Atto Corso 13-06-2015 Il ruolo del rene nell`ipertensione arteriosa

UNIVERSITÀ DEL PIEMONTE ORIENTALE
AZIENDA OSPEDALIERO - UNIVERSITARIA
"MAGGIORE DELLA CARITA’
DIPARTIMENTO DI MEDICINA TRASLAZIONALE
Il ruolo del rene
nell’ipertensione arteriosa resistente
Piero Stratta
Novara 13 giugno 2015
Il ruolo del rene
nell’ipertensione arteriosa resistente
Funzione renale
glomerulare
Patologia
arterie renali
Funzione renale
post-glomerulare
Il ruolo del rene
nell’ipertensione arteriosa resistente
•Diminuzione del filtrato glomerulare
Patologia
•Insufficienza renale acuta earterie
cronicarenali
•Ritenzione idro-sodica
Funzione renale
post-glomerulare
Diminuzione del filtrato glomerulare
e ritenzione idro-sodica
Sodio (Na+)
Il rene è il principale regolatore
del bilancio del sodio
poiché è in grado di eliminare e/o trattenere
pressochè tutto il sodio
introdotto
mantenendo costante
il pool sodico
Contenuto di sodio
= 55-65 mmol/Kg
3000 mmol in un uomo di 50 Kg
Extracellulare =14litri
Intracellulare
28 litri
Na = 10 mmol/lt
Na= 140 mmol/l
interstiziale
2.8
Dal punto di vista
teleologico,
la “mission”
del rene è
trattenere sodio
Sodio e rene
Sodio
acqua
Quantità
filtrata
25.000
mmol
180 l
Quantità %
eliminata riassorbita
100 mmol 99.6%
1 litro
99.4%
80%
contorto
prossimale
Natriuretici
aldosterone
Contorto
Ansa di Henel distale
Dal punto di vista
della evoluzione
Il dato
“ambientale”
che più si è modificato
è il contenuto
di sodio
della dieta
Il ruolo del rene
nell’ipertensione arteriosa resistente
•Diminuzione del filtrato glomerulare
Patologia
•Insufficienza renale acuta earterie
cronicarenali
•Ritenzione idro-sodica
Funzione renale
post-glomerulare
Resistant Hypertension Definition
A patient has Resistant Hypertension if BP >
140/90 (or > 130/80 with DM, CKD, or history of
cardiovascular disease) despite
Optimal Doses
Of a Minimum of Three
Complementary Antihypertensive Medications
One of which is a Diuretic
Il ruolo del rene
nell’ipertensione arteriosa resistente
Funzione renale
glomerulare
Patologia
arterie renali
Funzione renale
post-glomerulare
Il ruolo del rene
nell’ipertensione arteriosa resistente
Funzione renale
glomerulare
Patologia
Ipertensione
arterie renali
nefrovascolare
Funzione renale
post-glomerulare
IPERTENSIONE NEFROVASCOLARE
DEFINIZIONE
E’un tipo di ipertensione arteriosa secondaria
causata da stenosi o ostruzione, mono o
bilaterale,dell’arteria renale o dei suoi rami
intra o extraparenchimali.
IPERTENSIONE NEFROVASCOLARE
Esperimento di Goldblatt sul cane(1934)
Meccansimni patogenetici della
ipertensione resistente
Casi Clinici
Primo caso
A woman under 40 (with no other clear
secondary cause of hypertension) requiring
> 2 antihypertensives for BP control should
have an imaging test to exclude Renovascular
hypertension.
MRA or DSA renal angiogram
Fibrous renal artery disease
MRA or DSA renal angiogram
Fibrous renal artery disease
What should he do?
Secondo caso
Mr JH. European male aged 68
Chronic stable hypertension
Recent NSTEMI
Blood pressure normal on 2 agents (ACE-I and BB) creatinine 1.8 mg/dl
Referred to an interventional cardiologist for coronary angiography –
during the angiogram he makes incidental note (on single planar vie
ws) of what appears to be a severe left renal artery stenosis.
Secondo caso
Mr JH. European male aged 68
Chronic stable hypertension
Recent NSTEMI
Blood pressure normal on 2 agents (ACE-I and BB) creatinine 1.8 mg/dl
Referred to an interventional cardiologist for
during the angiogram he makes incidental note
be a severe left renal artery stenosis.
coronary angiography –
(on single planar views) of what appears to
What should he do?
