E.Ritz Heidelberg (Germany)

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1 Predictive capacity of renal function in cardiovascular disease E.Ritz Heidelberg (Germany)

2 If a cure is not achieved, the kidneys will pass on the disease to the heart Huang Ti Nei Ching Su Wen The Yellow Emperor s Classic of Internal Medicine ~2000 B.C.

3 Cumulative Mortality Per 100 Serum creatinine predictor of mortality Hypertension Detection and Follow-up Program Creatinine stratum limits (mg/dl) 2.50 n = n = n = n = n = 2,142 < 1.20 n = 8, Months of Follow Up Shulman. Hypertension. 1989;13:I80

4 (ml/min) < Chronic Kidney Disease stage Σ 10.9% ,000 (0.1%) 400,000 (0.2%) > ,600,000 (4.3%) 5,300,000 (3.0%) 5,500,000 (3.3%) Levey, Am J Kidney Dis (2002) S1: S1-S266

5 Death (currently still) more frequent than endstage kidney disease ,998 patients with GFR< 90ml/min/1.73m 2 GFR (ml/min/1.73m2) renal replacement therapy (%) death (%) CKD 2 (60-89) (30-59) (15-29) Keith, Arch.Int.Med.(2004) 164:659

6 What is good for the kidney is it also good for the heart? - lowering blood pressure - blocking the RAAS - lowering lipids - cessation of smoking - fighting the metabolic syndrome...

7 Renal function predictor of cardiovascular disease - GFR and cardiovascular events - albuminuria and cardiovascular events - pathogenetic explanation of the link between kidney and cardiovascular system - efficacy of egfr vs albuminuria

8 Mild reduction of glomerular filtration rate (GFR) by inulin clearance associated with increased CV mortality (Hoorn study) years n=631, age, sex and glucose tolerance stratified follow up 10 years RR CV death 1.26 per 5 ml/min/1.73m 2 decrease of GFR Henry (2002) Kidney Intern 62: 1402

9 instead of inulin clearance : estimated GFR (egfr) MDRD formula - for egfr < 60 ml/min/1.73m 2 (Modification of Diet in Renal Disease study; creatinine measurement according to Cleveland clinic criteria) Levey, Ann.Intern.Med.(1999) 130:461 CKD-EPI formula - also for egfr > 60 ml/min/1.73m 2 Levey, Ann.Intern.Med.(2009) 150:604

10 False increase of s-creatinine in cardiac patients e.g. antiarrythmic agent Dronedarone inhibits renal tubular secretion of creatinine and causes spurious elevation serum creatinine despite no change in GFR Tschuppert, Brit.J.Clin.Pharmacol.(2007) 64: 785

11 In the general population : individuals without cardiovascular problems cardiovascular death increased when GFR 90 ml/min/1.73m randomly selected apparently healthy individuals, 10 year follow-up Quartiles egfr (ml/min/1.73m 2 ) mortality standardized rate/ 1000 person years HR adjusted (95%CI) 1 < ( ) ( ) ( ) 4 > van Biesen, Europ.Heart J.(2007) 28:478

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

13 Relationship of egfr with survival in congestive heart failure (Cockcroft-Gault formula :Cox adjusted survival analysis) Hillege, Circulation (2000) 102:203 2

14 Heart failure even minor increase in S-creatinine associated with more adverse prognosis increase by: 10-24% RR 1.8 (95%CI ) 25-49% RR 3.0 (95%CI ) >50% RR 6.9 (95%CI ) Coca, Am.J.Kidn.Dis.,(2007) 50: 712

15 egfr versus Cystatin C Shlipak, New Engl.J.Med (2005) 352:2049

16 Cystatin C superior to S-creatinine and egfr in predicting all cause mortality Shlipak, New Engl J.Med.(2005) 352:2049

17 Prediction of CV events : particularly in the range of normal serum creatinin levels Cystatin C superior predictor Shlipak, Ann.Int.Med.(2006)145:237

18 independent correlates after adjustment for egfr: - CRP - age - smoking

19 Renal function predictor of cardiovascular disease - GFR and cardiovascular events - albuminuria and cardiovascular events - pathogenetic explanation of the link between kidney and cardiovascular system - efficacy of egfr vs albuminuria

20 Albuminuria predictor of : cardiovascular death cardiovascular events cardiac ischemic events coronary artery disease Klausen, Circulation (2004) 110:32) Hillege, Circulation (2002) 113:671 Romundstad, Am.J.Kidn.Dis.(2003) 42:466 Gerstein, JAMA (2001) 286:421 Wachtell, Ann.Int.Med.(2003) 139:901 survival after myocardial infarction Borch-Johnsen, Arteriosc.Thromb.Vasc.Biol. (1999) 19:1992 Tuttle, Am.J.Kidn.Dis.(1999) 34:918 Wright, Ann.Int.Med.(2002) 137:563 Anavekar,New Engl.J.Med.(2004) 351:1285

21 Progressive increase of renal and CV risk with albuminuria within the normoalbuminuric range in type 2 diabetics albuminuria (mg/day) relative risk of progression to microalbuminuria CV endpoint Rachmani, Diab Res (2000) 49: 187

