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Preeclampsia e rene: recenti
acquisizioni e future strategie
Preeclampsia e rene
Loreto Gesualdo
Università di Bari
PREGNANCY AND RENAL DISEASES
Complications in the normal pregnancy
Urinary abnormalities 15 - 25 %
Hypertension in pregnancy 10 - 12 %
Urinary tract infections 2 - 10 %
Renal calculi 0.03 - 1 %
Acute Renal Failure 0.05 - 0.15 %
Incidence
Hypertension in
pregnancy
60
70
80
90
100
110
120
130
140
150
10 20 28 32 38 weeksPre-pregnancy
6 12
NHLBI Working Group on Research on Hypertension during Pregnancy Roberts et al. Hypertension 2003; 41
Classification of hypertension in pregnancy
Delivery
Chronic Hypertension
160
Masked chronic hypertension
Pre-eclampsia super imposed
Pre-eclampsia/Eclampsia
Gestational Hypertension
When we’re talking about hypertension
during pregnancy ?
SBP > 140 mmHg
DBP > 90 mmHg
The woman should be rested
The blood pressure cuff should be of appropiate size and placed
on the right arm at the level of the heart
Recent studies have shown that the disappearance of the fifth
Korotkoff sound (K5) is greater than K4 to record diastolic
pressure in pregnancy.
Brown M.A.et al, Classification of hypertension in pregnancy, Clinical Obstetrics and Gynaecology;1999, 13
Walker J.J.,Pre-eclampsia, Lancet 2000; 356
Working group report on high blood pressure in pregnancy. NIH, Washington, DC 2000.
Hypertension in pregnancy: problem’s dimension
•Hypertensive disorders complicate 10-
12% of pregnancies
•Pre-eclampsia occurs in 3-4 % of
pregnancies (mild in 75% of cases and
severe in 25%)
•Chronic Hypertension complicates 2-
3% of pregnancies
•Gestational Hypertension occurs in 5-
6%
Hypertension in pregnancy: problem’s dimension
Risk factor for Preeclampsia
Maternal age < 17 years and > 35
Nulliparity
Multifetal gestation
Preeclampsia in previous pregnancy
Family history of pregnancy-induced hypertension
Chronic Hypertension
Chronic renal disease
Diabetes mellitus , insulin resistance
High BMI (obesity), dyslipidemia
Vascular or connective tissue diseases
Thrombophilia (AAS, fatt. V leiden, Antithrombin III, protein C orS deficiency)
Preeclampsia
Minime variazioni del volume plasmatico efficace
Aumento dell’ematocrito
Gittata cardiaca: normale o aumentata
Riduzione della Portata Renale Plasmatica (PRP)
e della VFG
Aumento delle resistenze vascolari periferiche
Gravidanza normale
Alto volume
Bassa pressione
Basse resistenze periferiche
Pre-eclampsia
Basso volume
Alta pressione
Alte resistenze periferiche
Pre-eclampsia
Eclampsia
Endotheliosis lesion and segmental
early thrombotic microangiopathy
Extensive severe thrombotic microangiopathy
Heptinstall’s Pathology of the Kidney - 6th edition - 2007
Severe arteriolar lesion with fibrinoid necrosis
and intraluminal fibrin
Maternal mortality associated with pre-eclampsia and eclampsia (UK)
Walker J.J, Lancet, 2000, 356
600.000 donne/anno muoiono per cause connesse alla gravidanza
Almeno 50.000 di questi decessi sono attribuibili alla pre-eclampsia /eclampsia
Solo 1 su 2000 gravidanze
in alcune nazioni in via di sviluppo:
!! 1 caso ogni 100 gravidanze
99% di questi eventi sono nei paesi in via di sviluppo
Maternal Mortality
USA: 15/100,000 live births
Mali: 800/100,000 live births
Hemorrhage
Embolism
Preeclampsia
Infection
Greene M. N Engl J Med 2003;348:275-276
Autopsy Specimen from a 40-Year-Old Woman with Severe Preeclampsia and Subarachnoid Hemorrhage
Clinical Manifestation(after 20 wks’ gestation)
Mild(75%): DBP < 110 mmHg
Proteinuria < 3 gr/24h
Severe(25%): DBP > 110 mmHg
Proteinuria > 3 g/24h
Other manifestations:- Headache
- Blurred vision
- Renal impairment
- Seizures (eclampsia)
Sistolica >160 mmHg
o
Diastolica >110 mmHgalmeno 2 volte a distanza di 6 ore
Piastrine < 100.000 mm3
Transaminasi x 2
Proteinuria >5g/24h
o
+++ dipstick in 2
campioni separati
Complicanze più gravi: Oliguria, edema
polmonare, incidente CV, coagulopatia
Pre-eclampsia severaInsorgenza di ipertensione e proteinuria e almeno 1 delle seguenti condizioni
Sintomi neurologiciRitardo crescita
HELLP Syndrome
Microangiopathic hemolysis
Platelet count <100.000/l
Elevated liver enzymes
Proteinuria
Lung edema, ascites
Acute renal failure
Disseminated intravascular coagulation
Hypertension
Abdominal pain
Neurological problem
Clinical Manifestation
Development and validation of the fullPIERS model
Gestational age
Chest pain or dyspnoea
Oxygen saturation
Platelet count
Creatinine and aspartate transaminase concentration
von Dadelszen P et al Lancet 377, 219-227, 2011
Prediction of adverse maternal
outcome in pre-eclampsia
Identificata la causa della pre-eclampsia?
