Nefroprotezione nell ipertensione arteriosa

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1 Simposio SIGG-SIN Insufficienza Renale Cronica e Nefroprotezione nell anziano: dalla prevenzione al trattamento 1 Dicembre 2010 Firenze Nefroprotezione nell ipertensione arteriosa Nicola Ferrara, MD Dipartimento di Scienze per la Salute Università del Molise

2 MODIFICAZIONI ETA CORRELATE MORFO - FUNZIONALI DEL RENE

3 Reduplication of the internal elastic lamina JE Martin* and MT Sheaff - J Pathol 2007; 211:

4 Hyaline Arteriosclerosis JE Martin* and MT Sheaff - J Pathol 2007; 211:

5 GFR Decreases As a Part of Normal Aging? often attributed to Lindeman J Am Geriat Soc 33: , 1985

6 Clearance della creatinina secondo Cockroft e Gault CCr (uomo) = (140 età) x peso corporeo [Kg] PCr [mg/dl] x 72 CCr (donna) = (140 età) x peso corporeo [Kg] x 0.85 PCr [mg/dl] x 72 Cockroft and Gault. Nephron 1976, 16: 31 Gault. Nephron 1992, 62: 249

7 Clearance della creatinina secondo la formula Modification of Diet in Renal Disease GFR = 186 X (P cr /88.4) X età X (se di razza nera) X (se di sesso femminile) Hallan S et all. Am J Kidney Dis 2004, 44:84

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11 Corbi, Acanfora, Iannuzzi, Longobardi, Cacciatore, Rengo, Ferrara Rejuvenation Res. 2008;11(1):129-38

12 Baseline egfr threshold below which risk for ESRD exceeded risk for death for each age group. O'Hare et al. J Am Soc Nephrol 18: , 2007

13 Corbi, Acanfora, Iannuzzi, Longobardi, Cacciatore, Rengo, Filippelli, Ferrara Rejuvenation Res. 2008;11(1):129-38

14 Hypermagnesemia and cognitivity in elderly Corbi, Acanfora, Iannuzzi, Longobardi, Cacciatore, Rengo, Filippelli, Ferrara Rejuvenation Res. 2008;11(1):129-38

15 Hypermagnesemia and disability in elderly Corbi, Acanfora, Iannuzzi, Longobardi, Cacciatore, Rengo, Filippelli, Ferrara Rejuvenation Res. 2008;11(1):129-38

16 Hypermagnesemia predicts mortality in elderly Corbi, Acanfora, Iannuzzi, Longobardi, Cacciatore, Rengo, Filippelli, Ferrara Rejuvenation Res. 2008;11(1):129-38

17 RENE E PRESSIONE ARTERIOSA UN RAPPORTO DIALETTICO

18 Spectrum of pressure/flow relationships in renal vascular bed in hypertension Bidani et al. Hypertension. 2004;44:

19 Danno d organo ed eventi clinici nell ipertensione Vasculopatie Ipertensione Disfunzione endoteliale (ATS) Ipertrofia & fibrosi vascolare Ipertrofia del ventricolo sinistro, rimodellamento, fibrosi, infarto, scompenso GFR = tasso di filtrazione glomerulare GFR, creatininemia, microalbuminuria, proteinuria, insufficienza renale

20 Fattori che possono determinare ipertensione nell Insufficienza Renale Iperattività del sistema renina-angiotensina angiotensina Iperattività del sistema simpatico Sovraccarico cronico di volume Effetti proinfiammatori e Growht-promoting

21 Fattori che possono determinare ipertensione nell Insufficienza Renale Iperattività del sistema renina-angiotensina angiotensina Iperattività del sistema simpatico Sovraccarico cronico di volume Effetti proinfiammatori e Growht-promoting

22 Mechanism of pressure-induced renal injury. Mori et al. Hypertension. 2004;43:

23 Mechanism of pressure-induced renal injury. Mori et al. Hypertension. 2004;43:

24 Adaptive changes in remnant nephrons after subtotal nephrectomy Pgc: Glomerular capillary pressure GBM: Glomerular Basement Membrane Whitworth et al. Ann Acad Med Singapore 2005;34:8-15

