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Selection Committee Member: Jessica Tangren

Jessica Tangren is a nephrologist at Massachusetts General Hospital. Her research and clinical practice in women’s kidney health focuses on reproductive planning and kidney disease management in pregnancy. She is also committed to patient advocacy and works with organizations to increase patient and medical provider awareness of reproductive health and kidney disease.

Selection Committee Member: Michelle Hladunewich @hladunewich

Michelle Hladunewich is a professor in the Temerty Faculty of Medicine at the University of Toronto. She is presently the Physician-in-Chief at Sunnybrook Health Sciences Centre, and is the Ontario Renal Network Medical Lead for Glomerulonephritis and Specialty Clinics. Since arriving at Sunnybrook, she developed a clinical and research program in women’s health and rare glomerular diseases. Dr. Hladunewich is a recognized expert in the diagnosis and management of kidney disease in pregnancy as well as glomerulonephritis.

Writer: Gilda Portalatin @GildaPortalatin

Gilda Portalatin is a current second-year nephrology fellow and chief fellow at Vanderbilt University Medical Center. She attended Ross University School of Medicine and completed residency at Cleveland Clinic Florida. Her areas of interest include women’s health, enhancing patient education on kidney disease, and mentorship.

Writer: Connor Grantham @cgranth510

Connor Grantham is a second-year nephrology fellow at Vanderbilt University Medical Center where he also serves as a chief fellow. He completed medical school and residency at the University of Kansas. His interests are CKD, fluid and electrolyte disorders, and medical education.

Competitors for the Preeclampsia Region

Team 1: Diagnosis and Treatment of Preeclampsia

 versus

Team 2: Risk Factors, Prevention, and Long-Term Sequelae in Preeclampsia

Image generated by Evan Zeitler using Image Creator from Microsoft Designer, accessed via https://www.bing.com/images/create, January, 2024. After using the tool to generate the image, Zeitler and the NephMadness Executive Team reviewed and take full responsibility for the final graphic image.

We are now moving into an area known to strike fear in the hearts of many nephrologists: obstetric nephrology (see previous NephMadness coverage in 2018 and 2015). In this region, we are specifically going to hone in on the most common glomerular disorder in the world, preeclampsia. Preeclampsia is a multi-system progressive disorder defined as new onset hypertension accompanied by either new onset of proteinuria or end organ damage, including thrombocytopenia, liver dysfunction, new kidney dysfunction, or new onset cerebral or visual disturbances occurring after 20 weeks of gestation. Eclampsia is the development of seizures or coma in a woman with preeclampsia.

As nephrologists, we have an important role in providing care to pregnant women with CKD by potentially modifying specific risk factors and decreasing the risk of preeclampsia. Nephrologists also play an important role post-preeclampsia in treating women who develop CKD after pregnancy and are at risk for progression to end-stage kidney disease (ESKD). Preeclampsia enters this year’s tournament as a favorite – let’s see if its two competitors can live up to the hype.

Copyright: Fernando Astasio Avila/Shutterstock

The diagnosis of preeclampsia is made based upon its definition: new onset hypertension accompanied by either new onset of proteinuria or end organ damage occurring after 20 weeks gestation. Preeclampsia with severe features is diagnosed when any of the criteria below are met. Preeclampsia with severe features is associated with increased morbidity and mortality.

Box 2 from Gonzalez Suarez et al, © National Kidney Foundation.

While the definition of preeclampsia has been revised throughout the years, there remain patients for whom it is difficult to be certain of the diagnosis. Picture the woman with underlying chronic kidney disease (CKD) with proteinuria and hypertension. Biomarkers are clearly needed. The placenta plays a major role in oxygen delivery, blood flow, and nutrients to the fetus throughout pregnancy and requires extensive angiogenesis to do this.When placental blood flow is impaired, the patient is at risk for preeclampsia, leading to the question: Are there markers released during this “ischemic” process that could guide us in potentially predicting and diagnosing preeclampsia?

Pregnancy involves a carefully orchestrated balance of proangiogenic and antiangiogenic factors. Vascular endothelial growth factor (VEGF) has a key role in the vascular formation in the placental growth process and promotes vasodilation during the entire pregnancy period. Placental growth factor (PIGF), another member of the VEGF family, is a circulating factor secreted by the placenta and has significant vasculogenic and angiogenic properties. It is a key component in spiral artery remodeling and the development of a low-resistance placental capillary network. During a normal pregnancy, PIGF increases in the second trimester corresponding to spiral artery remodeling at 16-18 weeks’ gestation. PIGF concentrations then peak between 20 and 32 weeks and then gradually fall until term. PlGF concentrations have been found to be decreased in women with preeclampsia. Some studies have suggested that In the setting of placental hypoxia, expression of PIGF may be inhibited in response to decreased blood flow and oxygen delivered to the placenta.

