The New Cardiorenal Syndrome

Transcription

1 The New Cardiorenal Syndrome Peter Sawaya, MD, FACP, FASN Professor of Medicine Fellowship Program Director University of Kentucky

2 The Old Cardiorenal Syndrome Heart Perfusion Na Retention Kidney

3 What is the estimated rate of cardiovascular disease in patients with CKD stage 4? (egfr ml/min/1.73 m 2 ; per 100 person-year) A) 5-10 B) C) D) E) > 40

4 Rate of Cardiovascular Events (per 100 person-yr) CKD & CVD > <15 egfr (ml/min/1.73m 2 ) Go et al., NEJM 2004

5 Adjusted HR for Death Hazard Ratio for Death after MI According to the egfr * > <45 egfr (ml/min/1.73m2) * * Anavekar et al. NEJM 2004

6 CKD & CVD Traditional risk factors The metabolic syndrome LVH and myocardial remodeling Anemia Increased inflammatory/oxidative stress The micro uremic melieu Endothelial dysfunction Proteinuria Abnormal mineral metabolism Low physical activity Renalism

7 % > 2 Risk Factors 100% CKD and CVD Risk Factors 80% 60% 40% 20% 0% NHANES III, N = 15,800 Smoking, Obesity, HTN, Hypercholesterolemia, CRP, HgbA1C, Homocysteine, Anemia, UP/C 120% Normal <30 egfr (ml/min/1.73m 2 ) Foley et al., Mayo Clinic Proc 2005

8 CKD Prevalence % CKD and the Metabolic Syndrome NHANES III: 6217 Patients Hypertriglyceridemia (>150), Low HDL (<40;50), Central Obesity (>40"), Increased FBS (>110) and HTN (>130/85) ATP III Guidelines Metabolic Syndrome Components Chen et al., Ann Intern Med 2004

9 OR for CKD CKD and the Metabolic Syndrome NHANES III or Metabolic Syndrome Components Chen et al., Ann Intern Med 2004

10 CKD vs. Hypercholesterolemia Cholesterol egfr 1 0 C G > 60 C G C G C G G < 15 MRFIT, JAMA 1984 Go et al., NEJM 2004

11 HTN, CKD & CVD 281 patients with essential HTN and normal GFR, Madrid, Spain Followed for an average 13 years 15% developed CKD (egfr < 60) 41% of pts with CKD had CVD Only 13% of pts without CKD had CVD CKD HR for CVD = 2.5 (multivariate analysis) Segura et al., JASN 2004

12 What is the most common cardiac abnormality in ESRD patients? A) Mitral regurgitation B) Tricuspid regurgitation C) Systolic dysfunction D) Diastolic dysfunction E) Both, systolic and diastolic dysfunction

13 LVH & LV Dysfunction in Incident HD Patients LVH 62% Diastolic dysfunction 57% Diastolic and systolic dysfunction 24% Systolic dysfunction 5% Normal 10% Vankatesan & Henrich, JASN 1998

14 % LV Fibrosis in ESRD Patients with Dilated Cardiomyopathy Control Dialysis 10 0 Myocyte Diameter Fibrosis > 40 mm > 45 % Aoki et al., KI 2005

15 LV Fibrosis A picture is worth a thousand words! Normal Fibrosis

16 LV Fibrosis in ESRD Patients and Risk of Death Multivariate Analysis Fibrosis >30% = HR 27.1* Aoki et al., KI 2005

17 What is the most common cause of cardiovascular death in ESRD patients? A) Acute myocardial infarction B) Pulmonary edema C) Chronic CHF D) Sudden death E) Atrial fibrillation with RVR

18 Sudden Cardiac Death % of Cardiac Deaths % of All-Cause Mortality Hemodialysis Peritoneal Dialysis USRDS 2006

19 Cardiac Remodeling Pressure/Volume Overload Sympathetic / RAAS Local Factors Inflammation Hypertrophy Fibrosis Adapted from GM London, Seminars in Dialysis, 2003

20 Anemia and LVH in CKD Reduced oxygen delivery to the myocardium Increased cardiac output and reduced SVR Increased oxidative stress Activation of sympathetic system JS Berns, UpToDate 2008

21 Prevalence of Anemia (%) 100 Anemia in CKD: NHANES III (Hgb < 12 M; < 11 F) > egfr (ml/min/1.73m 2 ) Astor et al., Arch Intern Med 2002

22 Inflammation/Oxidative Stress & CKD Healthy subjects CKD patients P value CRP mg/l IL-6 pg/ml Thiols mol/l <0.001 Carbonyls nmol/mg protein F 2 -isoprostanes ng/ml < <0.001 Oberg et al., KI 2004

23 Inflammation & CKD Decreased clearance of proinflammatory cytokines: TNFα, IL1, IL6 Altered intestinal permeability: Endotoxemia Increased oxidative stress: Free radical production & AGE accumulation Decreased levels of antioxidants: Low vitamin C Comorbid conditions: Periodontal disease Kalantar-Zadeh & Kopple, UpToDate 2008

24 The Micro Uremic Milieu

25 New Uremic Toxins Middle Molecules Dinucleoside polyphosphate Ang II variants α-fibrinogen fragments AGEs Oxidation products Cytokines Protein-Bound Dinucleoside polyphosphate Cytokines Phenols Indoles AGEs Phenylacetic acid Others Guanidines, ADMA, SDMA Adapted from R. Vanholder, Advances in CKD 2008

