A kidney-centric view of pre-eclampsia through the kidney-placental bidirectional lens

The knowledge that is acquired in medical school regarding pre-eclampsia (PE) reflects our significant gaps in understanding its pathophysiology, and, as such, it is often supplemented by accrued clinical experience and theories that are insufficiently evidence-based. This body of information largely has escaped the scrutiny of changing times and has influenced how we have taught, and sometimes still teach, PE to medical residents and nephrology fellows. PE remains an enigmatic disease, with little progress having been made regarding its etiology and pathogenesis. Consequently, flawed concepts (such as that PE is cured by delivery) were rarely questioned and were incorporated into the classic PE medical literature, achieving widespread acceptance, without critical assessment. Although the definition of PE has changed over time, it is widely accepted that it is characterized by hypertension, commonly proteinuria, but that, in the absence of proteinuria, the diagnosis is supported by the presence of multisystem involvement.S1–S7 In this editorial, we aim to explore some of the myths, misconceptions, and controversies regarding PE that have averted attention from improving care, and specifically kidney care, both at the time of diagnosis and in the years that follow. We will address the bidirectional relationship between PE and chronic kidney disease (CKD), which may lead to a vicious circle that endangers not only the mother’s health but also the health of her baby and of subsequent generations. PE is no longer considered a transitory cardiovascular and kidney disease cured by delivery, and its association with both short- and long-term health risks after delivery is increasingly being acknowledged.1Vikse B.E. Irgens L.M. Leivestad T. et al.Preeclampsia and the risk of end-stage renal disease.N Engl J Med. 2008; 359: 800-809Crossref PubMed Scopus (519) Google Scholar Most textbooks and official sites use the term “cure,” rather than treatment, for PE when referring to delivery and removal of the placenta. Although delivery is currently the only available urgent treatment to prevent life-threatening complications, it is not a cure for several reasons. First, many women who have experienced PE continue to have elevated blood pressure even after delivery and require close monitoring and treatment to prevent short-term cardiovascular and cerebrovascular events (Figure 1). Second, the concept of “cure” similarly diverts attention from the now well-acknowledged long-term health risks of PE.1Vikse B.E. Irgens L.M. Leivestad T. et al.Preeclampsia and the risk of end-stage renal disease.N Engl J Med. 2008; 359: 800-809Crossref PubMed Scopus (519) Google Scholar Third, this additionally creates confusion as for “postpartum PE,” an ill-defined syndrome that occurs after delivery in the absence of the placenta, and accounts for significant maternal and fetal morbidity and mortality, as discussed below. It has traditionally been believed that the placenta is the culprit in the development of PE. The corollary to that is that PE is unlikely to occur in the absence of the placenta, that is, after delivery. Postpartum hypertension and PE, however, have received substantial recognition and attention over the last decade.2Hauspurg A. Jeyabalan A. Postpartum preeclampsia or eclampsia: defining its place and management among the hypertensive disorders of pregnancy.Am J Obstet Gynecol. 2022; 226: S1211-S1221Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar The clinical distinction between “true” postpartum PE and worsening of antenatal hypertension may be difficult, and it is likely that these 2 conditions overlap significantly. Notably, antepartum dysregulation of the balance between angiogenic and anti-angiogenic factors, favoring the anti-angiogenic soluble fms-like tyrosine kinase-1, is an independent predictor of the severity of postpartum hypertension.3Rana S. Lemoine E. Granger J.P. Karumanchi S.A. Preeclampsia: pathophysiology, challenges, and perspectives.Circ Res. 2019; 124: 1094-1112Crossref PubMed Scopus (741) Google Scholar,S7 Also, in pre-eclamptic pregnancies, endothelial dysfunction has been shown to persist postpartum.2Hauspurg A. Jeyabalan A. Postpartum preeclampsia or eclampsia: defining its place and management among the hypertensive disorders of pregnancy.Am J Obstet Gynecol. 2022; 226: S1211-S1221Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar,4Weissgerber T.L. Milic N.M. Milin-Lazovic J.S. Garovic V.D. Impaired flow-mediated dilation before, during, and after preeclampsia: a systematic review and meta-analysis.Hypertension. 