Symposium 2.3 – Preeclampsia and kidney in 2021

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the speakers reviewed and approved the contents

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Endothelial dysfunction and activation in preeclampsia

Elisa Llurba Olivé, Spain

Preeclampsia (PE) is a pregnancy-specific complication characterized by high blood pressure and signs of multisystemic organ damage, predominantly affecting the liver and kidneys. Manifestations include severe headaches, changes in vision, upper abdominal pain, nausea, decreased urine output, swelling and shortness of breath, thrombocytopenia, haemolysis, abnormal liver enzymes, and proteinuria. PE is becoming an increasingly common diagnosis in the developed world and remains an important cause of maternal and foetal mortality in the developing world.

While the cause of this syndrome is still debated, clinical and pathological studies suggest that the placenta holds a central role in its pathogenesis. Deficient expression of decidual pro-angiogenic factors, the vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), reduce the activity of the heme oxygenase-1 (HO-1). Under normal conditions, HO-1 decreases oxidative stress and promotes an immune tolerant microenvironment thus allowing for placental development. It also plays a critical role in the prevention of vascular inflammation. Its impaired activity leads to trophoblast invasion and abnormal remodelling of spiral arteries, resulting in placental ischemia and eventually causing oxidative damage, endothelial dysfunction of the peripheral vasculature, and PE.

Figure 1. Stages of preeclampsia

Risk assessment in women with established PE remains challenging. Clinical manifestations alone might not be sufficient to predict adverse outcomes as a significant proportion of women may develop complications including eclampsia and HELLP syndrome without elevated blood pressure or proteinuria. Conversely, some patients with PE are able to carry the pregnancy to near full term without progression. It has recently been suggested that in symptomatic patients presenting at <34 weeks a soluble fms-like tyrosine kinase-1 (sFlt-1)/PIGF ratio ≥85 predicts the occurrence of PE-related maternal and foetal adverse outcomes irrespective of the presence of an established diagnosis of PE.

Recently the shift has been made to perceive PE as a systemic disease with the potential to affect the future cardiovascular status of the woman. The magnitude of cardiovascular risk seems to be related to the earlier onset of PE. It appears that angiogenic factors released during PE, such as PIGF, could identify women at higher risk of future cardiovascular disease who might benefit from early preventive measures.

Senescence and preeclampsia

Vesna Garovic, United States of America

Cellular senescence is a phenomenon characterized by cell cycle arrest and loss of cell proliferating ability. It can be triggered by several mechanisms, including DNA damage or genomic instability, oxidative and metabolic stress, oncogenes, inflammation, phototoxic and shear stress, which render cells resistant to growth-promoting stimuli. The biological role of senescence is essentially protective, as it prevents the growth and multiplication of malignant cells and contributes to adequate wound healing, tissue remodelling, and embryogenic development. Nevertheless, the number of senescent cells increases with age and they acquire a specific senescence-associated secretory phenotype (SASP) associated with age-related tissue dysfunction, loss of repairability, decreased resilience, and even chronic disease, including atherosclerosis, diabetes, neurodegenerative diseases, and cancer. Studies on animal models have proved that senescent cells can cause physical dysfunction and decreased survival even in young animals, while senolytics, i. e, agents that selectively clear senescent cells by inducing their apoptosis, can enhance remaining health- and lifespan in old mice. The SASP is easily identified with a senescence-associated beta-galactosidase (SABG) which is detected by histochemical staining.

Figure 2. The mechanisms of senescence

Senescence is also a physiological phenomenon appearing in pregnancy, triggered by cell fusion, to establish and expand the syncytiotrophoblast and it progresses with placental aging. Nevertheless, there is increasing evidence that accelerated senescence may lead to placental and clinical pathology, including the appearance of PE. A recent study investigated the role of senescence of mesenchymal stem cells (MSC), i. e. multipotent cells with pro-angiogenic activities, as a possible mechanism by which systemic inflammation exerts inhibitory effects on angiogenesis in PE. MSC isolated from women with PE demonstrated a higher senescent phenotype identified by more abundant staining for SABG, upregulation of senescence markers and SASP components, and lower angiogenic potential than MSC from normotensive pregnancies. The mechanistic link between senescence and impaired angiogenesis in PE was further confirmed by the regained angiogenic potential of PE-MSC following the treatment with the senolytic agent. A study currently under review corroborates these results observing a higher senescence burden in women with PE compared to normotensive pregnant women, and improvement of angiogenic potential of MSC from PE pregnant women following senolytic administration

Future studies are expected to examine the possible role of autologous stem cell transplantation and senolytics to decrease senescent cell burden after affected pregnancies and before the next one, and decrease the risk for cardiovascular morbidity in females in post reproductive years.

