Cardiovascular Disease In CKD: Is It for Children Gérard M. London Hopital Manhes Fleury-Mérogis France
Cardiovascular Disease Mortality General Population vs ESRD Dialysis Patients Foley RN, et al.  Am J Kidney Dis . 1998;32:...
Distribution (%) of causes of death for all dialysis patients by age (1994–96) 20–44 years Rate: 95 deaths/10 3  patient y...
The causes of Cardiovascular Diseases in CKD Arteriosclerosis  Atherosclerosis Ischemic Heart Disease Volume * Overload  ...
Approximate prevalence of CVD by target population Foley et al.  AJKD,  1998 50 15 Renal transplant recipients 75 40 Perit...
Baseline prevalence of LVH by degree of renal function 0 10 20 30 40 50 >50  35-49 25-34 <25 * p<0.001; Ccr <25 vs all oth...
Impact of LVH on survival rates Silberberg et al.  J Kidney Int , 1989 <125 g/m 2 >125 g/m 2 n=91 Survival rate (%) Time (...
Correlation in ESRD patients  between the stroke work index  and LVMI r = 0.62 p  < 0.0001 410 50 Stroke work index (g.m/m...
LV volume-pressure relationship during cardiac cycle  Ventricular volume Ventricular pressure Area under the curve represe...
Fibrosis Myocyte hypertrophy normal abnormal overload pressure volume GH T4 Load+ RAAS RAAS Local factors Infammation isch...
Determinants of LV mass in ESRD patients <ul><li>Independent variables </li></ul><ul><li>  t value   p  RMS error </li></u...
Hemodynamic factors of LV hypertrophy <ul><li>A-V fistula </li></ul><ul><li>Na+/H 2 0 retention </li></ul><ul><li>Chronic ...
0 100 200 300 400 500 600 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 interdialytic weight changes (kg) left ventricular mass ...
100 150 200 250 300 350 400 450 500 0 250 500 750 1000 1250 1500 1750 2000 Arterio-venous shunt  flow (ml) Left ventricula...
50 100 150 200 250 300 350 15 20 25 30 35 40 45 50 Hematocri t (%) LV mass index (g/m²) Correlation between hematocrit and...
r h r/h<0.45 r h r/h<0.45 r h r/h>0.45 Normalll Eccentric  LVH Concentric LVH r-radius h-wall thickness r/h- relative wall...
Echocardiographic measurements <ul><li>Measurement  ESRD  Controls    (n=210)  (n=150) </li></ul><ul><li>LV end-diastolic ...
0-4 5-9 10-14 15-19 Incidence of Cardiovascular Disease in Pediatric Dialysis Patients Herzog Ch Kidney Int
 
Distribution of Left Ventricular Mass Index and Relative wall thickness According the Stage of CKD in Pediatric Patients
Echocardiographic findings in pediatric patients with CKD and healthy controls
LVH regression after use of EPO in ESRD (hemodialysis)   Normal 50 100 150 200 250 6 month intervals LVMI (g/m 2 ) <ul><li...
50 100 150 200 250 300 350 400 80 100 120 140 160 180 200 220 240 Systolic BP (mm Hg ) Left ventricular mass index (g/m²) ...
0.50 0.83 1.15 1.48 1.80 80 100 120 140 160 180 200 220 240 Systolic BP (mm Hg ) interventricular septal thickness (cm) R=...
80 140 Mean BP Pulse pressure Mean BP: Cardiac output peripheral resistance mm Hg Pulse pressure: ventricular ejection art...
1-year Mortality predicted by SBP Experience at 782 US dialysis facilities Ref Klassen et al. JAMA 2002;287:1548-1555 n = ...
1-year Mortality predicted by DBP Experience at 782 US dialysis facilities Klassen et al. JAMA 2002;287:1548-1555 Adjusted...
One Year Mortality for Patients on Hemodialysis  Adjusted for level of systolic blood pressure Ref Klassen et al. JAMA 200...
Wave reflections (Augmentation Index %) 20 48 76 104 132 160 500 1000 1500 2000 2500 Aortic stiffness ( pulse wave velocit...
5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 .1 1 10 Arterial Stiffness (kPa 10- 3 ) Aortic PWV (m/s) London et al adapted f...
Diagrammatic representation of pressure-volume relationships Volume Pressure dP/dV Einc=1 Einc=2 Einc - incremental elasti...
