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Coronary atherosclerosis in CKD • Atherosclerosis plaque is the central feature of coronary arteries • Lead to MI, CHF, death • Term ASCVD replace CAD • Evidence of atherosclerosis in CKD • Autopsy • angiography KDOQI commentary on the 2012 KDIGO clinical practice guideline for the Evaluation and management of CKD www. Kdigo.org 1. All people with CKD be considered at increased risk for CVD 2. Level of care for ischemic heart disease ,CHF should be offered to CKD patients 3. Antiplatelet to CKD at risk for atherosclerotic events Pathobiology of uremia and its consequences for the pathogenesis of atherosclerosis McCullough P.A. Curr Opin Nephrol Hypertens;2004:591-600 1. Traditional risk factors 2. Non-traditional risk factors Traditional CVD risk factor Nontraditional CVD risk factors Diabetes Oxidative Stress AGEs Hypertension ADMA Dyslipidemia Inflammation Smoking Cellular senescence Atherosclerotic cardiovascular disease in CKD patient Risk factors for CVD specific to patients with CKD or that occur more frequently or with greater levels in patients with CKD Roberts et al. Am J Kid Dis ;2006:341-360 Major cardiovascular risk factors and cardiovascular outcomes Major risk factors Hypertension Diabetes mellitus Cigarette smoking Obesity (BMI>30) Microalbuminuria or estimated GFR < 60 ml/min Physical inactivity Dyslipidemia Age (men > 55 years, women > 65 years) Family history of premature cardio-vascular disease (men < 55 years, women < 65 years) Target-organ damage Heart LV hypertrophy Angina or prior MI Brain Stroke or transient ischemic attack Prior coronary revascularization Chronic kidney disease Heart failure Peripheral arterial disease Retinopathy McCullough P.A. Curr Opin Nephrol Hypertens;2004:591-600 Kidney International (2017) Pathophysiology • Calcification plaque accelerated by CKD (medial layer) • Contributed by secondary HPTH, uremic process • Degree calcification by spiral CT scan correlated with serum PO4, total calcium phosphorus product • Increase stimulation of macrophage • Release inflammatory mediator (TNF alpha) • Vascular smooth muscle death, impaired vascular reactivity, increase plaque rupture • Independent CAC score between site of aortic calcification and tracer uptake Coronary artery calcification (CAC) • Is a feature of CKD • Association with higher time integrated mean serum PO4 level, cumulative exposure to Ca containing oral phosphate binder • ESRD and advanced CKD associated with extensive calcification of coronary arteries and higher CAC score than without CKD • Presence of coronary atheroma, higher CAC score in ESRD Noninvasive detection ASCVD • Symptom, EKG, cardiac stress test is less reliable in CKD patients • Symptom • Chest pain is still most common presentation in CKD • Atypical symptom more common than in non-CKD, esp SOB • EKG • ST elevation in EKG is less common in CKD • Cardiac stress test • More likely to have positive cardiac stress test in CKD • Stronger correlation of atypical angina symptoms and true CAD in CKD Echocardiography KDOQI recommend : Echo after 1-3 month after RRT and every 3 years regardless of symptoms - GFR declines Incidence of obstructive CAD - Diffuse multi-vessel involvement with coronary calcification - Increased mortality - Limitation of diagnostic studies Exercise stress test CAG, contrast risk Radionuclide scan : less sensitivity EKG Exercise-pharmacological myocardial perfusion Myocardial Necrosis Troponin C , I ,T ( CTnI, c TnT ) Trop C : associate with actinomysin of the cardiac and skeletal muscle CTnI , cTnT : cardiac specific GFR - Troponin In HD patient , CTnT predicts mortality and cardiovascular events, poor outcome Strict glycemic control BP control Uncertain in CKD stage 5 Life style modification - ASA: should be given in individual with GFR < 45 ml/min per 1.73 m2 and CKD 5D Statin: SHARP Trial: Simvastatin + Ezetimibe Reduce CVD 17% but not overall mortality Management • Medication • 1.statin • Based on 3 trials : Die Deutsche Diabetes Dialysis, An Assessment of Survival and Cardiovascular Events, Study of Heart and Renal Protection • No benefit to primary, secondary prevention using statin in ESRD • Reduction in MACE in CKD not on dialysis, simvastatin+ezetimibe, but no different in mortality outcome • Meta-analysis : reduction in mortality and cardiovascular events • KDIGO : use on all patients with CKD >50yr and those with high risk for ASCVD aged 18-49 yr Management • 2.antiplatelet • Higher reactivity of platelets to adenosine diphosphate in CKD • Less reduction in platelet reactivity to P2Y12 inhibitors, limit efficacy of P2Y12 and ASA • Reduction in benefit following