2016; 67: 415-423Crossref PubMed Scopus (86) Google Scholar,S6,S7 These findings suggest that there may be a continuum of vascular abnormalities in PE pregnancies, with the onset of hypertension and vascular abnormalities before delivery and continuing thereafter. On the other hand, like some other conditions that occur postpartum (e.g., atypical hemolytic uremic syndrome), hypertension can be worsened or unmasked by delivery of the placenta and removal of the myriad of vasodilatory cytokines of placental origin.S6,S7 This fact is commonly ignored, and, for decades, the holy grail of PE research has remained finding a molecule (or molecules) of placental origin that causes maternal disease upon reaching the maternal circulation.5Bruel A. Kavanagh D. Noris M. et al.Hemolytic uremic syndrome in pregnancy and postpartum.Clin J Am Soc Nephrol. 2017; 12: 1237-1247Crossref PubMed Scopus (136) Google Scholar It is quite possible that antenatal PE is caused by excessive production of vasoconstrictor and proinflammatory cytokines of placental origin, whereas the removal of the placenta offsets the production of vasodilatory cytokines and may contribute to postpartum hypertension in susceptible individuals.6Qu H. Khalil R.A. Vascular mechanisms and molecular targets in hypertensive pregnancy and preeclampsia.Am J Physiol Heart Circ Physiol. 2020; 319: H661-H681Crossref PubMed Scopus (49) Google Scholar Increased awareness of postpartum PE and postpartum hypertension among both patients and physicians is critical for timely diagnosis and treatment and, ultimately, for decreasing the risk of hypertension-associated cardiovascular and renal complications after delivery.2Hauspurg A. Jeyabalan A. Postpartum preeclampsia or eclampsia: defining its place and management among the hypertensive disorders of pregnancy.Am J Obstet Gynecol. 2022; 226: S1211-S1221Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Indeed, the pathogenesis of PE is likely to be heterogeneous. The term PE, however, is conceptually wrong in the postpartum as it refers to a hypertensive disorder that occurs during and not after pregnancy. Future attempts to refine definitions and classification of hypertensive disorders of pregnancy should also consider these evolving concepts. The tenet that the risk of PE is higher during the first pregnancy is obsolete. Pregnancy is the necessary condition of and the major risk for PE. The role of pregnancy as a stress test increasingly is being recognized; underlying subclinical metabolic and vascular abnormalities in young women of reproductive age may be revealed for the first time with the physiological demands and challenges of pregnancy, hence the association between first pregnancy and PE. The risk of PE remains lower in women who have had a previous pregnancy without a hypertensive disorder, whereas it is higher in pregnancies after PE or other hypertensive disorders.7Hernández-Díaz S. Toh S. Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study.BMJ. 2009; 338: b2255Crossref PubMed Scopus (389) Google Scholar Although more attention should be paid to education of nulliparous women at their first pregnancy, to help them timely identifying the first signs of PE, emphasizing the risk associated with the first pregnancy may be misleading in 2 respects: PE may occur in any pregnancy, even when the previous one was uneventful, and, in the presence of a first complicated pregnancy, all subsequent ones should be considered at high risk of recurrence. Furthermore, some of the relevant risk factors may emerge over time (age and obesity), thus increasing the risk compared with the first pregnancy.S8–S25 Although most studies confirm that the risk of recurrence is the highest in women with early and severe PE, the risk is nonetheless higher in all women with previous PE, ranging from approximately 10% to more than 50%.7Hernández-Díaz S. Toh S. Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study.BMJ. 2009; 338: b2255Crossref PubMed Scopus (389) Google Scholar Notably, PE may be such a frightening experience that women are less prone to undergo a subsequent pregnancy. The presence of maternal diseases or predisposing factors, including kidney diseases, often associated with the hypertensive disorders of pregnancy, may be the basis for a more general increase in risk in subsequent pregnancies, even when PE is late and mild.8Cabiddu G. Mannucci C. Fois A. et al.Pre-eclampsia is a valuable opportunity to diagnose chronic kidney disease: a multicentre study.Nephrol Dial Transplant. 