial anemia correction (insufficient treatment) Myocardial fibrosis (delayed treatment) Only partial LV regression due to: Macdougall Pascual McMahon Zehnder Martinez Wizemann Normal month intervals LVMI (g/m 2 )

24 Systolic BP (mm Hg ) Left ventricular mass index (g/m²) R=0.385 p<0.001 Correlation between left ventricular mass index and systolic BP in ESRD patients on hemodialysis

25 Systolic BP (mm Hg ) interventricular septal thickness (cm) R=0.522 p<0.001 Correlation between systolic BP and interventricular septal thickness in ESRD patients on hemodialysis

26 Mean BP Pulse pressure Mean BP: Cardiac output peripheral resistance mm Hg Pulse pressure: ventricular ejection arterial stiffness wave reflection Systolic pressure Diastolic pressure time

27 1-year Mortality predicted by SBP Experience at 782 US dialysis facilities Ref Klassen et al. JAMA 2002;287: n = 37,069

28 1-year Mortality predicted by DBP Experience at 782 US dialysis facilities Klassen et al. JAMA 2002;287: Adjusted for level of systolic blood pressure n = 37,069 Hazard Ratio For Death

29 One Year Mortality for Patients on Hemodialysis Adjusted for level of systolic blood pressure Ref Klassen et al. JAMA 2002;287: n = 37,069

30 Wave reflections (Augmentation Index %) Aortic stiffness ( pulse wave velocity -cm/s) Pulse Pressure (mm Hg) Stroke volume (ml) Pulse Pressure (mm Hg) Pulse Pressure (mm Hg) R=0.47 p< R=0.60 p< R=0.16 p=0.025 Correlation between arterial pulse pressure, wave reflexion (Augmentation index) aortic pulse wave velocity (stiffness) and stroke volume in ESRD patients (n=230) Adapted from London et al KI 1996

31 Arterial Stiffness (kPa ) Aortic PWV (m/s) London et al adapted from Kidney Int 1996 Relationship between arterial stiffness (Einc - incremental modulus) and Aortic Pulse Wave Velocity (PWV) R=0.745 p<

32 Diagrammatic representation of pressure-volume relationships Volume Pressure dP/dV Einc=1 Einc=2 Einc - incremental elastic modulus characteristic of the mechanical properties of biomaterials

33 Arterial function and blood pressure Pure Conduit FunctionConduit and Cushioning Function Blood pressure Systole Diastole Mean pressure Blood pressure Systole Diastole Mean pressure

34 Blood pressure in end-stage renal disease Age (yrs) Systolic BP (mm Hg) Diastolic BP (mm Hg) Mean BP (mm Hg) Pulse pressure(mmHg) Controls (n = 100) 47 ± ± ± ± ± 16 ESRD (n = 100) 48 ± ± 23* 83 ± 14* 107 ± ± 18** London et al Kidney Int 1989

35 Determinants of LV afterload in ESRD Age (yrs) Stroke volume (ml) Peripheral résistances (dynes sec cm - 5 ) Aortic PWV (cm/s) Augmentation Index (%) Controls (n = 100) 47 ± ± ± ± ±4 ESRD (n = 100) 48 ± ± 24* ± ± 245** 24 ±6** London et al Kidney Int 1989 Common carotid artery distensibility (kPa ) 19.3 ± ± 8.8** Common carotid artery elastic modulus (kPa.10 3 ) ± 0.46***0.50 ± 0.22

36 Aortic pulse wave velocity (cm/sec) Left ventricular mass (g/m 2 ) r = 0.52 p < Correlation between aortic pulse wave velocity and left ventricular mass index in HD patients London et al Adv.Nephrol 1991

37 Echographic characteristics of common carotid artery Measurement ESRD Controls CCA end-diastolic diameter (mm)54±450±3 ** CCA Intima media thickness (mm)11±1.88.5±1.6** CCA relative wall thickness (mm)12.5±2.09.6±1.8** LV mass index (g/m 2 )197±48110±30 ** London et al. Advances in Nephrol 1991; 20: ** p < 0.001

38 Age (years) Aortic Pulse wave velocity (m/s) Age (years) Carotid wall thickness (mm) Carotid wall thickness (mm ) Aortic pulse wave velocity (cm/s) Carotid wall thickness (mm) Left ventricular wall thickness (cm ) r=0.631 P< r=0.561 P< r=0.564 P< r=0.508 P<0.0001

39 Correlation between Age and Aortic Pulse Wave Velocity in General population ( ) and ESRD patients ( ) Age (years) Aortic PWV (m/s) r=0.625 p< r=0.719 p< Age (years) Characteristic impedance ( r=0.525 P< r=0.340 P<0.01

40 Follow-up (months) CV Survival Follow-up (months) CV Survival Follow-up (months) CV Survival Aortic PWVBrachial PWV Femoral PWV ²=72.8 P< ²=1.78 P=0.411 ²=2.34 P= st tertile 2nd tertile 3rd tertile <9.7m/s >9.7 m/s >12 m/s Pannier et al Hypertension 2005