Arterial function and blood pressure Pure Conduit Function Conduit and Cushioning Function Blood pressure Systole  Diastol...
Blood pressure in end-stage renal disease Age (yrs) Systolic BP (mm Hg) Diastolic BP (mm Hg) Mean BP (mm Hg) Pulse pressur...
Determinants of LV afterload in ESRD Age (yrs) Stroke volume (ml) Peripheral résistances (dynes sec cm - 5 ) Aortic PWV (c...
200 100 Aortic pulse wave velocity (cm/sec) Left ventricular mass (g/m 2 ) 150 500 1000 1500 2000 r = 0.52 p < 0.001 Corre...
Echographic characteristics of common carotid artery <ul><li>Measurement  ESRD  Controls    </li></ul><ul><li>CCA end-dias...
5.0 7.5 10.0 12.5 15.0 17.5 20.0 10 20 30 40 50 60 70 80 90 Age (years) Aortic Pulse wave velocity  (m/s) 0.5 0.6 0.7 0.8 ...
Correlation between Age and Aortic Pulse Wave Velocity in General population (  ) and ESRD patients (  ) 5 10 15 20 25 25 ...
0.00 0.25 0.50 0.75 1.00 0.0 50 100 150 200 250 Follow-up (months) CV Survival 0.00 0.25 0.50 0.75 1.00 0.0 50 100 150 200...
Correlation Between CCr (C-G formula) and Aortic PWV 5 10 15 20 25 30 0 50 100 150 200 r  = –0.30 P  <0.0001 CCR (mL/min/m...
 
Covic A et al.   NDT 2006;21:729-735 Arterial and cardiac parameters in dialysis children
Mitsnefes MM et al JASN 2005;16:2796-2803. Carotid IMTh and Compliance in Children with CKD
 
De Lima JJG et al NDT 17;645,2002 Impact of renal transplantation on arterial and heart characteristics
Changes of mean blood pressure and aortic PWV Guérin and al. circulation 2001 ; 103 : 987 - 92 9 10 11 12 13 14 Survivors ...
All cause survival according to changes in aortic pulse wave velocity (   PWV) in response to BP decrease <ul><li> 2  = ...
Variables associated with aortic pulse wave velocity in ESRD (multiple regression) Independent  bcoefficient P value Seque...
5.0 7.5 10.0 12.5 15.0 17.5 20.0 0 4 8 12 16 20 24 Abdominal aortic calcification score Aortic PWV (ms) r = 0.754 P < 0.00...
Cardiovascular Calcification Is Increased in Dialysis Patients *Determined by EBT. CAD = coronary artery disease. † Rumber...
Coronary Artery Calcification in Young Dialysis Patients 0.1 1 10 100 1000 10000 0 5 10 15 20 25 30 35 Age (years) Calcifi...
Calcification score <ul><li>Probality of all-cause survival according to calcification score. Comparison  (log-rank test) ...
Inductors (+) and inhibitors (-) of vascular calcifications PO4 CBfa1 BMP2 ALP Osteocalcin Osteonectin Leptin Collagen I F...
Pit1 Na Pi hyperphosphatemia Pi Smooth muscle genes matrix vesicles Cbfa-1 Collagen-rich  extracel. matrix AP alkaline pho...
Multiple correlation study for variables associated with abdominal aortic calcification score (n=200) Pannier B et al. Art...
Median Percentage Change in  Coronary Scores at 52 Weeks 0 5 10 15 20 25 30 35 Calcium Sevelamer Median Percentage Change ...
Hypercalcemia   10.5 mg/dL (2.63 mmol/L) Percentage of Patients Study Week -2 0 3 6 9 12 16 20 24 28 32 36 40 44 48 52 0 ...
Calcium Balance in CKD 5 Intake 20 mMol 16 mmol 4 mMol ECF Ca 25mMol  270 mMol 266 mMol X U Ca V 4 mMol X Calcium load Dia...
Possible links between bone turnover  and vascular  calcification in CKD
0 4 8 12 16 20 24 0 3 6 9 12 15 18 21 24 27 r  =  –  0.489 P  < 0.01 Double tetracycline-labeled surfaces (%) Aortic calci...
Aortic pulse wave velocity (m/s) Log 10  25(OH)D(µg/L) Brachial artery  distensibility (kPa10 -1 .10 -3 ) 4 6 8 10 12 14 1...
