CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE

CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE BY CHRISTINA AMIRA MB.BS, M.Sc, FWACP, FISN NEPHROLOGY UNIT LUTH OUTLINE • • • • • • Introduction Epidemiology of CVD in CKD Spectrum of CVD in CKD Why is CKD a risk factor for CVD Therapeutic options Conclusion INTRODUCTION • The initial enthusiasm for dialysis as a survival measure for patients with chronic renal failure (CRF) was tempered in 1974 when Linder and colleagues noted the extraordinarily high frequency of coronary heart disease and cardiac death in the first patients who underwent dialysis in Seattle at that time • This observation lead to the hypothesis of accelerated atherosclerosis in CRF which has remained to date. INTRODUCTION • CKD is a world wide public health problem • Incidence and prevalence is rising worldwide with poor outcomes and high cost • NKF KDOQI new classification describes 5 stages of kidney disease and the complications associated with CKD particularly CV risk factors EPIDEMIOLOGY OF CVD • Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with chronic kidney disease & accounts for 40-50% of deaths in dialysis pts • CVD is defined as presence of CHF,CHD,CVD,PVD • 40-75% of pts starting dialysis already have CVD • CVD mortality in dialysis pts is 10-20 times higher than in general population • High CVD mortality is due to high prevalence of CVD and high case fatality Approximate Prevalence % of CVD POPULATION CAD LVH CHF General CRF HD 5-12 NA 42 20 25-50 75 5 NA 40 PD Tx recipient 40 15 75 50 40 NA CARDIOVASCULAR MORTALITY IN THE GENERAL POPULATION (NCHS) AND IN KIDNEY FAILURE PATIENTS TREATED BY DIALYSIS OR TRANSPLANT (USRDS) SURVIVAL RATE IN ESRD AND GENERAL POPULATION EPIDEMIOLOGY • Mortality after MI in 34, 189 long term dialysis pts (1977 – 1995) was 73% and 90% at 2yrs & 5yrs respectively Cf 25% at 2yrs in Diabetic men and 34% in diabetic women in the Worcester Heart Attack study • Pts with earlier stages of CKD also die from CVD. • Recently CKD is now considered to be a risk factor for CVD • The NKF task force on CVD in CRD issued report that CKD pts are in the highest risk for CVD SPECTRUM OF CVD IN CKD • Alteration in cardiac geometry (Cardiomyopathy) LVH - Eccentric and Concentric • Atherosclerosis is an intimal disease characterized by the presence of plaques and occlusive lesions Ischemia is due to large coronary artery disease and may also result from small vessel disease or assoc with severe LVH and fluid overload Arteriosclerosis Remodeling of large arteries with calcification Reduction in arterial wall compliance • CARDIOMYOPATHY- LVH • Concentric LVH is associated with pressure overload e.g. HTN, arteriosclerosis. Causes diastolic dysfunction. • Eccentric LVH is associated with anaemia, volume overload. It leads to systolic dysfunction • Prevalence of LVH increases with declining renal function PREVALENCE OF CARDIAC DISEASE IN DIALYSIS PATIENTS CLINICAL PRESENTATION OF ATHEROSCLEROSIS IN CKD • Ischaemic heart disease which could present as angina, myocardial infarction and sudden death • Cerebrovascular disease • Peripheral vascular disease • Heart failure INVESTIGATIONS OF ATHEROSCLEROSIS • Carotid intima-media thickness measured by B-mode ultrasonography • Coronary stress tests • Stress echocardiography • Radionuclear stress tests • Coronary angiographic ARTERIOSCLEROSIS • Disease of large vessels such as the carotids and aorta • Diffuse media involvement resulting in increased arterial stiffness and decreased distensibility or compliance • Increased stiffness results in increased pulse pressure, causing increased LV afterload and concentric LVH ARTERIOSCLEROSIS • Arteriosclerosis predisposes to IHD by decreasing sub-endocardial coronary perfusion • High SBP, wide pulse pressure, LVH are independent risk factors for CV morbidity & mortality in ESRD • Arterial stiffness is measured by aortic pulse wave velocity WHY IS CKD A RISK FACTOR FOR CVD • • • • • Increased Prevalence of CVD risk factors Shared risk factors for dev of CVD and CKD HTN, DM CKD causes CVD risk factors levels to rise Reverse causation; CVD causing CKD e.g. renal arterial disease, Heart failure CKD is an independent risk factor for CVD Proteinuria and decreased GFR INCREASED PREVALENCE OF CV RISK FACTORS • Traditional risk factors as defined in the General population in the Framingham Study. These are highly prevalent in CKD • Non-traditional risk factors a. Prevalence as kidney function declines i.