Preeclampsia and future renal disease

Giorgina  Barbara Piccoli, France

Understanding of hypertension during pregnancy and, in particular, PE has changed significantly in the previous decade. The new diagnostic criteria for PE have been proposed in 2014 by the International Society for the Study of Hypertension in Pregnancy (ISSHP) defining PE as de-novo hypertension occurring after 20 weeks of gestation combined with either proteinuria (>300mg/day), or other maternal organ dysfunction or foetal growth restriction. This definition has allowed establishing the diagnosis of PE in absence of proteinuria if other disorders, such as renal insufficiency, liver involvement, neurological or haematological complications, are present. Nevertheless the heterogeneity of this disease concurs to our still limited understanding. Therefore, questions remain open on how to optimize PE classification, predict PE-related chronic kidney disease (CKD) and improve the outcome of these patients.

The strict link between PE and CKD has been highlighted in 2008 when PE was associated with an increased risk of subsequent end-stage renal disease (ESRD). A systematic review and meta-analysis eleven years later confirmed a significant association between PE and risk of ESRD but also acknowledged lack of sufficient data to define the natural history of CKD after PE.

Conversely, several studies have demonstrated that the risk of developing PE is significantly increased in women with all kind of kidney diseases, including single kidney after organ donation, reflux nephropathy, and even nephrolithiasis. Furthermore, patients with glomerulonephritis and immunologic diseases are at higher risk of developing or increasing proteinuria and hypertension, a picture often difficult to differentiate from preeclampsia. Thus, previous renal impairment, whether acknowledged or not, predisposes to PE development, confirming the bidirectional relationship between the kidney and placenta.

Figure 3. PE and the risk for ESRD

PE is no longer considered a transitory kidney disease healed by delivery. This condition is associated, reveals and predisposes women to renal and cardiovascular diseases in later life, thus representing a window to the future health of the mother and the child. While the search continues for biomarkers that would effectively discriminate between PE and CKD in pregnant women, simple steps can be embraced to improve pregnancy outcomes. The pregnancy workup should always include serum creatinine and urinalysis, all pregnancies in women with previously known CKD should be considered as high risk, and all women who experienced PE should be followed up, with particular attention to later pregnancies.

Further reading

Rana S, Powe CE, Salahuddin S, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125(7):911-9. doi: 10.1161/CIRCULATIONAHA.111.054361.

Egeland GM, Skurtveit S, Staff AC, et al. Pregnancy-Related Risk Factors Are Associated With a Significant Burden of Treated Hypertension Within 10 Years of Delivery: Findings From a Population-Based Norwegian Cohort. J Am Heart Assoc. 2018;7(10):e008318. doi: 10.1161/JAHA.117.008318.

Nath MC, Cubro H, McCormick DJ, Milic NM, Garovic VD. Preeclamptic Women Have Decreased Circulating IL-10 (Interleukin-10) Values at the Time of Preeclampsia Diagnosis: Systematic Review and Meta-Analysis. Hypertension. 2020;76(6):1817-1827. doi: 10.1161/HYPERTENSIONAHA.120.15870.

Cubro H, Nath KA, Suvakov S, et al. Mechanisms of vascular dysfunction in the interleukin-10-deficient murine model of preeclampsia indicate nitric oxide dysregulation. Kidney Int. 2021;99(3):646-656. doi: 10.1016/j.kint.2020.09.034.

Suvakov S, Cubro H, White WM, et al. Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia. Biol Sex Differ. 2019;10(1):49. doi: 10.1186/s13293-019-0263-5.

Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246-1256. doi: 10.1038/s41591-018-0092-9.

Garovic VD, White WM, Vaughan L, et al. Incidence and Long-Term Outcomes of Hypertensive Disorders of Pregnancy. J Am Coll Cardiol. 2020;75(18):2323-2334. doi: 10.1016/j.jacc.2020.03.028.

Tranquilli AL, Dekker G, Magee L, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP. Pregnancy Hypertens. 2014;4(2):97-104. doi: 10.1016/j.preghy.2014.02.001.

Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. N Engl J Med. 2008;359(8):800-9. doi: 10.1056/NEJMoa0706790.

Covella B, Vinturache AE, Cabiddu G, Attini R, Gesualdo L, Versino E, Piccoli GB. A systematic review and meta-analysis indicates long-term risk of chronic and end-stage kidney disease after preeclampsia. Kidney Int. 2019;96(3):711-727. doi: 10.1016/j.kint.2019.03.033.

Attini R, Kooij I, Montersino B, Fassio F, Gerbino M, Biolcati M, Versino E, Todros T, Piccoli GB. Reflux nephropathy and the risk of preeclampsia and of other adverse pregnancy-related outcomes: a systematic review and meta-analysis of case series and reports in the new millennium. J Nephrol. 2018 Dec;31(6):833-846. doi: 10.1007/s40620-018-0515-1.

Kattah AG, Scantlebury DC, Agarwal S, et al. Preeclampsia and ESRD: The Role of Shared Risk Factors. Am J Kidney Dis. 2017;69(4):498-505. doi: 10.1053/j.ajkd.2016.07.034.

Cabiddu G, Castellino S, Gernone G, et al. A best practice position statement on pregnancy in chronic kidney disease: the Italian Study Group on Kidney and Pregnancy. J Nephrol. 2016;29(3):277-303. doi: 10.1007/s40620-016-0285-6.