Preeclampsia - the story of the underestimated glomerular injury

Written by: Cristina Popa, MD

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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

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My patient with lupus wants to get pregnant- what should the nephrologist know?

Written by: Cristina Popa, MD, Anoushka Krishnan FRACP

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Systemic lupus erythematosus (SLE) affects young women of childbearing age and has significant implications for pregnancy- for both the mother and the fetus. Given that most nephrologists will come across a scenario wherein a young lupus patient wishes to conceive a child, it is essential to have some basic concepts on the outcomes of lupus on pregnancy and vice versa, preconception counseling, and medication regimens that are safe in pregnancy. While some of these topics have been touched upon in the blog on Pregnancy and Transplantation, we will deep dive into lupus and pregnancy in this section.

Let us start by discussing maternal and fetal outcomes in patients with lupus. Perhaps the greatest risk for the mother is lupus flares, which can result in declining (or loss of) kidney function and a significant risk of pre-eclampsia. A systematic review looking at 37 studies, including 1,842 women with active (defined as presence of proteinuria 500 mg/24 hours and/or active urine sediment with or without an elevation in serum creatinine, at time of conception; lupus nephritis flare during pregnancy or a new diagnosis of lupus nephritis during pregnancy) and quiescent lupus nephritis, demonstrated that a systemic lupus flare was not uncommon and occurred in up to 26% of pregnancies. Active lupus nephritis occurred in 16.1% of pregnancies, hypertension was seen in 16.1%, pre-eclampsia in 7.6%, and eclampsia or stroke in 1%. Women with active LN had a higher risk of adverse outcomes. These are all major issues that should be discussed with the mother, emphasizing the need for preconception counseling. Additionally, maternal mortality is nearly 20-fold higher in women with lupus, with a 3-7 fold higher risk of thrombosis and infections. Notably, patients with class 3 or 4 SLE tend to be at higher risk of lupus nephritis (LN) flare and hypertensive complications.

There are several risks to the fetus as well, particularly in patients with active lupus nephritis. Risks include a higher need for cesarean section, spontaneous abortion (16%), higher risk of premature delivery (35%), stillbirth (3.6%), neonatal death (2.5%), and intra-uterine growth restriction (12%). There is also a small risk of neonatal lupus erythematosus (NLE), wherein maternal auto-antibodies cross the placenta and cause symptoms. The incidence rate is estimated at 5-10%, mostly in pregnancies exposed to anti-Ro and anti-La antibodies. The most severe manifestation is congenital heart block (1-2%), requiring early diagnosis and intervention, otherwise resulting in up to 20% perinatal mortality. Congenital heart block typically manifests between 18-24 weeks of pregnancy (when immunoglobulins can cross the placenta), and most surviving children will usually require a pacemaker at an early age. Other manifestations of NLE usually resolve within 3-6 months of birth (coinciding with the half-life of auto-antibodies).

How might women with quiescent disease fare? A large prospective study including patients in the United States and Canada evaluating 385 women at low risk of complications (quiescent disease, no lupus nephritis or active systemic disease {uPCR <1000 mg/g, serum creatinine <1.2 mg/dl, prednisolone use <20 mg}, follow-up in specialist centers, on hydroxychloroquine) demonstrated that severe flares mostly occurred in the second (2.5%) and third trimesters (3%). Nearly 81% had uncomplicated pregnancies. Of those who did have complications, risk factors included ethnicity (non-white or Hispanic), lupus anti-coagulant positive, and those on anti-hypertensive agents. Adverse outcomes, including fetal or neonatal death, preeclampsia or hypertension, in this group were high at 58%.

These data may suggest that women with well-managed lupus do not necessarily have a bad outcome. If pregnancy is planned, the disease is quiescent, the patient is on appropriate pharmacological therapy, and the risk of adverse outcomes can be reduced under close specialist surveillance. Nevertheless, the high-risk nature of this population warrants close supervision and the involvement of a multidisciplinary team.

The conundrum of symptoms: is this a flare or just typical pregnancy symptoms?