Terzo Caso
♀ 74 anni
Forte fumatrice attiva (20 sigarette/die da circa 50 anni)
Non eventi di rilievo in anamnesi
Nessuna terapia a domicilio
Giunge al DEA l’01/01/2015 per afasia ed emiparesi sx
PA 180/100
CREATININA
Filtr.Glom.CKD-EPI
0,67
88
mg/dL 0,60 - 1,10
Ricoverata in Neurologia per le cure del caso
Terapia antipertensiva con ACE-inibitore e Ca- antagonista
con soddisfacente controllo pressorio (140/90).
Avviati statina e antiaggregante
10/01/2015
CREATININA
Filtr.Glom.CKD-EPI
H
1,54
33
mg/dL
0,60 - 1,10
Avviato studio per ricerca di cause secondarie di ipertensione
ECOCOLORDOPPLER ARTERIA RENALE 12/01/2015
Entrambe le arterie renali presentano marcata
ateromasia all'origine determinante stenosi di grado
serrato (>90%; VPS >4 m/s) al tratto prossimale
dell'arteria renale destra e di grado moderato-severo
(70% circa; VPS 1,8 m/s circa) a sinistra.
A giudizio clinico si consiglia integrazione mediante
esame angio-TC delle arterie renali.
Angio-TC
QUALE TERAPIA ?
(1) PTA renal artery
(2) PTA and stent renal artery
(3) Nothing
Anatomical presence of renal artery
stenosis is not on it’s own a
mandate for intervention!
“Le”
Stenosi dell’Arteria Renale
Atherosclerotic renal artery stenosis – common (80%)
Fibrous renal artery disease less common (20%)
Medial fibroplasia (FMH)
Perimedial fibroplasia
Intimal fibroplasia
Medial hyperplasia
Fibrous renal artery disease
Suspect in young ( mainly women)
with difficult hypertension.
Atherosclerotic renal artery stenosis
Clinical Syndromes
(1) Majority asymptomatic
(2) Renovascular hypertension
(3) Ischaemic nephropathy
Most atherosclerotic RAS occurs in individuals over 50 with other ev
idence of vascular disease, particularly PVD and CAD
Clinical Clues
Severe or refractory hypertension/ malignant hypertension
Short duration of hypertension
An acute elevation of creatinine – either spontaneous or
following introduction of an ACE-inhibitor
Assymetry of renal size (the artery supplying the smaller
kidney is often occluded)
“Flash” pulmonary oedema
What do we do when
renal artery stenosis has
been detected on MRA or
angiogram?
Riunione interdisciplinare
richiesta dai Chirurghi vascolari
anche sulla base
delle importanti complicanze
osservate:
•Decesso intraoperatorio
•Perdita del rene
• Embolismo colesterinico
What do we do when renal artery stenosis
has been detected on MRA or angiogram?
Fibrous
Atherosclerotic
What do we do when renal artery stenosis
has been detected on MRA or angiogram?
Fibrous
Yes,
intervention
Atherosclerotic
It
depends
Factors to consider…
-Low incidence of progresssion of stenotic lesions to occlusion
-Most studies show equivalent outcome of angioplasty/ stenting for
atherosclerotic RAS vs medical treatment
-To date, no randomised clinical trial has clearly identified a
group in whom intervention is superior to medical therapy
-Angioplasty (particularly without stenting) can hasten the
progression of stenotic lesions
-No evidence that intervention in patients with controlled BP or
stable renal function improves outcome
(Possible)Predictors of beneficial
outcome from intervention
Uncontrolled BP on several agents
Rapidly worsening renal function
Flash pulmonary oedema
Beneficial effect of ACEI on BP
ACEI-induced uraemia
Doppler resistance index < 80
What is a haemodynamically significant lesion??
More than 75% stenosis
or
More than 50% with
- post stenotic dilatation
or
- reduction in renal size
How can we functionally assess the haemodynamic
significance of a stenosis?
Bilateral stenoses
Good BP response to ACE-inhibitor
Decrease GFR with ACE-inhibitor
Unilateral stenoses
Positive captopril renogram
Doppler resistance index (< 80 is most predictive
determinant of response to revascularisation)
Assessment of a patient with known atherosclerotic RAS
Detection of atheromatous RAS > 50%
↓
Initiate lifelong therapy for atherosclerosis
↓
Optimise antihypertensive and medical therapy
↓
Undertake quantitative functional assessment
BP
Creatinine Clearance
Proteinuria
Single Kidney GFR
Renal Size
RAS Severity
What interventions are available?
