6. Glomerular Disease and Pregnancy
KeywordsGlomerular disease and pregnancyPregnancy and glomerular diseaseFocal segmental glomerulosclerosisMinimal change diseaseANCA-associated vasculitisAnti-GBM antibody disease
It is not uncommon for glomerular diseases, either primary or secondary, to present or, if preexisting, to relapse during pregnancy. Development of de novo primary and secondary glomerular diseases although rare can also occur during pregnancy. Both maternal and fetal complications can occur due to the presence of nephrotic syndrome during pregnancy. A recent retrospective single-center study of women with nephrotic syndrome from biopsy-proven primary glomerular disease during pregnancy found heavy proteinuria to be an important risk factor for poor maternal and fetal outcomes . Nineteen women with 26 pregnancies and serum creatinine (Scr) levels <1.5 mg/dl at presentation of nephrotic syndrome were included in this study . Mean Scr at presentation however was 0.85 mg/dl. The mean gestational age at the time of presentation of nephrotic syndrome was 18.6 weeks, and the mean 24-h proteinuria was 8.3 g . Seven women in this case series had preexisting primary glomerular disease. Out of the remaining 12 women, 8 underwent kidney biopsy during pregnancy (mean gestational at time of kidney biopsy was 21 weeks) and 4 in the postpartum period . In this study, the most common kidney biopsy diagnosis was FSGS (42%) followed by IgA nephropathy (16%) and membranous nephropathy (16%). Several maternal complications were seen including preeclampsia, acute kidney injury, premature rupture of membranes, and cellulitis . While the live birth rate was 100% in this study, preterm delivery and low birth weight were common fetal complications. Intrauterine growth restriction (IUGR) was also seen in a small number of pregnancies .
In addition to the general approach to diagnosing and treating glomerular disease during pregnancy, this chapter will specifically review the major primary glomerular diseases complicating pregnancy. Systemic diseases including ANCA-associated vasculitis and anti-GBM antibody disease will also be reviewed. Preeclampsia-related kidney disease and other secondary glomerular diseases including diabetic nephropathy and lupus nephritis will be reviewed elsewhere in this book.
Clinical Approach to Glomerular Disease During Pregnancy
To improve maternal and fetal outcomes, women with established history of glomerular disease should undergo preconception counseling prior to planned pregnancy. This counseling should be preferably provided by a multidisciplinary team consisting of a high-risk obstetrician, nephrologist, and other relevant specialists (e.g., rheumatologist for women with history of lupus, endocrinologist for women with diabetes). Pregnancy should be planned when the glomerular disease is stable and in remission for at least 6 months. Blood pressure (BP) and proteinuria should also be well controlled prior to conception. Well-known teratogenic drugs including renin-angiotensin-aldosterone system (RAAS) inhibitors and certain immunosuppressives (such as cyclophosphamide, mycophenolic acid) should be discontinued and replaced with agents that are known to be relatively safe during pregnancy. During the preconception counseling meeting, all maternal and fetal risks (based on the assessment of disease activity at that time) should be reviewed with the patient. Risks of possible relapse of the underlying glomerular process during the pregnancy should also be reviewed in patients with stable disease. After conception, women with glomerular disease should be closely monitored by both the obstetrician and nephrologist.
Women who develop de novo or worsening proteinuria with new or worsening hypertension during the second half of pregnancy may have superimposed preeclampsia. However, as discussed later in the chapter, de novo primary and secondary glomerular diseases although rare may also masquerade as preeclampsia, and such patients who do not present with typical manifestations may need further evaluation by the nephrologist. The approach to new-onset proteinuria is similar to the evaluation of nonpregnant individuals. Firstly, urine should be examined under light microscopy to establish whether there is bland or active sediment. An active urinary sediment with the presence of dysmorphic red blood cells and/or red blood cell casts suggests a nephritic process. In addition to a thorough history and physical examination, serological work-up may be indicated, including antinuclear antibody, anti-double-stranded DNA titers, complement levels, antineutrophil cytoplasmic antibodies, or anti-glomerular basement membrane antibody titers depending on the clinical scenario. Testing for infectious etiologies such as hepatitis C virus, hepatitis B virus, HIV, or parvovirus may also be indicated. In addition, measurement of circulating anti-phospholipase A2 receptor (PLA2R) antibodies may be indicated. The likelihood of primary glomerular diseases increases if systemic or secondary causes are excluded. While there are several challenges in performing a kidney biopsy during pregnancy, this procedure can be considered in women in whom the benefits of establishing the diagnosis outweigh the risks. Kidney biopsy can be performed safely during pregnancy .
