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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Treatment of C3GN: What's next for complement's alternative pathway?

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By: Gerren Hobby MD (@ghobby)

The complement system has been implicated in glomerulonephridities since the 1960s. Since that time, its role in the pathogenesis of glomerular disorders has been expanding. C3 glomerulopathy (C3GN) is a term introduced around a decade ago to describe the clinical phenotype of glomerular disease arising from an overactivation of the alternative complement pathway. In 2013, a consensus report defined C3GN as glomerular disorders characterized histologically by the accumulation of C3 with the absence of immunoglobulin or the dense accumulation of deposits seen with dense deposit disease. This definition keeps with the general movement that shifts glomerular disorder taxonomy away from eponyms towards a classification based on the pathophysiological driver of disease. This trend is notably seen with ANCA vasculitis and anti-GBM disease, but the C3GN definition was special due to the existence of the complement inhibitor, eculizumab – a treatment that could benefit this group specifically. That’s the purpose of this definition – identifying a group of people that could benefit from medications tailored to the particular driver of their kidney disease.

The potential treatments for C3GN have now expanded with the development of iptacopan which targets the alternative complement pathway. The APPEAR-C3G trial is a phase III trial that marks the next step in evaluating iptacopan for C3GN treatment. To understand how this medication works and how it is different from eculizumab requires a good understanding of the alternative complement pathway.

The Complement System

The complement system is composed of more than 30 soluble and membrane-bound proteins which make up the classical, lectin-binding, and alternative pathways. These pathways are complex and a good portion of their Rube Goldberg nature can be explained by the fact that many of these proteins are zymogens which need to be cleaved in order to become active. It’s also important to know that after cleavage, the taxonomy denotes the smaller cleavage fragment “a” and the larger fragment “b” (i.e. C3a and C3b, respectively). The end result of any of these pathways is the formation of the membrane attack complex (MAC), but the initiation and regulation of the specific pathways is distinct and explains why the alternative complement pathway causes C3GN.

Figure 1. Overview of the classical, lectin-binding and alternative complement pathway

The classical pathway is initiated when the C1qrs complex binds the Fc region of IgG or IgM. The bound C1qrs complex cleaves the zymogens C4 and C2 to form the C4bC2b C3 convertase. The lectin-binding pathway is initiated when hexamers of mannose-binding lectins bind bacterial carbohydrate motifs and associated with MBL-associated serine proteases to cleave C4 and C2 to again form the C4bC2b C3 convertase.

In contrast, the initiation of the alternative pathway is distinct in the fact that activation is continuous (figure 2). In a process called “tick over” C3 associates with water to recruit factor D which cleaves factor B, a zymogen, to form it into the active serine esterase Bb (a.k.a. C3 convertase) that cleaves C3 to C3a and C3b. Next, C3b associates with Bb to form C3bBb, a C3 convertase that in turn amplifies the entire process noted above.

Figure 2. The alternative complement pathway

Due to the constitutive nature of the alternative complement pathway activation, regulation is key to keeping the system in check. Some of the regulatory proteins include:

• Factor H: a serum protein that promotes the decay of C3 and C5 convertases

• Membrane cofactor protein (MCP): a surface protein which is a cofactor for serum factor I, which cleaves and inactivates C3b

• Complement receptor 1 (CR1): accelerates decay of C3 and C5 convertases; also a cofactor for serum factor I

• Decay accelerating factor (DAF): accelerates decays of C3 and C5 convertases

This tight regulation of the alternative pathway can be dysregulated through several mechanisms. The first and most common way are autoantibodies that stabilize C3 convertase thereby delaying its decay. These autoantibodies are referred to as C3 nephritic factors (C3NeFs). Secondly, loss of regulator activity can happen due to:

• Autoantibodies to factor H that prevent it’s action on C3b

• Monoclonal immunoglobulins that inhibit factor H

• Hereditary deficiency of factor H

• Mutations in complement factor H proteins that cause them to compete with factor H to bind to C3b

Any of the above mechanisms can trigger C3GN. When that occurs, patients present with proteinuria with or without hematuria. Around half of patients will have low C3 levels. A decline in kidney function can be seen and on average, 50% will develop ESKD ten years after diagnosis. On kidney biopsy, a variety of findings can be seen on light microscopy including mesangial proliferative, membranoproliferative, endocapillary proliferative, or crescentic glomerulonephritis. Immunofluorescence shows more characteristic findings with bright C3 staining along glomerular, tubular, and Bowman’s capsule membranes. Mesangial C3 staining can be observed too. Electron microscopy can show subendothelial, mesangial, and subepithelial deposits.

