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
Incidence
Urinary abnormalities
15 - 25 %
Hypertension in pregnancy 10 - 12 %
Urinary tract infections
Renal calculi
Acute Renal Failure
2 - 10 %
0.03 - 1 %
0.05 - 0.15 %
Hypertension in
pregnancy
Classification of hypertension in
pregnancy
Delivery
160
150
140
130
120
110
100
90
80
70
Chronic Hypertension
Masked chronic hypertension
Pre-eclampsia super imposed
Pre-eclampsia/Eclampsia
60
Gestational Hypertension
Pre-pregnancy
10
20
28
32
38
6
weeks
12
NHLBI Working Group on Research on Hypertension during Pregnancy Roberts et al. Hypertension 2003; 41
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 1012% of pregnancies
•Pre-eclampsia occurs in 3-4 % of
pregnancies (mild in 75% of cases and
severe in 25%)
•Chronic Hypertension complicates 23% of pregnancies
•Gestational Hypertension occurs in 56%
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 or
S 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
Severe arteriolar lesion with fibrinoid necrosis
and intraluminal fibrin
Heptinstall’s Pathology of the Kidney - 6th edition - 2007
Maternal mortality associated with
pre-eclampsia and eclampsia (UK)
Walker J.J, Lancet, 2000, 356

Solo 1 su 2000 gravidanze
in alcune nazioni in via di sviluppo:
!! 1 caso ogni 100 gravidanze
600.000 donne/anno muoiono per cause connesse alla gravidanza
Almeno 50.000 di questi decessi sono attribuibili alla pre-eclampsia /eclampsia
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
Autopsy Specimen from a 40-Year-Old Woman with Severe Preeclampsia
and Subarachnoid Hemorrhage
Greene M. N Engl J Med 2003;348:275-276
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)
Pre-eclampsia severa
Insorgenza di ipertensione e proteinuria e almeno 1 delle seguenti condizioni
Sintomi neurologici
Ritardo crescita
Transaminasi x 2
Sistolica >160 mmHg
o
Diastolica >110 mmHg
Piastrine < 100.000 mm3
almeno 2 volte a distanza di 6 ore
Complicanze più gravi: Oliguria, edema
polmonare, incidente CV, coagulopatia
Proteinuria >5g/24h
o
+++ dipstick in 2
campioni separati
Clinical Manifestation
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
Prediction of adverse maternal
outcome in pre-eclampsia
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
Identificata la causa della pre-eclampsia?
Preeclampsia
Eziologia:
Sconosciuta, patologia inesistente negli animali
Patogenesi:
Non chiarita
Obiettivo principale:
Individuazione della pre-eclampsia e trattamento per
prevenire severe complicanze.
Non disponiamo al momento di terapia specifica
preventiva per la malattia!
DISFUNZIONE ENDOTELIALE
SISTEMICA
Tutte le manifestazioni cliniche della PREECLAMPSIA
possono essere spiegate come una risposta materna ad una
disfunzione endoteliale generalizzata.
L’alterato controllo endoteliale del tono vascolare determina
ipertensione arteriosa, incremento della permeabilità
vascolare con conseguente edema e proteinuria ed anomala
espressione endoteliale di fattori procoagulanti in grado di
attivare la cascata coagulativa.
Queste modificazioni causano inoltre ischemia di organi
bersaglio, 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
Two-stage model of the pathophysiology of
preeclampsia
Roberts, J. M. et al. Hypertension 2005; 46:1243-1249
Stage 2 develops in
some, but not all
women with stage 1
Poor placentation and preeclampsia
C. W. Redman et al., Science 308, 1592 -1594 (2005)
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…
Coagulazione
Bilancia
vasocostrittiva/
vasodilatativa
PREECLAMPSIA
Sistema delle Integrine
ed Angiogenesi
Rimodellamento
Vasale adeguato
↑ Flusso
Ematico
Normale Funzione
Endoteliale
Normossia
Placenta
Utero
Gravidanza Normale
Normale funzione
---------------------------------------• Normotensione
• Normale Funzione
Glomerulare
• Non Proteinuria
• Non Edema Cerebrale
• Non Edema Epatico
• Non Anomalie della
Coagulazione
Utero
Pre-eclampsia
Rimodellamento
Vasale inefficace
↓ Flusso
Placenta
Ematico
Ipossia
Disfunzione Endoteliale
Disfunzione Multiorgano
---------------------------------------• Ipertensione
• Disfunzione Glomerulare
• Proteinuria
• Edema Cerebrale
• Edema Epatico
• Anomalie della
Coagulazione
Rimodellamento
Vasale adeguato
Normali livelli sierici di
VEGF e PlGF
↑ Flusso
Ematico
↓
Normale Funzione
Endoteliale
Normossia
Placenta
Utero
Gravidanza Normale
sFlt-1
Normale funzione
---------------------------------------• Normotensione
• Normale Funzione
Glomerulare
• Non Proteinuria
• Non Edema Cerebrale
• Non Edema Epatico
• Non Anomalie della
Coagulazione
Utero
Pre-eclampsia
Rimodellamento
Vasale inefficace
↑ sFlt-1
↓ Flusso
Placenta
Ematico
Ipossia
?
↑ sFlt-1
↓
Riduzione dei livelli
sierici di VEGF e PlGF
↓
Disfunzione Endoteliale
Disfunzione Multiorgano
---------------------------------------• Ipertensione
• Disfunzione Glomerulare
• Proteinuria
• Edema Cerebrale
• Edema Epatico
• Anomalie della
Coagulazione
Fms-like tyrosine kinase 1 (Flt-1) and
his soluble form (sFlt-1)
Plasma membrane
Intracellular
kinase
domain
Extracellular Ig domains 1-7
Flt-1
1
2
3
4
5
6
sFlt-1
1
2
3
4
5
6
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).
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
Nat Med 2006; 12(6): 642-649
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
A. Coomarasamy
Obstet Gynecol 98, 861-866, 2001
A. Coomarasamy
Obstet Gynecol 101, 1319-1332, 2003
Previous history of preeclampsia
Chronic hypertension
Diabetes
Renal disease
Prevent Preeclampsia
Prevent Preeclampsia
Prevent Perinatal Death
Prevent Preeclampsia
Prevent Perinatal Death
Prevent Preeclampsia
Identificata la causa della pre-eclampsia?