Treatment for relapsing or de novo glomerular disease (as reviewed below) is challenging as several immunosuppressive agents are either contraindicated or have limited safety data for use in pregnancy. Generally, corticosteroids are the first-line treatment of many glomerular diseases. However, alternative immunosuppressive medications may need to be considered for achieving optimal maternal and fetal outcomes.
Glomerular Diseases and Pregnancy
IgA Nephropathy (IgAN)
IgAN is common in women of childbearing age. The renal outcome in women with preexisting IgAN and preserved renal function who become pregnant seems to be good. An early prospective study compared the long-term renal outcome (5 years) in women with IgAN who became pregnant to those that did not conceive . Both groups were well matched and had normal renal function, normal BP readings, and non-nephrotic range proteinuria at baseline. At the end of the study, the glomerular filtration rates were comparable in the both groups suggesting that there were no adverse effects of pregnancy on the natural course of IgAN . More recent studies have also confirmed that pregnancy does not seem to change the course of IgAN in patients with normal renal function. A much larger (223 patients) multicenter (35 centers) longitudinal cohort Italian study determined the long-term (median follow-up of 10 years) renal outcomes in women of childbearing age with biopsy-proven IgAN and serum creatinine levels ≤1.2 mg/dl . Women who became pregnant in this study were compared with women who did not become pregnant. Except for the degree of proteinuria (higher in the pregnant group versus the nonpregnant group), both groups had similar baseline data. The long-term decline in renal function did not differ between the groups. Pregnancy also did not affect the changes in proteinuria over time or the risk of developing hypertension . Similarly, a retrospective single center-matched cohort Chinese study of women with IgAN and preserved renal function did not find pregnancy to be an independent risk factor for kidney disease progression . Of note, the median proteinuria in the pregnant group was 1.27 g per day . However, another recent retrospective Chinese study suggested proteinuria at the time of conception to be an independent risk factor for rapid progression of kidney disease following delivery in women with preexisting IgAN . This study also suggested improved postpartum renal outcomes in patients with IgAN in whom the proteinuria was reduced (>30%) prior to pregnancy .
Women with IgAN and abnormal kidney function prior to pregnancy are at increased risk for poor maternal and fetal outcomes [7–9]. The presence of consistently elevated blood pressure readings (>140/90 mm Hg) prior to conception has also been correlated to poor fetal outcomes [7, 9]. The presence on kidney biopsy of superimposed focal and segmental proliferative lesions , tubulointerstitial injury [7, 9], or arteriolosclerosis  has also been associated with poor pregnancy-related outcomes.
The approach and treatment of pregnant women with IgAN should be similar to nonpregnant patients. In hypertensive patients, blood pressure needs to be well controlled in order to improve both fetal and maternal outcomes. However, RAAS inhibitors such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are contraindicated during pregnancy due to their potential for teratogenicity. Optimally these agents should be discontinued prior to conception. If this is not possible, these medications should be discontinued immediately at the time of diagnosis of pregnancy. While there is limited data on the treatment of severe IgAN , corticosteroids can be used as first-line therapy in patients who develop rapidly progressive renal failure from crescentic IgAN. The use of cyclophosphamide is contraindicated in pregnancy.
Membranous Nephropathy (MN)
The reported maternal and fetal outcomes of pregnant women with preexisting MN have varied. An early study analyzed clinical outcomes of 33 pregnancies in 24 patients with MN and found that proteinuria worsened significantly in 55% of the pregnancies while 46% developed gestational hypertension . Of note, the development of gestational hypertension preceded the occurrence of worsening proteinuria. Renal function also declined in 9% of the pregnancies. Fetal loss was seen in 24% of the pregnancies, and another 43% resulted in premature delivery. In this study, the presence of nephrotic range proteinuria during the first trimester predicted poor fetal and maternal outcomes . More recent case reports of pregnant women with preexisting MN also showed poor maternal and fetal outcomes [12, 13]. On the other hand, a retrospective study of nine women with multiple (≥2) pregnancies that occurred after the diagnosis of MN reported good fetal outcomes . Of the 30 pregnancies studied, 90% resulted in live births with only one fetal loss reported . In addition, another study reported good fetal outcomes in patients with MN .