Is PlGF our biomarker?

PlGF measured between 11 and 13 weeks gestation has detection rates of 55% and 33% for the identification of early- and late-onset preeclampsia. These detection rates are significantly increased with the Fetal Medicine Foundation (FMF) triple test algorithm which combines PlGF measured between 11 and 13 weeks gestation with mean arterial pressure, uterine artery pulsatility index, and serum placental growth factors. A prospective, multi-center study of this algorithm in 8,775 first trimester singleton pregnancies including 230 women with preeclampsia and reported detection rates of 100%, 75%, and 43% for very early (<32 weeks’ gestation), preterm, and term preeclampsia, respectively.

When screening in the third trimester between 30-34 weeks gestation, 98% of preterm preeclampsia can be predicted, but over half of term cases fail to be detected. Not a surprise, as PIGF progressively falls towards term.

Are there other biomarkers we can combine with PlGF to improve detection rates?

As we previously noted, pregnancy involves a carefully orchestrated balance of proangiogenic and antiangiogenic factors. We have yet to discuss the antiangiogenic factors and their role. The anti-angiogenic protein known as soluble fms-like tyrosine kinase 1 (sFlt-1) acts as a potent antagonist to VEGF and PIGF and is mainly produced by the placenta in pregnancy. In healthy pregnancies, it plays essential roles in maintaining the appropriate depth of the placenta in the uterine wall. In women with preeclampsia, the sFlt-1 level can be up to four times greater than normotensive women. Animal studies have found that excess sFlt-1 can cause endothelial cell damage and vasoconstriction and in pregnant rats leads to a preeclampsia phenotype.

In 2004, it was first demonstrated that up to five weeks before the onset of clinical symptoms, increased levels of sFlt-1 and reduced levels of PIGF can predict subsequent development of preeclampsia. Since then, multiple sFlt-1/PlGF assays have been developed. The FDA recently approved the first of these for clinical use in the United States. These assays have demonstrated that women with suspected preeclampsia with a higher ratio have a significantly shorter time to delivery and an increased risk of preeclampsia-related adverse outcomes. In the outpatient setting, women in the PROGNOSIS study who had a lower ratio were able to be ruled-out for onset of preeclampsia for up to 4 weeks with a NPV of 94.3%. On the other hand, in the INSPIRE trial, an elevated ratio in hospitalized women correctly identified all women that developed preeclampsia within 7 days (100% sensitive and 100% NPV).

Smaller studies have assessed the utility of PlGF and sFLT-1/PlGF levels in women with CKD. A small study of women with systemic lupus erythematosus found that  sFLT-1/PlGF ratio and PlGF levels were able to differentiate between women with active lupus nephritis and preeclampsia.

In a prospective study of women with CKD, lower PlGF levels were still able to predict early delivery due to superimposed preeclampsia, but the predictive performance was reduced in women with CKD stages 3-5 compared to those with stages 1-2. PlGF is excreted by the kidneys which may account for the difference in predictive performance between early and later stage CKD. Conflictingly, in this same study, the sFlt-1/PlGF ratio did not predict the development of superimposed preeclampsia. However, another small study found that the sFlt-1/PlGF ratio and the PlGF level were able to be used to discriminate between 1) women with normal baseline kidney function and preeclampsia and 2) pregnant women with proteinuric CKD and hypertension without superimposed preeclampsia, suggesting that these biomarkers may be useful in the setting where the woman’s past medical history is unknown and there is the possibility of underlying proteinuric CKD.

There is even less evidence for these biomarkers in patients with ESKD. This evidence rises to the level of case reports only. Interestingly, sFlt-1 and PlGF have been noted to increase significantly when measured immediately post-hemodialysis as compared to pre-hemodialysis, without a significant change in the ratio. Further study is needed in this area to better understand if and how these biomarkers should be used in monitoring pregnant patients with ESKD.

SFLT-1 and PlGF  biomarkers can help screen, predict, and manage patients with suspected preeclampsia. While not perfect, they perform better at predicting the development of preeclampsia than other standard clinical measures including blood pressure, serum creatinine, serum liver tests, and platelet count.

Treatment

Delivery remains the only definitive treatment of preeclampsia. The timing of delivery is dependent upon the current gestational age and the presence or absence of severe features of preeclampsia.  Delivery is recommended for women who are >37 weeks gestation, those with preeclampsia with severe features who are >34 weeks gestation, and those with unstable maternal or fetal conditions irrespective of gestational age. This is in an attempt to minimize the risk for both serious fetal complications (e.g. growth restriction, demise) and maternal complications (e.g. kidney failure, pulmonary edema, seizure, cerebral hemorrhage, myocardial infarction). Expectant management is recommended for women without severe features <37 weeks gestation. In women <34 weeks gestation with preeclampsia with severe features, it is recommended to treat with corticosteroids to promote lung maturity and to transfer the woman to a hospital with appropriate neonatal ICU availability.

