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Chronic Kidney Disease & Cardiovascular Disease: A clinical update from KDIGO

Current & future management of chronic kidney disease. Chronic Kidney Disease & Cardiovascular Disease: A clinical update from KDIGO. Eberhard Ritz University of Heidelberg Germany. Rationale. Bidirectional nature of heart-kidney interactions : primary disorders of one organ causing

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Chronic Kidney Disease & Cardiovascular Disease: A clinical update from KDIGO

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  1. Current & future management of chronic kidney disease Chronic Kidney Disease & Cardiovascular Disease: A clinical update from KDIGO Eberhard Ritz University of Heidelberg Germany

  2. Rationale Bidirectional nature of heart-kidney interactions : primary disorders of one organ causing secondary dysfunction or injury to the other new classification reflecting pathophysiology and time frame in order to speak one common language Ronco, J.Am.Coll.Cardiol.(2008) 51:1268

  3. Cardiorenal syndrome (ping-pong, table tennis) Reduced cardiac output Reduced net renal perfusion pressure (?) Increased protein synthesis Cardiac hypertrophy (compensating hypervolemia) Renal insufficiency ROS ER stress Chronic heart failure ANGII, AVP, aldosterone sympathetic activation

  4. nephrologists being notoriously polite, accepted the sequence : first heart, then kidney heart kidney heart kidney acute cardiorenal syndrome type 1 chronic cardiorenal syndrome type 2 kidney heart kidney heart acute renocardial syndrome type 3 chronic renocardial syndrome type 4 heart kidney systemic condition cardiorenal syndrome type 5

  5. Type 1 acute heart kidney

  6. Type 1 acute worsening of heart dysfunction acute kidney injury (AKI) heart (trigger) : • hypertensive pulmonary edema with preserved LV systolic function • acutely decompensated chronic heart failure • cardiogenic shock • predominant right ventricular failure Mebazaa, Crit.Care Med.(2008) 36:S129 kidney(target) • moresevererenaldysfunctionwhen LV functionisimpaired • AKI independentpredictor of 1 yearmortality(inflammatorypathways?) • decreasedresponsetodiuretictreatment(braking, post-diuretic Na retention) • risk of hyperkalemia(ACEi;ARB;Spironolactone,Eplerenone) - aggravationbyradiocontrast Goldberg, Am.Heart J. (2005) 150:330 Berl, Clin.J.Am.Soc.Nephrol.(2006) 1:8 Ellison, Semin.Nephrol.(1999) 19:581 Verma Curr.Heart Fail.Rep.(2007) 4:183 McCullough, JACC(2008) 51:1419

  7. Type 1 acuteworsening of heartdysfunctionacutekidneyinjury (AKI) Assessment of renal (dys)-function : classic serum marker : s-creatinine : delayed, confounded, imprecise novel markers : s-cystatin C : more costly, not absolutely specific urine markers ? : NGAL (neutrophil gelatinase-associated lipocalin) KIM 1 (kidney injury molecule)

  8. Cumulative all causemortality in patientswith a rise in Cystatin C within 48h after hospitalisationforacuteheartfailure > 0.1 mg/L > 0.3 mg/L Lassus, Europ.Heart J.(2011) 31:2791 > 0.5 mg/L

  9. Worsening kidney function in decompensated heart failure:“treat the heart, don‘t mind the kidney“ Ruggenenti, Europ.Heart J.,(2011) 32:2476 EVEREST trial (Tolvaptan)

  10. Renalimpairmentin patientswithcardiacdysfunction -decreasedcardiacoutputorvenouscongestion? RBF renalbloodflow RAP rightatrialpressure Damman, Eur.Heart Fail.(2007) 9:872

  11. Comparison of the prognostic usefulness of N-terminal pro-brain natriuretic peptide in patients with heart failure with versus without chronic kidney disease areaunderthecurve 0.81 ±0.03 without CKD with CKD Bruch, Am.J.Cardiol.(2008) 102:469

