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Cardiovascular disease and vascular calcification in CKD Professor Philip A Kalra Consultant and Honorary Professor of Nephrology Salford Royal Hospital.

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Presentation on theme: "Cardiovascular disease and vascular calcification in CKD Professor Philip A Kalra Consultant and Honorary Professor of Nephrology Salford Royal Hospital."— Presentation transcript:

1 Cardiovascular disease and vascular calcification in CKD Professor Philip A Kalra Consultant and Honorary Professor of Nephrology Salford Royal Hospital and University of Manchester, UK

2 Key topics Epidemiology of CVS risk – In dialysis patients – Non-dialysis CKD – SCD Non-traditional CVS risk factors – Cardiac structural changes – CKD-MBD : importance of phosphate

3 Rates of death and cardiovascular events rise as renal function declines Age-standardised rate per 100 person years Death from any cause Cardiovascular events Go et al et al. NEJM : 351(13): Estimated GFR (ml/min/1.73 m 2 )

4 Chronic Renal Insufficiency Standards Implementation Study (CRISIS) Mean age 65 yrs eGFR 31 ml/min Diabetes 32% CVS disease (baseline) 47% 1325 patients with mean FU of 34 months

5 CRISIS : survival

6 Cause of death (ONS) %

7 Adapted from Levey AS et al. Am J Kidney Dis 1998; 32: Cardiovascular Mortality Rates are Higher among Dialysis Patients General population: male General population: female Dialysis: male Dialysis: female

8 Placebo Atorvastatin Relative Risk Reduction 8 % (95 % CI: -23%, +10%, P=0.37) N=1255 HD pts with type 2 diabetes Cardiac death, non-fatal MI or stroke Mean follow-up 4 years Cumulative incidence (%) years Placebo Atorvastatin 20 mg Years from Randomization Wanner et al NEJM 2005;353: D Study: Primary composite endpoint

9 Cardiovascular Disease in CKD : Multifactorial Pathogenesis Cardiovascular Disease Chronic inflammation Exogenous vitamin D / deficit Oxidative stress Duration of dialysis Elevated PTH/ 2°HPT Hypertension Dyslipidemia Diabetes Mellitus Genetics Increased homocysteine levels Elevated Ca × P product Exogenous Ca intake Hyperphos- phatemia Smoking Traditional risk factors Non Traditional risk factors

10 Definition of Sudden Cardiac Death (SCD) Sudden cardiac death is the unexpected natural death from a cardiac cause within one hour of the onset of symptoms in a person not known to have a condition that is potentially fatal

11 Epidemiology of SCD : general population 1 in every 1000 deaths thought to be due to SCD SCD is usually the 1 st cardiac event that a patient will suffer 80% have abnormal coronary arteries Risk is > in immediate post-MI period Poor LV function (particularly due to ischemic cardiomyopathy) and a documented history of significant ventricular arrhythmia, are the strongest predictors of SCD

12 Mechanism of SCD : general population Myocardial infarction and poor left ventricular function both lead to risk of re-entrant ventricular tachycardia (VT) : – MI : by post-infarction scarring – LV failure : by abnormal fibrotic myocardial remodelling These areas of abnormal tissue may still contain functioning myocytes, but the surrounding scar tissue is thought to cause bundle branch block, and predispose to subsequent re-entrant tachycardia

13 Epidemiology of SCD : CKD populations CKD stages 3-5 (not dialysis) SCD risk by HR of 1.1 for every 10ml/min decline in eGFR Event rate 0.8% per yr in non-dialysis CKD In non-diabetic dialysis patients, rate is 7% in 1 st yr of RRT SCD risk is > for HD than PD patients during 1 st 6 months of dialysis, but equalises thereafter General CKD Dialysis

14 Karnik JA et al (Kidney International 2001:60: ) : Characteristics associated with arrest on haemodialysis – Monday or Tuesday (greatest risk last 12 hrs before dialysis) – Low potassium dialysate – Older age – Diabetic – Catheter for access

15 CVS risk factors in CKD Cardiac structural changes – LVH and CCF CAD Vascular calcification/arterial stiffness Phosphate Vitamin D deficiency Anaemia Metabolic changes Inflammation

