CARDIO-RENAL SYNDROME

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1 CARDIO-RENAL SYNDROME Luis M Ruilope Athens, October 216 DISCLOSURES: ADVISOR/SPEAKER for Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Esteve, GSK Janssen, Lacer, Medtronic, MSD, Novartis, Pfizer, Relypsa, Sanifit, Takeda, Theravance, Vifor

2 CARDIO-RENAL SYNDROME 1- HF FACILITATES AKI 2- CKD FACILITATES HF 3- CV AND RENAL DISEASES DEVELOP SIMULTANEOUSLY Ronco C et al, JACC 28

3 Cardio-renal continuum REGRESS Target organ damage Asymptomatic PREVENT CKD New risk factors Atherosclerosis RETARD Target organ damage Symptomatic Risk factors ESRD Death CKD=chronic kidney disease; ESRD=end-stage renal disease

4 Cardio-renal continuum: cost and death %Events 1 75 % % Cost

5 The "heavyweights" of modifiable CVD risk factors Hypertension Cholesterol LDL HDL Diabetes Smoking Global CVD risk CVD=cardiovascular disease; HDL=high-density lipoprotein; LDL=low-density lipoprotein

6 Prevalence and causes of ESRD Number of dialysis patients Diabetes Hypertension Prevalence (1 s) CI=confidence interval ,24 281, , Year Projection 95% CI

7 RISK PREDICTION IS IMPROVED BY ADDING MARKERS OF SUBCLINICAL ORGAN DAMAGE TO SCORE Sehestedt T, et al. Eur Heart J 21; 31: CONCLUSION: Subclinical organ damage predicted cardiovascular death independently of SCORE and the combination my improve risk prediction The analysis included LVMI, carotid plaques, PWV and Albumin/creatinine ratio

8 HRs and 95% CIs for all-cause and CV mortality according to spline egfr and ACR 8 All-cause mortality; egfr All-cause mortality; ACR HR (95% CI) CV mortality; egfr CV mortality; ACR HR (95% CI) egfr (ml/min/1.73m 2 ) (.3) (.6) (1.1) (3.4) (33.9) (113.) ACR (mg/g [mg/mmol]) HRs and 95% CIs (shaded areas) according to egfr and ACR adjusted for each other, age, sex, ethnic origin, history of CV disease, SBP, diabetes, smoking, and total cholesterol. The reference (diamond) was egfr 95 ml/min/1.73 m 2 and ACR 5 mg/g, respectively. Circles represent statistically significant and triangles represent not significant. ACR=albumin-to-creatinine ratio; CV=cardiovascular; egfr=estimated glomerular filtration rate; HR=hazard ratio; SBP=systolic blood pressure Chronic Kidney Disease Prognosis Consortium. Lancet 21;375:273 81

9 HRs and 95% CIs for all-cause and CV mortality according to spline egfr and categorical albuminuria HR (95% CI) All-cause mortality; ACR studies 33.9 mg/mmol ( 3 mg/g) mg/mmol (3-299 mg/g) <3.4 mg/mmol (<3 mg/g) CV mortality; ACR studies.5.5 HR (95% CI) All-cause mortality; dipstick studies Dipstick urine protein 2+ or more Dipstick urine protein 1+ Dipstick urine protein negative or trace CV mortality; dipstick studies egfr (ml/min/1.73m 2 ) egfr (ml/min/1.73m 2 ) Shaded areas represent 95% CIs. Models included spline egfr, categorical albuminuria, and their interaction terms as well as adjustment for age, sex, ethnic origin, history of CV disease, SBP, diabetes, smoking, and total cholesterol. The reference (diamond) was egfr 95 ml/min/1.73 m² plus ACR less than 3.4 mg/mmol (3 mg/g) or dipstick test result negative or trace. Circles represent statistically significant and triangles represent not significant. Chronic Kidney Disease Prognosis Consortium. Lancet 21;375:273 81

10 HR (95% CI) for ESRD associated with urine albumin excretion 4 Adjusted HR for ESRD Normal Microalbuminuria Macroalbuminuria ACR (mg/g) Hallan et al. J Am Soc Nephrol 29;2:169 77

11 The definition, classification and prognosis of chronic kidney disease: a KDIGO Controversies Conference report Levey AS et.al. Kidney Int 21; doi: 1.138/ki

12 Cross-talk between CVD and CKD Cardiovascular risk factors CVD Cardiovascular or renal protection CKD Renal risk factors Figure 1 Ruiz-Hurtado, G. & Ruilope, L. M. Nat. Rev. Cardiol. advance online publication 8 July 214

