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

Distribution (%) of causes of death for all dialysis patients by age (1994–96) 20–44 years Rate: 95 deaths/103 patient years 45–64 years Rate: 173 deaths/103 patient years 21 7 12 6 53 22 11 16 6 45 21 10 19 6 44 Cardiac arrest Acute MI Other cardiac Cerebrovascular Non-cardiac +65 years Rate: 341 deaths/103 patient years USRDS. AJKD, 1998

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

Approximate prevalence of CVD by target population Coronary artery disease(%) Left ventricular hypertrophy (%) General population 5–12 20 Chronic renal failure N/a 25–50 Hemodialysis (HD) 40 75 Peritoneal dialysis (PD) 40 75 Renal transplant recipients 15 50 Foley et al. AJKD, 1998

Baseline prevalence of LVH by degree of renal function % patients * p<0.001; Ccr <25 vs all others 50 * 40 30 20 10 Cr clearance (ml/min) >50 35-49 25-34 <25 Levin et al. AJKD, 1999

Impact of LVH on survival rates 100 80 60 <125 g/m2 40 n=91 >125 g/m2 20 1 2 3 4 5 Time (years) Silberberg et al. J Kidney Int, 1989

Correlation in ESRD patients between the stroke work index and LVMI 410 r = 0.62 p < 0.0001 LVMI (g/m2) 50 20 170 Stroke work index (g.m/m2) London et al. Seminar Dial 1999

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

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

Determinants of LV mass in ESRD patients Dependent variable: LV mass (g) Independent variables t value p RMS error Stroke volume (ml/beat) 7.52 <0.001 21.1 Age (years) 5.18 <0.001 0.3 Body height (cm) 4.52 <0.001 7.8 Mean aortic systolic 4.51 <0.001 7.8 pressure (mmHg) Gender (1 M; 2 F) -2.0 0.045 1.3 r2=0.65; p<0.0001

Hemodynamic factors of LV hypertrophy Volume overload Pressure overload A-V fistula Na+/H20 retention Chronic anemia increased stroke volume increased heart rate Hypertension Arteriosclerosis Aortic stenosis

Correlation between left ventricular mass and interdialytic body weight changes in ESRD patients on hemodialysis 600 500 400 left ventricular mass (g) 300 200 100 R=0.29 p<0.01 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 interdialytic weight changes (kg) London et al advanc.Nephrol 1991

Correlation between arteriovenous shunts flow and left ventricular mass in ESRD patients 500 450 400 350 Left ventricular mass (g) 300 250 200 R=0.537 p<0.015 150 100 250 500 750 1000 1250 1500 1750 2000 Arterio-venous shunt flow (ml) London et al advanc.Nephrol 1991

Correlation between hematocrit and left ventricular mass index in ESRD patients 350 r=-0.331 p<0.001 300 250 200 LV mass index (g/m²) 150 100 50 15 20 25 30 35 40 45 50 Hematocrit (%) London et al Kidney Int 1987

r r r h h h r/h>0.45 r/h<0.45 r/h<0.45 Normalll Eccentric LVH Concentric LVH Geometric characteristics of left ventricular hypertropy r-radius h-wall thickness r/h- relative wall thickness

Echocardiographic measurements Measurement ESRD Controls (n=210) (n=150) LV end-diastolic diameter (mm) 54 ± 4 50 ± 3 ** Posterior wall thickness (mm) 11 ± 1.8 8.5 ± 1.6 ** Interventricular septal thickness (mm) 12.5 ± 2.0 9.6 ± 1.8 ** LV mass index (g/m2) 197 ± 48 110 ± 30 ** ** p < 0.001 London et al. Advances in Nephrol 1991; 20: 249-73

Incidence of Cardiovascular Disease in Pediatric Dialysis Patients Herzog Ch Kidney Int 0-4 5-9 10-14 15-19

According the Stage of CKD in Pediatric Patients 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) Macdougall Pascual McMahon Zehnder Martinez Wizemann LVMI (g/m2) Multifactorial origin (partial treatment) Partial anemia correction (insufficient treatment) Myocardial fibrosis (delayed treatment) Only partial LV regression due to: 250 200 150 Normal 100 50 6 month intervals

