Preeclampsia is a complex hypertensive disorder that affects women during pregnancy, characterized by new-onset hypertension and often accompanied by proteinuria—excretion of more than 300 mg of protein in a 24-hour urine sample after the 20th week of pregnancy. The condition poses significant risks to both the mother and the fetus, including the potential for developing into eclampsia, which can lead to seizures and is a major cause of maternal and perinatal morbidity and mortality worldwide. The pathogenesis of preeclampsia is multifactorial, involving genetic, immunologic, and environmental factors, but the precise mechanisms leading to proteinuria remain a subject of intensive research. This article explores the current understanding of the causes of proteinuria in preeclampsia, focusing on the pathophysiological processes involved.
The Role of Placental Ischemia and Angiogenic Imbalance
Central to the pathogenesis of preeclampsia is placental ischemia, resulting from abnormal cytotrophoblast invasion and remodeling of the spiral arteries. This maladaptation leads to intermittent perfusion and hypoxia of the placenta, triggering the release of various factors into the maternal circulation that contribute to endothelial dysfunction, a hallmark of preeclampsia. Among these factors, the imbalance between pro-angiogenic (e.g., vascular endothelial growth factor [VEGF] and placental growth factor [PlGF]) and anti-angiogenic (e.g., soluble fms-like tyrosine kinase-1 [sFlt-1]) substances plays a crucial role. Elevated levels of sFlt-1, in particular, act as a decoy receptor, sequestering VEGF and PlGF and preventing them from performing their normal functions in maintaining endothelial health. This angiogenic imbalance contributes to the widespread endothelial dysfunction observed in preeclampsia, leading to increased permeability of the glomerular endothelium and resulting in proteinuria.
Endothelial Dysfunction and Glomerular Injury
The endothelial dysfunction characteristic of preeclampsia affects various organs, including the kidney, where it leads to glomerular endotheliosis. This specific form of glomerular injury involves swelling of endothelial cells, leading to reduced capillary lumens and compromised filtration. The damaged endothelium, together with the altered glomerular basement membrane and podocyte injury, disrupts the kidney’s selective filtration barrier. As a result, proteins, particularly albumin, which would normally be retained in the bloodstream, pass into the urine, manifesting as proteinuria.
Immunologic Factors and Systemic Inflammation
Immunological factors also play a significant role in the pathogenesis of preeclampsia and the development of proteinuria. Abnormal placentation is thought to elicit an excessive maternal inflammatory response, characterized by activation of leukocytes and the release of inflammatory cytokines. This systemic inflammation further exacerbates endothelial dysfunction throughout the body, including in the kidneys, promoting the leakage of proteins into the urine. Additionally, autoantibodies such as the agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) have been implicated in preeclampsia. These autoantibodies can induce vasoconstriction and hypertension, as well as contribute to endothelial damage and proteinuria.
Genetic Susceptibility and Environmental Influences
While not directly causing proteinuria, genetic predispositions and environmental factors influence the risk of developing preeclampsia and, by extension, proteinuria. Genetic studies have identified variants in genes related to angiogenesis, blood pressure regulation, and immune function that are associated with an increased risk of preeclampsia. Environmental factors, such as diet, obesity, and exposure to certain pollutants, can also impact the development of preeclampsia and its severity. These factors likely interact with the aforementioned pathophysiological processes, modulating the extent of endothelial dysfunction and the severity of proteinuria.
Conclusion
Proteinuria in preeclampsia results from a complex interplay of placental, vascular, immunologic, and possibly genetic factors that lead to systemic endothelial dysfunction and specific injury to the renal glomeruli. The central role of placental ischemia and the resulting angiogenic imbalance, together with systemic inflammation and immunologic responses, are key to understanding the mechanisms leading to proteinuria in preeclampsia. Ongoing research continues to unravel the detailed pathophysiology of this condition, aiming to improve the prediction, prevention, and management of preeclampsia and its complications, including proteinuria. Future studies are expected to focus on identifying biomarkers for early detection, understanding the genetic basis of susceptibility, and developing targeted therapies to address the underlying causes of endothelial dysfunction and renal injury in preeclampsia.