Preeclampsia
Eziologia:
Sconosciuta, patologia inesistente negli animali
Patogenesi:
Non chiarita
Obiettivo principale:
Individuazione della pre-eclampsia e trattamento perprevenire severe complicanze.
Non disponiamo al momento di terapia specifica preventiva per la malattia!
DISFUNZIONE ENDOTELIALE SISTEMICA
Tutte le manifestazioni cliniche della PREECLAMPSIApossono essere spiegate come una risposta materna ad unadisfunzione endoteliale generalizzata.
L’alterato controllo endoteliale del tono vascolare determinaipertensione arteriosa, incremento della permeabilitàvascolare con conseguente edema e proteinuria ed anomalaespressione endoteliale di fattori procoagulanti in grado diattivare la cascata coagulativa.
Queste modificazioni causano inoltre ischemia di organibersaglio, quali il cervello, il fegato e la placenta.
The capillary lumen is decreased secondary to swelling of the endothelial cell (END.) The intercapillary
cell mass, including mesangium (MES), appears increased, and there is an increase in amorphous
material along the inner surface of basement membrane, especially in the region of the intercapillary cell
mass. Epithelial cell (EPITH) changes are mild, except for occasional large blebs showing almost no
filamentous matrix or cytoplasmic particulates.
Heptinstall’s Pathology of the Kidney - 6th edition - 2007
Etiology
Multiple theories: toxins, nephritis, parasites,
malnutrition, vitamin deficiency, genetic,
immunologic, inflammation, oxidation,
prostaglandin imbalance, angiogenic
factors,……..
Pathophysiology
Endothelial cell injury
Generalized vasoconstriction
Pathophysiology
Maternal immunologic intolerance
Abnormal placental implantation
Genetic, nutritional, and environmental
factors
Cardiovascular and inflammatory
changes
Atherosis in placental bed
Rogers et al: Obst Gynecol Survey 54:189,1999
Roberts, J. M. et al. Hypertension 2005; 46:1243-1249
Two-stage model of the pathophysiology of preeclampsia
Stage 2 develops in
some, but not all
women with stage 1
C. W. Redman et al., Science 308, 1592 -1594 (2005)
Poor placentation and preeclampsia
Uterine spiral artery
“unwinds” and becomes
a wider, flaccid tube to
accommodate increased
blood flow.
Uterine spiral artery
remains tightly coiled,
diminishing placental
blood flow
The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 11 November 2010
March 2011 | Volume 8 | Issue 3 |
Defective invasion of
endovascular trophoblast into the
myometrial segments of spiral
arteries?
