Preeclampsia - the story of the underestimated glomerular injury

Written by: Cristina Popa, MD

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Eclampsia has been known since Hippocratic times as neurologic symptoms accompanying pregnancy. Prior to the 18th century, the term was used only for visual phenomena during pregnancy. In the 19th century, French pathologist Pierre François Rayer observed proteinuria in 3 pregnant women, the landmark discovery that led to defining preeclampsia. In the same century, John Charles Lever pointed out the resemblance between preeclampsia and his colleagues’ Bright nephritis, but with a noticeable difference: proteinuria remission after delivery.

Today we understand preeclampsia to be a separate disease entity. Preeclampsia is a pregnancy disorder, onset after 20 weeks, with multisystem involvement. The main characteristic is hypertension (blood pressure >140/90mmHg), often accompanied by new-onset proteinuria (≥300 mg/24h). In the absence of proteinuria, women with preeclampsia may have other clinical manifestations suggestive of specific organ damage.

Background

Preeclampsia affects 3-5% of pregnancies, and there are 385 000 births every day, consequently, there are roughly 11,500 cases of preeclampsia every day. Given these findings, preeclampsia may be one of the most underrated glomerular injury worldwide.

A pragmatic overview of preeclampsia risk factors would reveal preexisting endothelial dysfunction as a common feature. Preeclampsia and chronic kidney disease (CKD) have common risk factors: obesity, hypertension, and insulin resistance. Pregnancy with CKD has a tenfold increased risk of preeclampsia. Surprisingly, preeclampsia is more likely in women with non-diabetic nephropathy, yet, from the standpoint of endothelial dysfunction, that is counterintuitive.

Figure 1. Preeclampsia risk factors (created with BioRender.com)

Diagnostics

Preeclampsia is defined as new-onset hypertension and new-onset end-organ damage, including, but not necessarily proteinuria, after 20 weeks of gestation (figure 3). Hypertension is considered blood pressure greater than or equal to 140/90 mmHg on 2 occasions at least 4 hours apart or greater than or equal to 160/110 mmHg on one occasion. Proteinuria must be greater than or equal to 300-mg/24-hour urine or spot urine protein: creatinine ratio of 0.3 (dipstick 1+). In case of no proteinuria, preeclampsia can be diagnosed in the presence of other end-organ manifestations: elevated serum creatinine

greater than 1.1 mg/dL or doubling of serum creatinine in the absence of other renal diseases, thrombocytopenia (<100,000/mL), elevated liver transaminases greater than or equal to 2 times normal, pulmonary edema, or cerebral/visual symptoms.

Figure 2. Preeclampsia diagnostics - old criteria (after ACOG and ISSHP) B. Preeclampsia diagnostic - angiogenic factors as a possible new diagnostic tool (created with BioRender.com).

Pathophysiology

During pregnancy, significant adaptive changes occur. The key anomaly in preeclampsia is abnormal maternal blood vessel formation in the uterus. In normal pregnancies, spiral arteries are high capacitance, low flux arteries allowing fetus nutrition that lose their smooth muscle in the arterial wall, thereby increasing arterial permeability. Artery remodeling is a result of vasoactive substances, growth factors, adhesion molecules, and proteases secreted by the placenta.

In preeclampsia, spiral artery remodeling is impaired, resulting in altered placental perfusion. A crucial pathophysiologic element essential for preeclampsia and glomerular injury is the imbalance between pro-angiogenic and anti-angiogenic factors (table 1 - Armaly Z, et al, 2018, Gillis et al, 2016, Leal CRV et al, 2022). The main angiogenic factors driving placental adaptations are vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF). In preeclampsia, incomplete spiral artery remodeling causes ischemia, leading to increased (anti-)angiogenic markers: soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1 is proposed as a primary driver of the underlying mechanism of preeclampsia. It binds to and decreases vascular VEGF and PIGF, important mediators of endothelial cell function in fenestrated endothelium (brain, liver, glomeruli). Endothelial dysfunction develops, leading to vasoconstriction, oxidative stress, and microemboli, explaining preeclamptic patients’ systemic symptoms.

Table 1. Preeclampsia vs. physiologic pregnancy: angiogenic and vasoactive factors

Glomerular endotheliosis is pathognomonic for preeclampsia, resulting from Flt-1 inhibition of VEGF. Glomerular endotheliosis is characterized by swollen, vacuolated endothelial cells with fibrils, swollen mesangial cells, subendothelial protein deposits reabsorbed from the glomerular filtrate, and tubular casts (ACOG: Practice Bulletin, 2019). Biopsies reveal an enlarged bloodless glomerulus with an obliterated capillary lumen (usually not accompanied by prominent capillary thrombi as in thrombotic microangiopathy). High sFlt-1 levels inhibit podocyte-specific VEGF, resulting in fenestrae formation, thereby contributing to proteinuria. The damage to podocytes is mainly responsible for proteinuria. Slit diaphragm proteins (nephrin, podocin, and synaptopodin) are essential in maintaining glomerular barrier integrity. The detection of said proteins in the urine precedes the clinical features of preeclampsia by several weeks, suggesting that podocyte damage contributes to proteinuria development (figure 1). Physiologically, thrombomodulin maintains vascular homeostasis by regulating coagulation, inflammation, and apoptosis. It is necessary to maintain the glomerular filtration barrier whereby perturbed thrombomodulin signaling leads to increased apoptosis of glomerular endothelial cells and podocytes and increased glomerular complement activation, resulting in aggravated proteinuria and glomerulosclerosis.