Clinicians face a real challenge distinguishing symptoms of an SLE flare in pregnancy because the many physiological signs and symptoms of pregnancy overlap with the clinical features of a lupus flare (Figure 1). Fortunately, most of the time, flares of SLE activity in pregnancy are not severe. In most studies, skin, joint, and constitutional symptoms are the most commonly reported. SLE activity scores were adapted to differentiate between SLE activity and pregnancy.

Figure 1. Common manifestations in lupus and pregnancy (created with BioRender.com)

SLE is associated with a higher risk of flares during pregnancy and a higher risk of preeclampsia. Preeclampsia and lupus activity may have common clinical features, often challenging the differentiation between said entities (Table 1). A kidney biopsy may be advised, but know it is associated with a higher complication rate and a higher bleeding risk, particularly at 23-26 weeks of gestation. The 2019 UK guideline recommends biopsy in the first and early second pregnancy trimesters only if the histological diagnosis is likely to change management (class 1C).

Table 1. Differential diagnostics in SLE flare vs Preeclampsia: laboratory findings (Clowse WE, 2007, Zeisler H, et al, 2016, Dijkstra DJ et al, 2022)

Anti-phospholipid antibody syndrome and pregnancy: a dreaded combination

Up to 40% of patients with lupus have antiphospholipid syndrome (APS). Pregnancy complications in obstetric APS (OAPS) include unexplained, recurrent, early pregnancy loss (before ten weeks gestation), fetal death, or premature birth due to severe preeclampsia, eclampsia, and intrauterine growth restriction. Anti-b2-glycoprotein antibodies, lupus anticoagulant (LAC), and anti-cardiolipin antibodies should be tested. The presence of LAC conveys the greatest risk of adverse outcomes in pregnant women with or without SLE. Other risk factors include younger age and a history of prior thrombotic events. Treating OAPS early improved pregnancy outcomes; in a European registry study of 1000 women with OAPS, 45% received recommended OAPS treatment, and subsequently, nearly 85% had a good live-birth rate.

Preconception planning:

Pre-conception counseling is a pivotal parts of ensuring safe pregnancy for both mother and baby. Clinicians should aim to work with their patients to optimize disease control and work towards the shared goal of a safe pregnancy and healthy baby.

SLE's systemic activity must be evaluated clinically and biochemically, as a recent lupus nephritis flare is a risk factor for recurrence. Ideally, kidney function should be stable, on a safe medical regimen, and without evidence of a flare for at least six months before conception.

Antepartum care must be provided in a multi-disciplinary setting involving obstetricians and nephrologists/ rheumatologists. Expectant mothers should be monitored on a monthly basis (and more frequently if at higher risk). Serial fetal ultrasounds should be performed to evaluate growth.

Pharmacotherapy in pregnancy:

Appropriate pharamco-therapy is also crucial to avoid the associated risks of fetal malformations and miscarriages.

Immunosuppressants: Immunosuppressive drugs safe to use in pregnancy include corticosteroids and azathioprine.

Tacrolimus has been used on occasion, although we lack well-controlled studies on safety in pregnant women. Tacrolimus is considered safe to be used in pregnancy, with a small risk of neonatal hyperkalemia and renal dysfunction, and these parameters should be monitored in the newborn. Any of these three agents may also be used to treat a flare in pregnancy.

Hydroxychloroquine should be continued throughout pregnancy or initiated if there are no contraindications.

Immunosuppressive agents that are unsafe in pregnancy include mycophenolate (risk of miscarriage, first-trimester pregnancy loss, malformations like cleft lip and cleft palate), cyclophosphamide (severe birth defects) and methotrexate (risk of miscarriage and possible birth defects).

Rituximab lacks adequate safety data. EULAR guidelines suggest that while sound data is unavailable for rituximab, registry data have not shown an increased risk of congenital malformations. While it may be considered for use in early pregnancy, its use in late pregnancy can result in severe B-cell depletion in the neonate. The American College of Rheumatology conditionally recommends its use in life/ organ threatening disease. The use of belimumab is also not recommended in pregnancy.

Intravenous immunoglobulins (IVIG) may be used in a flare of LN refractory to other therapies but can be associated with a risk of kidney insufficiency.

