1. Renal Function in Cardiovascular Disease: New Understandings

2. Hypertension: Treatment and control rates Patients treated*Patients controlled on treatment to <140/90 mmHg* Percentage 100 80 60 40 20 0 JNC-V. Arch Intern Med 1993; 153: 154–183 JNC-VI. Arch Intern Med 1997; 157: 2413–2449 1971–19721974–19751976–19801988–19911991–1994 * For 1971–1972 and 1974–1975 hypertension is defined as levels  160/95 mmHg

3. Hypertension and end-organ function Persistently elevated blood pressure Left ventricular hypertrophy Coronary heart disease Heart failure End-stage renal disease Stroke

4. Hypertension and left ventricular hypertrophy Presence of hypertension (  160/95 mmHg or on antihypertensive therapy) Increase in systolic blood pressure of 20 mmHg Increase in left ventricular mass/height (g/m) Levy D et al. Ann Intern Med 1989; 110: 101–107 ** * *p<0.05; **p<0.01

5. Hypertension and heart failure Females Males Biennial age-adjusted rate of heart failure by hypertensive status per 1,000 Kannel WB. Am J Cardiol 1996; 77: 6B–11B RR=3.0 RR=4.0

6. Hypertension, coronary heart disease and stroke Relative risk of CHD or stroke 4.00 2.00 1.00 0.50 0.25 76849198105 Approximate mean usual diastolic blood pressure (mmHg) Stroke CHD MacMahon S et al. Lancet 1990; 335: 765–774

7. Hypertension and renal damage Annual incidence of hypercreatinemia per 1,000 Diastolic blood pressure (mmHg) Whelton PK et al. J Hypertens 1992; 10(Suppl): S77–S84 90–104105–114  115

8. Renal impairment: Prevalence The progression of renal impairment can lead to end-stage renal disease which has huge medical, social and financial consequences End-stage renal disease is particularly prevalent in: –The elderly –African-Americans –Patients with diabetes Nearly half of the hypertensive population displays some abnormality of renal function

9. Early hypertrophy of renal tissue and increased glomerular filtration rate (GFR) Development of glomerular lesions without any clinically appreciable disease (GFR remains increased) Incipient nephropathy with microalbuminuria (GFR normal or slightly increased) Clinical nephropathy with marked proteinuria and decreased GFR GFR continues to decrease and end-stage renal disease develops In type 1 diabetes, progression to end-stage renal disease has been sequenced into five stages: Progression to end-stage renal disease

10. Measurement of GFR as a marker of renal disease Endogenous creatinineExogenous markers Serum creatinine Creatinine clearance InulinRadioisotopes 51 Cr-EDTA 99 Tc-DTPA 125 I-iothalamate

11. Serum creatinine and creatinine clearance: Normal values Moore MA et al. Am Fam Physician 1992; 45: 1248–1256 2.0 1.5 1.0 0.5 0.0 150 125 100 Serum creatinine (mg/dl) Creatinine clearance (ml/min) MaleFemale

12. Serum creatinine level of 1.4 mg/dl: What is the renal function? Serum creatinine (mg/dl) 12 10 8 6 4 2 0 Large muscular male Normal male Small female 120603015 Fraction of normal renal function (%) Sica DA. Unpublished data 10050250 GFR (ml/min)

13. Calculating creatinine clearance urinary creatinine concentration (mg/dl) x volume (ml) plasma creatinine concentration (mg/dl) x time (min) or 140 – age (years) x weight (kg) x 0.85 (for women) 72 x serum creatinine (mg/dl) Cockroft DW et al. Nephron 1976; 16: 31–41

14. Urinary albumin excretion Mogensen CE et al. Lancet 1995; 346: 1080–1084 Clinical proteinuria >300 mg/24 hrs (>200 µg/min) Microalbuminuria 30–300 mg/24 hrs (20–200 µg/min) Normal excretion <30 mg/24 hrs (<20 µg/min)

15. Microalbuminuria: Prevalence and predictive power in diabetics Type 1 diabetes –Prevalence: 50% –Predictive value for the development of nephropathy: 75% Type 2 diabetes –Prevalence: 25–60% (depending on ethnic origin) –Predictive value for the development of nephropathy: 25% Savage MW et al. Br J Hosp Med 1995; 54: 429–435 Viberti GC et al. In: International Textbook of Diabetic Medicine, 1992