13 Bakris et al. Lancet 21;375:

14 ACCOMPLISH: progression of CKD* for the intention-to-treat population Number at risk: Benazepril plus HCTZ Benazepril plus amlodipine Proportion of patients (%) Benazepril plus HCTZ (215 events) Benazepril plus amlodipine (113 events) Time to event (months) Log-rank p< *Defined as: doubling of serum creatinine concentration, egfr <15 ml/min/1.73 m 2, or need for dialysis; HCTZ=hydrochlorothiazide Bakris et al. Lancet 21;375:

15 ACCOMPLISH: progression of CKD* plus CV death for the intention-to-treat population Proportion of patients (%) Number at risk: Benazepril plus HCTZ Benazepril plus amlodipine Benazepril plus HCTZ (345 events) Benazepril plus amlodipine (22 events) Log-rank p< Time to event (months) *Defined as: doubling of serum creatinine concentration, egfr <15 ml/min/1.73 m 2, or need for dialysis Bakris et al. Lancet 21;375:

16 Cumulative incidence of CV endpoints Cumulative incidence Primary endpoint* CKD, placebo No CKD, placebo CKD, rosuvastatin No CKD, rosuvastatin No. at risk Follow-up (years) CKD Rosuvastatin Placebo No CKD Rosuvastatin *Primary endpoint: non-fatal MI, nonfatal stroke, hospital stay for UA, arterial revascularization, or CV death Placebo MI=myocardial infarction; UA=unstable angina Ridker et al. J Am Coll Cardiol 21;55:

17 Evolution of albuminuria and percentage of patients with normo-, micro- and macroalbuminuria during the follow-up. Baseline Year 1 Year 2 Year 3 p Total.28 Normal 1141 (1) 992 (86.9) 929 (83.6) 946 (82.9) Micro 142 (12.4) 17 (15.3) 184 (16.1) Macro 7 (.6) 12 (1.1) 11 (1.) No Diabetes.39 Normal 154 (1) 929 (88.1) 862 (84.1) 885 (84.) Micro 122 (11.6) 154 (15.) 162 (15.4) Macro 3 (.3) 9 (.9) 7 (.7) Diabetes.259 Normal 87 (1) 63 (72.4) 67 (77.9) 61 (7.1) Micro 2 (23.) 16 (18.6) 22 (25.3) Macro 4 (4.6) 3 (3.5) 4 (4.6) p DM vs no DM NA <.1.49 <.1 Normal:. Micro: microalbuminuria. Macro: macroalbuminuria. For definitions, see Methods. In the 2 year visit, data on albuminuria were not available for 3 patients. Ruilope LM. et al. (In press 211)

18 Development of new-onset albuminuria among hypertensive patients according to previous cardiovascular events Ruilope LM. et al. (In press 211)

19 Primary composite endpoint of the LIFE stratified by time-varying albuminuria Endpoint rate (%) Losartan Atenolol Month >3 mg/mmol 1 3 mg/mmol.5 1 mg/mmol.5 mg/mmol Change from BL (median, mg/mmol) Time from baseline (years) * ** Losartan Atenolol *p =.1, **p<.1, by Wilcoxon rank-sum test Median changes in albuminuria (urine albumin/creatinine ratio, mg/mmol) on losartan versus atenolol treatment * ** ** LIFE=Losartan Intervention For Endpoint Reduction Ibsen et al. J Hypertension 24;22:185 11

20 ONTARGET: changes in UAE 2.5 p= p<.1 p= UAE initial (mg/mmol) Second year ratio to initial Final ratio to initial Occurrence proteinuria Ramipril Telmisartan Ramipril + Telmisartan Mann et al. Lancet 28;372:547 53

21 Prevention of cardiorenal damage Blockade of Ang II effects BP control + Low Na intake Low protein intake Albuminuria

22 Schematic presentation of the decline in GFR over years in a patient with albuminuria and in a patient with normal UAE 1 9 No albuminuria Normal ageing Early intervention egfr 5 4 With albuminuria 3 2 Late intervention 1 Follow-up (years) UAE=urinary albumin excretion Gansevoort et al. J Am Soc Nephrol 29;2:465 68

23 Cardio-renal continuum REGRESS Target organ damage Asymptomatic PREVENT CKD New risk factors Atherosclerosis RETARD Target organ damage Symptomatic Risk factors ESRD Death CKD=chronic kidney disease; ESRD=end-stage renal disease

1. Albuminuria an early sign of glomerular damage and renal disease. albuminuria

1. Albuminuria an early sign of glomerular damage and renal disease. albuminuria 1. Albuminuria an early sign of glomerular damage and renal disease albuminuria Cardio-renal continuum REGRESS Target organ damage Asymptomatic CKD New risk factors Atherosclerosis Target organ damage

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