Tubular function is insufficiently studied in patients with preeclampsia, as elevated serum creatinine often goes unnoticed because its levels most often stay within average nonpregnant laboratory reference values. Serum creatinine should decrease during a normal pregnancy due to increased kidney blood flow and subsequently increased creatinine clearance. The central hypothesis of proximal tubular injury in preeclampsia is complement activation. Complement proteins, including C5b-9, are either filtered through injured glomeruli or directly activated at the level of the proximal tubule. C5b-9 has been shown to directly cause renal cell injury in animal models by inserting it into target cell membranes. Moreover, it activates neutrophils and promotes the release of ROS and cytokines, causing further injury. Preeclampsia podocyte injury is not temporally associated with terminal complement activation because there are no elevated concentrations of C5b-9 at the end of the second trimester when podocyturia occurs in patients with preeclampsia. Complement activation is accompanied by elevated excretion of proximal tubular biomarkers (KIM1, IGFBP-7, or TIMP-2) - which does not correlate with the clinical onset of the disease.

Figure 3. Preeclampsia: glomerular and tubular injury (created with BioRender.com)

Preeclampsia impasses in CKD:

In 2017, ACC/AHA lowered the threshold for hypertension diagnosis, and BP of 130/80 mmHg is considered stage 1 hypertension. Nevertheless, ACOG defines hypertension as BP ≥140/90mmHg. How would redefining hypertension change the clinician’s perspective on preeclampsia in this setting? A retrospective cohort study applied ACC/AHA new criteria to 137 390 pregnant women and showed an increased prevalence of chronic and gestational hypertension (17.8% absolute increase; the overall prevalence of hypertension increased from 10.3% to 28.1%). The benefits of redefining hypertension in pregnancy include identifying women at risk for preeclampsia and adverse fetal/neonatal risk.

Secondly, in women with CKD, preeclampsia diagnosis is complicated by coexisting chronic hypertension or proteinuria, estimated only in small cohort studies, to be present in one-third and one-half of pregnancies, respectively. Therefore, preeclampsia diagnosis in the CKD realm seems redundant, creating enough context for a more efficient diagnostic need. In the general population, the PROGNOSIS study showed that the sFlt-1:PIGF ratio predicted the short-term absence of preeclampsia (sensitivity - 80.0%, specificity 78.3%), but with a low positive predictive value of 36.7% (95% CI, 28.4 to 45.7). One prospective cohort study revealed that PIGF has accuracy comparable to patients without CKD (sensitivity - 60.0%, specificity 78.9%). Unfortunately, due to low sensitivity, these biomarkers are not used on a large scale, and preeclampsia diagnostics remain mainly clinical (figure 3A).

The kidney biopsy may look like a good alternative if the diagnostics can sometimes be challenging. However, it has been performed only for research purposes, revealing the above-mentioned aspect of endotheliosis or recurrent kidney disease. Kidney biopsy in pregnancy has a higher complication rate (7%) with a higher bleeding risk peeking in 23-26 weeks of gestation. However, kidney biopsy should not be discouraged if the result may change treatment. The 2019 UK guideline recommends biopsy in the first and early second pregnancy trimesters only if the histologic diagnostic changes management (class 1C).

Treatment

Preeclampsia prevention & supportive treatment

• Low-dose aspirin: Preeclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor, and stimulant of platelet aggregation. Knowing this, antiplatelet agents, like low-dose aspirin, might prevent or delay the development of preeclampsia. Aspirin is the only medication considered efficient in preeclampsia prevention and should be used in all pregnant women with CKD. A Cochrane meta-analysis disclosed small-to-moderate benefits, including reductions in preeclampsia (16 fewer per 1,000 women treated), preterm birth (16 fewer per 1,000 treated), the baby being born small-for-gestational age (7 fewer per 1,000 treated), and fetal or neonatal death (five fewer per 1,000 treated). Overall, administering antiplatelet agents to 1,000 women led to 20 fewer pregnancies with serious adverse outcomes. Regarding CKD, low-dose aspirin showed little benefit in a small retrospective cohort study.- remove the small study reference. Aspirin should be used in all women with CKD to prevent preeclampsia as prophylaxis.