PCI esp. stent thrombosis • High risk for thrombotic events and bleeding event • ASA for primary prevention in SIHD is limited in CKD to prevention of MI but not for mortality • Newer P2Y12 inhibitors have not been adequately studied in CKD patients - Use of ASA Clopidogrel β blockers ACEi/ARB Same as in non-CKD patients - PTCA should be used No benefit from PCI and medication In 320 patients with CKD stage 3-4 No difference in primary end point (death, MI, Stroke) between PCI and CABG in CKD patients SHARP Trial : No efficacy of statin in CKD stage 5D IV Thrombolysis : Benefit in stroke if given within 4-5 hr of symptom onset Management • Revascularization for SIHD • COURAGE and Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI2D) • PCI, CABG not superior to medical therapy in reducing all cause mortality, MI • BARI2D excluded all patients with Cr>2 • COURAGE enrolled 16 patients with GFR<30(5%) • Hage et al, 260/2287 had GFR<60 evaluation for KT, neither presence nor severity of CAD on angiography affected survival, revascularization had survival benefit in TVD • Limitation : underpower with GFR<60, prospective cohorts CKD have better outcome with DES than bare metal stents CABG in CKD : risk of operative complication PCI : additional risk of radiocontrast Management • Renal transplant • Improve CV outcomes in ESRD • US Renal Data Service • Never wait listed or KT: 3.4 times to experience hospitalization for ACS than who wait listed • Wait listed and transplanted had rate ratio 0.34 for ACS hospitalization compared with who were wait listed and never underwent transplant • Even older had KT lead to improved survival Congestive heart failure Pathophysiology Abnormal calcium and phosphate metabolism Risk for vascular calcification in CKD 1CRP, C-reactive protein Cannata-Andia et al. J Am Soc Nephrol ;2006:S267-S273 • • High Phosphorus Potent stimulus to differentiation of smooth vascular cells into osteoblast-like cells Mineralization Sites: All calibers : high-caliber arteries aorta medium vessels small-size vessels cardiac valve Non traumatic fraction Strategies to reduce vascular calcifications : • Control serum phosphate • Sevelamer Reduce the progression of both coronary and aortic calcifications Fetuin A • Circulating inhibitor of vascular calcification • Low level predict cardiovascular event and mortality Vitamin D analog : Effect on proliferation cardiovascular Immune disorder Calcium mimetics : Bisphosphonates : Potential role in the management of vascular calcification Increase bone mass Reduce bone nontraumatic fragilily fractures Reduce vascular calcification in experiment Diet Control: Dialysis Prescription : Short daily , nocturnal Vitamin D Protection Mechanism 15 27 Neutrophil gelatinase - associaled lipocalin Kidney injury molecule- 1 Interleukin-18 Mid-regional proadrenomedultin Catalytic iron Media of oxidative stress Specific CV biomarkers and potential interventions that may be indicated if levels are abnormal Roberts et al. Am J Kid Dis ;2006:341-360 Asymmetric dimethylarginine (ADMA) • • • • Elevated ADMA levels predict acute coronary events ADMA accumulates in the patient with CKD Predict all-cause mortality and cardiovascular events Correlate with left ventricular mass index and negatively with ejection fraction ADMA Cardiac troponin : Strong predictor of all cause mortality in CKD 5D BNP : associate with LVH LV dysfunction Interleukin – 6 Stimulate CRP secretion from the liver Increase as GFR decrease Tumor necrosis factor α Proinflammatory cytokine Greater in patients with decreases GFR Fibrinogen Produced by hepatocyte Significantly predict CVD event in CKD patient Oxidative stress • Imbalance between oxidant and antioxidant compounds • Antioxidant therapy dose not reduce cardiovascular event in large trials • Treatment : Vitamin E N - acelylcysteine Sympathetic Nervous System Activation Neuropeptide Y • associated with LVH , systolic dysfunction • Predicts cardiovascular events but not mortality • Plasma norepinephrine predicts mortality and CVD events • Therapy : Blocking sympathetic nervous system Homocysteine Sulfhydryl containing aminoacid from methionine Proatherogenic - Oxidative stress - Alteration in endothelial antithrombotic mechanism - Direct damage to the vascular matrix GFR Homocystine level Treatment : Folate Vitamin B6 Vitamin B12 But did not reduce cardiovascular event C – reactive Protein PREVEND study • ESRD patient : CRP strongly associated with CVD events and death • plasma fibrinogen directly associated with left atrial volume • (CREED) data base C-reactive protein (CRP) • Best studied cardiovascular biomarkers of inflammation • Produced by hepatocyte under the