16 p <0.003 (trend analysis) Prevalence of Left Ventricular Hypertrophy in Relation to Creatinine Clearance Patients with diabetes = 24% Adapted from Levin A et al. Am J Kidney Dis 1999; 34: n = 246

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19 Intra-dialytic myocardial ischaemia C McIntyre and colleagues (Derby, UK) : Haemodialysis induces reversible intra-dialytic myocardial stunning stunning associated with greater propensity to arrhythmia stunning associated with worse mortality Some relationship between endotoxaemia and myocardial ischaemia

20 Calcification of the coronary arteries Khogali and Townend NEJM 2002;347:1584 Pre-contrast Post-contrast

21 Arterial Medial Calcification in ESRD London GM, et al. Nephrol Dial Transplant. 2003;18:

22 Patients New to Dialysis and Established Patients Prevalence of Vascular Calcification in CKD *Russo et al AJKD 2004 (CrCl =33 ml/min) **Spiegel D et al. Hemod Internat 2004: 8:265 ***Chertow et al KI 2002 *Russo et al AJKD 2004 (CrCl =33 ml/min) **Spiegel D et al. Hemod Internat 2004: 8:265 ***Chertow et al KI 2002 * ** *** Stage 3-4 CKD

23 Probability of All-Cause Survival According to Calcification Status *Comparison Between Curves Was Highly Significant (x2=42.66, P<0.0001) Source: Blacher A, et al. Hypertension: , October 2001 Probability of Survival Duration of Follow-Up (Months) Calcification Score: 0 Calcification Score: 1 Calcification Score: 2 Calcification Score: 3 Calcification Score: 4

24 Augmentation index : Applanation Tonometry Aortic Augmentation Index (%) = P x 100 (AIx) PP

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26 Importance of phosphate

27 Serum Phosphorus and Mortality in Hemodialysis Patients <3 < >9 Serum Phosphorous Concentration (mg/dL) Relative Risk of Death* n = 40,538 P < *Multivariable Adjusted *Multivariable Adjusted Block G, J Am Soc Neph 15: , 2004

28 CRISIS study : analysis of serum phosphate (Eddington H et al, CJASN 2010) 1213 patients Baseline demographics – Phosphate divided into quartiles Cox regression Baseline phosphate and survival Time-averaged phosphate and survival

29 Baseline demographics N=1213All PO 4 <1.01 N=318 PO – 1.16 N=300 PO N=293 PO N=302 P value Age64.2 (13.9)64 (14)65 (14) 62 (14)0.037 Female sex 429 (35.4%)76 (24%)109 (36%)124 (42%)120 (40%)< Calcium2.29 (0.14)2.29 (0.13)2.29 (0.19)2.30 (0.13)2.28 (0.19)ns PTH89 (86)58 (42)77 62)86 (77)135 (124)< Hb124 (18)135 (18)125 (16)123 (14)114 (17)< eGFR31.6 (15)40 (14)34 (13)31 (14)20 (11)< Proteinuria1.1 (1.8)0.5 (0.7)0.8 (1.2)0.9 (1.2)2.1 (2.7)< CVD380 (31%)99 (31%)109 (36%)99 (34%)73 (24%)0.009 DM385(32%)84 (27%)89 (29%)90 (29%)122 (40%)0.002

30 Phosphate <1.01 Phosphate Phosphate Phosphate >1.33 Baseline phosphate and survival Adjusted for eGFR, Age, Gender, Hb, Diabetes, CVD, proteinuria, PTH Mean follow-up 4.3 years Hazard ratio 1.8 P = 0.04 n=946 n=810 n=624 n=375 n=136

31 12mth time-average PO 4 survival Phosphate <1.01 Phosphate Phosphate Phosphate >1.34 Hazard ratio 2.12 P = 0.01 Phosphate <1.01 Phosphate Phosphate Phosphate >1.34 Hazard ratio 2.59 P = Adjusted for eGFR, Age, Gender, Hb, Diabetes, CVD, proteinuria, PTH Mean follow-up 3.6 years n=810 n=622 n=375 n=136

