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?