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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
Corbi , Acanfora , Iannuzzi, Longobardi, Cacciatore, Rengo, Filippelli, Ferrara Rejuvenation Res. 2008;11(1):129-38
Hypermagnesemia and cognitivity in elderly
Corbi , Acanfora , Iannuzzi, Longobardi, Cacciatore, Rengo, Filippelli, Ferrara Rejuvenation Res. 2008;11(1):129-38
Hypermagnesemia and disability in elderly
Corbi , Acanfora , Iannuzzi, Longobardi, Cacciatore, Rengo, Filippelli, Ferrara Rejuvenation Res. 2008;11(1):129-38
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
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
ACE
Bradichinina Frammentiinattivi
• Vasodilatazione• Inibizione della
proliferazione• Chinine
AT2
AT1
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
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
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
0
5
10
15
20Prevalence (%)
Non DMNon HBP
HBP HBPDM
6.6
11.5
16.4
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
0
1.5
3
Adju
sted
haz
ard
ratio
*
0.5
2
<2.21
Decile of urine albumin-creatinine ratio (mg/g)
2.5
1
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
>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
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
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
CV death, fatal/non fatal stroke, fatal/non fatal MI; n=8206CV death, fatal/non fatal stroke, fatal/non fatal MI; n=8206
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
Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes
JNC 7° Hypertension 2003;42;1206-1252
Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes
JNC 7° Hypertension 2003;42;1206-1252
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
Basi et al. Am J Kidney Dis 47:927-946
Studies evaluating treatment effects: impact on long-term renal outcomes
Basi et al. Am J Kidney Dis 47:927-946
Studies evaluating treatment effects: impact on long-term renal outcomes
Basi et al. Am J Kidney Dis 47:927-946
ACE-I
Change in risk for renal outcomes associated with treatment-induced decreases in albuminuria.
Basi et al. Am J Kidney Dis 47:927-946
Mann et al. Lancet 2008; 372: 547–53
Relative risk for primary renal outcome in subgroupsComparison of ramipril and telmisartan.
Mann et al. Lancet 2008; 372: 547–53
Relative risk for primary renal outcome in subgroupsComparison of ramipril and telmisartan.
Mann et al. Lancet 2008; 372: 547–53
Relative risk for primary renal outcome in subgroupsComparison of ramipril and telmisartan.
Mann et al. Lancet 2008; 372: 547–53
Relative risk for primary renal outcome in subgroupsComparison of ramipril and telmisartan plus ramipril.
Mann et al. Lancet 2008; 372: 547–53
Relative risk for primary renal outcome in subgroupsComparison of ramipril and telmisartan plus ramipril.
Mann et al. Lancet 2008; 372: 547–53
Kaplan-Meier curves for primary renal outcome (dialysis, doubling of serum creatinine, and death),
Mann et al. Lancet 2008; 372: 547–53
Kaplan-Meier curves for secondary renal outcome (dialysis and doubling of serum creatinine)
• 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
Criteri di scelta della terapia antipertensiva per la prevenzione del danno renale