32 Survival according to previous KDOQI phosphate guidelines Below Target In Target Above Target Hazard ratio: In target 1.9 ( ) P = 0.08 Above target 2.6 ( ) P = 0.03

33 Phosphate : general population

34 CARDIA (Coronary artery risk development in young adults) Prospective multi-centre observational study of CVS disease development in fit young adults (age yrs) in 4 US regions (Birmingham, Alabama; Chicago, Illinois; Minneapolis,Minnesota; Oakland, California) 5113 participants

35 CARDIA (Coronary artery risk development in young adults) Various baseline variables assessed LVMI assessed by echocardiography 5 years after entry Coronary artery calcification assessed by CT scan 15 years later

36 Left ventricular hypertrophy (LVH) : Foley RN et al Kid Blood Press Res 2009; 32(1): of 5113 participants underwent echocardiography Baseline data Mean age 25 years Mean phosphate 3.7 mg/dl eGFR ml/min/1.73m 2 Results Each SD of baseline phosphate above the mean was associated with presence of LVH 5 years later (AOR 1.301, p=0.0018)

37 Coronary artery calcification (CAC) : Foley RN et al J Am Soc Neph 2009; 20(2): of 5113 participants underwent CT at 15 years Baseline data Mean age 25.2 years mean phosphate 3.6 mg/dl, calcium 9.5 mg/dl Mean eGFR ml/min/1.73m 2 0.2% with eGFR < 60 ml/min/1.73m 2

38 Coronary artery calcification (CAC) : Foley RN et al J Am Soc Neph 2009; 20(2): Year 15 CAC scores Minimal % Mild % Moderate % Severe>3000.5%

39 P-Spline plot relating adjusted odds ratio of CAC 100 and serum phosphorus AOR, with 95% confidence intervals. Adjusted for all variables except calcium-phosphorus product and diastolic blood pressure except calcium-phosphorus product and diastolic blood pressure

40 Studies of phosphate in general population : conclusions Phosphate levels even at the upper end of normal range appear to be a risk factor for : Coronary artery calcification (surrogate of coronary atherosclerosis) Left ventricular hypertrophy ? Pathogenetic effect or association

41 FGF-23/Klotho: New players in CKD-MBD Adapted from: Emmett M, et al. Kidney International 2008;73:3–5 Kuro-o. Keynote lecture from ERA-EDTA 2008, ASN 2008 Pi 1,25D Small bowel Reduces Ca and Pi absorption in small bowel 1,25D 1α(OH)D 3 Inhibits 1α-hydroxylase FGF-23 Parathyroid Possibly stimulates Phosphaturia + Klotho Stimulates Skeleton Possibly inhibits mineralization FGF23 inhibits PTH mRNA transcription and protein secretion Kidney

42 Haemodialysis patients within the highest range of FGF-23 levels had nearly 6x greater risk of death Gutierrez OM et al; N Engl J Med 2008 :359;

43 Temporal aspects of mineral disorders in progressive CKD and post transplantation Wolf JASN 2010

44 How might FGF-23 be associated with CVS risk? FGF-23 associated with vitamin D, CKD progression and mortality in CKD FGF-23 associated with LVH (Gutierrez OM et al, Circulation 2009; 119 : ) FGF-23 associated with ADMA (asymmetric di-methyl arginine; an inhibitor of NO synthase) FGF-23 associated with flow-mediated dilatation (FMD) in CKD patients (Yilmaz MI et al, Kidney Int, 2010; 78 : )

45 Vitamin D levels very low in dialysis patients London GM et al JASN 2007: 18; (latitude 48 o ) 52 Vitamin D naïve haemodialysis patients (>90% deficient) Mean PTH 345pg/ml ± 37 (245) Mean 25(OH)D 14.2 ± 1 (13.5)

46 Vitamin D levels assoc with arterial function London GM et al JASN 2007: 18; (latitude 48 o )

47 Studies of intervention for vascular calcification

48 Sevelamer Calcium * * Treat-to-Goal Study : Prevalent haemodialysis patients *Within treatment P<0.0001; between treatment groups P=0.02 Chertow et al. Kidney Int Median percentage change