PTA
Procedure of choice in FMH – low recurrence rate
In atherosclerotic RAS 40% restenosis in 1 year – reduced to 10%
by PTA + Stenting
Surgical revascularisation
Up to 5% surgical mortality but low incidence of recurrent
stenosis – some enthusiasts, but not widely used now except in
patients requiring concomitant aortic surgery
Nephrectomy
High grade RAS, uncontrollable BP, small kidney with very low
GFR on split renal function
TRATTAMENTO ENDOVASCOLARE
Come ?
PTRA
con o senza stenting
STENT one step
(primary stent)
Risultato dopo angioplastica sinistra
Risultato dopo angioplastica + stent
Primo caso
A woman under 40 (with no other clear secondary cause o
f hypertension) requiring > 2 antihypertensives for BP co
ntrol should have an imaging test to exclude Renovascular
hypertension.
Fibrous renal artery stenosis
Treatment of FMH is angioplasty
- low incidence of recurrence
Risk of renal arterial occlusion or CRF very low
Main benefit of intervention is BP control (reduce or
remove need for antihypertensives)
Secondo caso
Mr JH. European male aged 68
Chronic stable hypertension
Recent NSTEMI
Blood pressure normal on 2 agents (ACE-I and BB) creatinine 1.8 mg/dl
Referred to an interventional cardiologist for coronary angiography –
during the angiogram he makes incidental note (on single planar views) of what a
ppears to be a severe atherosclerotic left renal artery stenosis.
What should he do?
Mr JH should not have angioplasty because….
(1) Unilateral disease
(2) BP and renal function OK
(3) Tolerating an ACE-inhibitor
(4) Functional importance of the right RAS has not been assessed
(5) No current clinical trial evidence that he is likely to benefit
(6) May actually end up being a harmful procedure
Terzo Caso
♀ 74 anni
Forte fumatrice attiva (20 sigarette/die da circa 50 anni)
Marcata ateromasia all'origine determinante stenosi di grado serrato (>90%;
VPS >4 m/s) al tratto prossimale dell'arteria renale destra e di grado moderatosevero (70% circa; VPS 1,8 m/s circa) a sinistra.
Trattamento
Sospensione ACE_inibitore
Quali indicazioni dalla letteratura?
large randomised trials comparing medical therapy +/- angiopasty with stent
placement
STAR
ASTRAL
CORAL
Radiology 2000; 216:78–85
28
33
6
19
24
32
28
32
Ann Intern Med. 2009;150:840-848.
Participants: 140 pts with Cr Clearance less than 80 mL/min/1.73 m2
and ARAS of 50% or greater.
Intervention: Stent placement and medical treatment (64 patients)
or medical treatment only (76 patients). Medical treatment consisted
of antihypertensive treatment, a statin, and aspirin.
Measurements: The primary end point was a 20% or greater
decrease in creatinine clearance. Secondary end points included
safety and cardiovascular morbidity and mortality.
N Engl J Med 2009;361:1953-62.
Randomized, unblinded trial,
806 patients with atherosclerotic renovascular disease either to
undergo revascularization in addition to receiving medical
therapy or to receive medical therapy alone.
The primary outcome was renal function, as measured by the
reciprocal of the serum creatinine (that has a linear
relationship with creatinine clearance).
Secondary outcomes were blood pressure, the time to renal and
major cardiovascular events, and mortality
p = 0.06
947 participants with atherosclerotic renal-artery stenosis and
systolic hypertension or chronic kidney disease
Intervention: medical therapy plus renal-artery stenting or medical
therapy alone.
Participants were followed for the occurrence of adverse
cardiovascular and renal events (a composite end point of death
from cardiovascular or renal causes, myocardial infarction, stroke,
hospitalization for congestive heart failure, progressive renal
insufficiency, or the need for renal-replacement therapy).
Quindi non si deve sottoporre più nessuno a
PTA/stenting delle arterie renali?
467 patients with renal artery stenosis ≥50%, managed according to
clinical presentation
PREDICTORS:
Presentation with flash pulmonary edema (n = 37 [7.8%]), refractory hypertension
(n = 116 [24.3%]), or rapidly declining kidney function (n = 46 [9.7%]) compared
to low-risk presentation with none of these phenotypes (n = 230 [49%]).