2022; 37: 1488-1498Crossref Scopus (9) Google Scholar For several decades, few clinical issues provoked more debate than the question of how, if at all, to treat mild-to-moderate hypertension in pregnancy, commonly defined as elevated blood pressure, but not exceeding 160/110 mm Hg. Central to this controversy was the lack of studies to support the benefit of treatment for mild hypertension in pregnant patients, which was further confounded by the concerns with respect to fetal safety, from both a theoretical decrease in fetoplacental circulation due to a drop in maternal blood pressure and possible adverse fetal effects due to drug exposure in utero. There were significant differences, consequently, among international guidelines regarding the blood pressure levels for initiating and titrating antihypertensive agents in pregnancy. A recently published study indicated that using a cutoff blood pressure of 140/90 mm Hg, as the threshold for initiation or titration of medical therapy for pregnant women with chronic hypertension, improves maternal outcomes, while not exerting adverse fetal/neonatal effects.9Tita A.T. Szychowski J.M. Boggess K. et al.Treatment for mild chronic hypertension during pregnancy.N Engl J Med. 2022; 386: 1781-1792Crossref PubMed Scopus (122) Google Scholar Although these results apply to women with chronic hypertension, future studies need to address the efficacy and safety of applying lower blood pressure goals for the treatment of hypertension in the context of PE, as well as whether there is an additional benefit to lowering blood pressure in pregnant patients with chronic hypertension to levels that are commonly considered ideal for hypertensive nonpregnant subjects (i.e., <130/80 mm Hg). Interestingly, this attention to lower blood pressure thresholds is also in line with the proposal to lower the threshold for the diagnostic definition of PE to 130/80 mm Hg.10Sisti G. Colombi I. New blood pressure cut off for preeclampsia definition: 130/80 mmHg.Eur J Obstet Gynecol Reprod Biol. 2019; 240: 322-324Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar,S25,S26 The association between PE and CKD has been confirmed in population studies worldwide.11Barrett P.M. McCarthy F.P. Kublickiene K. et al.Adverse pregnancy outcomes and long-term maternal kidney disease: a systematic review and meta-analysis.JAMA Netw Open. 2020; 3e1920964Crossref Scopus (56) Google Scholar The intervals between PE and the development of end-stage kidney disease (ESKD) were longer in Norway and Sweden, countries with a relatively low prevalence of ESKD, but much shorter in Taiwan, which has the highest incidence of ESKD in the world.11Barrett P.M. McCarthy F.P. Kublickiene K. et al.Adverse pregnancy outcomes and long-term maternal kidney disease: a systematic review and meta-analysis.JAMA Netw Open. 2020; 3e1920964Crossref Scopus (56) Google Scholar This suggests the presence of still unknown genetic and environmental factors, but may also indicate that pregnancy can unmask underlying CKD and/or that underlying CKD may lead to pregnancy complications. The role of pre-existing CKD is supported by studies showing a CKD prevalence of approximately 20% in women who were evaluated after a PE episode, both in Europe and in the United States.8Cabiddu G. Mannucci C. Fois A. et al.Pre-eclampsia is a valuable opportunity to diagnose chronic kidney disease: a multicentre study.Nephrol Dial Transplant. 2022; 37: 1488-1498Crossref Scopus (9) Google Scholar,12Kattah A.G. Scantlebury D.C. Agarwal S. et al.Preeclampsia and ESRD: the role of shared risk factors.Am J Kidney Dis. 2017; 69: 498-505Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar In both settings, nonproteinuric diseases, including interstitial nephropathies, congenital anomalies of the kidney and of the urinary tract, and polycystic kidney diseases, accounted for a significant proportion of cases, thus suggesting that relying on proteinuria and hypertension may not be enough for early diagnosis of CKD after PE. Furthermore, women who undergo a kidney biopsy after PE largely fall into 2 groups: those with a need for a kidney biopsy within 5 years of the PE episode and those with a late biopsy, that is, more than 1 decade after the PE episode. The first group mainly consists of women with pre-existing glomerular disease, brought to light or accelerated by PE. In the second group, PE may have been the “first hit,” with the role of acute injury to podocytes, cells that have distinct physiology, biology, and genetics, increasingly being recognized.13Craici I.M. Wagner S.J. Weissgerber T.L. et al.Advances in the pathophysiology of pre-eclampsia and related podocyte injury.Kidney Int. 2014; 86: 275-285Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Early referral to nephrology is needed to ensure timely and expert kidney care given the broad spectrum of kidney injury presentations after PE pregnancies. This was addressed in the recent National Institute for Health and Care Excellence and International Society for the Study of Hypertension in Pregnancy guidelines that call for close monitoring during the immediate postpartum period. However, to date, only the Italian Society of Nephrology has officially suggested systematic kidney assessment after PE.14Piccoli G.B. Cabiddu G. Castellino S. et al.A best practice position statement on the role of the nephrologist in the prevention and follow-up of preeclampsia: the Italian study group on kidney and pregnancy.J Nephrol. 