Tims PM et al. QJ Med 95:787,2002 MMP9 is inversely correlated to serum 25(OH)D3
Copyright ©2005 American Heart Association Yasmin,  et al. Arterioscler Thromb Vasc Biol 2005;25:372-378 Relationship betw...
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  • This graph shows that the incidence of death due to cardiovascular disease is dramatically higher in ESRD dialysis patients compared to the general population. Data are stratified in both groups by age, race, and gender. 1 Death due to cardiovascular disease is defined by arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema. 1. Foley RN, et al. Am J Kidney Dis . 1998;32:S112-S119.
  • That question is addressed by adjusting for level of systolic blood pressure in the Cox proportional hazards model. When systolic pressure is adjusted for, there is a dramatic and consistent association between higher pulse pressure and greater risk of death. To give this a clinical face, this relationship suggests that when considering a group of patients with a systolic blood pressure of 180, those with a diastolic pressure of 90 (and a pulse pressure of 90) have a death risk that is four to six times higher than those with a diastolic pressure of 120 (and a pulse pressure of 60). CHANGED
  • Key Point: The risk for coronary heart disease is dramatically increased in dialysis patients, and it increases with age. Braun and colleagues assessed the value of electron beam computed tomography (EBT) for detection of coronary artery calcifications and calcification of heart valves of dialysis patients. They compared results from 49 chronic hemodialysis patients (28-74 years old) versus 102 nondialysis patients (32-73 years old) with documented or suspected coronary artery disease (CAD). They calculated a coronary artery calcium score and assessed calcification of mitral and aortic valves. The coronary artery calcium score was from 2.5- to 5-fold higher in the dialysis patients than in the nondialysis patients. Mitral valves were calcified in 59% of dialysis patients, whereas the aortic valve was calcified in 55%. Coronary artery calcium score also increased with age in dialysis patients, with mean scores in the 60- to 69-year-old group over 2-fold higher than those in the 40- to 49-year-old group. [Braun, 1996, 394A, 396A, 397A-C] In the general population, coronary artery calcium scores &gt;400 by EBT are associated with very high cardiovascular risk. [Rumberger et al, 1999, 250A] Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis . 1996;27:394-401. Rumberger JA, Brundage BH, Rader DJ, Kondos G. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc . 1999;74:243-252.
  • Key Point: There is significant coronary artery calcification in young dialysis patients that progresses rapidly as they grow older. In a study by Goodman and colleagues, 39 dialysis patients younger than 30 years underwent electron beam computed tomography (EBT) scans, which were compared with those of age- and sex-matched controls. Fourteen of 16 dialysis patients 20 to 30 years of age had positive EBT scans, with a mean score of 1157. Only 3 of 60 control patients had positive scans, with scores ranging from 1 to 77. In 10 patients with positive initial scans who underwent repeat EBT evaluation after an average of 20 months, the mean calcification score nearly doubled, demonstrating the rapidly progressive nature of cardiac calcification in the dialysis population. [Goodman, 2000, 1478A, 1479A, 1480A, 1481A, 1482A] Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med . 2000;342:1478-1483.
  • What could be the possible link between bone turnover and vascular calcifications and uremic bone disease We could speculate that the impairment of the calcium phosphorus metabolism observed in uremic patients could be the link between Bone and vessel diseases . Too high levels of PTH increase calcium and phosphorus release from bone while too low levels prevent bone from playing its buffering role. want to conclude with just a few words about the assessment of PTH and our PTH targets and ask the question: “Does it really matter whether bone turnover is high or PTH is high or if it is too low?” And then ask: “What is too low?” Here you can see that if bone turnover is high and PTH is high in typical hyperparathyroidism, calcium and phosphorus can be mobilized from the skeleton. Perhaps that can facilitate its deposition into peripheral tissues and cause this calcification, like the vascular calcification I showed you On the other hand, if bone turnover is low and PTH levels are low and the bone is relatively inactive and not making matrix, then calcium and phosphorus that come into the body won’t be able to be deposited in the skeleton. If it can’t be deposited in bone, perhaps it gets deposited elsewhere. So in other words a PTH of too high is bad. A PTH of too low is bad.