  12. GFR fromadmissiontodischarge(% change GFR) - absenceorpresence of hemoconcentration Potential effect of aggressive decongestion on renalfunction in patientswithdecompensatedheartfailure Testani, Circulation (2010) 122:265

  13. Type 2 chronic heart kidney but also heart kidney

  14. Type 2 chronic heart dysfunction progressive chronic kidney disease (CKD) Chronic congestive heart failure - even slight decrease of eGFR – significantly increased mortality and Hillege, Circulation (2006) 113: 671 – marker of severity of vascular disease • no evidence of simple association between LV ejection fraction and eGFR or survival Bhatia, New Engl.J.Med.(2006) 355:260

  15. Renal function (eGFR) –a predictor of CV death or readmission for CV complications eGFR (ml/min/1.73m2) Hillege, Circulation (2006) 113:671

  16. In contrast to renal function outcome of heart failure (survival)virtually independent of ejection fraction Bhatia, New Engl.J.Med. (2006) 355:260

  17. Type 2 chronic heart dysfunction progressive chronic kidney disease (CKD) Chronic congestive heart failure • balance between vasoconstriction and vasodilatation upset • of relevance : vasoconstrictive mediators ↑ (epinephrine, angiotensin, endothelin,…) reduced sensitivity against, vasodilators ↓ (NO, natriuretic peptides) EPO ↓

  18. Cras(CardiorenalAnemia Syndrome) impaired renal function heart failure anemia thirdpartner in crime

  19. Hospitalised patients with heart failure (OPTIMIZE-HF registry) (in hospital mortality is a function of Hb) 48,612 admissions 259 hospitals 50% pat. Hb < 12.1 g/dl 25% pat. Hb 5-10.7 g/dl # in hospital mortality : 4.8% vs 3% # readmission by 90 days 33.1% vs 24.2% Young, Am.J.Cardiol.(2008) 101:223

  20. Causes of anemia in heartfailure[Cardio-renalanemiasyndrome] Haehling, Contrib.Nephrol.(2011) 171:211 Hypervolemia Hemodilution Diminished EPO production in kidney Reduced renal function Inflammatory milieu EPO resistance RAS blockade treatment Erythrocyte precursor proliferation inhibited Aspirin, anticoagulants Gastrointestinal bleeding Disturbance of iron metabolism Increased hepcidin synthesis – iron availabilty↓ - Inhibition of intestinal Fe absorption - Retention of Fe in Mø

  21. Efficacy and safetyof erythropoiesisstimulatingagents (ESA) in heartfailure 9 randomized controlled trial (n=747 patients with heart failure) EMBASE,Medline, Cochrane Library ESA compared with controls : significant reduction in CHF related hospitalizations OR 0.41 (CI 0.24-0.69) inconclusive effect on mortality OR 0.60(CI 0.32-1.11) improved quality of life, LV ejection fraction, lower BNP, increased exercise tolerance test performance Lawler, J.Card.Fail. (2010) 16:649

  22. Prevalence of iron deficiency in patients with heart failure Gender NYHA class NT- pro BNP CRP ♀ p=0.007 NYHA III-IV Prevalence p=0.004 Jankowska, Eur.Heart J.,(2010) 31:1872

  23. Prevalence of iron deficiency in patients with heart failure impact on survival Cumulative event free survival Patients without iron deficiency survival 66.7% p=0.0002 Patients with iron deficiency survival 53.6% Jankowska, Eur.Heart J.,(2010) 31:1872

  24. Iron deficiency: an ominous sign in patients with systolic chronic heart failure(prospective observational study) Hypothesis : Beyond erythropoiesis iron is involved in numerous biological processes Prevalence and consequences : 546 patients with stable congestive heart failure; LVEF 26±7%; NYHA I-IV; a conservative definition Fe deficiency: # ferritin<100µg/l or #100-300µg/l with transferrin saturation < 20% Iron deficiency 37±4% overall; 32% in patients without anemia and 57% with anemia Prevalence increased:women, advanced NYHA class,N-terminal pro- BNP,CRP(all p<0.05) Risk of death (or heart transplantation) HR 1.58 (CI 1.14-2.17) Jankowska, Europ.Heart J.(2010) 31:1872