In the relatively rare but important scenario of a severe life-threatening flare whereby treatment typically involves teratogenic therapy, shared decision-making should be undertaken with the clinical team and the patient and the patient’s family to discuss the option of termination of pregnancy.

Figure 2. Lupus flare - treatment (created with BioRender.com)

Anti-hypertensive agents: This has already been discussed in detail in our ‘Hypertension in Pregnancy’ segment, but labetalol, nifedipine, and methyldopa are generally safe bets. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are avoided in the second and third trimesters of pregnancy as they are associated with severe birth defects (oligohydramnios, renal failure, and pulmonary hypoplasia, amongst others). Some evidence suggests that using an ACEi in the first trimester may not be associated with significant anomalies or adverse outcomes. So if your patient is dependable and has reliable menstrual cycles, it may be an idea to continue the ACEi or ARB until she falls pregnant and then cease it (to achieve the maximal anti-proteinuric effect).

ACEi, such as enalapril or captopril, are considered safe during lactation, more on a common practice ground. In a little study, both drugs have been shown to be relatively safe when breastfeeding, with minimal amounts secreted into breast milk. It may be associated with a small risk of neonatal hypotension, and monitoring is recommended.

Anticoagulation: If deep vein thrombosis prophylaxis is required, either unfractionated heparin or low molecular weight heparin may be used. Warfarin is contraindicated in pregnancy due to the risk of fetal birth malformations, spontaneous abortion, perinatal bleeding, and risk of fatal hemorrhage to the fetus in utero (it can cross the placental barrier). Data is limited on direct-acting oral anticoagulants in pregnancy and should therefore be avoided until robust evidence is available. As pregnancy is a pro-coagulant state, low-dose aspirin and therapeutic anticoagulation are advised for all patients with a history of anti-phospholipid (APS) antibody syndrome and a history of the thrombotic events (characterized by venous, arterial, and/or small vessel thrombosis with persistently positive anti-phospholipid antibodies). Treatment is advised throughout pregnancy and 6-12 weeks post-partum. Low-dose aspirin and prophylactically dosed anti-coagulation are recommended for women with known obstetric APS. Close surveillance may be considered in those with APS antibodies who do not meet the criteria for APS, or either low-dose aspirin or anti-coagulation may be used. Prophylactic anticoagulation should also be considered in pregnant women with nephrotic syndrome in the absence of APS antibodies (figure 2). Low-dose aspirin is recommended for all pregnant women with SLE at the beginning of the first trimester.

Lupus remains a tricky condition to manage, and given the population it affects, a working knowledge of how to manage fertility and pregnancy around this challenging condition is important. A shared decision-making process with the treating team and the patient incorporating the patient’s core values and preferences is the key to ensuring optimal maternal and fetal outcomes.

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Primary Glomerulonephritis and Pregnancy

Written by : Priyadarshini John DM

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The incidence of primary glomerulonephritis ranges between 0.2/100,000/year and 2.5/100,000/year. Pregnancy can take a toll on the kidney or vice versa. There is sparse literature about pregnancy counseling and managing primary glomerulonephritis during pregnancy.

Disease activity is the most important factor that affects maternal and fetal outcomes, and therefore control of the active disease should be undertaken prior to conception. This study which studied outcome of pregnancy in chronic kidney disease including chronic glomerulonephritis reported stable renal function in 79% of pregnant women, out of which 20% of the women had a 25% decline in renal function postpartum and 10% progressed to end-stage renal disease by six months postpartum, which probably undermines the importance of contributing factors like presence of HTN, amount of proteinuria and etiology of renal dysfunction at the time of conception. Fetal outcomes in terms of birth weight and gestational period were better in women with renal dysfunction without proteinuria than in women with proteinuria.

Control of proteinuria prior to embarking on pregnancy is of utmost priority, and evidence stems from outcomes of pregnancies in lupus. It is recommended to achieve complete remission of proteinuria for at least 3 to 6 months prior to pregnancy.

For glomerular diseases that mandate treatment with RAS inhibitors, these drugs can safely be used before pregnancy and are not considered teratogenic in the first trimester. Nevertheless, the best practice is to stop RAS inhibitors prior to conception.