22 P Composite endpoint ( % ) Deciles of urinary albumin Life study x4 30 Non-diabetes Diabetes 25 Normo- Micro- Macro- Albuminuria Courtesy H Ibsen (Glostrup) unpublished 20

23 Ruggenenti,Kidn.Intern.(2006) 70:1214

24 Albuminuria predicts longterm all cause mortality in patients with acute MI quartiles of ACR on 3rd day of MI Berton, Am.Heart J. (2008) 156:760

25 Change of albuminuria translates into change of cardiovascular endpoints (CEP) high baseline/ high year 1 high baseline/ low year 1 low baseline/ high year 1 low baseline/ low year 1 Ibsen,Hypertension(2005) 45:198

26 Baseline albuminuria predicts efficacyof antihypertensive treatment to lower CV events albuminuria (mg/day) <15 >15 >30 Boersma, Brit.J.Clin.Pharmacol.(2008) 65:723

27 Microalbuminuria amplifies the risk of ischemic heart disease at any given blood pressure Normoalbuminuria Microalbuminuria <140 mm Hg mm Hg >160 mm Hg systolic BP Borch-Johnsen, Arterioscler Thromb Vasc Biol. (1999)19:1992

28 50% reduction of microalbuminuria less cardiovascular events in diabetic patients microalbuminuria treatment target Araki, Diabetes (2007) 56:1727

29 CV events in controlled trials in renal patients (metaanalysis) relative power of egfr plus proteinuria GFR<60 no proteinuria GFR<60+ proteinuria Tonelli, Brit.Med.J.(2006) 332:1426

30 Both urinary albumin excretion and egfr at baseline predict CV and renal events (Advance study in type 2 diabetes) albuminuria GFR albuminuria GFR Ninomiya, J.Am.Soc.Nephrol.(2009) 20:1813

31 Beyond albuminuria : Urinary neutrophil gelatinase associated lipocalin (NGAL) a marker of tubular damage increased in heart failure NGAL albumin Damman, Europ.J.Heart Fail.(2008) 10:997

32 Renal function predictor of cardiovascular disease - GFR and cardiovascular events - albuminuria and cardiovascular events - pathogenetic explanation of the link between kidney and cardiovascular system - efficacy of egfr vs albuminuria

33 Early onset of insulin resistance in renal failure ( renal insulin resistance syndrome ) GFR (ml/min/1.73m 2 ) control > <45 Becker, J.Am.Soc.Nephrol(2005) 16:1091

34 Impaired kidney function ( microalbuminuria, reduction of glomerular filtration) endothelial cell - dysfunction vasculature sensitized to injury by # hypertension # dyslipdemia # hyperglycemia # aldosterone # salt

35 Endothelial cell dysfunction von Willebrand factor Landray, Am.J.Kid.Dis. (2004) 43:244

36 In chronic kidney disease: high serum concentration of soluble VEGF receptor Flt-1 antagonising effect of VEGF and causing endothelial cell apoptosis correlated to predictor of endothelial dysfunction predicts myocardial infarction Di Marco, J.Am.Soc.Nephrol. (2009) 20:2235

37 High serum concentration of soluble VEGF receptor Flt-1 - causing endothelial cell apoptosis - effect overcome by high concentrations of VEGF Di Marco, J.Am.Soc.Nephrol. (2009) 20:2235

38 Flt-1 protein (and mrna) in monocytes of CKD patients Di Marco, J.Am.Soc.Nephrol. (2009) 20:2235

39 Renal function predictor of cardiovascular disease - GFR and cardiovascular events - albuminuria and cardiovascular events - pathogenetic explanation of the link between kidney and cardiovascular system - efficacy of egfr vs albuminuria

40 All cause mortality as a function of egfr participants, person years, 14 studies Lancet (2010) 375: 2073

41 Cardiovascular mortality as a function of egfr participants, person years, 14 studies Lancet (2010) 375: 2073

42 Cardiovascular mortality as a function of albumin / creatinine ratio (ACR) participants, person years, 14 studies Lancet (2010) 375: 2073

43 Albumin / creatinine ratio (mg/mmol) prediction of all cause mortality at different levels of egfr (pooled estimates of adjusted hazard ratios) albumin / creatinine ratio at given level of egfr additional information provided by urinary albumin Lancet (2010) 375: 2073

Albumin / creatinine ratio (mg/mmol) prediction of cardiovascular mortality at different levels of egfr (pooled estimates of adjusted hazard ratios)

44 Albumin / creatinine ratio (mg/mmol) prediction of cardiovascular mortality at different levels of egfr (pooled estimates of adjusted hazard ratios) albumin / creatinine ratio albumin / creatinine ratio at given level of egfr additional information provided by urinary albumin Lancet (2010) 375: 2073

45 Hazard ratio measurement How good in predicting CV mortality is : dipstick vs quantitation of albuminuria dipstick Lancet (2010) 375: 2073

46 Thank you for your attention

Kidney and heart: dangerous liaisons. Luis M. RUILOPE (Madrid, Spain)

Kidney and heart: dangerous liaisons Luis M. RUILOPE (Madrid, Spain) Type 2 diabetes and renal disease: impact on cardiovascular outcomes The "heavyweights" of modifiable CVD risk factors Hypertension