25 Effect of angiotensin II and ET-1 on the glomerular wall. Hypertension. 2006;48:

26 Effect of angiotensin II and ET-1 on the glomerular wall. Hypertension. 2006;48:

27 IL SISTEMA RENINA-ANGIOTENSINA

28 Sistema-renina-angiotensina-aldosterone Angiotensinogeno renina Vie non-ace (e.g., chimasi) Angiotensina I Vasocostrizione Proliferazione cellulare Ritenzione di Na/H 2 O Attivazione simpatica Aldosterone AT1 ACE Angiotensina II AT2 Bradichinina Frammenti inattivi Vasodilatazione Inibizione della proliferazione Chinine

29 IL SISTEMA NERVOSO ADRENERGICO

30 Interactions between Sympathetic Nervous System (SNS), RAS and Endothelin System (ETS) in regulating BP 29 Wenzel et al. Antihypertensive Drugs and the Sympathetic Nervous System. J of Cardiovascular Pharmacology. 35:S43-S52, 2000

31 Age and Muscle Sympathetic Nerve Activity controls (r 0.66; P 0.001); PKD (r 0.65; P 0.001). Regression line of PKD was steeper than the one of controls (P 0.01). Klein et al. J Am Soc Nephrol 12: , 2001

32 Changes in MAP and Muscle Sympathetic-Nerve Activity in Patients with Chronic Renal Failure Ligtenberg et al. N Engl J Med 1999;340:1321-8

33 DALLA FISIOPATOLOGIA ALLA EPIDEMIOLOGIA

34 Trends in incident rates of ESRD, by primary diagnosis (adjusted for age, gender, race). Source: United States Renal Data System JNC 7 Hypertension 2003;42;

35 Cumulative Incidence of ERSD according to Blood-Pressure in 332,544 Men Screened for MRFIT. Klag et al. N Engl J Med 1996;334:13-8

36 Risk of a decline in kidney function according to BP in SHEP (Systolic Hypertension in the Elderly Program) Young et al. J Am Soc Nephrol 13: , 2002

37 Risk of a decline in kidney function according to BP in SHEP (Systolic Hypertension in the Elderly Program) Young et al. J Am Soc Nephrol 13: , 2002

38 Risk of a decline in kidney function according to BP in SHEP (Systolic Hypertension in the Elderly Program) Young et al. J Am Soc Nephrol 13: , 2002

39 IL RUOLO DELLA ALBUMINURIA

40 Relationship between RAAS and albuminuria. Basi et al. Am J Kidney Dis 47: , 2006

41 Relationship between RAAS and albuminuria. Basi et al. Am J Kidney Dis 47: , 2006

42 Urine Albumin Excretion Normal albumin excretion Microalbuminuria Proteinuira

43 Definitions of abnormalities in albumin excretion Category 24 hour collection Timed collection Spot collection (mg/24h) (µg/min) (µg/mg Cr) Normal < 30 < 20 < 30 Microalbuminuria Clinical albuminuria Because of variability in urinary albumin excretion, 2 of 3 specimens over 3-6 should be abnormal before considering diagnostic threshold positive False positive: exercise < 24 hours, fever, CHF, marked hyperglycemia, marked HTN, pyuria and hematuria.

44 Prevalence of Microalbuminuria: Hypertension and Diabetes Prevalence (%) Non DM Non HBP HBP HBP DM Hillege, J Intern Med 20001

45 Crude association between systolic blood pressure and annual decrease in egfr (A) patients without albuminuria (B) patients with albuminuria Vlek et al Am J Kidney Dis 2009; 54(5):

46 Hypertensive Patients with ( ) and without ( ) microalbuminuria. Adapted from Bianchi et al, American J of Hypertension,1994: 7:23-29

47 Cardiovascular Mortality and Urine Albumin Excretion Circulation 2002;106:1777

48 Microalbuminuria and Mortality PREVEND study (Ciculation 2002;106:1777) 2-fold increase in urine albumin RR 1.29 for CV mortality RR 1.12 for non-cv mortality Independent of all classical CVD risk factors