• Calcium supplementation has also been shown to reduce the incidence of preeclampsia. In a Cochrane review of 12 randomized, controlled trials including 15,000 women, 1 g calcium supplementation was compared with placebo revealing that calcium supplementation significantly reduced the risk of preeclampsia (RR, 0.48; 95% CI, 0.33 to 0.69), particularly in those with low-calcium diets (low-grade evidence). A proposed mechanism is calcium supplementation may reduce uterine smooth muscle contractility and improve uteroplacental blood flow, preventing preterm labor and delivery.

• Metformin has also been proposed to reduce the risk of preeclampsia. Preliminary data from a randomized controlled trial of metformin for the prevention of large-for-gestational-age fetuses in obese pregnant women without diabetes revealed that metformin was associated with a 76% reduction in the incidence of preeclampsia (3.0% vs. 11.3%; OR 0.24, CI= 95%, 0.10 - 0.61). The presumed underlying mechanism is the reduction of anti-angiogenic factors production (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and improving endothelial dysfunction.

• Antihypertensive therapy: Hypertension raises the risk for preeclampsia (OR 1.7, 95% CI,1.1-2.5). In 2022, after CHAP trial results, ACOG lowered the threshold for starting hypertension treatment in pregnant women from 160/110 mmHg to 140/90 mmHg, but CHAP trial excluded women with preeclampsia. Hypertension treatment in pregnancy is discussed in a different section.

Curative

• Delivery is the only definitive treatment. If symptoms of preeclampsia are severe, delivery is recommended in pregnancies ≥34 weeks. If there is no severe preeclampsia, the delivery can occur at ≥37 weeks, and the patient will be closely monitored. According to ACOG, severe preeclampsia is defined when end-organ damage is present: severe hypertension, neurologic involvement, pulmonary edema, hepatic dysfunction, and kidney injury (Cr>1.1 mg/dl or doubling serum value, in the absence of other kidney diseases), or platelets less than 100 000/mm3.

Regarding pathophysiology, the main research focus in preeclampsia treatment relates to angiogenic factor imbalance (VEGF/PIGF- sFlt-1). Correcting angiogenic imbalance may be the answer by reducing circulating anti-angiogenic factors or promoting proangiogenic factors. A small study including 11 pregnant women with very preterm preeclampsia (23-32 weeks of gestation) demonstrated that sFlt-1 removal by apheresis reduced proteinuria and prolonged pregnancy by 2–21 days (depending on the number of apheresis treatments undergone by the women), without causing significant adverse maternal or fetal consequences.

Figure 4. Preeclampsia prevention and treatment (created with BioRender.com)

Preeclampsia outcomes

• Cardio-vascular: A 2017 systematic review including more than 6.4 million women showed that those with a history of preeclampsia have a 4-times higher risk of heart failure, 2.5-times greater risk of coronary heart disease, 1.8-times higher risk of stroke, and an overall 2.2-times higher risk of death from cardiovascular disease than women with no history of preeclampsia.

• Kidney outcomes: Three months postpartum, 14% of women with preeclampsia still have proteinuria, which decreases to 2% after two years. A meta-analysis showed an increased risk of ESKD after preeclampsia (meta-analytic risk ratio 6.25, 95%CI 2.73-14.79), but statistical significance was not reached for albuminuria (4.31; 0.95- 19.58) and CKD (2.03; 0.58-7.32). Translating data into patient numbers needed to follow to detect an adverse effect, 310 patients with preeclampsia would need monitoring to identify one with ESKD, 157 for CKD, and 4 for albuminuria.

• Perinatal: The risk of intrauterine death or stillbirth is high in severe preeclampsia cases (21 per 1000). However, this risk is over 50% lower in patients with mild preeclampsia (stillbirth rate nine per 1000). Preeclampsia is determined by decreased uteroplacental blood flow and consequent ischemia, which is why preeclampsia is the most common cause of intrauterine growth restriction. Severe and early-onset preeclampsia is associated with significant intrauterine growth restriction but not mild preeclampsia.

Conclusion

Preeclampsia might be one of the most glomerular injury worldwide. As with all preeclampsia systemic manifestations, glomerular injury is an expression of endothelial dysfunction. Because pregnant women with CKD have proteinuria and hypertension, it can be a challenge to diagnose preeclampsia. This is a practical example where clinicians can use new biomarkers for a more accurate diagnosis. Preeclampsia glomerular injury has no specific treatment, but it can be prevented in high-risk pregnancies. Delivery is the only definitive cure, but preeclampsia can leave glomerular scars resulting in increased risk for CKD and ESRD; therefore, screening for kidney disease is helpful in post-preeclampsia women.

Reviewed by: Sophia Ambruso, DO, Amy Yau, MD, Shina Menon, MD, Brian Rifkin, MD, Shilpa Jesudason, MD, Silvi Shah, MD

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.