16. Microalbuminuria: Prevalence and predictive power in non-diabetics Non-diabetics –Prevalence: 25–40% (depending on level of antihypertensive control) –Predictive value for the development of nephropathy: Thought to be lower than in diabetic patients Bigazzi R et al. Nephron 1992; 61: 94–97 Ljungman S. Am J Hypertens 1990; 3: 956–960

17. Therapeutic options in hypertension Hypertension ACE inhibitors Calcium antagonists Angiotensin II antagonists  -blockers  1 -antagonists Diuretics

18. Therapeutic options in heart failure Task Force of the ESC. Eur Heart J 1997; 18: 736–753 ACE inhibitors Digoxin Digitoxin Diuretics Indicated for the symptomatic treatment of heart failure when fluid overload is present Indicated when a fast ventricular rate in atrial fibrillation is present in any degree of symptomatic heart failure due to systolic dysfunction Indicated in all stages of symptomatic heart failure due to systolic dysfunction, irrespective of presence or absence of signs of volume overload Heart failure

19. The RAS and ACE inhibition Angiotensinogen Angiotensin I Angiotensin II Bradykinin Inactive kinin fragments ACE Non-ACE enzyme Serine peptidase Renin

20. ACE inhibitors in hypertension and heart failure In hypertension, ACE inhibitors Lower blood pressure Reduce the progression of end-organ damage In heart failure, ACE inhibitors Improve cardiovascular hemodynamics Improve symptomatolgy and exercise capacity Decrease morbidity and mortality

21. Fosinopril improves symptomatology in heart failure Dyspnea Fatigue Paroxysmal nocturnal dyspnea Placebo Fosinopril –40–20020406080 Worsened (%)Improved (%) Brown EJ et al. Am J Cardiol 1995; 75: 596–600

22. Fosinopril prevents worsening of heart failure Event rate (%) 25 20 15 10 5 0 Placebo Fosinopril SupplementarySupplementaryHospitalizationWithdrawal diureticdiuretic or emergency room visit Erhardt L et al. Eur Heart J 1995; 16: 1892–1899 *** * *** *p=0.002 vs. placebo; **p=0.001 vs. placebo; ***p<0.001 vs. placebo

23. ACE inhibitors and renal impairment: Considerations Occasional cases of renal impairment and hyperkalemia have been reported with ACE inhibitors Dose modifications are a consideration in patients with renal impairment (except for fosinopril) ACE inhibitors show renoprotective effects over and above blood pressure control ACE inhibitors

24. Adrenergic agents and renal impairment: Considerations Post-dose temporary reduction in renal blood flow and GFR Modification of initial dosing is a consideration for hydrophilic  -blockers There is no evidence of renoprotective effects over and above blood pressure control Adrenergic agents

25. Calcium antagonists and renal impairment: Considerations The effect of renal impairment on metabolism of some active metabolites of calcium antagonists (e.g. diltiazem, verapamil) is unknown There is no evidence of a class-specific renoprotective effect over and above blood pressure control Calcium antagonists

26. Diuretics and renal impairment: Considerations Efficacy may be reduced in renal impairment Thiazides may decrease renal blood flow and GFR There is no evidence of renoprotective effects over and above blood pressure control Diuretics

27. Antihypertensive treatment in diabetes: Additional considerations Adapted from Cziraky MJ et al. Ann Pharmacother 1996; 30: 791–801

28. Fosinopril can improve the lipid profile in diabetic patients Change from baseline 7654321076543210 TotalLDLPlasma cholesterolcholesterollipoprotein(a) (mmol/l)(mmol/l)(mg/dl) Schlueter WA et al. Am J Cardiol 1993; 72: 37H–44H Placebo Fosinopril *p<0.05 vs. placebo * * *

29. Schematic diagram of ACE inhibition and renal function Normotensive Hypertensive Hypertensive treated with an ACE inhibitor Renal function (%) Time (years)