Cases of de novo primary MN presenting for the first time during pregnancy although rare have been reported [15, 16]. Two such cases were recently reported in the literature, one presenting at the end of the first trimester at 12 weeks and the other at week 13 of pregnancy. Both had severe hypoalbuminemia and developed progressively worsening proteinuria and body edema. In one case , pregnancy was terminated at 21 weeks as the patient developed worsening symptoms despite pulse and oral corticosteroid therapy. A kidney biopsy was performed soon after the termination of pregnancy and showed MN with features suggestive of lupus nephritis. However, there were no other clinical or serological findings of SLE in this case. The patient’s symptoms resolved, and the patient underwent partial remission of nephrotic syndrome after termination of pregnancy . In the other case of de novo MN , kidney biopsy was performed during pregnancy. The patient was subsequently started on tacrolimus and oral corticosteroid therapy. The pregnancy was complicated by preterm labor and delivery. The patient’s symptoms improved following initiation of corticosteroid therapy and completely resolved following delivery. Of note, all work-up for secondary causes of MN was negative in this case except for positive ANA result. Also, the patient had a negative PLA2R staining on kidney biopsy .
The approach to either preexisting or de novo primary MN during pregnancy should be similar to that in nonpregnant patients. In patients with preexisting primary MN who have significant proteinuria, it is important to decrease the degree of proteinuria prior to conception. In hypertensive individuals, blood pressure also needs to be well controlled in order to improve both fetal and maternal outcomes. ACE-Is and ARBs are commonly used to decrease proteinuria in patients with MN . However as mentioned earlier, these agents are contraindicated during pregnancy. In patients in whom immunosuppressive agents are needed, prednisone, tacrolimus, cyclosporine, and azathioprine may be used. Prednisone has been used alone or in combination with either calcineurin inhibitors or azathioprine in pregnant patients with primary MN [12, 13, 15, 16]. Results with either corticosteroid monotherapy or in combination with other immunosuppressive agents have been mixed. While rituximab can be considered for treatment of primary MN , the safety of this agent during pregnancy is unknown.
Focal Segmental Glomerulosclerosis (FSGS)
Most descriptions of de novo FSGS during pregnancy are reported in patients with histological lesions of preeclampsia [17, 18]. Hence, the de novo FSGS seen in preeclamptic patients is secondary in nature. The occurrence of de novo primary FSGS during pregnancy seems to be rare. However, a recent retrospective single-center study found FSGS in 8 out of 19 women with nephrotic syndrome from biopsy-proven primary glomerular disease during pregnancy . Two of these eight women with primary FSGS had three pregnancies each. Acute kidney injury (AKI) was seen in two pregnancies. However, none required hemodialysis during pregnancy. Few of these patients were treated with prednisone during pregnancy resulting in improvement in proteinuria. An additional case of primary collapsing FSGS that was diagnosed prior to pregnancy was also included in this study . This woman with collapsing FSGS presented with nephrotic syndrome at 23 weeks’ gestation. Scr was 1.0 mg/dl at presentation but increased to 3.1 mg/dl during pregnancy. Patient developed preeclampsia and had preterm delivery at 28 weeks. This patient did not recover renal function and was initiated on hemodialysis within a year of delivery. Of note, this patient did not receive any immunosuppressive medication for her collapsing FSGS . Another recent large retrospective multicenter cohort study from the United Kingdom found FSGS in nearly one third of the women who underwent kidney biopsy either during pregnancy (6/19) or within 1 year of pregnancy (50/154) . In this study, FSGS was more commonly seen in the pregnancy-related group (32.4%) compared to matched controls (9.7%). The six women who were diagnosed with FSGS during pregnancy had significant proteinuria and mean serum creatinine of 0.92 mg/dl at the time of biopsy . Due to the absence of complete pregnancy-related data, pregnancy outcomes including the diagnosis of preeclampsia were not known to the investigators of this study. Hence, it is unknown if the FSGS lesions seen on kidney biopsy during pregnancy in this study were either from preexisting or de novo primary FSGS or related to preeclampsia. Of note, during the long follow-up period, women with FSGS in the pregnancy-related group did not have significant difference in the rate of decline in renal function (estimated GFR) when compared to matched controls . Also, the need for renal replacement therapy did not differ between the two FSGS groups .