  • Cardiovascular Disease In CKD: Is It for Children

    1. 1. Cardiovascular Disease In CKD: Is It for Children Gérard M. London Hopital Manhes Fleury-Mérogis France
    2. 2. 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 (%) 0.001 0.01 0.1 1 10 100 25-34 35-44 45-54 55-64 66-74 75-84 >85 GP Male GP Female GP Black GP White Dialysis Male
    3. 3. Distribution (%) of causes of death for all dialysis patients by age (1994–96) 20–44 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 Cardiac arrest Acute MI Other cardiac Cerebrovascular Non-cardiac 21 7 12 6 53 22 11 16 6 45 21 10 19 6 44
    4. 4. 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)
    5. 5. Approximate prevalence of CVD by target population Foley et al. AJKD, 1998 50 15 Renal transplant recipients 75 40 Peritoneal dialysis (PD) 75 40 Hemodialysis (HD) 25–50 N/a Chronic renal failure 20 5–12 General population Left ventricular hypertrophy (%) Coronary artery disease(%)
    6. 6. Baseline prevalence of LVH by degree of renal function 0 10 20 30 40 50 >50 35-49 25-34 <25 * p<0.001; Ccr <25 vs all others * Levin et al. AJKD , 1999 Cr clearance (ml/min) % patients
    7. 7. Impact of LVH on survival rates Silberberg et al. J Kidney Int , 1989 <125 g/m 2 >125 g/m 2 n=91 Survival rate (%) Time (years) 100 80 60 40 20 0 0 1 2 3 4 5
    8. 8. Correlation in ESRD patients between the stroke work index and LVMI r = 0.62 p < 0.0001 410 50 Stroke work index (g.m/m 2 ) LVMI (g/m 2 ) 20 170 London et al . Seminar Dial 1999
    9. 9. LV volume-pressure relationship during cardiac cycle Ventricular volume Ventricular pressure Area under the curve represents the stroke work
    10. 10. Fibrosis Myocyte hypertrophy normal abnormal overload pressure volume GH T4 Load+ RAAS 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
    11. 11. Determinants of LV mass in ESRD patients <ul><li>Independent variables </li></ul><ul><li> t value p RMS error </li></ul><ul><li>Stroke volume (ml/beat) 7.52 <0.001 21.1 </li></ul><ul><li>Age (years) 5.18 <0.001 0.3 </li></ul><ul><li>Body height (cm) 4.52 <0.001 7.8 </li></ul><ul><li>Mean aortic systolic 4.51 <0.001 7.8 pressure (mmHg ) </li></ul><ul><li>Gender (1 M; 2 F) -2.0 0.045 1.3 </li></ul>Dependent variable: LV mass (g) r 2 =0.65; p <0.0001
    12. 12. Hemodynamic factors of LV hypertrophy <ul><li>A-V fistula </li></ul><ul><li>Na+/H 2 0 retention </li></ul><ul><li>Chronic anemia </li></ul><ul><ul><li>increased stroke volume </li></ul></ul><ul><ul><li>increased heart rate </li></ul></ul><ul><li>Hypertension </li></ul><ul><li>Arteriosclerosis </li></ul><ul><li>Aortic stenosis </li></ul>Volume overload Pressure overload
    13. 13. 0 100 200 300 400 500 600 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 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
    14. 14. 100 150 200 250 300 350 400 450 500 0 250 500 750 1000 1250 1500 1750 2000 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
    15. 15. 50 100 150 200 250 300 350 15 20 25 30 35 40 45 50 Hematocri t (%) LV mass index (g/m²) Correlation between hematocrit and left ventricular mass index in ESRD patients r=-0.331 p<0.001 London et al Kidney Int 1987
    16. 16. r h r/h<0.45 r h r/h<0.45 r h r/h>0.45 Normalll Eccentric LVH Concentric LVH r-radius h-wall thickness r/h- relative wall thickness Geometric characteristics of left ventricular hypertropy
