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

Size: px

Start display at page:

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

Logan Berry
5 years ago
Views:

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

2 Cardio-renal continuum REGRESS Target organ damage Asymptomatic CKD New risk factors Atherosclerosis Target organ damage Symptomatic Risk factors ESRD Death

3 %EVENTS 1 75 % % COST

4 The "heavyweights" of modifiable CVD risk factors Hypertension Cholesterol Diabetes Smoking LDL HDL Global CVD risk

5 Double jeopardy : type 2 diabetes and hypertension and cardiovascular risk CVD death rate (per 10,000 person-year) 250 No diabetes Diabetes < Systolic blood pressure (mmhg)

Prevalence and causes of end-stage renal disease Number of dialysis patients 700 600 500 400 300 200

6 Prevalence and causes of end-stage renal disease Number of dialysis patients diabetes 243,524 hypertension 281, , Projection 95% CI

7 RISK PREDICTION IS IMPROVED BY ADDING MARKERS OF SUBCLINICAL ORGAN DAMAGE TO SCORE Sehestedt T, et al. Eur Heart J 2010; 31: CONCLUSION: Subclinical organ damage predicted cardiovascular death independently of SCORE and the combination improves risk prediction The analysis included LVMI, carotid plaques, PWV and Albumin/creatinine ratio

8 The Epidemiology

9 Hazard ratios and 95% CIs for all-cause and cardiovascular mortality according to spline estimated glomerular filtration rate (egfr) and albumin-to-creatinine ratio (ACR) Hazard ratios and 95% CIs (shaded areas) according to egfr (A, C) and ACR (B, D) adjusted for each other, age, sex, ethnic origin, history of cardiovascular disease, systolic blood pressure, diabetes, smoking, and total cholesterol. The reference (diamond) was egfr 95 ml/min/1.73 m2 and ACR 5 mg/g, respectively. Circles represent statistically significant and triangles represent not significant. ACR plotted in mg/g. Lancet May 18, 2010 (Published Online)

Hazard ratios and 95% CIs for all-cause and cardiovascular mortality according to spline estimated glomerular filtration rate (egfr) and categorical albuminuria Shaded areas represent 95% CIs.

10 Hazard ratios and 95% CIs for all-cause and cardiovascular mortality according to spline estimated glomerular filtration rate (egfr) and categorical albuminuria 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 cardiovascular disease, systolic blood pressure, diabetes, smoking, and total cholesterol. The reference (diamond) was egfr 95 ml/min/1.73 m² plus ACR less than 3.4 mg/mmol (30 mg/g) or dipstick test result negative or trace. Circles represent statistically significant and triangles represent not significant. Lancet May 18, 2010 (Published Online)

11 Estimated cumulative distribution function Mortality and CVD Endpoints by Albuminuria Status CHARM Study CVD Death or Admission for HF in Patients with CHF Macroalbuminuria Microalbuminuria Normoalbuminuria No. at risk: Time (yrs) Normoalbuminuria Microalbuminuria Macroalbuminuria Jackson CE et al. Lancet. 2009;374: All-cause Mortality in Patients with CHF Time (yrs)

12 Cumulative incidence (%) Cumulative Incidence of Venous Thromboembolism 5 Log-rank P< Microalbuminuria 2 1 Normoalbuminuria No. at risk Follow-up (yr) Microalbuminuria Normoalbuminuria Mahmoodi BK et al. JAMA. 2009;301:

13 Association of egfr levels during follow-up with the risk for CV events *Adjusted for age, sex, HbA 1c, serum lipids, BMI, smoking, alcohol use, and study drug Ninomiya T, et al. J Am Soc Nephrol 2009; On-line.

14 Association of albuminuria levels during follow-up with the risk for CV events *Adjusted for age, sex, HbA 1c, serum lipids, BMI, smoking, alcohol use, and study drug Ninomiya T, et al. J Am Soc Nephrol 2009; On-line.

15 3. Albuminuria an early sign of glomerular, but also generalized vascular damage healthy blood vessel albumin vascular damage albumin albuminuria albuminuria

Age- and gender-adjusted risk to develop a cardiovascular event (defined as a fatal or nonfatal myocardial infarction or cerebrovascular accident) and to develop a renal event (defined as an egfr

16 Age- and gender-adjusted risk to develop a cardiovascular event (defined as a fatal or nonfatal myocardial infarction or cerebrovascular accident) and to develop a renal event (defined as an egfr slope of more than three times the mean of the normal genderstratified population) in the PREVEND cohort that had at least three egfr measurements available during 7 yr of follow-up Gansevoort, R. T. et al. J Am Soc Nephrol 2009;20:

17 Annual Transition Rates Through Stages of DN No nephropathy Microalbuminuria Macroalbuminuria Elevated plasma creatinine or Renal replacement therapy DN = diabetic nephropathy. Adler et al. Kidney Int. 2003;63: % (1.9% to 2.2%) 2.8% (2.5% to 3.2%) 2.3% (1.5% to 3.0%) 1.4% (1.3% to 1.5%) 3.0% (2.6% to 3.4%) 4.6% (3.6% to 5.7%) 19.2% (14.0% to 24.4%)