There are multiple ongoing trials utilizing novel therapeutic strategies to treat preeclampsia. The main goal with these is to restore angiogenic balance.  These strategies range from therapeutics such as sFLT-1 ligands and small interfering RNA based therapies to reduce the production of sFLT-1 to procedures such as apheresis paired with columns utilizing monoclonal antibodies to selectively deplete sFLT-1.

Check out this podcast episode of GN in Ten featuring Anna Burgner, Kenar Jhaveri, and Koyal Jain:

Episode 4: NephMadness Special! Anna Burgner on Preeclampsia

Copyright: NOWIK my stock/Shutterstock

Preeclampsia is a progressive disease with a broad spectrum of clinical findings. This disease can lead to grave consequences for both the mother and offspring. Preeclampsia and eclampsia affect up to 5% of all pregnancies and contribute to 70,000 maternal deaths and 500,000 fetal deaths per year worldwide. It is the largest contributor to preterm delivery worldwide. For the offspring, consequences of preeclampsia include intrauterine growth restriction and other sequelae of preterm birth including the development of future CKD in the child, creating a vicious circle of illness in families.

Previous US studies have shown that there is approximately one maternal death due to preeclampsia/eclampsia per 100,000 live births, with a case fatality rate of 6.4 deaths per 10,000 cases. There’s a significant impact on low and middle income countries, where the maternal mortality rate is substantially higher at approximately 40 per 100,000 live births. Over time, the incidence of preeclampsia in rich countries has risen, likely because of population level increases in risk factors (e.g. older age of first pregnancy and presence of diabetes mellitus) for the disease. The national partnership for maternal safety has deemed hypertensive disorders of pregnancy (including preeclampsia) among the most preventable causes of maternal death.

In spite of these statistics, treatment innovations in maternal health medicine are lacking. A 2009 study of active clinical trials found that maternal health clocked in with a dismal 17 active clinical trials, compared to 660 and 2,318 for cardiovascular health and cancer, respectively. The healthcare community has ample room for improvement in providing care for these patients. Identifying modifiable risk factors and employing preventive strategies could be key in curbing the maternal health crisis.

There are many risk factors for the development of preeclampsia, and some risk factors are ‘riskier’ than others. Systematic reviews of preeclampsia risk factors have identified the strongest one as a prior history of preeclampsia which carries with it a RR of 8.4, (95% CI, 7.1-9.9). The severity of past preeclampsia impacted this risk with the highest risk being carried by patients with a history of severe features of preeclampsia in the second trimester. Conversely, patients who had a normotensive first pregnancy developed preeclampsia in less than 1% of second pregnancies. Risk factors for preeclampsia are divided into high and moderate risk. High risk factors for the development of preeclampsia include a prior history of preeclampsia, preexisting chronic hypertension, type 1 and type 2 diabetes mellitus, multifetal gestation, chronic kidney disease, systemic lupus erythematosus, and antiphospholipid antibody syndrome. Moderate risk factors for the development of preeclampsia include nulliparity, family history of preeclampsia, maternal age of 35 years or older, obesity, personal history of low birth weight, socio-demographic characteristics, small for gestational age, and past pregnancy complications, and in vitro fertilization.

Table 2 from Bajpai et al, © National Kidney Foundation.

The increase in prevalence of these risk factors may be what is also driving the increased incidence of preeclampsia in the population. And while we cannot reverse someone’s age, we certainly can treat hypertension and metabolic health. 

Pertinent to nephrologists, CKD of all stages and causes is a significant risk factor for preeclampsia in addition to other adverse pregnancy outcomes. The risk of preeclampsia increases as the degree of CKD progresses. Further, preeclampsia is more common in proteinuric kidney diseases and in those with diabetes and hypertension. Notably, there are disease related findings that affect the rate of preeclampsia. In lupus nephritis, for example, both active and quiescent nephritis increase the risk of adverse maternal and fetal outcomes in pregnancy including the risk of preeclampsia.  However, preeclampsia occurs more frequently in women with active lupus nephritis compared to those women with quiescent lupus nephritis.  In women with diabetes mellitus, another disease of rising incidence, increasing the amount of proteinuria increases the risk of preeclampsia. As such, treating the underlying kidney disease and minimizing proteinuria can improve pregnancy outcomes; while managing hypertension benefits women at all stages of CKD including those on dialysis or who have had a kidney transplant. Nephrologists, therefore, have a huge role to play in both preparing women for pregnancy and caring for them during pregnancy.

Table 2 from Burgner and Hladunewich, AJKD, © National Kidney Foundation.