control of IL-6 CRP provide overall measure of systemic inflammatory activity Inflammation Atherosclerosis is an inflammatory disease - Oxidative stress - Clearance of proinflammatory substances ( advanced glycosylation end products ) - Inflammation has been linked to alteration in protein metabolism Hyperhomocysteinemia May trigger renal damage Level increase as renal function ( 20-50 µmol/L in ESRD patients ) Wald et al : 5% homocysteine 42% high CVD risk Glycosylation of proteins Advanced glycation end products ( AGEs ) • Nonenzymatic modification of proteins level correlate with GFR • Independent risk factor for death in HD patients Left Ventricular structure and function • Cardiac ventricles produces B-type natriuretic peptide (BNP) • BNP leave to active C-terminal end (BNP-32) • Inactive N-terminal end (pro BNP1-76) • BNP32 correlated with • HT • Coronary artery disease • predict cardiovascular death • Pro BNP1 predict • combined end point of CVD events • progression of kidney disease mortality Therapy • Reduce left ventricular wall tension • Ultrafiltration by dialysis treatment • Angiotensin-converting enzyme inhibitor • β-blocker Dietary salt restriction Diuretic – aldosterone antagonist : ACEi, ARB : little evidence in CKD CKD increase risk of stroke 1.4 times Stage 5D increase risk of stroke 5-10 times Overall stroke rate 4% per year (CHOICE Trial) Independent predictor : age and diabetes Prevention : BP lowering Antiplatelet Statin Carotid endarterectomy Stroke in HD • Retrospectively examined 1671 incident • hemodialysis patients with atrial fibrillation • warfarin use compared with nonuse • increased risk of stroke (HR, = 1.93; 95% CI1.29 to 2.90) Warfarin • Warfarin for prevent stroke • selection of patients with NVAF • not proven to be beneficial in ESRD and NVAF • Warfarin has thin margin of benefit over risk in patients with ESRD • Meta-analysis of warfarin in NVAF and ESRD • • • • warfarin had no effect on risks of stroke (hazard ratio, 1.12; 95%CI, 0.69 to 1.82; P=0.65) or mortality (hazard ratio, 0.96; 95%CI, 0.81 to 1.13; P=0.60) but was associated with increased risk of major bleeding (hazard ratio, 1.30; 95%CI, 1.08 to 1.56; P<0.01). Guideline • The 2005 KDIGO/ KDOQI guidelines • not recommend warfarin anticoagulation for primary prevention of stroke • in patients with ESRD and NVAF receiving dialysis • Canadian Cardiovascular Society suggested • patients with ESRD (eGFR,15 ml/min per 1.73 m2) • not routinely receive anticoagulation or acetylsalicyclic acid • for stroke prevention in atrial fibrillation Prevalence 15-20% in dialysis patients Increase incidence of stroke Cerebral embolism CHADS 2 score CHF Hypertentsion Age older than 75 Diabetes Score >1 Risk for stroke and need warfarin Warfarin for primary prevention : questionable in CKD 5D - Direct Thrombin Inhibitor : dabigatran 150 mg twice daily Can use in CKD Stage 3 RE-LY Study (Randomized Evaluation of long-Term anticoagulation Therapy) Coagulation cascade of oral anticoagulant • apixaban is the most likely drug to move forward in patients with ESRD and NVAF • Apixaban was associated with • less major bleeding than dabigatran and rivaroxaban • but not edoxaban in patients with moderate renal impairment CKD is an independent risk factors for PAD CKD and peripheral arterial disease • we recommend that adults with CKD be regularly examined for signs of peripheral arterial disease and be considered for usual approaches to therapy • We suggest that adults with CKD and diabetes are offered regular podiatric assessment Screening CKD 5D at the time of dialysis initiation - The Ankle – Brachial Index < 0.5 = diagnostic value - Stop smoking - Antiplatelet - Statins - ACEi - Cilostagol (phosphodiesterase inhibitor) Risk of SCD with declining of GFR Arrhythmia Metabolic derangement In CKD 5D : Frequent, long, slow HD β blockers Implantable cardioverter defibrillators. - Correcting anemia, minimize vascular calcification - Adequate ultrafiltration in CKD-5D Anemia and Erythropoietin therapy Anemia Increase mortality due to LVH Vasodilatation Increase cardiac output Relative risk for mortality 5-6% lower for every 1 g/dl greater Hb concentration Summary • Atherosclerotic plaque is central feature of disease coronary arteries • CKD is an ASCVD equivalent • CKD have medial calcification • Diagnosis test in ASCVD in CKD is less reliable • CAC scores have been demonstrated to identify CKD at higher risk for ASCVD • Statin recommended in CKD age > 50yr • Antiplatelets less efficacy in CKD • Revascularization not superior benefit than medication • TVD in ESRD may benefit from CABG than PCI • Renal transplant improve in cardiovascular outcome in CKD