Nefroprotezione nell’ipertensione arteriosa

Nicola Ferrara, MDDipartimento di Scienze per la SaluteUniversità del Molise

Simposio SIGG-SINInsufficienza Renale Cronica e Nefroprotezione nell’anziano: dalla prevenzione al trattamento

1 Dicembre 2010 – Firenze

MODIFICAZIONI ETA’ – CORRELATE

MORFO - FUNZIONALI DEL RENE

JE Martin* and MT Sheaff - J Pathol 2007; 211: 198–205

Reduplication of the internal elastic lamina

JE Martin* and MT Sheaff - J Pathol 2007; 211: 198–205

Hyaline Arteriosclerosis

GFR Decreases As a Part of “Normal” Aging? often attributed to Lindeman J Am Geriat Soc 33:278-285, 1985

Clearance della creatinina secondoCockroft e Gault

CCr (uomo) = (140 – età) x peso corporeo [Kg]

PCr [mg/dl] x 72

CCr (donna) = (140 – età) x peso corporeo [Kg] x 0.85PCr [mg/dl] x 72

Cockroft and Gault. Nephron 1976, 16: 31Gault. Nephron 1992, 62: 249

Clearance della creatinina secondo la formula “Modification of Diet in Renal Disease”

GFR =186 X (Pcr/88.4)-1.154 X età-0.203

X 1.212 (se di razza nera) X 0.742 (se di sesso femminile)

Hallan S et all. Am J Kidney Dis 2004, 44:84

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

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: 2758–2765, 2007

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

Hypermagnesemia and cognitivity in elderly

Hypermagnesemia and disability in elderly

Hypermagnesemia predicts mortality in elderly

RENE E PRESSIONE ARTERIOSA

UN RAPPORTO DIALETTICO

Spectrum of pressure/flow relationships in renal vascular bed in hypertension

Bidani et al. Hypertension. 2004;44:595-601

Danno d’organo ed eventi clinici nell’ipertensione

IpertensioneIpertensione

Disfunzione endoteliale (ATS)Ipertrofia & fibrosi vascolare

VasculopatieVasculopatie

GFR, creatininemia, microalbuminuria,

proteinuria, insufficienza renale

GFR, creatininemia, microalbuminuria,

proteinuria, insufficienza renale

Ipertrofia del ventricolo sinistro,rimodellamento, fibrosi,

infarto, scompenso

Ipertrofia del ventricolo sinistro,rimodellamento, fibrosi,

infarto, scompenso

GFR = tasso di filtrazione glomerulare

Fattori che possono determinare Fattori che possono determinare ipertensione nellipertensione nell’’Insufficienza RenaleInsufficienza Renale

••IperattivitIperattivitàà del sistema reninadel sistema renina--angiotensinaangiotensina••IperattivitIperattivitàà del sistema simpaticodel sistema simpatico••Sovraccarico cronico di volumeSovraccarico cronico di volume

Effetti proinfiammatori eEffetti proinfiammatori eGrowhtGrowht--promotingpromoting

Fattori che possono determinare Fattori che possono determinare ipertensione nellipertensione nell’’Insufficienza RenaleInsufficienza Renale

••IperattivitIperattivitàà del sistema reninadel sistema renina--angiotensinaangiotensina••IperattivitIperattivitàà del sistema simpaticodel sistema simpatico••Sovraccarico cronico di volumeSovraccarico cronico di volume

Effetti proinfiammatori eEffetti proinfiammatori eGrowhtGrowht--promotingpromoting

Mori et al. Hypertension. 2004;43:752-759

Mechanism of pressure-induced renal injury.

Mori et al. Hypertension. 2004;43:752-759

Mechanism of pressure-induced renal injury.

Adaptive changes in remnant nephrons after subtotal nephrectomy

Whitworth et al. Ann Acad Med Singapore 2005;34:8-15

Pgc: Glomerular capillary pressure GBM: Glomerular Basement Membrane

Effect of angiotensin II and ET-1 on the glomerular wall.

Hypertension. 2006;48:834-837

Effect of angiotensin II and ET-1 on the glomerular wall.

Hypertension. 2006;48:834-837

IL SISTEMA

RENINA-ANGIOTENSINA

Sistema-renina-angiotensina-aldosterone

AngiotensinogenoAngiotensinogeno

Vie non-ACE(e.g., chimasi)

• Vasocostrizione• Proliferazione cellulare• Ritenzione di Na/H2O• Attivazione simpatica• Aldosterone

renina Angiotensina IAngiotensina I

Angiotensina IIAngiotensina II

Bradichinina Frammentiinattivi

• Vasodilatazione• Inibizione della

proliferazione• Chinine

IL SISTEMA NERVOSO

ADRENERGICO

Interactions between Sympathetic Nervous System (SNS), RAS and Endothelin System (ETS) in regulating BP

29Wenzel et al. Antihypertensive Drugs and the Sympathetic Nervous System.J of Cardiovascular Pharmacology. 35:S43-S52, 2000

Klein et al. J Am Soc Nephrol 12: 2427–2433, 2001

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).