  25. Ferriccarboxymaltose in patientswithheartfailureandirondeficiency Kansas City Cardiomyopathyquestionaire NYHA functionalclass Anker, New Engl.J.Med.(2009) 361:2436

  26. Ferriccarboxymaltose in patientswithheartfailure and irondeficiency improvement of: # 6-minute walk test and # EQ-5D Visual Analog Scale Anker, New Engl.J.Med.(2009) 361:2436

  27. Type 3 acute kidney heart (mechanisms involved)

  28. Type 3 acute kidney dysfunction acute cardiac dysfunction Primary worsening of kidney function: acute kidney injury (AKI),e.g. ischemia, glomerulonephritis … ) cardiac malfunction, e.g. heart failure, arrhythmia, ischemia …) AKI (RIFLE criteria : risk; injury; failure; loss; endstage kidney disease) Bagshaw, Nephrol.Dial.Transplant.(2008) 23:1203 Clinically relevant repercussions on the heart and its consequences : • fluid overload - pulmonary edema • hyperkalemia - arrhythmia, cardiac arrest • myocardial depressant factors - myocardial contractility ↓ • pericarditis • acidemia - pulmonary vasoconstriction, arrhythmia • pharmacokinetics !!

  29. Type 4 chronic kidney heart eGFR 60 ml/min/1.73m2 evolution of CKD

  30. Frequency of chronic kidney disease in the Netherlands (albuminuria and / or reduced glomerular filtration;GFR) Stage GFR % Population (glomerular filtration rate) • >90 1.3 • 0-89 3.8 • 30-59 5.3 • 15-29 0.1 • <15 0.1 Σ 10.6 % 10.4% 0.2% de Jong, CJASN (2008) 3:616

  31. Mild reduction of glomerular filtration rate (GFR) associated with increased CV mortality (Hoorn study) 50-75 years n=631, age, sex and glucose tolerance stratified follow up 10 years RR CV death 1.26 per 5 ml/min/1.73m2 decrease of GFR Henry (2002) Kidney Intern 62: 1402

  32. Mild renal dysfunction associated with incident coronary disease in young males 23,964 males follow-up 3.5 yrs CHD: >50% narrowing or MI Hr 10 ! Pereg, Europ.Heart J.(2008)29:198

  33. Both urinary albumin excretionand eGFR at baseline independently predict CV and renal events Ninomiya, J.Am.Soc.Nephrol.(2009) 20:1813

  34. Risk of CKD (< 60 ml/min/1.73m2) in 281 hypertensive patients after 13 years follow-upaccording to baseline s-creatinine quartiles within normal range quartile 4 S-Crea >1.2 mg/dl quartile 3 1.1-1.2 mg/dl quartile 2 1.0-1.1 mg/dl quartile 1 < 1 mg/dl Segura, J.Am.Soc.Nephrol.(2004) 15:1616

  35. Inflammation – # main driving force for adverse outcomes of CV damage indicated by biomarkers e.g. CRP, pentraxin3, IL-6 … Stenvinkel P., Nature Reviews Nephrol.(2012) 8:72 # magnifies the risk of poor outcome, exacerbates wasting, triggers vascular calcification … Carrero, CJASN (2009) 4:S49

  36. BaselineS-Ppredicts 15 yearslatercoronarycalcium (EB scan) in 3015 healthyyoungmen(CARDIA study) Foley,J.Am.Soc.Nephrol.(2009) 20:397

  37. Serum phosphorous and incidence of cardiovascular disease in the community(Framingham offspring study) 3368 individuals, follow-up 16.1 years.524 incident CV events highest vs lowest quartile RR 1.55 (1.16-2.07) p=0.004 Dhingra, Arch.Intern.Med. (2007) 167:879