Cyclophosphamide and Mycophenolate mofetil should be discontinued six weeks prior to planning pregnancy and it is recommended to wait for at least a year after rituximab.

Chronic hypertension is also common in patients with CKD and GN.The strict control of blood pressure is critical in pregnant women with glomerulonephritis, as severe hypertension in the first trimester is associated with adverse pregnancy outcomes. Methyldopa, extended-release dihydropyridine calcium channel blockers, and hydralazine are preferred antihypertensive drugs during pregnancy.Beta blockers labetalol are also first line. Labetalol crosses the placenta and can cause neonatal bradycardia and hypoglycemia. RAS inhibitors cause congenital cardiac abnormalities like atrial and ventricular septal defects, patent ductus arteriosus, pulmonary hypoplasia in the fetus, and oligohydramnios. For a comprehensive review about hypertension in pregnancy check here.

However, patients with glomerulonephritis may also experience difficulty getting pregnant or difficulties during their pregnancy.

Infertility in glomerulonephritis is secondary to disease processes of advanced chronic kidney disease, which causes hypothalamic pituitary dysfunction and impaired ovulation. In chronic kidney disease, there is defective pulsatile release of Gonadotropin releasing hormone(GnRH) and hence decreased release of Follicular stimulating hormone(FSH) and luteinizing hormone(LH) from pituitary.(Figure 1)

Figure 1 Hypothalamic-Pituitary axis in Normal Vs ESKD

Pharmacological therapy like cyclophosphamide can sometimes put women at risk for infertility. Oral cyclophosphamide and older age put women at risk for gonadal failure. It is emphasized that intense hemodialysis or transplantation might improve fertility.

Superimposed preeclampsia can develop on chronic hypertension, and patients with CKD are at particularly higher risk of preeclampsia compared to the general population. Worsening proteinuria and blood pressure after 20 weeks of gestational age should prompt evaluation for preeclampsia. Diagnosis of preeclampsia can be ruled out if sFlt1/PlGF ratio<38, but again the utility of these markers in underlying chronic kidney disease or glomerulonephritis is unclear. Kate et al studied the utility of markers of preeclampsia like serum sFLT1, PIGF in a spectrum of chronic kidney disease patients and inferred that cut off of these markers are similar to those who do not have chronic kidney disease population.Until these assays are validated in CKD for commercial purpose, high resistance patterns and low-velocity waveforms in uterine and umbilical arteries can differentiate chronic kidney disease (normal flow waves) from preeclampsia (high resistance flows with a pulsatility index >1.4) as suggested by Piccoli et al.

Despite best efforts, some patients may develop worsening renal function or proteinuria or de novo AKI or proteinuria that may necessitate renal biopsy.Indications for renal biopsy in pregnancy include rapid deterioration of renal function and de novo nephrotic syndrome. Renal biopsy should be considered, especially when diagnosing the underlying pathology will change the management of the patient and cannot wait until the delivery time.Complications of Kidney biopsy like the need for renal artery embolization, blood transfusion, preterm delivery, or fetal death occur in around 2% of pregnant women and were more common after 23 weeks of gestational age and during the postpartum period.

Medications:Prenatal supplementation of folic acid 5 mg, oral/IV iron, Vit D, and calcium are recommended.Calcium and low-dose aspirin (75-100mg/day) are known to reduce the risk of preeclampsia in high-risk women.Erythropoietin stimulating agents are safe to be used in pregnancy and help reduce the need for blood transfusion. Anticoagulation and thromboprophylaxis should be considered in women with albumin less than 2.5mg/dl. Treatment with low molecular weight heparin is deemed safe during pregnancy. Warfarin crosses the placenta and causes fetal loss and skeletal and central nervous system defects. Thromboprophylaxis is usually held before delivery and reinitiated at the earliest and continued until six weeks postpartum as the risk of thrombosis increases during the postpartum period.