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

DALLA FISIOPATOLOGIA

ALLA EPIDEMIOLOGIA

Trends in incident rates of ESRD, by primary diagnosis(adjusted for age, gender, race).

Source: United States Renal Data System. 2002.JNC 7° Hypertension 2003;42;1206-1252

Cumulative Incidence of ERSD according to Blood-Pressurein 332,544 Men Screened for MRFIT.

Klag et al. N Engl J Med 1996;334:13-8

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: 2776–2782, 2002

IL RUOLO DELLA ALBUMINURIA

Basi et al. Am J Kidney Dis 47:927-946, 2006

Relationship between RAAS and albuminuria.

Basi et al. Am J Kidney Dis 47:927-946, 2006

Relationship between RAAS and albuminuria.

Urine Albumin Excretion

Normal albumin excretion

Microalbuminuria

Proteinuira

Category 24 hour collection(mg/24h)

Timed collection(µg/min)

Spot collection(µg/mg Cr)

Normal < 30 < 20 < 30

Microalbuminuria 30-299 20-199 30-299

Clinical albuminuria

≥ 300 ≥ 200 ≥ 300

Because of variability in urinary albumin excretion, 2 of 3 specimens over3-6 should be abnormal before considering diagnostic threshold positiveFalse positive: exercise < 24 hours, fever, CHF, marked hyperglycemia, marked HTN, pyuria and hematuria.

Definitions of abnormalities in albumin excretion

Prevalence of Microalbuminuria: Hypertension and Diabetes

20Prevalence (%)

Non DMNon HBP

HBP HBPDM

Hillege, J Intern Med 20001

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):820-829

Hypertensive Patients with (○) and without (●) microalbuminuria.

Adapted from Bianchi et al, American J of Hypertension,1994: 7:23-29

Cardiovascular Mortality and Urine Albumin Excretion

Circulation 2002;106:1777

Microalbuminuria and Mortality

PREVEND study (Ciculation 2002;106:1777)2-fold increase in urine albumin

RR 1.29 for CV mortalityRR 1.12 for non-CV mortality

Independent of all classical CVD risk factors

LIFE StudyContinuous Relation of Albuminuria to Primary Outcome

Wachtell K et al., Ann Intern Med. 2003; 139:901-906

Adjusted for LV mass, age, gender, smoking, serum creatinine, race, study treatment allocation

Decile of urine albumin-creatinine ratio (mg/g)

2.21-3.6

3.6-5.2

5.2-7.3

7.3-10.3

10.3-14.8

14.8-22.4

22.4-38.2

38.2-83.4

CV death, fatal/non fatal stroke, fatal/non fatal MI; n=8206CV death, fatal/non fatal stroke, fatal/non fatal MI; n=8206

LIFE StudyReduction in Albuminuria Translates to Reduction in

Cardiovascular Events in Hypertensive Patients

Ibsen H et al., Hypertension 2005; 45:198-202

RUOLO DELLA TERAPIA

19901990

19801980

ANTIHYPERTENSIVE DRUGSANTIHYPERTENSIVE DRUGS

DiureticsDiuretics

GuanethidineGuanethidine

Reserpine19601960

MethyldopaMethyldopa

ClonidineClonidine

PrazosinPrazosin β -blockersβ -blockers19701970

Ca++-antagonistsCa++-antagonists

ACE inhibitorsACE inhibitors

Angiotensin IIreceptors antagonist

Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes

JNC 7° Hypertension 2003;42;1206-1252

UAE before and 4 and 8 weeks after treatment with enalapril, nitrendipine, diuretics, or atenolol

Bianchi et al. American Journal of Kidney Diseases, 1999; 34: 973-995

*P < 0.01.

55% of patients 55% of patients (Immediate decrease in UAE (Immediate decrease in UAE

by 4 weeks)by 4 weeks)

160 mg160 mg ‐‐49%49%

320 mg320 mg ‐‐52%52%

640 mg640 mg ‐‐52%52%

45% of patients 45% of patients (No change in UAE(No change in UAE

by 4 weeks)by 4 weeks)

160 mg160 mg +5%+5%

320 mg320 mg +1.5%+1.5%

640 mg640 mg ‐‐19.5%19.5%

DROPDROP% Median Change in UAE% Median Change in UAE

Hollenberg, J Hypertens. 2007 Sep;25(9):1921-6Hollenberg, J Hypertens. 2007 Sep;25(9):1921-6

Valsartan Dose

Studies evaluating treatment effects: impact on albuminuria, including both cardiovascular and renal

studies

Basi et al. Am J Kidney Dis 47:927-946

Studies evaluating treatment effects: impact on albuminuria, including both cardiovascular and renal

studies

Studies evaluating treatment effects: impact on long-term renal outcomes

Change in risk for renal outcomes associated with treatment-induced decreases in albuminuria.