1. The case of microalbuminuria prevention: the ROADMAP study Department for Clinical Pharmacology and Hypertension Charité – University Medicine Berlin, Germany Reinhold Kreutz, FAHA

2. Charité, AG R. Kreutz Kannel WB et al. Am Heart J 1984;108:1347-52 Age-adjusted annual incidence per 1000 Women Men Proteinuria present 10 20 30 15 25 35 5 0 40 Women Men Proteinuria absent Cardiovascular Mortality Overall Mortality 5209 men and women, 16 years follow up Mortality and Proteinuria: Framingham-Study

3. Charité, AG R. Kreutz Survival without CV death A: U-Prot <150 mg/LB: U-Prot 150–300 mg/LC: U-Prot >300 mg/L 1 0.9 0.8 0.7 0.6 0.5 0 0102030405060708090 stroke coronary events p <0.001 for stepwise trend (%) months A B C p <0.001 0 10 20 30 40 Miettinen H et al. Stroke. 1996;27:2033-2039. Proteinuria: cardiovascular events in T2D mellitus Incidence (%) -1056 pts in Finland -7 year follow up

4. Charité, AG R. Kreutz Independent Predictive Variables for Combined Endpoint of CV Death, MI, and Stroke VariableHazard Ratio Microalbuminuria 1.59 Coronary artery disease1.51 Peripheral artery disease1.49 Diabetes mellitus1.42 Male gender1.20 Age1.03 Mann JFE et al. Ann Int Med 2001;134:629-636 Prognostic effect of microalbuminuria in cardiovascular risk patients Heart Outcomes Prevention Evaluation (HOPE) study 9,297 patients  55 years follow-up 4.5 years

5. Charité, AG R. Kreutz Hallan S et al. Arch Intern Med. 2007;167:2490-2496. Second Nord-Trøndelag Health Study (HUNT II) - Norway - 9709 individuals - community based - 8.3 years follow-up - 71% participation rate recommended cut off for micro- albuminuria Albumin to creatinine ratio in spot urine and cardiovascular mortality in the normal population RR: median of ACR =1 (albumin to creatinine ratio) Albuminuria is a continuous parameter

6. Charité, AG R. Kreutz Determination of urinary albumin excretion (UAE) in cardiorenal medicine UAE or MAU

7. Charité, AG R. Kreutz SpotNight24 hour mg/24 h mg/min mg/mmol Cr mg/g Cr Urine sample Units UAE: samples and units of measurement *Witte EC et al. J Am Soc Nephrol. 2009;20:436-443 – first morning urine suggested.

8. Charité, AG R. Kreutz SpotNight24 hour mg/24 h 30-299 mg/min 20-199 mg/mmol Cr 3-29 mg/g Cr 30-299* Urine sample Units UAE: samples and units of measurement *Witte EC et al. J Am Soc Nephrol. 2009;20:436-443 – first morning urine suggested.

9. Charité, AG R. Kreutz Reduction in Albuminuria Translates to Reduction in CV Events in Hypertension Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study Albuminuria (mg/mol) Number of patients BaselineYear 2Year 4 ≤0.5196133852458 0.5-1159115871814 1-3221918271946 >3243517081760 24 22 20 18 16 14 12 10 8 6 4 2 0 0612243036424854606618 Endpoint ratio (%) ≤ 0.5 mg/mmol 0.5-1 mg/mmol 1-3 mg/mmol > 3 mg/mmol Month Number of at-risk patients in the strata indicates patients shifted from higher level of UACR at baseline to lower level at years 2 and 4 Risk for composite endpoint was lower with reduced albuminuria 9193 hypertensives BP: 200-160/115-95 mmHg and LVH ECG positive randomized: losartan vs. atenolol endpoint: death, MI, stroke Ibsen H et al. Hypertension2005;45:198-202

10. Charité, AG R. Kreutz Availability, prognostic value and cost of some markers of organ damage ESC / ESH Hypertension guidelines 2007 Mancia G et al. J Hypertens 2007 2007;25:1105-1187

11. Charité, AG R. Kreutz Increased permeability Macromolecules/ plasma proteins What is the link between a renal phenotype, i.e. albuminuria and cardiovascular disease?