30. Renoprotection: ACE inhibitors vs. other antihypertensives Calcium antagonistsACE inhibitors Diuretics and/or  -blockers Urinary protein Mean systemic blood pressure 0–10–20–30–40–50 Decrease from baseline (%) Böhlen L et al. Am J Hypertens 1994; 7: 84S–92S

31. ACE inhibitors are renoprotective Patients with type 2 diabetes Patients with type 1 diabetes Non-diabetic patients with nephropathy Non-diabetic patients with hypertension and nephropathy Non-diabetic hypertensive patients without pre-existing nephropathy ACE inhibitors have demonstrated renoprotective potential in:

32. ACE inhibition: Renoprotection in type 2 diabetes Initial value of reciprocal creatinine (%) 105 100 95 90 85 80 0123456701234567 Treatment (years) Ravid M et al. Arch Intern Med 1996; 156: 286–289 ACE inhibitor (years 1–5) and placebo (years 6 and 7) ACE inhibitor (years 1–7) Placebo (years 1–5) and ACE inhibitor (years 6 and 7) Placebo (years 1–7)

33. ACE inhibition: Renoprotection in type 1 diabetes Placebo Captopril 50 40 30 20 10 0 Died or needed dialysis or transplantation (%) 0123401234 Follow-up (years) Placebon=2021981921861711211005926 Captopriln=2072072042011951401036437 Lewis EJ et al. N Engl J Med 1993; 329: 1456–1462 p=0.006

34. ACE inhibition: Renoprotection in non-diabetic nephropathy Patients not reaching an endpoint (%) 100 90 80 70 60 50 01230123 Treatment (years) Adapted from Maschio G et al. N Engl J Med 1996; 334: 939–945 Placebo Benazepril

35. ACE inhibition: Renoprotection in hypertension and nephropathy 05101520253035 Hannedouche T et al. Br Med J 1994; 309: 833–837 Log rank test p<0.05 Treatment (months) Placebo ACE inhibitor Cumulative survival rate (%) 100 90 80 70 60 50

36. ACE inhibition: Renoprotection in hypertensive patients Time (months) 061218243036 0 –1 –2 –3 –4 –5 –6 –7 Decrease in GFR (ml/min/1.73 m 2 ) Himmelmann A et al. Am J Hypertens 1996; 9: 850–853 ACE inhibitor  -blocker

37. Correlation between beneficial renal effects and albuminuria Controls ACE inhibitors 0.4 0 –0.4 –0.8 Change in GFR (ml/min/1.73 m 2 /month) Baseline albuminuria (mg/day) 300 Lebovitz HE et al. Kidney Int 1994; 45(Suppl 45): S150–S155 * *p=0.02 vs. controls

38. Dual and compensatory drug elimination If function of the liver is impaired, excretion via the kidney increases If function of the kidney is impaired, excretion via the liver increases Elimination via the kidney and liver PLUS Dual and compensatory elimination Elimination via the kidney and liver ONLY Dual elimination

39. 0 20 40 60 80 100 Fosinopril: Renal clearance in patients with renal dysfunction *Singhvi SM et al. Br J Clin Pharmacol 1988; 25: 9–16 **Hui KK et al. Clin Pharmacol Ther 1991; 49: 457–467 Hepatic clearance Renal clearance None*Mild**Moderate**Severe** Clearance (%) Renal failure

40. Accumulation of lisinopril and enalapril in renal dysfunction Sica DA et al. Clin Pharmacokinet 1991; 20: 420–427 *p<0.05 vs. enalaprilat **p<0.001 vs. lisinopril Fosinoprilat Enalaprilat Lisinopril Accumulation index * ** 1.01.52.02.53.0

41. Dosing of different ACE inhibitors depending on renal function Sica DA. J Cardiovasc Pharmacol 1992; 20(Suppl 10): S13–S20

42. Simplifying antihypertensive treatment in the presence of renal failure ACE inhibitors are the only antihypertensives with established renoprotective potential Hypertension accelerates the decline in GFR and many hypertensive patients have some degree of renal impairment If you consider treatment with an ACE inhibitor, consider dual and compensatory elimination If some degree of renal dysfunction is found, consider treatment with an ACE inhibitor Measure renal function Consider that the patient may have renal impairment If a patient presents with hypertension WHY?