The Cause of Proteinuria in Preeclampsia
Proteinuria in preeclampsia is primarily caused by endothelial dysfunction and podocyte injury resulting from an imbalance of angiogenic and anti-angiogenic factors released by the ischemic placenta.
Pathophysiological Mechanism
Preeclampsia develops in two stages: inadequate placental implantation followed by a maternal hypertensive state resulting from placental hypoxia, oxidative stress, and inflammation 1
Early-pregnancy placental ischemia leads to the release of soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating soluble isoform of the vascular endothelial growth factor receptor with antiangiogenic properties 1
sFlt-1 binds free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), creating an imbalance of antiangiogenic and proangiogenic factors 1
This imbalance results in maternal endothelial dysfunction, hypertension, proteinuria, and glomerular endotheliosis 1
Renal Manifestations
The hallmark renal lesion in preeclampsia is glomeruloendotheliosis, characterized by enlargement of the glomerulus caused by hypertrophy of endothelial cells 1
This unique renal lesion is not seen in any other form of hypertension and supports the theory that endothelial dysfunction is central to preeclampsia pathophysiology 1
Recent findings show that podocytes (specialized cells in the glomerular filtration barrier) are crucially involved in the loss of filtration capacity of the preeclamptic kidney 2
VEGF is essential for maintaining glomerular filtration barrier function; elevated concentrations of placental-derived VEGF inhibitors like sFlt-1 explain the renal alterations observed 2
Role of Angiotensin II Receptor Autoantibodies
Increased levels of circulating angiotensin II type 1 receptor (AT1R) autoantibodies are found in women with preeclampsia 1
These autoantibodies are directed to a specific epitope on the second extracellular loop of the AT1R and bind to human trophoblasts 1
Multiple studies suggest these antibodies play an important role in preeclampsia pathophysiology by inducing vasoconstriction, hypertension, and increased coagulation 1
Antibodies derived from women with preeclampsia induce placental sFlt-1 production through AT1R activation in pregnant mice, human placental villous explants, and human trophoblast cells 1
Clinical Significance of Proteinuria
Proteinuria is one of the hallmarks for diagnosing preeclampsia, though recent guidelines have moved away from requiring it for diagnosis 2
The amount of proteinuria is not strongly associated with the severity of preeclampsia once proteinuria is detected, but its presence is related to disease severity 3
Proteinuria is a poor predictor of maternal complications in women with preeclampsia 4
The degree of proteinuria during preeclampsia does not predict vascular dilatation or renal function 5-6 years after preeclamptic pregnancy 5
Relationship to Fetal Outcomes
Birth weight is significantly lower in patients with proteinuria >3g/L in a 24-hour urine collection 3
The incidence of fetal growth restriction or stillbirth is significantly higher in patients with proteinuria >5g/L 3
Adverse fetal outcomes appear to be more a function of prematurity rather than proteinuria itself 3
Summary likelihood ratios show proteinuria is a poor predictor of either maternal or fetal complications in women with preeclampsia 4
Long-term Implications
The severity of the maternal antiangiogenic state correlates with maternal and perinatal outcomes 6
Recent evidence has revealed preeclampsia as a significant risk factor for future cardiovascular diseases in affected women 6
Assessing angiogenic imbalance and vascular function tests have emerged as methods for detecting systemic vascular dysfunction during pregnancy 6