  38. Increasing CV mortality with progressively higher serum phosphate within the normal range – patients with coronary heart disease Hazard ratio mg/dl mg/dl <2.5 2.5-3.4 3.5-3.9 >4 <2.5 2.5-3.4 3.5-3.9 >4 Tonelli, Circulation (2005) 112: 2627

  39. FGF23(fibroblast growth factor) predicts future cardiovascular events before HD treatment Is it phosphate ? Is it FGF23 ? Seiler, Nephrol.Dial.Transplant (2010) 25:3983

  40. FGF23 (but not klotho) increased # LV mass index and # ejection fraction in CKD patients Faul, J.Clin.Invest.(2011) e-pub Oct 10th

  41. Sham 5/6 nephrectomy 5/6 Nephrectomy in rat + FGF23 inhibitor PD173074 partial prevention of altered heart morphology (LV mass, wall thickness) and improved function (ejection fraction, LV endiastolic diameter) Faul, J.Clin.Invest.(2011) e-pub Oct 10th

  42. Diastolic BP on treatment and risk of MI – type 2 diabetic patients with nephropathy (IDNT study) lower diastolic BP higher risk of MI Berl, J.Am.Soc.Nephrol.(2005) 16:2170

  43. CV disease control lower aortic diastolic pressure Why do renal patients tolerate poorly low diastolic pressure ? reduced coronary perfusion (in diastole) higher LV enddiastolic pressure

  44. Antihypertensive treatment with triple medication 3 drugs in the morning vs 2 (morning) 1 (at bedtime) Hermida, Hypertension (2008) 51:69

  45. Consequentlywhenaiming for lowbloodpressurestwocaveats • donotriskhypotensiveepisodes (also BP measurement in uprightposition, particularly in diabeticpatients !) • donotattempt aggressive lowering of systolicbloodpressure, ifdiastolicbloodpressureisverylow

  46. Asymptomatic or symptomatic coronary artery disease in CKD or ESRD To treat or not to treat ? Observational studies 640 Endstage renal disease patients Acute myocardial infarction One year survival: - medical therapy 45 % - percutaneous coronary intervention (PCI) 54 % • coronary artery bypass grafting (CABG) 69 % Chertow, AJKD (2000) 35:1044

  47. Prospective data collection non-dialysis dependent kidney disease and in dialysis dependent CKD CABG – survival advantage for all categories of kidney function PCI – lower risk of death in dialysis and reference patients compared with no revascularisation Hemmelgarn, Circulation (2004) 110:1890 Yasuda, JASN (2005) 17:2322 study in hemodialysis patients (n=259) coronary angiography (137 had lesions), optional PCI (decided by patient), all cause and cardiac 5-year survival higher in PCI group Yasuda, JASN (2005) 17:2322

  48. ENDSTAGE KIDNEY DISEASE CARDIOVASCULAREVENTS if 70%-90% kidney function lost results of treatment poor de Jong, CJASN (2008) 3:616

  49. Survival on hemodialysis- CV events the major cause of death on dialysis survival on hemodialysis is like adding 50 years to the patient‘s life Eknoyan, MEM(1999) 25:100 the life expectancy of the 30 year old grandson on dialyisis is the same as that of his 85 year old grandmother 100 GP Male 10 GP Female GP Black 1 GP White Annual Mortality (%) Dialysis Male 0.1 Dialysis Female Dialysis Black 0.01 Dialysis White 0.001 25-34 35-44 45-54 55-64 65-74 75-84 > 85 Age (years) Sarnak . Am J Kidney Dis. 2000;35(suppl1):S117

  50. Stunning – ischemia induced global or regional LV wall contraction abnormalities and impaired systolic LV function Previously stunned myocardial segments – reduced ejection fraction at rest and during dialysis Progressive reduction of shortening fraction in LV segments with regional motion abnormalities (stunning) Burton, CJASN (2009) 4:1925

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