49 LIFE Study Continuous Relation of Albuminuria to Primary Outcome CV death, fatal/non fatal stroke, fatal/non fatal MI; n= Adjusted hazard ratio* Adjusted for LV mass, age, gender, smoking, serum creatinine, race, study treatment allocation 0 < Decile of urine albumin-creatinine ratio (mg/g) >83.4 Wachtell K et al., Ann Intern Med. 2003; 139:

50 LIFE Study Reduction in Albuminuria Translates to Reduction in Cardiovascular Events in Hypertensive Patients CV death, fatal/non fatal stroke, fatal/non fatal MI; n=8206 Ibsen H et al., Hypertension 2005; 45:

51 LIFE Study Reduction in Albuminuria Translates to Reduction in Cardiovascular Events in Hypertensive Patients CV death, fatal/non fatal stroke, fatal/non fatal MI; n=8206 Ibsen H et al., Hypertension 2005; 45:

52 LIFE Study Reduction in Albuminuria Translates to Reduction in Cardiovascular Events in Hypertensive Patients CV death, fatal/non fatal stroke, fatal/non fatal MI; n=8206 Ibsen H et al., Hypertension 2005; 45:

53 RUOLO DELLA TERAPIA

54 ANTIHYPERTENSIVE DRUGS Diuretics Guanethidine Reserpine Ca++-antagonists ACE inhibitors Methyldopa Prazosin Angiotensin II receptors antagonist Clonidine β -blockers

55 Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes JNC 7 Hypertension 2003;42;

56 Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes JNC 7 Hypertension 2003;42;

57 Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes JNC 7 Hypertension 2003;42;

58 Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes JNC 7 Hypertension 2003;42;

59 UAE before and 4 and 8 weeks after treatment with enalapril, nitrendipine, diuretics, or atenolol *P < Bianchi et al. American Journal of Kidney Diseases, 1999; 34:

60 55% of patients (Immediate decrease in UAE by 4 weeks) DROP % Median Change in UAE Valsartan Dose 160 mg 49% 320 mg 52% 640 mg 52% 45% of patients (No change in UAE by 4 weeks) 160 mg +5% 320 mg +1.5% 640 mg 19.5% Hollenberg, J Hypertens Sep;25(9):1921-6

61 Studies evaluating treatment effects: impact on albuminuria, including both cardiovascular and renal studies Basi et al. Am J Kidney Dis 47:

62 Studies evaluating treatment effects: impact on albuminuria, including both cardiovascular and renal studies Basi et al. Am J Kidney Dis 47:

63 Studies evaluating treatment effects: impact on longterm renal outcomes Basi et al. Am J Kidney Dis 47:

64 Studies evaluating treatment effects: impact on longterm renal outcomes ACE-I Basi et al. Am J Kidney Dis 47:

65 Change in risk for renal outcomes associated with treatment-induced decreases in albuminuria. Basi et al. Am J Kidney Dis 47:

66 Relative risk for primary renal outcome in subgroups Comparison of ramipril and telmisartan. Mann et al. Lancet 2008; 372:

67 Relative risk for primary renal outcome in subgroups Comparison of ramipril and telmisartan. Mann et al. Lancet 2008; 372:

68 Relative risk for primary renal outcome in subgroups Comparison of ramipril and telmisartan. Mann et al. Lancet 2008; 372:

69 Relative risk for primary renal outcome in subgroups Comparison of ramipril and telmisartan plus ramipril. Mann et al. Lancet 2008; 372:

70 Relative risk for primary renal outcome in subgroups Comparison of ramipril and telmisartan plus ramipril. Mann et al. Lancet 2008; 372:

71 Kaplan-Meier curves for primary renal outcome (dialysis, doubling of serum creatinine, and death), Mann et al. Lancet 2008; 372:

72 Kaplan-Meier curves for secondary renal outcome (dialysis and doubling of serum creatinine) Mann et al. Lancet 2008; 372:

73 Criteri di scelta della terapia antipertensiva per la prevenzione del danno renale Valutazione delle comorbilità Valutazione multidimensionale Utilizzo di farmaci efficaci sul danno d organo e sugli end points primari La massima riduzione possibile della pressione arteriosa con la terapia meglio tollerata dal paziente

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