- Same found to be risk factors for general population Homocysteine, LP(a), Lip remnants b.Unique to CKD i. - Anaemia ii - Increased PTH iii - Increased Ca and Phosphate INCREASED PREVALENCE OF CV RISK FACTORS MDRD STUDY A cross sectional study with 1795 Patients with CRI • Looked at traditional risk factors. They computed the Coronary Point Score (CPS) which predicts the probability of developing CAD over 5-10yrs in individuals free from CVD • The results showed that the coronary point score in patients with CKD was no different from those in the general population thus suggesting that the traditional risk factors could not sufficiently account for the burden of CVD in CKD. CVD RISK FACTORS • • • • • • • • • • • TRADITIONAL Older age > 55yrs for men & 65yrs for women Male sex HTN Higher LDL cholesterol Lower HDL cholesterol DM Smoking Physical inactivity Menopause F History of CVD LVH • • • • • • • • • • • • NONTRADITIONAL Albuminuria Homocysteine LP(a) and apo (a) isoforms Lp remnants Anaemia Abnormal Ca/PO4 metabolism ECF overload Oxidative stress Inflammation (CRP) Malnutrition Thrombogenic factors Endothelial dysfunction INCREASED PREVALENCE OF CV RISK FACTORS • Traditional risk factors  HTN, DM , Smoking, Dyslipidemia HTN ≈ 90% in dialysis pts Cholesterol not as high as in general population In our centre mean total cholesterol was3.56 HDL 1.24 LDL 1.85 TG 1.05 DM : most common cause of ESRD in US TRADITIONAL RISK FACTORS CARDIOVASCULAR RISK FACTORS UNIQUE TO CKD ANAEMIA • Anaemia is associated with CVD in kidney disease • Increases CO • Limited myocardial O2 supply • Decreases PR • Volume overload • LV dysfunction • CHF CARDIORENAL ANAEMIA SYNDROME CKD A vicious cycle CHF Anaemia Each of the entities of CKD, CHF, and anaemia precipitates the others ANAEMIA • Hastens progression to ESRD • Increases CV risks • Increases the risks for retinopathy and blindness • Increases the risk of death • Increases the risk of developing renal failure • Decreases quality of life ANAEMIA • The bulk of the evidence supports the treatment of anaemia in patients with kidney disease. • Nevertheless, research has demonstrated that anaemia is not adequately treated in CKD patients who are starting dialysis CALCIUM/PHOSPHATE • Elevated Ca/ PO4 product has been associated with ↑ mortality • ↑ vessel calcification • PTH is a growth factor for SM cells sclerosis of major arteries LV dysfunction • Endothelial Dysfunction in CKD caused by increased levels of ADMA, NOS inhibitor • Increased oxidative stress- injure epithelium, • Accumulation of oxLDL REVERSE CAUSATION • Levin et al in Canada • Multicentre observational study involving 313pts • Mean GFR 36ml/min • 46% had CVD to start • Looked at probability of reaching RRT • Pts with CVD ended up on dialysis more frequently RR 1.58 DEFINITIONS OF PROTEINURIA Urine Normal collection method Total Protein 24 hr excretion Dipstick PCR <300mg/d Microalbuminuria Albuminuria or clinical proteinuria NA < 30mg/dl NA < 200mg/g NA ≥ 300mg/dl ≥ 30mg/dl ≥ 200mg/g Albumin 24 hr excretion < 30mg/d 30-300mg/d ACR (men) <17mg/g 17-250mg/g (women) <25mg/g 25-355mg/g > 300mg/d > 250mg/g > 355mg/g CKD IS AN INDEPENDENT RISK FACTOR FOR CVD - MICROALBUMINURIA • Microalbuminuria is assoc. with a  prevalence of traditional CVD risk factors in both DM & non DM BP, dyslipidaemia, obesity, insulin resistance • Microalbuminuria is assoc. with surrogates of CVD like  CIMT in HTN pts, LVH & ECG abnormalities