Percutaneous revascularization (performed in 32% of flash pulmonary edema, 28% of
rapidly declining kidney function, and 28% of refractory hypertension patients)
compared to medical management.
OUTCOMES: Death, cardiovascular (CV) event, end-stage kidney disease.
CONCLUSIONI
Nella patologia aterosclerotica delle arterie renali,
PTA/stenting non ha dimostrato vantaggi in termini
di mortalità, eventi cardiovascolari e peggioramento
della funzione renale, rispetto alla sola terapia
medica.
L’indicazione al trattamento invasivo della stenosi
delle arterie renali può avere ancora un ruolo in
pazienti ad alto rischio, con edema polmonare,
monorene e rapido declino della funzione renale.
La stenosi delle arterie renali è da trattare
con PTA/stenting?
INDICAZIONI ALLO STENTING
Stenosi > 60-70%
Ipertensione arteriosa non controllata da terapia medica
Edema polmonare ricorrente
Insufficienza renale evolutiva non altrimenti spiegabile
Volume renale conservato
Indici di resistenza < 0.8
Take Home Messages
(1) Don’t look for RAS unless the patient has a probable
indication for intervention eg uncontrolled BP or progressive
renal failure
(2) Most people with RAS will die of CAD or stroke and
cornerstone of management is treatment or cardiovascular risk
factors
(3) The presence of significant RAS is on it’s own not an
indication for intervention
(4) Intervention is indicated in a minority with narrowly defined
parameters
Il ruolo del rene
nell’ipertensione arteriosa resistente
Funzione renale
glomerulare
Patologia
Funzione
renale
Ipertensione
Patologie
arterie renali
post-glomerulare
dei
canali ionici
nefrovascolare
tubulari
CASO CLINICO n 1
L.F 45 anni
Iperteso da anni
Due accessi al PS per pousseè ipertensiva
Nel secondo accesso crisi stenocardica
con coronaro negativa
In triplice terapia
( ACE-I + diuretico, calcio antagonista, doxazosina)
Funzione renale normale
CASO CLINICO n 2
 40 y/ female with hypertension from 10
years
 BP 200/115 HR 88, hypertensive retinopathy
 1 + proteinuria
 Unresponsive to diuretic + three drugs
 ( clonidine, ACE_I , calcium channel blocking)
 normal renal function
Resistant Hypertension Definition
A patient has Resistant Hypertension if BP >
140/90 (or > 130/80 with DM, CKD, or history of
cardiovascular disease) despite
Optimal Doses
Of a Minimum of Three
Complementary Antihypertensive Medications
One of which is a Diuretic
Screening per ipertensione secondaria
•Stenosi arteria renale
•Potassiemia ( + Ega venoso)
•Renina aldosterone
•Tiroide
•Cortisolo
CASO CLINICO n 1
L.F 45 anni
Iperteso da anni
Due accessi al PS per pousseè ipertensiva
Nel secondo accesso crisi stenocardica con coronaro negativa
In triplice terapia ( ACE-I + diuretico, calcio antagonista, doxazosina)
Funzione renale normale
K4
-Potassiuria normale
-Sodiemia normale
Renina bassa Aldosterone alto con rapporto R/A elevato
-Test di soppressione con fisiologica :
Positivo ( aldosterone rimane alto)
Iperaldosteronismo
Iperaldosteronismo
PA is a group of disorders in which aldosterone
production is inappropriately high, relatively
autonomous from the renin-angiotensinsystem,
and nonsuppressible by sodium loading.
Such inappropriate production of aldosterone
causes cardiovasculardamage, suppression of
plasma renin, hypertension, sodium retention,
and potassium excretion that if prolonged and
severe may lead to hypokalemia.