    17. 17. Echocardiographic measurements <ul><li>Measurement ESRD Controls (n=210) (n=150) </li></ul><ul><li>LV end-diastolic diameter (mm) 54 ± 4 50 ± 3 ** </li></ul><ul><li>Posterior wall thickness (mm) 11 ± 1.8 8.5 ± 1.6 ** </li></ul><ul><li>Interventricular septal thickness (mm) 12.5 ± 2.0 9.6 ± 1.8 ** </li></ul><ul><li>LV mass index (g/m 2 ) 197 ± 48 110 ± 30 ** </li></ul>London et al. Advances in Nephrol 1991; 20: 249-73 ** p < 0.001
    18. 18. 0-4 5-9 10-14 15-19 Incidence of Cardiovascular Disease in Pediatric Dialysis Patients Herzog Ch Kidney Int
    19. 20. Distribution of Left Ventricular Mass Index and Relative wall thickness According the Stage of CKD in Pediatric Patients
    20. 21. Echocardiographic findings in pediatric patients with CKD and healthy controls
    21. 22. LVH regression after use of EPO in ESRD (hemodialysis) Normal 50 100 150 200 250 6 month intervals LVMI (g/m 2 ) <ul><li>Multifactorial origin (partial treatment) </li></ul><ul><li>Partial anemia correction (insufficient treatment) </li></ul><ul><li>Myocardial fibrosis (delayed treatment) </li></ul>Only partial LV regression due to: Macdougall Pascual McMahon Zehnder Martinez Wizemann
    22. 23. 50 100 150 200 250 300 350 400 80 100 120 140 160 180 200 220 240 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
    23. 24. 0.50 0.83 1.15 1.48 1.80 80 100 120 140 160 180 200 220 240 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
    24. 25. 80 140 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
    25. 26. 1-year Mortality predicted by SBP Experience at 782 US dialysis facilities Ref Klassen et al. JAMA 2002;287:1548-1555 n = 37,069
    26. 27. 1-year Mortality predicted by DBP Experience at 782 US dialysis facilities Klassen et al. JAMA 2002;287:1548-1555 Adjusted for level of systolic blood pressure n = 37,069 Hazard Ratio For Death
    27. 28. One Year Mortality for Patients on Hemodialysis Adjusted for level of systolic blood pressure Ref Klassen et al. JAMA 2002;287:1548-1555 n = 37,069
    28. 29. Wave reflections (Augmentation Index %) 20 48 76 104 132 160 500 1000 1500 2000 2500 Aortic stiffness ( pulse wave velocity -cm/s) Pulse Pressure (mm Hg) 20 48 76 104 132 160 20 55 90 125 160 Stroke volume (ml) Pulse Pressure (mm Hg) 20 48 76 104 132 160 -40 -15 10 35 60 Pulse Pressure (mm Hg) R=0.47 p<0.0001 R=0.60 p<0.0001 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
    29. 30. 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 .1 1 10 Arterial Stiffness (kPa 10- 3 ) 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<0.00001
    30. 31. 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
    31. 32. Arterial function and blood pressure Pure Conduit Function Conduit and Cushioning Function Blood pressure Systole Diastole Mean pressure Blood pressure Systole Diastole Mean pressure
    32. 33. 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 ± 12 144 ± 21 88 ± 15 107 ± 17 56 ± 16 ESRD (n = 100) 48 ± 14 151 ± 23* 83 ± 14* 107 ± 17 68 ± 18** London et al Kidney Int 1989
    33. 34. 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 ± 12 60 ± 17 1 521 ± 458 914 ±185 12 ±4 ESRD (n = 100) 48 ± 14 65 ± 24* 1 563 ± 426 1185 ± 245** 24 ±6** London et al Kidney Int 1989 Common carotid artery distensibility (kPa -1 .10 - 3 ) 19.3 ± 7.1 15.8 ± 8.8** Common carotid artery elastic modulus (kPa.10 3 ) + 0.74 ± 0.46*** 0.50 ± 0.22
    34. 35. 200 100 Aortic pulse wave velocity (cm/sec) Left ventricular mass (g/m 2 ) 150 500 1000 1500 2000 r = 0.52 p < 0.001 Correlation between aortic pulse wave velocity and left ventricular mass index in HD patients London et al Adv.Nephrol 1991