Correlation between left ventricular mass index and systolic BP in ESRD patients on hemodialysis 400 350 R=0.385 p<0.001 300 250 Left ventricular mass index (g/m²) 200 150 100 50 80 100 120 140 160 180 200 220 240 Systolic BP (mm Hg)

Correlation between systolic BP and interventricular septal thickness in ESRD patients on hemodialysis 1.80 1.48 interventricular septal thickness (cm) 1.15 0.83 R=0.522 p<0.001 0.50 80 100 120 140 160 180 200 220 240 Systolic BP (mm Hg)

140 80 time Systolic pressure mm Hg Mean BP Diastolic pressure Pulse pressure Mean BP 80 Diastolic pressure time Mean BP: Cardiac output peripheral resistance Pulse pressure: ventricular ejection arterial stiffness wave reflection

1-year Mortality predicted by SBP Experience at 782 US dialysis facilities Ref Klassen et al. JAMA 2002;287:1548-1555

1-year Mortality predicted by DBP Experience at 782 US dialysis facilities Adjusted for level of systolic blood pressure n = 37,069 Hazard Ratio For Death Klassen et al. JAMA 2002;287:1548-1555

One Year Mortality for Patients on Hemodialysis Adjusted for level of systolic blood pressure n = 37,069 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 Ref Klassen et al. JAMA 2002;287:1548-1555

Correlation between arterial pulse pressure, wave reflexion (Augmentation index) aortic pulse wave velocity (stiffness) and stroke volume in ESRD patients (n=230) 160 160 R=0.47 p<0.0001 R=0.60 p<0.0001 132 132 104 104 Pulse Pressure (mm Hg) Pulse Pressure (mm Hg) 76 76 48 48 20 20 -40 -15 10 35 60 500 1000 1500 2000 2500 Wave reflections (Augmentation Index %) Aortic stiffness ( pulse wave velocity -cm/s) 160 R=0.16 p=0.025 132 104 Pulse Pressure (mm Hg) 76 48 20 Adapted from London et al KI 1996 20 55 90 125 160 Stroke volume (ml)

Arterial Stiffness (kPa 10-3) Relationship between arterial stiffness (Einc - incremental modulus) and Aortic Pulse Wave Velocity (PWV) 25.0 R=0.745 p<0.00001 22.5 20.0 17.5 Aortic PWV (m/s) 15.0 12.5 10.0 7.5 5.0 .1 1 10 Arterial Stiffness (kPa 10-3) London et al adapted from Kidney Int 1996

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

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

Blood pressure in end-stage renal disease 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** Age (yrs) Systolic BP (mm Hg) Diastolic BP (mm Hg) Mean BP (mm Hg) Pulse pressure(mmHg) London et al Kidney Int 1989

Determinants of LV afterload in ESRD 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** Age (yrs) Stroke volume (ml) Peripheral résistances (dynes sec cm -5) Aortic PWV (cm/s) Augmentation Index (%) Common carotid artery elastic modulus (kPa.103)+ 0.50 ± 0.22 0.74 ± 0.46*** Common carotid artery distensibility (kPa-1.10-3) 19.3 ± 7.1 15.8 ± 8.8** London et al Kidney Int 1989

Correlation between aortic pulse wave velocity and left ventricular mass index in HD patients 200 Left ventricular mass (g/m2) 150 r = 0.52 p < 0.001 100 500 1000 1500 2000 Aortic pulse wave velocity (cm/sec) London et al Adv.Nephrol 1991

Echographic characteristics of common carotid artery Measurement ESRD Controls CCA end-diastolic diameter (mm) 54 ± 4 50 ± 3 ** CCA Intima media thickness (mm) 11 ± 1.8 8.5 ± 1.6 ** CCA relative wall thickness (mm) 12.5 ± 2.0 9.6 ± 1.8 ** LV mass index (g/m2) 197 ± 48 110 ± 30 ** ** p < 0.001 London et al. Advances in Nephrol 1991; 20: 249-73