Early diagnosis and management of preeclampsia  may decrease the risk of some of the most serious sequelae from occurring,  but perhaps there is no better treatment for disease than avoiding it altogether, so recognizing preventative strategies to avoid preeclampsia is of vital importance for both the baby and the mother.

The pathogenesis of preeclampsia is complex, thus it is not surprising that many randomized controlled trials employing a simple approach have failed to decrease the risk of preeclampsia:

•   Fish oil
•   Vitamin C
•   Vitamin E
•   Garlic Supplementation
•   Folic Acid
•   Sodium Restriction
•   Calcium (in healthy low-risk patients)
•   Vitamin D supplements

The most useful preventive pharmacologic intervention is low-dose aspirin prophylaxis. Data from multiple meta-analyses have shown that prophylactic aspirin administration reduces the frequency of preeclampsia and its sequelae. It is safe, with no increase in the risk of fetal bleeding and only a small increase in postpartum hemorrhage. When taken by patients at moderate to high risk of the disease it reduces the risk of preeclampsia by 10%-20%. The rationale for aspirin use came from observations that preeclampsia is associated with increased platelet turnover and increased levels of platelet derived thromboxane. Low-dose aspirin diminishes platelet thromboxane synthesis while maintaining vascular wall prostacyclin synthesis. Modulation of inflammation, which is exacerbated in patients with preeclampsia, may be connected to the beneficial effect of low dose aspirin for prevention of preeclampsia. However, the magnitude of benefit is variable and depends on several factors.

Patients at high risk for developing preeclampsia are afforded the greatest benefit by low-dose aspirin in preventing the disease. If a patient has any high risk factor present, then it is recommended that low-dose aspirin be started at 11-13 weeks of gestation and continued until 36 weeks of gestation. This includes every woman with CKD.

In patients with two or more moderate risk factors, the United States Preventive Services Task Force (USPSTF) and the American College of Obstetricians and Gynecologists (ACOG) recommend low-dose aspirin for preeclampsia prevention. In patients with only one moderate risk factor, the incidence of preeclampsia is estimated to be less than 8%. However, this increases with multiple moderate risk factors.

More recently, the Chronic Hypertension and Pregnancy Trial Consortium (CHAP) found a reduction in the incidence of any preeclampsia, preeclampsia with severe features, and medically indicated preterm birth less than 35 weeks when targeting pregnant patients’ blood pressures to less than 140/90 mmHg compared with the strategy of reserving treatment only for severe hypertension. This strategy also decreased the risk for the development of severe hypertension in pregnancy.

The two interventions of low-dose aspirin and blood pressure control are the main ways to decrease the risk of preeclampsia for everyone, including our patients with CKD. In addition, women with proteinuric CKD should be seen and have their kidney disease treated and proteinuria reduced prepartum. Women with lupus nephritis should be counseled to wait until their lupus nephritis has been quiescent for at least 6 months and be maintained on hydroxychloroquine during pregnancy. Patients with other glomerulonephritides also need to be treated, in remission, and on pregnancy-safe immunosuppression prior to pregnancy.

There are some select populations that may benefit from calcium supplementation, pre-pregnancy weight loss and appropriate gestational weight gain, as well as exercise. There are ongoing studies assessing possible roles of statins, anticoagulation, and metformin. Decreasing the risk of preeclampsia remains an important part of combating the maternal healthcare crisis and an area in need of ongoing research!

Long-Term Sequelae

Women with a history of preeclampsia are at risk for recurrent preeclampsia with future pregnancies, with the risk of recurrence based on severity and time of onset of the initial episode. There is a 25-65% risk of recurrence in those who had early-onset severe preeclampsia compared to a much lower risk of 5-7% in those without severe features. 

Women with a history of preeclampsia are also at increased risk for cardiovascular disease (CVD), heart failure, stroke, diabetes, and kidney disease later in life, especially if two or more pregnancies were affected or delivery indicated before 34 weeks. It is believed that preeclampsia induces physiologic and metabolic changes that remain after giving birth thus leading to CVD. Other maternal risks include developing mental health disorders (i.e. PTSD and depression) and vascular dementia.

It is important for clinicians to counsel their patients both on the risks of recurrent preeclampsia and the risk for long-term sequelae post pre-eclampsia. At this time, there is no consensus on how often or a specific time-frame these patients should be followed or screened for CVD. Some say to start as early as 6-8 weeks postpartum, and others recommend 6-12 months postpartum, then yearly afterwards. Despite this uncertainty of when to start, regular monitoring and follow up opens up the opportunity for clinicians to educate patients on healthy behaviors, weight loss, smoking cessation, diet and regular exercise in order to prevent future complications. 

– Executive Team Members for this region: Anna Burgner @anna_burgner and Samira Farouk @ssfarouk | Meet the Gamemakers

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on May 31, 2024.

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