    35. 36. Echographic characteristics of common carotid artery <ul><li>Measurement ESRD Controls </li></ul><ul><li>CCA end-diastolic diameter (mm) 54 ± 4 50 ± 3 ** </li></ul><ul><li>CCA Intima media thickness (mm) 11 ± 1.8 8.5 ± 1.6 ** </li></ul><ul><li>CCA relative wall thickness (mm) 12.5 ± 2.0 9.6 ± 1.8 ** </li></ul><ul><li>LV mass index (g/m 2 ) 197 ± 48 110 ± 30 ** </li></ul>London et al. Advances in Nephrol 1991; 20: 249-73 ** p < 0.001
    36. 37. 5.0 7.5 10.0 12.5 15.0 17.5 20.0 10 20 30 40 50 60 70 80 90 Age (years) Aortic Pulse wave velocity (m/s) 0.5 0.6 0.7 0.8 0.9 1.0 1.1 10 20 30 40 50 60 70 80 90 Age (years) Carotid wall thickness (mm) 5.0 7.5 10.0 12.5 15.0 17.5 20.0 0.5 0.6 0.7 0.7 0.8 0.9 1.0 1.0 1.1 Carotid wall thickness (mm ) Aortic pulse wave velocity (cm/s) 0.4 0.6 0.9 1.1 1.3 1.6 1.8 0.5 0.6 0.7 0.7 0.8 0.9 1.0 1.0 1.1 Carotid wall thickness (mm) Left ventricular wall thickness (cm ) r=0.631 P<0.0001 r=0.561 P<0.0001 r=0.564 P<0.0001 r=0.508 P<0.0001
    37. 38. Correlation between Age and Aortic Pulse Wave Velocity in General population ( ) and ESRD patients ( ) 5 10 15 20 25 25 50 75 100 Age (years) Aortic PWV (m/s) r=0.625 p<0.00001 r=0.719 p<0.00001 0 100 200 300 400 500 600 10 20 30 40 50 60 70 80 90 100 Age (years) Characteristic impedance (dynes .s.cm-5) r=0.525 P<0.00001 r=0.340 P<0.01
    38. 39. 0.00 0.25 0.50 0.75 1.00 0.0 50 100 150 200 250 Follow-up (months) CV Survival 0.00 0.25 0.50 0.75 1.00 0.0 50 100 150 200 250 Follow-up (months) CV Survival 0.00 0.25 0.50 0.75 1.00 0.0 50 100 150 200 250 Follow-up (months) CV Survival Aortic PWV Brachial PWV Femoral PWV  ²=72.8 P <0.00001  ²=1.78 P =0.411  ²=2.34 P =0.310 1st tertile 2nd tertile 3rd tertile <9.7m/s >9.7 m/s >12 m/s Pannier et al Hypertension 2005
    39. 40. Correlation Between CCr (C-G formula) and Aortic PWV 5 10 15 20 25 30 0 50 100 150 200 r = –0.30 P <0.0001 CCR (mL/min/m²) Aortic PWV (m/s) Bortolotto et al KI 2001
    40. 42. Covic A et al. NDT 2006;21:729-735 Arterial and cardiac parameters in dialysis children
    41. 43. Mitsnefes MM et al JASN 2005;16:2796-2803. Carotid IMTh and Compliance in Children with CKD
    42. 45. De Lima JJG et al NDT 17;645,2002 Impact of renal transplantation on arterial and heart characteristics
    43. 46. Changes of mean blood pressure and aortic PWV Guérin and al. circulation 2001 ; 103 : 987 - 92 9 10 11 12 13 14 Survivors 110 120 Inclusion At target BP End of follow up MBP (mmHg ) PWV (m/s) 9 10 11 12 13 14 Non Survivors 100 110 120 Inclusion At target BP End of follow up MBP (mmHg ) PWV (m/s) 100
    44. 47. All cause survival according to changes in aortic pulse wave velocity (  PWV) in response to BP decrease <ul><li> 2 = 28.01 </li></ul><ul><li>P<0.00001 </li></ul>Guérin et al. Circulation . 2001. Decreased PWV 0.25 0.50 0.75 1 0 0 35 70 105 140 Unchanged or increased PWV Duration of follow-up (months) Survival rate
    45. 48. Variables associated with aortic pulse wave velocity in ESRD (multiple regression) Independent bcoefficient P value Sequential Partial r 2 variable r 2 (adj. for rest ) Age (years) 6.1 0.00003 0.4115 0.1729 Gender (0-M,1-F) -67.4 0.06700 0.4444 0.0300 Systolic BP (mm Hg) 3.04 0.00000 0.5795 0.1884 Heart rate (b/m) 3.33 0.02136 0.5898 0.0420 CRP (mg/l) 5.15 0.01334 0.6186 0.0615 Duration of HD (months) -1.0 0.00023 0.6308 0.1254 Aortic calcification (0-no ; 1-yes) 193 0.00018 0.6869 0.1520 Adjusted sequential r 2 0.6652 ; F ratio 31.65 ; p< 0.00000
    46. 49. 5.0 7.5 10.0 12.5 15.0 17.5 20.0 0 4 8 12 16 20 24 Abdominal aortic calcification score Aortic PWV (ms) r = 0.754 P < 0.0001 Pannier et al. Artery 2007 Correlation between aortic calcification score and aortic PWV in ESRD patients