41 Correlation Between CCr (C-G formula) and Aortic PWV r = –0.30 P < CCR (mL/min/m²) Aortic PWV (m/s) Bortolotto et al KI 2001


43 Covic A et al. NDT 2006;21: Arterial and cardiac parameters in dialysis children

44 Mitsnefes MM et al JASN 2005;16: Carotid IMTh and Compliance in Children with CKD


46 De Lima JJG et al NDT 17;645,2002 Impact of renal transplantation on arterial and heart characteristics

47 Changes of mean blood pressure and aortic PWV Guérin and al. circulation 2001 ; 103 : Survivors Inclusion At target BP At target BP End of follow up MBP (mmHg) PWV (m/s) Non Survivors Inclusion At target BP End of follow up MBP (mmHg) PWV (m/s) 100

48 All cause survival according to changes in aortic pulse wave velocity ( PWV) in response to BP decrease 2 = P< Guérin et al. Circulation Decreased PWV Unchanged or increased PWV Duration of follow-up (months) Survival rate

49 Variables associated with aortic pulse wave velocity in ESRD (multiple regression) Independent bcoefficientP valueSequentialPartial r 2 variable r 2 (adj. for rest ) Age (years) Gender (0-M,1-F) Systolic BP (mm Hg) Heart rate (b/m) CRP (mg/l) Duration of HD (months) Aortic calcification (0-no ; 1-yes) Adjusted sequential r ; F ratio ; p<

50 Abdominal aortic calcification score Aortic PWV (ms) r = P < Pannier et al. Artery 2007 Correlation between aortic calcification score and aortic PWV in ESRD patients

51 Cardiovascular Calcification Is Increased in Dialysis Patients *Determined by EBT. CAD = coronary artery disease. Rumberger JA et al. Mayo Clin Proc. 1999;74: Braun J et al. Am J Kidney Dis. 1996;27: Age (years) Mean Coronary Artery Calcium Score* Non-dialysis, No CAD (n=22) Non-dialysis, CAD (n=80) Dialysis (n=49) Very high CV risk

52 51 Coronary Artery Calcification in Young Dialysis Patients Age (years) Calcification Score* N=39 *Determined by EBT. Goodman WG et al. N Engl J Med. 2000;342: Calcification scores nearly doubled in a majority of patients with positive initial scan when rescanned at 20 months

53 Calcification score Probality of all-cause survival according to calcification score. Comparison (log-rank test) between curves was highly significant ( Chi P<0.0001). Calcification score : Calcification score : 1 Calcification score : 2 Calcification score : 3 Calcification score : 4 Duration of follow-up (months) Probality of survival Blacher et al Hypertension 2001

54 PO4 CBfa1 BMP2 ALP Osteocalcin Osteonectin Leptin Collagen I Fibronectin LDLox TNF- Dexamethasone Klotho-/- PTH Vit D3 Ca + Oncostatin - Osteoprotegerin MGP Osteopontin BMP7 Collagen IV Fetuin PTHrP PTH pyrophosphate + Inductors (+) and inhibitors (-) of vascular calcifications

55 Pit1 Na Pi hyperphosphatemia Pi Smooth muscle genes matrix vesicles Cbfa-1 Collagen-rich extracel. matrix AP alkaline phosphatase Calcium-binding proteins (osteocalcin, MGP, osteopontin,..)

56 Multiple correlation study for variables associated with abdominal aortic calcification score (n=200) Variablet - valueP-value smoking (packs.year) age (years) hCRP (mg/L) serum phosphates (mMol/L) CaCO 3 (g Ca element/day) iPTH (pg/mL) – Ca 2+ / total Ca (%) – serum albumin (g/L) – R 2 = Pannier B et al. Artery research 2007

57 Median Percentage Change in Coronary Scores at 52 Weeks CalciumSevelamer Median Percentage Change 25%* 6% *Within treatment P<0.0001; between treatment groups P=0.02. Patients with a baseline score >30.

58 Hypercalcemia 10.5 mg/dL (2.63 mmol/L) Percentage of Patients Study Week SevelamerCalcium

59 Calcium Balance in CKD 5 Intake 20 mMol Calcium load 16 mmol 4 mMol ECF Ca 25mMol Dialysate 270 mMol 266 mMol X U Ca V 4 mMol X

60 Possible links between bone turnover and vascular calcification in CKD

61 r = – P < 0.01 Double tetracycline-labeled surfaces (%) Aortic calcification score Aortic pulse wave velocity (m/s) r = – P < London GM et al JASN 2008

62 Aortic pulse wave velocity (m/s) Log 10 25(OH)D(µg/L) Brachial artery distensibility (kPa ) (10 µg/L) r = – P < n = (10 µg/L) r = P < n = 42 Cross-sectional correlation between serum 25(OH)D and aortic stiffness and brachial artery distensibility London GM et al (JASN 2007)

63 Tims PM et al. QJ Med 95:787,2002 MMP9 is inversely correlated to serum 25(OH)D3

64 Copyright ©2005 American Heart Association Yasmin, et al. Arterioscler Thromb Vasc Biol 2005;25: Relationship between aortic PWV and serum MMP-9 levels

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