2017; 30: 307-317Crossref PubMed Scopus (61) Google Scholar The identification of the subsets of women with higher risk of having undiagnosed CKD or developing CKD after pregnancy is a clinical research priority.S27–S42 Proteinuria is no longer a requisite for the diagnosis of PE, and the degree of proteinuria is only loosely related to the clinical severity and long-term risks after PE.15Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on hypertension in pregnancy.Obstet Gynecol. 2013; 122: 1122-1131Crossref PubMed Scopus (855) Google Scholar,S42–S49 The importance of the new definition is to underline that severe outcomes may occur in the absence of proteinuria but not to undermine its value with respect to immediate and possible long-term kidney injury. The absence of proteinuria in a subgroup of patients with PE may reflect the clinical and physiopathologic heterogeneity of PE.S50 Conversely, the occurrence or the increase of proteinuria may be useful in diagnosing superimposed PE in women with chronic hypertension or with glomerulonephritides or CKD. Studies on the mechanism of proteinuria have underscored the role of podocyte dysregulation, indicating that the origin of proteinuria is not only related to endothelial injury.13Craici I.M. Wagner S.J. Weissgerber T.L. et al.Advances in the pathophysiology of pre-eclampsia and related podocyte injury.Kidney Int. 2014; 86: 275-285Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Of note, the presence of viable podocytes in the urine antedates the occurrence of proteinuria and the clinical features of PE, thus offering opportunities for screening and addressing further studies on mechanisms of glomerular injury.16Garovic V.D. The role of the podocyte in preeclampsia.Clin J Am Soc Nephrol. 2014; 9: 1337-1340Crossref PubMed Scopus (44) Google Scholar Women with residual proteinuria after PE commonly demonstrate focal segmental glomerulosclerosis on their kidney biopsies, a renal lesion that has been associated with podocytopathy, thus underscoring the role of podocyte injury both at the time of pregnancy and thereafter.S51–S55 There is no misconception in this regard, just no attention. The maturation of kidney tissue is slow and delicate. Its normal development occurs during the intrauterine period, and while, to some extent, maturation may continue after preterm delivery, the process usually is significantly impaired. Children born prematurely or small for gestational age consequently tend to have a lower nephron number compared with children born at term and of normal birth weight. Maturation of kidney tissue, however, is extremely variable, and the number of nephrons may vary widely according to yet unknown factors.17Luyckx V.A. Brenner B.M. Birth weight, malnutrition and kidney-associated outcomes—a global concern.Nat Rev Nephrol. 2015; 11: 135-149Crossref PubMed Scopus (197) Google Scholar Prematurity and small for gestational age are also associated with an array of metabolic alterations—including early development of hypertension, metabolic syndrome, obesity, and cardiovascular diseases—which, in turn, represent risk factors or causes of CKD. The risk of ESKD is the one that can be assessed most easily, but less is known regarding the initial phases of CKD and what favors early progression. Despite the many uncertainties, the fact that females weighing less than 2.5 kg at birth have a 4-fold increased risk of developing PE themselves compared with females of normal birth weight has been known for over 20 years.18Innes K.E. Marshall J.A. Byers T.E. Calonge N. A woman's own birth weight and gestational age predict her later risk of developing preeclampsia, a precursor of chronic disease.Epidemiology. 1999; 10: 153-160Crossref PubMed Scopus (45) Google Scholar Although further studies are needed to better identify baseline risk patterns and risk factors for the progression of CKD or the development of PE and related disorders, these observations call for action to address the multigenerational vicious circle linking PE and future kidney health (Figure 1). Given the presented evidence, we suggest that the following principles be implemented in clinical practice. First, a multidisciplinary approach is needed when following up women after PE, as the relative risk of ESKD increases along with the number of PE episodes. Second, the concept that only women with severe PE need to be assessed for risk factors of future kidney disease is fallacious, as PE may occur in the setting of subclinical kidney disease, with the probability of underlying, and undiagnosed CKD reported to be as high as 20%. Third, the current approach of advising women with a history of PE without proteinuria and hypertension that no further follow-up is necessary is likewise misleading. Potentially progressive kidney diseases may present in the absence of proteinuria and hypertension after delivery and can be detected only when imaging and functional data are gathered.