Iperaldosteronismo
Clinica
Primary Aldosteronism (Conn’s Syndrome)
Autonomous overproduction of aldosterone by the
adrenal glands
1-2% of mild hypertension
Up to 20% of resistant hypertension
Hypokalaemia is a late and variable manifestation;
More than 50% are normokalaemic
Aetiology
• bilateral adrenal hyperplasia (common)
• discrete aldosterone-producing adenoma
• unilateral adrenal hyperplasia (rare)
Iperaldosteronismo
Meccansimi di danno ipertensivo
Aldosterone and HTN
• Retention of Salt and Water
• Reduced Endothelial Mediated Relaxation
(Am.J Physiol. 1992; 263:974-9)
• Increasing Pro-Inflammatory Adipokines
• Potentiate the effect of Angiotensin II
Iperaldosteronismo
Meccansimi di danno ipertensivo
Adipose Factors Involved in Obesityrelated HTN
■ Aldosterone
■ Endothelin
■ Nonesterified fatty acids and other FFA
■ Interleukin 6
■ Leptin
■ Renin
■ Tumor necrosis factor
Iperaldosteronismo
Meccansimi di danno vascolare
Obesity/Metabolic stimulation of Aldosterone
• Secretion of Angiotensinogen and AT II by Visceral Adipose
Tissue
• Increased Renin Activity
• Aldosterone secretion increased by Non-esterified FFAs
• Hyperinsulinemia
• Increased CNS sympathetic activity
• Production of a mineralocorticoid releasing factor by
adipose tissue .Acad Sci USA, 2003;100:14211-16 .
Complement C1q TNF –related protein 1 (CTRP1)? FASEB
J.2008;22:1502-11
• Increased cortisol and bounding to 11 -Beta hydroxysteroid
receptor in non-renal tubular cells
Iperaldosteronismo
Diagnosi
Diagnostic workup of suspected Primary Aldosteronism
Seated resting mid-morning plasma
renin and aldosterone
↓
If suppressed renin (<10mU/l) + elevated aldosterone
(> 400ug/l) + A/R ratio > 40
↓
Saline suppression test (2000 ml IV normal saline over 4
hours with per and post aldosterone)
↓
If post-aldosterone non-suppressible (> 200ug/l)
↓
Adrenal CT scan
↓
↓
Iperaldosteronismo
Diagnosi
La Ratio tra R/A in base alle tecniche di laboratorio utilizzate
CASO CLINICO n 2





40 y/ female with hypertension from 10 years
BP 200/115 HR 88, hypertensive retinopathy
1 + proteinuria
Unresponsive to diuretic + three drugs
( clonidine, ACE_I , calcium channel blocking)
K 2.8, alcalosi metabolica ,
potassiuria elevata
Sodiemia normale
sodiuria bassa……..
Iperaldosteronismo
??????????????
CASO CLINICO n 2





40 y/ female with hypertension from 10 years
BP 200/115 HR 88, hypertensive retinopathy
1 + proteinuria
Unresponsive to diuretic + three drugs
( clonidine, ACE_I , calcium channel blocking)
K 2.8, alcalosi metabolica , potassiuria
elevata
Sodiemia normale
sodiuria bassa,
Renina e aldosterone bassi
NO
Liddle’s Syndrome
(Pseudohypoaldosteronism type 1)
Liddle syndrome
rare
Grant Liddle 1963
Autosomal dominant, young onset
Appears like hyperaldosteronism:
HT
volume expansion
salt retention
 K+
However, low renin / aldo
Response to amiloride / triamterene (ENaC inhibitors)
must also be on low-salt diet
Liddle’s Syndrome
Clinica
Liddle’s Syndrome: Characteristic Features
- Prevalence < 1% hypertensives
- Mechanism
Autosomal Dominant activating mutation(s) in ENaC of collecting duct
Impaired regulatory mechanism leads to increased no. ENaC channels on luminal
membrane
-Presentation: severe salt sensitive hypertension, hypokalaemia, low renin +
aldosterone
- Presents in children and young adults
- Diagnosis
– Genetic analysis of ENaC gene
- Treatment
NOT responds to anti-aldosteronic drugs !!!!!!
Responds to low protein and salt diet and triamterene
Hypertension and hypokalaemia
↓
Measure renin and aldosterone
↑ renin + aldo
↓
↓
N or ↓ renin + ↑aldo
↓
↓ renin + ↓aldo
↓
Malignant hypertension
Primary aldosteronism
Apparent
mineralocortocoid excess
Renovascular
Idiopathic aldosteronism
– genetic (11BHSD2 mutation)
– acquired (glycerrhetinic acid)
Diuretics
Glucorticoid remediable
hyperaldosteronism
Cushing’s Syndrome
Coarctation
Renin-secreting tumour
Renal infarct
Vasculitis
DOC Excess
Congenital adrenal
hyperplasia
Liddle’s Syndrome
Activating MR Mutation
Il ruolo del rene
nell’ipertensione arteriosa resistente
Funzione renale
glomerulare
Patologia
Funzione
renale
Ipertensione
Patologie
arterie renali
post-glomerulare
dei
canali ionici
nefrovascolare