in crosssectional analysis. • Microalbuminuria is assoc with a higher prevalence of clinical CVD • Microalbuminuria was independently assoc. with increased risk for CVD in longitudinal studies. CKD IS AN INDEPENDENT RISK FACTOR FOR CVD • In the HOPE Study, microalbuminuria • Was assoc with 1.97-fold ↑in CVD outcomes and 2.15-fold ↑in CVD death in diabetics • Microalbuminuria in non diabetics was assoc. with a 61% increased risk of Stroke, MI and CVD deaths and 2 fold increased risk for all cause mortality • Framingham study, there was significant independent assoc btw proteinuria and CVD death in women but not in men CKD IS AN INDEPENDENT RISK FACTOR FOR CVD • Prevention of Renal and Vascular End Stage Disease (PREVEND) Study • Community study in Netherlands • Doubling of urine albumin concentration was assoc. with a 29% increase in RR for CVD mortality REASONS WHY ALBUMINURIA IS RISK FACTOR FOR CVD • Is assoc with high prevalence of traditional risk factors • May reflect generalised endothelial dysfunction, increased vascular permeability and abnormal of coagulation system • May be assoc with markers of inflammation • May indicate the severity of end organ damage CKD AND CVD OUTCOMES CKD AND CVD OUTCOMES MINOR RI OR GFR AS RISK FACTOR FOR CVD • Studies across diff population show that CKD is an independent risk factor for CVD • Framingham Heart Study • 6233 adults mean age 54yrs • CRI defined as Scr 136-265µmol/L in men & 120-265 µmol/L in women • Follow up 15yrs. • Mild RI was assoc with increase in all cause mortality in men but not in women REDUCED GFR OR MILD RENAL DYSFUNCTION • Reduced GFR is associated with high prevalence of CVD risk factors, CVD surrogates, and Clinical CVD • Reduced GFR is associated with CVD outcomes in several prospective studies, HOPE study, WISE, BARI study MINOR RI OR GFR AS RISK FACTOR FOR CVD • • • • • ARIC Study 15 350 Age 45-64 Data stratified according to GFR In multivariate analysis minor renal dysfunction was risk factor for CV events and death • 10ml/min /1.73m2 lower GFR was assoc with 5% higher adjusted CV risk REASONS FOR THE ASSOCIATION OF ↓GFR WITH CVD OUTCOMES • ↓ GFR is associated with ↑ level of nontraditional risk factors • May be a marker of vascular disease • May be a measure of residual confounding from traditional risk factors (HPT, dyslipidaemia) • Subjects are less likely to receive medications or therapies such as ACEI, ASA,β blockers, thrombolytics, PCI THERAPEUTIC OPTIONS • Although many identifiable risk factors and therapeutic strategies exist for treatment of CVD, most of them are underused in the care of patients who have kidney disease. • Early recognition of both CKD and attendant CVD is becoming the responsibility of the primary care physicians in conjunction with members of subspecialty teams (Nephrologists & Cardiologists). THERAPEUTIC OPTIONS • Data from the general population show the efficacy of treatment of traditional CVD risk factors, but few such data are available in kidney disease populations. • Unfortunately, the lack of data may have contributed to less intensive treatment of risk factors in CKD patients. • Despite the well-known protective effects of angiotensinconverting enzyme (ACE) inhibitors, lipid-lowering agents, and aspirin, their use is less than optimal in patients with CKD who have a high CVD risk. THERAPEUTIC OPTIONS • Reports suggest that only 22% of dyslipidemic patients with CKD are taking lipid-lowering agents, 60% are using ACE inhibitors, and few are taking aspirin • Similarly, blood pressure control, well known to both delay the progression of kidney disease and attenuate overall cardiovascular risk, is rarely achieved to within recommended target guidelines (<130/80 mm Hg). THERAPEUTIC OPTIONS • • • • • • • Tonelli & colleagues 304 pts with CRI (mean GFR 30ml/min) Hyperlipidemia 43% History of CVD 39% ASA 27% HMG Co A 18% β blockers 34% THERAPEUTIC OPTIONS • Early recognition of both CKD and attendant CVD • Utilization