26 Dinucleoside Polyphosphates Two nucleosides linked by a variable number of phosphates Increased concentration in ESRD patients Induce smooth muscle cell proliferation Jankowski et al., KI 2001

27 Arbitrary Units Vascular Smooth Muscle Cells Proliferation Control Patients C-PPADS P-PPADS Adapted from Jankowski et al., KI 2001

28 Uridine Adenosine Tetraphosphate (Up4A) Endothelium-derived Potent vasoconstrictor Nonpeptidic Accumulates in renal failure Jankowski et al., Nature Medicine 2005

29 P-Cresylsulphate From the metabolism of tyrosine and phenylalanine by intestinal flora MW 108 Da, but highly protein-bound Accumulates in renal failure Significantly increases the percentage of leukocytes displaying oxidative burst activity Schepers et al., NDT 2007

30 Asymmetric Dimethyl Arginine Shear stress (ADMA) Nucleulus Proteins Methylated Protein Oxidized lipoprotein Vasoconstriction?AT1 ADMA Nitric oxide DDAH Urine DDAH: Hyperlipidemia, hyperglycemia, smoking, hyperhomocysteinemia Kielstein and Zoccali, AJKD 2005

31 Hazard Ratio ADMA & CV Events Plasma ADMA Adapted from: Kielstein et al., AJKD 2005 Zoccali et al., Lancet 2001

32 Hazard Ratio All-Cause Mortality and Proteinuria Taiwan Health Management Institution Study (462,293 Adults screened 56,977 CKD) egfr > Normal Proteinuria Minimal Proteinuria Overt Proteinuria Lancet 2008, 371:

33 Hazard Ratio Proteinuria & CVD Mortality < > 300 Proteinuria mg/dl Muntner et al., JASN 2002

34 Cardiovascular Ossification & CKD 15% of children on dialysis 30% 70% of CKD patients Arterial dysfunction: Stiffness Valvular disease Conduction abnormalities Mechanism is complex: Ca, P, vitamin D, PTH, inflammation, imbalance between promoters and inhibitors

35 Survival Probability Calcification Score and Mortality F/U Duration (Months) Blacher J, Hypertension 2001

36 Physical Function Scale Score Lack of Physical Activity in CKD P. Painter, Hemodialysis Int l 2005

37 Renalism is the aggressive management of CKD patients because of their high risk for cardiovascular disease. A) True B) False

38 Renalism Less ACEI/ARB Fear of K + or AKI Less ASA Fear of bleeding Less beta blocker Fear of? K + or pulse Less angioplasty Fear of radiocontrast Less CABG - Fear of increased morbidity and mortality Post MI death was less likely if CKD patients received acute reperfusion therapy, ASA or BB (each HR 0.7) Wright et al, Ann Intern Med 2002

39 The New Cardiorenal Syndrome Traditional Risk Factors Novel and Uremia- Related Risk Factors -Oxidative stress, inflammation -Endothelial dysfunction -Anemia -Vascular calcification -Coagulation disorders -Atherosclerotic plaque Age, Male, HTN, Smoking, LVH, DM, Dyslipidemia -Sympathetic activation -Subclinical hypothyroidism -Uremic bone disease -Volume overload -Protein energy wasting -Insulin resistance -Uremic toxins -Adipokine imbalance -Genetics/epigenetics Adapted from: Stenvinkel et al., CJASN March 2008

40 Which of the following diabetic drugs is/are contraindicated in CKD patients with egfr < 50 ml/min/1.73 m 2? A) Metformin B) Glipizide C) Glyburide D) Sitagliptin E) A & C F) B & D

41 Strategies to Reduce CVD Burden in CKD Smoking secession Exercise Proper diet: Low Na, fat and phosphorus BP control: < 130/80, ACEI/ARB, diuretics Dyslipidemia control: LDL < 100 mg/dl, statins Diabetes control: A1C < 7%, avoid metformin and glyburide Anemia management: Hgb g/dl Mineral metabolism management The Greek phosphorus is lucifer in Latin!

42 Secondary Prevention of Small Subcortical Strokes (SPS3) Study Over 2800 patients International, multicenters, NIH-sponsored Two intervention strategies Anti platelets therapy Blood pressure control Usual SBP arm ( ) and intensive control (<130) University of KY enrolled thus far 54 patients Trial Registration: NCT NIH-NINDS (Grant #2 U01 NS A1).

43 Achieving SBP <130 in SPS3 at As of last visit (September 2010) Mean SBP ; Median % SBP > 130 Mean follow up 42 months Mean # of meds Most common limiting factors to intensify therapy Side effects (BP-related, not class) Fluctuation in BP Dependency on home BP monitoring

44 Treatment of CAD in CKD Same as in non-ckd patients Specific attention to drug dosing Acute coronary syndrome Therapies should include PCI, CABG, antiplatelet agents, beta-blockers, thrombolytic therapy, and lipid-lowering agents as indicated Chronic CAD Therapies should include ASA, beta-blockers, nitroglycerin, ACEI/ARB, statins, and/or calciumchannel blockers as indicated K/DOQI Guidelines, AJKD 2005