Current Treatment of C3GN

Now that we’ve talked about the pathogenesis and presentation of C3GN, let’s move to treatment. The current treatment of C3GN is based on case reports/case series and is initially based on if a monoclonal gammopathy is present or absent. If present, it’s treated accordingly. If a monoclonal gammopathy is absent, treatment depends on the severity of the disease:

• Mild disease (hematuria, <1.5g/g proteinuria, normal kidney function): RAAS inhibition

• Moderate/severe disease (>1.5g/g proteinuria and/or abnormal kidney function: supportive measure + MMF + steroids. If no response is seen, eculizumab is considered in the absence of an inherited factor H mutation

• RPGN: MMF or cyclophosphamide + steroids

As mentioned above, eculizumab is used in the setting of moderate disease refractory to initial therapy. Eculizumab is a humanized monoclonal antibody which binds to C5, preventing its cleavage into C5a and C5b which prevents formation of the membrane attack complex (MAC). Notice that inhibition of the complement pathway at this late step still allows for continuation of the amplification loop and formation of C3a. We’ll talk more about the significance of this in the section below.

Figure 3. Site of action of eculizumab in the alternative complement pathway

The APPEAR-C3G Trial

Could there be a more targeted treatment for C3GN though? Mouse studies of C3GN are informative. Mice with a factor H mutation expectedly develop C3GN. If however, a mutation in factor B is also introduced, C3GN does not develop. Subsequently, iptacopan which is an orally-administered small molecule inhibitor of factor B has been developed. A phase II trial in biopsy-proven C3GN patients showed that iptacopan led to a reduction in proteinuria, preservation of GFR, and reduction in C3 deposits on kidney biopsy.

It is more beneficial to inhibit the alternative complement pathway in earlier, rather than later steps. Inhibition of the alternative pathway at the level of factor B prevents cleavage of C3 into C3a and C3b, preventing propagation of the pathway while preventing the amplification loop thereby blocking the production of the anaphylatoxin C3a. A terminal complement pathway inhibitor like eculizumab, although preventing formation of the MAC, would still allow for significant formation of C3a. This is an important point since the role of C3a and the C3a receptor (C3aR) has been been observed in multiple types of glomerular disease. C3aR is abundant in renal tubular epithelial cells and less so in glomerular epithelial cells. The interaction of C3a and C3aR has a variety of effects, but in general promotes the release of inflammatory factors and is involved in formation of the histologic lesions in IgA nephropathy, minimal change disease, FSGS, lupus nephritis, and diabetic kidney disease.

Figure 4. Site of action of iptacopan in the alternative complement pathway

This brings us to the APPEAR-C3G Trial which is a randomized, double-blind, parallel group, placebo-controlled, and pivotal phase III study in 68 patients with C3GN. The inclusion criteria include

• Biopsy-proven C3GN

• Low C3

• >1g/day proteinuria

• eGFR >30

Outcomes

• Primary objective: proteinuria reduction at 6 months

• Secondary objectives will also be assessed

The results of this trial are expected in August 2023. Although C3GN is rare, there are a host of other kidney diseases as mentioned above affected by the alternative complement pathway. Additionally, it was recently shown that ANCA vasculitis patients with C3 deposition on kidney biopsy have worse outcomes. It’s likely that the nephrology community will find a role of complement in an ever expanding list of disorders. If iptacopan shows promise in this trial, we could be seeing upcoming studies in other glomerular disorders. This could be an exciting space to follow in the future.

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