Aortic Pulse wave velocity (m/s) Carotid wall thickness (mm) 1.1 20.0 r=0.561 P<0.0001 r=0.631 P<0.0001 1.0 17.5 0.9 15.0 Aortic Pulse wave velocity (m/s) Carotid wall thickness (mm) 12.5 0.8 10.0 0.7 7.5 0.6 5.0 0.5 10 20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 80 90 Age (years) Age (years) 1.8 20.0 r=0.508 P<0.0001 r=0.564 P<0.0001 1.6 17.5 1.3 15.0 Aortic pulse wave velocity (cm/s) 12.5 1.1 Left ventricular wall thickness (cm) 10.0 0.9 7.5 0.6 5.0 0.4 0.5 0.6 0.7 0.7 0.8 0.9 1.0 1.0 1.1 0.5 0.6 0.7 0.7 0.8 0.9 1.0 1.0 1.1 Carotid wall thickness (mm) Carotid wall thickness (mm)

Correlation between Age and Aortic Pulse Wave Velocity in General population ( ) and ESRD patients ( ) 25 600 500 r=0.525 P<0.00001 20 400 r=0.625 p<0.00001 Characteristic impedance (dynes.s.cm-5) 15 300 Aortic PWV (m/s) 200 r=0.340 P<0.01 10 100 r=0.719 p<0.00001 5 25 50 75 100 10 20 30 40 50 60 70 80 90 100 Age (years) Age (years)

Aortic PWV Brachial PWV CV Survival CV Survival ²=72.8 P<0.00001 1.00 1.00 <9.7m/s 0.75 0.75 CV Survival 0.50 >9.7 m/s CV Survival 0.50 0.25 ²=72.8 P<0.00001 0.25 ²=1.78 P=0.411 >12 m/s 0.00 0.00 0.0 50 100 150 200 250 0.0 50 100 150 200 250 Follow-up (months) Follow-up (months) Femoral PWV 1.00 0.75 CV Survival 0.50 1st tertile 0.25 ²=2.34 P=0.310 2nd tertile 3rd tertile 0.00 0.0 50 100 150 200 250 Follow-up (months) Pannier et al Hypertension 2005

Correlation Between CCr (C-G formula) and Aortic PWV 30 r = –0.30 P <0.0001 25 20 Aortic PWV (m/s) 15 10 5 50 100 150 200 CCR (mL/min/m²) Bortolotto et al KI 2001

Arterial and cardiac parameters in dialysis children Covic A et al. NDT 2006;21:729-735

Carotid IMTh and Compliance in Children with CKD Mitsnefes MM et al JASN 2005;16:2796-2803.

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

Changes of mean blood pressure and aortic PWV MBP (mmHg) PWV (m/s) MBP (mmHg) PWV (m/s) 120 14 120 14 13 13 12 12 110 110 11 11 10 10 100 9 100 9 Inclusion At target BP End of follow up Inclusion At target BP End of follow up Survivors Non Survivors Guérin and al. circulation 2001 ; 103 : 987 - 92

Duration of follow-up (months) All cause survival according to changes in aortic pulse wave velocity ( PWV) in response to BP decrease 1 0.75 Decreased PWV Survival rate 0.50 0.25 Unchanged or increased PWV 2 = 28.01 P<0.00001 35 70 105 140 Duration of follow-up (months) Guérin et al. Circulation. 2001.

Variables associated with aortic pulse wave velocity in ESRD (multiple regression) Independent bcoefficient P value Sequential Partial r2 variable r2 (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 r2 0.6652 ; F ratio 31.65 ; p< 0.00000

Correlation between aortic calcification score and aortic PWV in ESRD patients 20.0 17.5 15.0 Aortic PWV (ms) 12.5 10.0 7.5 r = 0.754 P < 0.0001 5.0 4 8 12 16 20 24 Abdominal aortic calcification score Pannier et al. Artery 2007

Cardiovascular Calcification Is Increased in Dialysis Patients 2500 Non-dialysis, No CAD (n=22) Non-dialysis, CAD (n=80) 2000 Dialysis (n=49) 1500 Mean Coronary Artery Calcium Score* 1000 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 >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. 500 Very high CV risk† 28-39 40-49 50-59 60-69 Age (years) *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.