12. Charité, AG R. Kreutz Increased permeability Macromolecules/ plasma proteins Steno hypothesis: Albuminuria reflects widespread vascular damage Deckert T et al. Diabetologia. 1989;32:219 –226. oxidative stress inflammation metabolic syndrome de Zeeuw D et al. Kidney Int Suppl 2005 ;98:S25-S29, Ritz E et al. Diabetologia 2010;53:49-57

13. Charité, AG R. Kreutz oxidative stress inflammation metabolic syndrome de Zeeuw D et al. Kidney Int Suppl 2005 ;98:S25-S29, Ritz E et al. Diabetologia 2010;53:49-57 What is the link between microalbuminuria and cardiovascular events ? microalbuminuria endothelial dysfunction MI stroke

14. Charité, AG R. Kreutz 32.0 16.0 8.0 4.0 2.0 1.0 0.5 0.25 330300 MA Baseline UACR (mg/g) P for trend < 0.0001 Hazard ratio (95% CI) Albuminuria predicts renal events in diabetes ACR predicted renal events in patients with type 2 diabetes in the ADVANCE study 10,640 patients followed for 4.3 years 10-fold increase in baseline ACR –3.3-fold increase in risk of renal event ADVANCE = Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation Albuminuria is considered a continuous event and these ranges serve only as an orientation Ninomiya T, et al. J Am Soc Nephrol. 2009;20:1813–21. death as a result of kidney disease, requirement for dialysis or transplantation or doubling of serum creatinine to >200  mol/L

15. Charité, AG R. Kreutz Causes of chronic kidney disease UrsacheProzent Diabetes mellitus 44.9 Typ 1 3.9 Typ 2 41.0 Hypertension 27.2 Glomerulonephritis (GN) 8.2 Chronic interstitial nephritis or obstruction 3.6 Genetic causes (e.g. PKD) 3.1 Secondary GN or vasculitis 2.1 Malignancies 2.1 Others, e.g. HIV 4.6 Unclear or unknown 5.2 Abboud H & Henrich WL New Engl J Med 2010;362:56-65

16. Charité, AG R. Kreutz The cardiorenal continuum Risk factors Target organ damage Asymptomatic CKD microalbuminuria Atherosclerosis Target organ damage Symptomatic ESRD Diabetes Hypertension Cardiorenal continuum describes the interrelated progression of CVD and renal disease MI, HF, stroke Death

17. Charité, AG R. Kreutz Randomised Olmesartan and Diabetes Microalbuminuria Prevention study (ROADMAP) First study to examine whether an ARB can prevent or delay the onset of Microalbuminuria in patients with T2DM 4,400 patients with T2DM and normoalbuminuria and with at least 1 cardiovascular risk factor randomized to olmesartan 40 mg /d or placebo Haller H, et al. J Hypertens. 2006;24:403–8.

18. Charité, AG R. Kreutz ROADMAP: study design CrCl=creatinine clearance (ml/min) Randomization to double-blind treatment 4-week pre- randomization Follow-up until 326 MA cases End of study MA detected MI, stroke, or CrCl <30 Observation only Open-label olmesartan 40 mg/day MI, stroke, or CrCl <30 Olmesartan 40 mg/day (n=2200) Placebo (n=2200) Haller H, et al. J Hypertens. 2006;24:403–8.

19. Charité, AG R. Kreutz ROADMAP: preliminary results Patients were followed for a mean of 3.2 years Approximately 80% achieved the diabetes blood pressure goal of  130/80 mm Hg Time to first occurrence of microalbuminuria was significantly different after one year –178 patients in the olmesartan group vs. 210 in the placebo group (p<0.05) Haller H et al. Late-breaking clinical trial. Presented at: Renal Week 2009; Oct. 27-Nov. 1; San Diego.

20. Charité, AG R. Kreutz The cardiorenal continuum Risk factors Target organ damage Asymptomatic CKD microalbuminuria Atherosclerosis Target organ damage Symptomatic ESRD Death Diabetes Hypertension Measure urinary albumin excretion and prevent diabetic kidney disease MI, HF, stroke

21. Thank you !