of therapeutic strategies for treatment of CVD in the care of patients who have kidney disease. • ACEI should be part of the BP-lowering regimen because their effect on BP, kidney function & proteinuria • Combination of ACEI & ARBs have synergistic effects in the reduction of proteinuria and BP control THERAPEUTIC OPTIONS • Control diabetes (Diabetes Control Complication Trials, UKPDS) – Targets FBS ≤ 110mg/dl – Post priandial ≤ 140mg/dl • Statins lower elevated cholesterol & TG and also have antiproliferative effect on smooth muscle • AHA & ACC recommend measurement of homocysteine (HCY) and empirical treatment with folic acid vitamin B12 & vitamin B6 to achieve target HCY levels THERAPEUTIC OPTIONS • Routine use of ACE inhibitors and aspirin is encouraged in all patients with CKD, and strict glycaemic and blood pressure control is recommended for optimal outcomes. • In addition, patients should be screened and treated for risk factors particularly associated with kidney disease and CVD morbidity and mortality, including anemia, hyperphosphatemia, and hyperparathyroidism. THERAPEUTIC GOAL The goal of patient management is to reduce CV risk and slow down the progression of renal disease. THERAPEUTIC TARGETS • Target BP < 130/80; if proteinuria > 1g lower to < 120/70mmHg • LDL <2.5mmol/L • Proteinuria< 200mg/g • Stop smoking • Regular exercise • Metabolic control in diabetic • Use of ACEI, ARB • Statins for dyslipidaemia • Treat anaemia with erythropoietin • Treat calcium/ phosphate abnormality ALGORITHM FOR SCREENING FOR CKD AND REDUCING CVD RISK • One or more risk factors present: Age>60yrs, DM, HTN, Family Hx of kidney Dx Obtain Scr and estimate kidney function using formulae equations Perform urinalysis to detect abnormal amounts of protein Kidney fxn abnormal (CCr < 60ml/minor urinalysis indicates microalbuminuria Treatment goals Achieve BP control < 130/80, Reduce proteinuria, Treat dyslipidaemia, control blood glucose, treat elevated homocysteine Additional diagnostic tests: Measure PTH, Ca, P, HB Abnormal results in diagnostic tests above CONSULT NEPHROLOGIST FORMULAE EQUATIONS 1. Cockcroft – Gault formula: Ccr (ml/min) = [140 – age (yrs)] x wt (kg) PCr (mg/dl) x 72 For women multiply by 85 (not 72) cant use in obese or oedematous patients MDRD equation: GFR/1.73m2 = (170 x (PCr [mg/dL]) exp [-0.999]) x (Age exp[-0.176]) x ((SUrea [mg/dL])exp[-0.170]) x ((Albumin [g/dL])exp[+0.318]) Abbreviated MDRD GFR, in mL/min per 1.73 m2 = 186.3 x ((serum creatinine) exp [-1.154]) x (Age exp [0.203]) x (0.742 if female) x (1.21 if African American) where exp is the exponential. Calculators available on-line 2. 3. • • • CONCLUSION • There is no doubt that CVD and CKD are interconnected • Thus primary care physicians physicians are urged to look for evidence of kidney dysfunction in patients with CVD and also heart disease or its risk factors in patients with kidney disease • Targets have been clearly defined and are achievable for BP control, DM control & lipid treatment CONCLUSION • CVD accounts for more than 50% of all morbidity and mortality in CKD patients who have undergone RRT • CVD is also prevalent in patients with mild and moderately severe kidney disease. • To help address the elevated risks of these patients, primary care physicians need to maintain vigilance in (1) identifying patients who have CKD and (2) implementing strategies for reducing the prevalence of CVD in this population. CONCLUSION • At each stage of CKD, physicians should evaluate for CVD risk factors and severity of CVD, then review possibility of reducing progression of both CVD and CKD • Screen patients for mild CKD by measurement of Scr and microalbuminuria and calculate GFR using equations CONCLUSION Finally, physicians should be careful to avoid therapeutic nihilism in patients with kidney disease; these patients are at highest risk of CVD and are likely to receive the greatest benefit from cardiovascular therapies. THANK YOU FOR YOUR ATTENTION