    47. 50. Cardiovascular Calcification Is Increased in Dialysis Patients *Determined by EBT. CAD = coronary artery disease. † Rumberger JA et al. Mayo Clin Proc . 1999;74:243-252. Braun J et al. Am J Kidney Dis. 1996;27:394-401 . 0 500 1000 1500 2000 2500 28-39 40-49 50-59 60-69 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 †
    48. 51. Coronary Artery Calcification in Young Dialysis Patients 0.1 1 10 100 1000 10000 0 5 10 15 20 25 30 35 Age (years) Calcification Score* N=39 *Determined by EBT. Goodman WG et al. N Engl J Med . 2000;342:1478-1483. Calcification scores nearly doubled in a majority of patients with positive initial scan when rescanned at 20 months
    49. 52. Calcification score <ul><li>Probality of all-cause survival according to calcification score. Comparison (log-rank test) between curves was highly significant ( Chi  P<0.0001). </li></ul>Calcification score : 0 0.25 0.50 0.75 1 0 0 20 40 60 80 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
    50. 53. Inductors (+) and inhibitors (-) of vascular calcifications PO4 CBfa1 BMP2 ALP Osteocalcin Osteonectin Leptin Collagen I Fibronectin LDLox TNF-  Dexamethasone Klotho-/- PTH 7-84 + + + + + + + + + + + + + + Vit D3 Ca + Oncostatin - Osteoprotegerin MGP Osteopontin BMP7 Collagen IV Fetuin PTHrP PTH 1-34 - - - - - - - - pyrophosphate +
    51. 54. 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,..)
    52. 55. Multiple correlation study for variables associated with abdominal aortic calcification score (n=200) Pannier B et al. Artery research 2007 Variable t - value P-value smoking (packs.year) 8.34 0.00001 age (years) 6.93 0.00001 hCRP (mg/L) 4.51 0.0001 serum phosphates (mMol/L) 3.33 0.001 CaCO 3 (g Ca element/day) 3.18 0.01 iPTH (pg/mL) – 3.74 0.001 Ca 2+ / total Ca (%) – 2.91 0.01 serum albumin (g/L) – 1.96 0.05 R 2 = 0.757
    53. 56. Median Percentage Change in Coronary Scores at 52 Weeks 0 5 10 15 20 25 30 35 Calcium Sevelamer Median Percentage Change 25%* 6% *Within treatment P <0.0001; between treatment groups P =0.02. Patients with a baseline score >30.
    54. 57. Hypercalcemia  10.5 mg/dL (2.63 mmol/L) Percentage of Patients Study Week -2 0 3 6 9 12 16 20 24 28 32 36 40 44 48 52 0 5 10 15 20 25 Sevelamer Calcium
    55. 58. Calcium Balance in CKD 5 Intake 20 mMol 16 mmol 4 mMol ECF Ca 25mMol 270 mMol 266 mMol X U Ca V 4 mMol X Calcium load Dialysate
    56. 59. Possible links between bone turnover and vascular calcification in CKD
    57. 60. 0 4 8 12 16 20 24 0 3 6 9 12 15 18 21 24 27 r = – 0.489 P < 0.01 Double tetracycline-labeled surfaces (%) Aortic calcification score Aortic pulse wave velocity (m/s) 6 8 10 12 14 16 18 0 3 6 9 12 15 18 21 24 27 r = – 0.655 P < 0.0001 London GM et al JASN 2008
    58. 61. Aortic pulse wave velocity (m/s) Log 10 25(OH)D(µg/L) Brachial artery distensibility (kPa10 -1 .10 -3 ) 4 6 8 10 12 14 16 18 20 0.40 0.60 0.80 1.00 (10 µg/L) 1.20 1.40 1.60 r = – 0.535 P < 0.0001 n = 52 0 1 2 3 4 5 6 7 0.40 0.60 0.80 1.00 (10 µg/L) 1.20 1.40 1.60 r = 0.616 P < 0.0001 n = 42 Cross-sectional correlation between serum 25(OH)D and aortic stiffness and brachial artery distensibility London GM et al (JASN 2007)
    59. 62. Tims PM et al. QJ Med 95:787,2002 MMP9 is inversely correlated to serum 25(OH)D3
    60. 63. Copyright ©2005 American Heart Association Yasmin, et al. Arterioscler Thromb Vasc Biol 2005;25:372-378 Relationship between aortic PWV and serum MMP-9 levels
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