49 Percentage change from baseline in CAC score at week 52 Absolute change in CAC score at week 52 Absolute and percentage change from baseline in – Aortic calcification at week 52 – Aortic valve calcification at week 52 – Laboratory parameters at end of study (weeks 44 through 52) Proportion of patients achieving > 15% progression of CAC at week 52 Safety Secondary Endpoints Percentage change from baseline in CAC score at week 52 Primary Endpoint Secondary Endpoints ADVANCE :Study Endpoints Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

50 737 patients were screened and 360 were randomized, 180 to each group. –Mean (SD) age was 61.5 (12.7) years, 58% were male and 24% were black –Median (P10, P90) time on hemodialysis was 36.7 (9.5, 107.0) months. The efficacy analysis included 235 subjects: –115 assigned to cinacalcet plus low dose vitamin D –120 assigned to flexible doses of vitamin D sterols Patient characteristics Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

51 Primary Analysis Median % Change (P10, P90) in CAC Cinacalcet (n=115) Control group (n=119) p-value 24 (-22, 119)31 (-9, 179)0.073 Primary analysis based on a generalised Cochran-Mantel-Haenszel test on ranks Percent Change in Total Coronary Artery Calcification Score (CAC) – Agatston Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

52 Supportive analysis (as planned in the protocol) using a generalised linear model to adjust for the baseline imbalance in phosphorous levels between treatment groups. Analysis adjusted for baseline phosphorus Geometric Mean % Change (95% CI) in CAC Cinacalcet (n=115) Control group (n=119) p-value 26 (16, 36)42 (31, 54)0.031 Percent Change in Total Coronary Artery Calcification Score (CAC) - Agatston Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

53 Does reducing vascular calcification translate into survival benefit?

54 DCOR study: Primary Endpoint Time in Study (Years) Cumulative Incidence of All-Cause Mortality Sevelamer Calcium RR 0.91 ( ), p = 0.30 n=2103 Suki et al, Kidney Int 2007;72:

55 Time on Study (Years) Cumulative Incidence of All-Cause Mortality No. at Risk Calcium Sevelamer Sevelamer Calcium Sevelamer therapy resulted in a statistically significant reduction in the relative risk for all-cause mortality in pre-specified subset [RR 0.78 ( )] Sevelamer therapy resulted in a statistically significant reduction in the relative risk for all-cause mortality in pre-specified subset [RR 0.78 ( )] 22% 22% p = 0.03 DCOR : All-Cause Mortality in Patients 65 years

56 Final KDIGO Grading of Recommendations Grading Options: 1A, 1B, 1C, 1D, 2A, 2B, 2D, 2D, & not graded

57 KDOQI Mineral and PTH targets Stage 3Stage 4Stage 5 Calcium Normal range mmol/l Phosphate mmol/l mmol/l mmol/l Ca x P <3.6 mmol/l <3.6 mmo/l/ < 4.3 mmol/l PTH pmol/l pmol/l pmol/l National Kidney Foundation. Am J Kidney Dis 2003;42:S1-S202

58 Diagnosis of CKD-MBD: Vascular Calcification In patients with CKD Stages 3-5D, we suggest a lateral abdominal radiograph can be used to detect the presence or absence of vascular calcification, and an echocardiogram can be used to detect the presence or absence of valvular calcification, as reasonable alternatives to computed tomography (CT)-based imaging (2C) We suggest that patients with CKD Stages 3-5D with known vascular/valvular calcification be considered at highest cardiovascular risk (2A). It is reasonable to use this information to guide management of CKD-MBD (not graded).

59 Summary Patients with CKD are at high CVS risk and CKD- MBD is a major contributor Observational data show the importance of several factors (low vitamin D, Phosphate, ? Calcium dose, PTH) Early phosphate rise seems to be important in earlier CKD and even in the general population (relevance of FGF-23?) Interventional studies suggest that calcification can be slowed Further interventional studies (eg EVOLVE) are necessary to guide optimal treatment in CKD- MBD


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