Immunosuppression:Corticosteroids are the mainstay of therapy in many glomerular diseases and are considered safe to use in pregnancy. The placenta acts as a barrier and inactivates maternal cortisol by 11-beta-hydroxysteroid dehydrogenase type 2 on syncytiotrophoblasts, and low-doses do not cause thymic hyperplasia and adrenal suppression. Betamethasone and dexamethasone bypass this step, and fetal levels will be around 30% of maternal levels and hence used to accelerate fetal lung maturation. Adrenal suppression should be considered and treated during labor and delivery if a woman is on more than 20mg of steroids for greater than three weeks within six months prior to delivery.

Azathioprine in doses <2 mg/kg/day is safe to use in pregnancy as the fetal liver lacks inosinate pyrophosphorylase, essential in conversion to the active metabolite. Increased risk of congenital malformations, prematurity, and perinatal mortality is seen with azathioprine. Still, these adverse effects were not confirmed by the National Transplantation Pregnancy Registry.

Evidence regarding the safety of calcineurin inhibitors comes from their use in transplantation. These drugs can aggravate maternal hypertension. Dosages of CNI should be regularly monitored and adjusted due to the increased volume of distribution.

Rituximab safety is not well documented. Though there is some reassuring data about the usage of rituximab during pregnancy, it is recommended to delay pregnancy for at least 6-12 months after exposure to rituximab.

Cyclophosphamide and Mycophenolate are potential teratogens. Mycophenolate, a purine biosynthesis inhibitor, causes cleft lip and palate microtia with atresia of the external auditory canals, micrognathia, and hypertelorism. Cyclophosphamide causes calvarial defects, abnormalities of the ear, craniofacial structure, limb, and visceral organs, and developmental delay.

Table 1. Summary of immunosuppression in pregnancy

Glomerular disease-specific outcomes in pregnancy:There is meager data about pregnancy outcomes in minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Few of the oldest studies by Jungers et al and Barcelo et al reported fair maternal and fetal outcomes if hypertension and proteinuria are well controlled. Proteinuria in the first trimester of idiopathic membranous nephropathy is associated with worsening nephrotic syndrome, gestational hypertension, renal dysfunction, fetal loss, and prematurity.

Pregnancy has minimal effect on IgA nephropathy as long as the renal function is preserved, and pregnancy did not have a significant impact on disease progression over a period of 4 years when compared to the non-pregnant population. Proteinuria at the time of conception is an independent risk factor for the postnatal decline in renal function. Shimizu et al in study concluded that renal function at the time of conception has a significant impact over a period of five years or thereafter. They observed that women who had eGFR <45 ml/min/m2 had progressed to CKD stage 4 during pregnancy and reached stage 5 within five years postpartum. Perinatal death in 3%, premature delivery in 10%, HTN in 21%, and 8.5% had superimposed preeclampsia are some of the Maternal and fetal outcomes in IgA nephropathy

Literature regarding pregnancy in Anti GBM disease is sparse. Significant maternal morbidity in the form of infections, preeclampsia, and need for renal replacement therapy are seen, and IUGR, prematurity, fetal demise, and congenital malformations contribute to fetal morbidity. Anti-GBM antibodies cross the placenta, which is detectable in the blood of neonates without renal or pulmonary disease.

Pregnancy in ANCA vasculitis is rare, unlike SLE. Active vasculitis at the time of conception might result in spontaneous abortions and deterioration of renal function. Relapse during pregnancy is seen in 18% and postnatal flare in 21.3% of patients. Vasculitis Clinical Research Consortium Patient Contact Registry looked into the pregnancies before and after vasculitis and concluded that there is an increased risk of fetal demise and preterm delivery in women who conceived after vasculitis. Case reports of neonatal vasculitis are secondary to transplacental passage of anti-MPO and anti-PR3 antibodies.

Conclusions:

• Women with glomerulonephritis can plan conception after discussing it with a multidisciplinary team of obstetricians, nephrologists, and pediatricians.

• Safe maternal and fetal outcomes depend on renal function, which includes control of HTN and proteinuria

• Timely maternal and fetal monitoring is the key to optimal outcomes.

Figure 2. Holistic approach to women with glomerulonephritis who wish to get pregnant.

Reviewed by : Amy Yau MD, Sophia Ambruso MD, Silvi Shah MD

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