Villi Coriali
Placenta Normale
Villi Coriali
Placenta Gestosica
L. Resta & L. Gesualdo Placenta 27:735-739, 2006.
Ipotesi Patogenetica
Predisposizione Genetica↓
Mancato o incompleto impianto del trofoblasto nelle arterie spiraliformi materne
↓Ridotta perfusione del citotrofoblasto
↓Attivazione del sistema immune
↓Aumentata produzione di radicali liberi dell’ossigeno
↓
Danno Endoteliale
↓Alterazione di…
Bilancia vasocostrittiva/ vasodilatativa
Coagulazione
PREECLAMPSIA
Sistema delle Integrine ed Angiogenesi
Gravidanza Normale
Pre-eclampsia
Ute
ro
Rimodellamento
Vasale adeguato↑ Flusso
Ematico
Rimodellamento
Vasale inefficace↓ Flusso
Ematico
Normossia
Ipossia
Pla
cen
taU
tero
Pla
cen
ta
Disfunzione Endoteliale
Normale Funzione
Endoteliale
Disfunzione Multiorgano
----------------------------------------
• Ipertensione
• Disfunzione Glomerulare
• Proteinuria
• Edema Cerebrale
• Edema Epatico
• Anomalie della
Coagulazione
Normale funzione
----------------------------------------
• Normotensione
• Normale Funzione
Glomerulare
• Non Proteinuria
• Non Edema Cerebrale
• Non Edema Epatico
• Non Anomalie della
Coagulazione
Gravidanza Normale
Pre-eclampsia
Ute
ro
Rimodellamento
Vasale adeguato↑ Flusso
Ematico
Rimodellamento
Vasale inefficace↓ Flusso
Ematico
Normossia
Ipossia
↑ sFlt-1
sFlt-1
?
Pla
cen
taU
tero
Pla
cen
ta
Normali livelli sierici di
VEGF e PlGF
↑ sFlt-1
Riduzione dei livelli
sierici di VEGF e PlGF
Disfunzione Endoteliale
Normale Funzione
Endoteliale
↓
↓
↓
Disfunzione Multiorgano
----------------------------------------
• Ipertensione
• Disfunzione Glomerulare
• Proteinuria
• Edema Cerebrale
• Edema Epatico
• Anomalie della
Coagulazione
Normale funzione
----------------------------------------
• Normotensione
• Normale Funzione
Glomerulare
• Non Proteinuria
• Non Edema Cerebrale
• Non Edema Epatico
• Non Anomalie della
Coagulazione
Fms-like tyrosine kinase 1 (Flt-1) and his soluble form (sFlt-1)
7654321
654321
Flt-1
sFlt-1
Plasma membrane
Intracellular
kinase
domain
Extracellular Ig domains 1-7
Unique 31
AA C-terminus(alternative splicing)
VEGF and PlGF binding domanis
Possibile ruolo di sFlt1 nella Patogenesi della PE
Mancato rimodellamento delle arteriole spirali materne
↓
Ipoperfusione placentare (?)
↓
Ischemia placentare (?)
↓
Incremento di sFlt1
↓
Riduzione delle frazioni libere di VEGF e PlGF
↓
Disfunzione endoteliale materna sistemica
↓
Trombosi arteriolare
Ipertensione
Disfunzione multiorgano, soprattutto a carico di
rene, fegato e cervello
S.E. Maynard et al. J. Clin. Invest. 111:649–658 (2003).
S.E. Maynard et al. J. Clin. Invest. 111:649–658 (2003).
Nat Med 2006; 12(6): 642-649
Renal, placental and hepatic histological changes and
peripheral blood smears in pregnant rats after sEng and sFlt1
treatment
Serum levels of sEng and sFlt1 in
individuals with varying degrees of
preeclampsia, control pregnancies and
nonpregnant healthy volunteers
N Engl J Med 2006;355:992-1005
The capillary lumen is decreased secondary to swelling of the endothelial cell (END.) The intercapillary
cell mass, including mesangium (MES), appears increased, and there is an increase in amorphous
material along the inner surface of basement membrane, especially in the region of the intercapillary cell
mass. Epithelial cell (EPITH) changes are mild, except for occasional large blebs showing almost no
filamentous matrix or cytoplasmic particulates.
Heptinstall’s Pathology of the Kidney - 6th edition - 2007
Prevention
Obstet Gynecol 101, 1319-1332, 2003
Previous history of preeclampsia
Chronic hypertension
Diabetes
Renal disease
A. Coomarasamy
Obstet Gynecol 98, 861-866, 2001A. Coomarasamy
Prevent Preeclampsia
Prevent Preeclampsia
Prevent Perinatal Death
Prevent Preeclampsia
Prevent Perinatal Death
Prevent Preeclampsia
Identificata la causa della pre-eclampsia?