19 Schematic presentation of the decline in GFR over years in a patient with albuminuria and in a patient with normal urinary albumin excretion Gansevoort, R. T. et al. J Am Soc Nephrol 2009;20:

20 Primary composite endpoint of the LIFE stratified by time-varying albuminuria. Ibsen H et.al J Hypertension 2004;22:1805

21 ONTARGET Changes in UAE during the trial, from baseline to study end (ONTARGET) Adapted from Mann et al. Lancet 2008

Uso (%) Tratamiento Inicial en ONTARGET/TRANSCEND y HOPE Inhibidores ECA/Estatinas 70 60 50 40 30 20 10 Final

22 Uso (%) Tratamiento Inicial en ONTARGET/TRANSCEND y HOPE Inhibidores ECA/Estatinas Final del Estudio ONTARGET TRANSCEND HOPE 0 IECA Estatinas ONTARGET/TRANSCEND Investigators, Am Heart J (2004): 52-61

23 METHODS We have reviewed the evolution of albuminuria in 1433 patients (mean age 60.5 years; 50.3% male), arriving in our unit as a consequence of arterial hypertension with varying degrees of associated cardiovascular risk factors. All had in common the existence of previous therapy with an ACEi or an ARB for a minimum of two years before arrival in the Unit. The follow-up period was maintained for at least 3 years time.

24 Albuminuria evolution (Rate in %) 20 Total DM No DM Yes , ,5 10 9,1 9, ,3 6,7 6,8 8,6 7,6 4 5,2 2 0 Baseline Year 1 Year 2 Year 3 Total p=0.019 (Y3 vs Baseline) DM No p=0.024 (Y3 vs Baseline) DM Yes p=0.041 (V3 vs Baseline) Basal p=0.021 (DM Yes vs DM No) Year 1 p=0.001 (DM Yes vs DM No) Year 2 p=0.008 (DM Yes vs DM No) Year 3 p=0.001 (DM Yes vs DM No)

25 Table 5. 5 Albuminuria Groups Basal Year 1 Year 2 Year 3 p Total Normal High-Normal Micro Proteinuria No DM Normal High-Normal Micro Proteinuria DM Normal High-Normal Micro Proteinuria 970 (67.7) 171 (11.9) 234 (16.3) 58 (4.0) 906 (70.0) 148 (11.4) 198 (15.3) 43 (3.3) 64 (46.4) 23 (16.7) 36 (26.1) 15 (10.9) 862 (60.2) 213 (14.9) 267 (18.6) 91 (6.4) 789 (63.0) 184 (14.7) 217 (17.3) 62 (5.0) 73 (40.3) 29 (16.0) 50 (27.6) 29 (16.0) 754 (54.1) 256 (18.4) 291 (20.9) 94 (6.7) 669 (56.1) 222 (18.6) 235 (19.7) 67 (5.6) 85 (42.1) 34 (16.8) 56 (27.7) 27 (13.4) 766 (54.9) 223 (16.0) 302 (21.6) 104 (7.5) 682 (58.2) 184 (15.7) 238 (20.3) 67 (5.7) 84 (37.5) 39 (17.4) 64 (28.6) 37 (16.5) p DM <0.001 <0.001 <0.001 <

26 Occurrence of MAU during antihypertension treatment Urinary albumin excretion mg/24h 250 Progressors (n=22) Non-progressors (n=165) Baseline 1 (n) (187) 2 (135) Years of follow-up 3 (105) 4 (72) Redón et al. Hypertens 2002; 39:

27 Factors related to occurrence of MAU during antihypertensive treatment Slope of regression lines over time 22 p<0.001 Progressors (n=22) Non-progressors (n=165) UAE p<0.03 Uric acid SBP DBP p<0.03 Glucose -4-6 p<0.05 Redón et al. Hypertens, 2002

28 Can Microalbuminuria be Prevented? Studies of BP Lowering and RAS Inhibition

29 Arterial blood pressure (mm Hg) Blood Pressure in Hypertensive Type 2 DM With Normoalbuminuria The BENEDICT Study Systolic Diastolic Follow-up (mo) Trandolapril Verapamil Trandolapril plus verapamil Placebo Ruggenenti P et al. N Engl J Med. 2004;351:

30 Cumulative incidence of microalbuminuria (%) Risk of Microalbuminuria in Type 2 DM with Hypertension and Normoalbuminuria The BENEDICT Study A.F. (95 % CI) = 0.47 ( ) P=0.01 Placebo (30 events) 5 Trandolapril (18 events) No. at risk Trandolapril Placebo Follow-up (mo) Ruggenenti P et al. N eengl J Med. 2004;351:

31 Patients with ECG-LVH (%) Preventing Left Ventricular Hypertrophy by ACEi in Hypertensive Type 2 DM Patients The BENEDICT Study HR (95% CI): 0.34 ( ) P= A prespecified analysis ACEi No 5 ACEi Yes No. at risk ACEI NO ACEI YES Months Ruggenenti et al. Diabetes Care. 2008;31:

32 Mean blood pressure (mm Hg) Effect of Add-on Fixed Dose Combination of Perindopril (8 mg/od) and Indapamide (1.25 mg/od) vs Placebo on BP in 11,140 Patients With Type 2 DM at High Risk of CVD Δ 5.6 mm Hg (95% CI ) P< Systolic Placebo Perindopril-indapamide Δ 2.2 mm Hg (95% CI ) P< R Follow-up (mo) Diastolic ADVANCE Collaborative Group. Lancet. 2007;370:

33 Effect of Perindopril-indapamide Combination on Risk of Death, Macro- and Microvascular Events, and Renal Events in Type 2 DM No. (%) of patients with event Favors perindoprilindapamide Perindoprilindapamide (n=5569) Placebo (n=5571) Favors placebo Relative risk reduction (95% CI) Combined 861 (15.5%) 938 (16.8%) 9% (0 to 17) Macrovascular 480 (8.6%) 520 (9.3%) 8% (-4 to 19) Microvascular 439 (7.9%) 477 (8.6%) 9% (-4 to 20) All Deaths 408 (7.3%) 471 (8.5%) 14% (2 to 25) Cardiovascular death 211 (3.8%) 257 (4.6%) 18% (2 to 32) Total Renal Events Total renal events 1243 (22.3%) 1500 (26.9%) 21% (15 to 27) New or worsening nephropathy 181 (3.3%) 216 (3.9%) 18% (-1 to 32) New microalbuminuria 1094 (19.6%) 1317 (23.6%) 21% (14 to 27) ADVANCE Collaborative Group. Lancet. 2007;370: Hazard ratio

34 Baseline Characteristics of Patients Randomly Assigned to Study Drugs. Ruggenenti P et al. N Engl J Med 2004;351:

35 Cumulative proportion Incidence of Microalbuminuria in Diabetic Patients With Normoalbuminuria by Treatment Group Direct-renal Study Candesartan Placebo Time from randomization (yrs) No. at risk Placebo Candesartan Bilous et al. Ann Intern Med. 2009;151(1): e-publication. P=0.60 HR (95% CI) = 0.95 ( )

36 Primary endpoint: Time to Onset of Microalbuminuria Sub-population with BP >140/90 mmhg and/or anti-htn treatment Total ROADMAP population Hypertensive patients HR: 0.770; 95.1%CI: to 0.941; p-value: Risk reduction in favour of OM 40 mg: 23% HR: 0.774; 95%CI: to 0.960; expl. p-value: Risk reduction in favour of OM 40 mg: 23% 36 Kaplan Meier curve for the cumulative proportion of patients with adjudicated primary efficacy endpoint: microalbuminuria during the double-blind period; Restricted Full Analysis Set (double-blind period)

37 Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis Conclusions egfr less than 60 ml/min/1.73 m 2 and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. Lancet May 18, 2010 (Published Online)

38 Prevent OBJECTIVES: BP goal <140/90 mmhg with ACEi, ARBs, CCB s Other CVRF control, lipid profile Spot urine albumin/creatinine ratio Prevent Microalbuminuria Pre-Hypertension Hypertension Prevent IGT Metabolic Syndrome Diabetes OBJECTIVES: Intensive diabetes control (HbA1c <6.5% or lower, PG fasting, postprandial) Intensive BP control <130/80mmHg RAS blockade Lipid profile: TChol, LDL, HDL, TGL goals Microalbuminuria - Proteinuria Serum creatinine, GFR Eye examination, ECG Prevent CKD Prevent Stroke/CVD Microalbuminuria Chronic Kidney Disease Prevent ESRD Ruilope R Ruilope et al, et Blood al, Blood Press Press 2007r 2007 Prevent CVD/Stroke OBJECTIVES: BP goal <130/80 mmhg ACEi, ARBs, combination Treat other CRFs Monitor urine Alb/Cr ratio annually OBJECTIVES: BP <130/80 mmhg (<125/75 mmhg if U/prot >1 g/24h) with ACEi, ARBs, CCB s, diuretics Start with 2 drug-fixed dose combination if SBP >20 mmhg and/or DBP >10 mmhg above target Reduce proteinuria using ACEi, ARBs, Aldoantagonists ndccbs (dccbs may increase proteinuria) Slow GFR decline with ACEi, ARBs (dccbs may not alter GFR decline, in the absence of an ACEi/ARB) Reduce CV Risk with ACEi ACEi, ARBs and diuretics reduce CHF, ACEi and ARBs do not worsen IR

CARDIO-RENAL SYNDROME

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,