Coronary Artery Calcification in Young Dialysis Patients 10000 1000 100 Calcification Score* 10 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. 1 0.1 5 10 15 20 25 30 35 Age (years) N=39 Calcification scores nearly doubled in a majority of patients with positive initial scan when rescanned at 20 months *Determined by EBT. Goodman WG et al. N Engl J Med. 2000;342:1478-1483.

Blacher et al Hypertension 2001 Calcification score Probality of all-cause survival according to calcification score. Comparison (log-rank test) between curves was highly significant ( Chi D =42.66 ; P<0.0001). 1 Calcification score : 0 0.75 Calcification score : 1 Calcification score : 2 Probality of survival 0.50 Calcification score : 3 0.25 Calcification score : 4 20 40 60 80 Duration of follow-up (months) Blacher et al Hypertension 2001

Inductors (+) and inhibitors (-) of vascular calcifications CBfa1 BMP2 Osteonectin PO4 + + Leptin Dexamethasone Osteocalcin + + + + + ALP + + PTH 7-84 + Collagen I Fibronectin + TNF- + + Oncostatin LDLox + + + Vit D3 Ca Klotho-/- - - - pyrophosphate - Fetuin - - - Osteopontin MGP - BMP7 Osteoprotegerin Collagen IV - PTHrP PTH 1-34

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

CaCO3 (g Ca element/day) iPTH (pg/mL) Ca2+/totalCa(%) Multiple correlation study for variables associated with abdominal aortic calcification score (n=200) Variable t - value P-value smoking (packs.year) 8.34 0.00001 age (years) 6.93 hCRP (mg/L) 4.51 0.0001 serum phosphates (mMol/L) 3.33 0.001 CaCO3 (g Ca element/day) 3.18 0.01 iPTH (pg/mL) –3.74 Ca2+/totalCa(%) –2.91 serum albumin (g/L) –1.96 0.05 R2 = 0.757 Pannier B et al. Artery research 2007

Median Percentage Change in Coronary Scores at 52 Weeks 35 30 25%* 25 20 Median Percentage Change 15 10 6% 5 Calcium Sevelamer *Within treatment P<0.0001; between treatment groups P=0.02. Patients with a baseline score >30.

Hypercalcemia 10.5 mg/dL (2.63 mmol/L) 25 Sevelamer Calcium 20 15 Percentage of Patients 10 5 -2 3 6 9 12 16 20 24 28 32 36 40 44 48 52 Study Week

X X Calcium Balance in CKD 5 ECFCa 25mMol Calcium load Dialysate Intake 20 mMol Calcium load Dialysate ECFCa 25mMol 266 mMol 4 mMol X 270 mMol X 16 mmol UCaV 4 mMol

Possible links between bone turnover and vascular calcification in CKD 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.

Aortic pulse wave velocity (m/s) 24 18 r = – 0.489 P < 0.01 r = – 0.655 P < 0.0001 20 16 16 14 Aortic pulse wave velocity (m/s) Aortic calcification score 12 12 8 10 4 8 6 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27 Double tetracycline-labeled surfaces (%) London GM et al JASN 2008

distensibility (kPa10-1.10-3) Cross-sectional correlation between serum 25(OH)D and aortic stiffness and brachial artery distensibility r = – 0.535 P < 0.0001 n = 52 r = 0.616 P < 0.0001 n = 42 20 7 18 6 16 5 14 distensibility (kPa10-1.10-3) Brachial artery Aortic pulse wave velocity (m/s) 4 12 3 10 2 8 6 1 4 0.40 0.60 0.80 1.00 (10 µg/L) 1.20 1.40 1.60 0.40 0.60 0.80 1.00 (10 µg/L) 1.20 1.40 1.60 Log10 25(OH)D(µg/L) London GM et al (JASN 2007)

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

Relationship between aortic PWV and serum MMP-9 levels Yasmin, et al. Arterioscler Thromb Vasc Biol 2005;25:372-378 Copyright ©2005 American Heart Association