The presentation of primary FSGS during pregnancy can be very similar to that of preeclampsia. As the approach and treatment are different for primary FSGS and preeclampsia, it is important to establish a correct diagnosis. However, this may not always be possible, and it may be necessary to empirically treat for both underlying conditions. Patients who develop primary FSGS can be treated initially with oral corticosteroid therapy. Calcineurin inhibitors could be used for patients who fail to respond or are intolerant to corticosteroid treatment. The use of RAAS inhibitors is contraindicated in pregnancy.
Minimal Change Disease (MCD)
Occurrence of de novo primary MCD is rare during pregnancy. A recent review of four (two biopsy proven and two suspected) cases of de novo MCD during pregnancy suggested good fetal and maternal outcomes . These patients presented with nephrotic range proteinuria although one case had acute kidney injury requiring transient hemodialysis . Three patients who received treatment with oral corticosteroids responded well with clinical remission of nephrotic syndrome. Hence, the approach and treatment to de novo MCD during pregnancy should be similar to nonpregnant patients. Calcineurin inhibitors (tacrolimus or cyclosporine) can be considered in patients who are either corticosteroid dependent or intolerant.
ANCA-Associated Vasculitis (AAV)
ANCA-associated vasculitis (AAV) including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis predominately affect older individuals and are rarely seen in women of childbearing age. Although rare, occurrence of de novo GPA during pregnancy has been described. In a literature review of previously published cases, de novo GPA occurred in 11 pregnancies . Patients with established history of AAV can also relapse during pregnancy. Eight such relapses were seen in 21 pregnancies in the above literature review . All these relapses occurred in patients whose established GPA was in remission at the onset of pregnancy. The majority of these relapses occurred in the first or second trimester, while some also experienced relapses soon following delivery or the termination of pregnancy. In this review, preterm delivery was common in GPA patients who relapsed or developed de novo disease . However, all four patients with active GPA at the onset of pregnancy had poor fetal outcomes (two spontaneous abortions and two therapeutic abortions) . Women with active AAV during pregnancy are also at increased risk for developing preeclampsia and worsening renal function [23, 24].
Treatment for AAV can be challenging during pregnancy. While corticosteroid therapy and azathioprine are relatively safe in pregnancy, these agents may be inadequate for inducing remission in patients who develop moderate and severe disease. Cyclophosphamide is commonly used as an induction agent in the nonpregnant patient with AAV . However, cyclophosphamide is relatively contraindicated in pregnancy especially in first trimester due to its teratogenic effects. Successful treatment of GPA with cyclophosphamide during late pregnancy with good fetal outcome and without any adverse fetal effects has also been reported . As mentioned above, rituximab may also need to be considered as an induction agent for AAV during pregnancy. Plasmapheresis and intravenous immunoglobulin have also been used safely to treat GPA during pregnancy [24, 26].
Anti-GBM Antibody Disease
Anti-GBM antibody disease commonly presents clinically with rapidly progressive kidney failure and crescentic glomerulonephritis. Occurrence of de novo anti-GBM antibody disease during pregnancy has rarely been reported. A recent study reviewed fetal and maternal outcomes in seven previously reported cases and one unpublished case of de novo anti-GBM antibody disease that occurred during pregnancy . Two patients presented at the end of first trimester, while the remaining presented later during their pregnancy. Most (six of eight) pregnancies resulted in live births. However, all were premature. IUGR and small for gestational age infants were commonly reported. Maternal outcomes were poor with most (five of ten) requiring hemodialysis during pregnancy . Overall seven of eight patients required hemodialysis during the clinical course with two patients recovering renal function to a point where they did not need dialysis support. Two of eight patients developed preeclampsia. Pulmonary involvement was also seen in five of eight patients. However, no permanent pulmonary injury was reported. Patients received treatment with corticosteroids, plasmapheresis, cyclophosphamide, and azathioprine .
Supportive Management of Nephrotic Syndrome During Pregnancy
Patients who develop nephrotic syndrome usually present with severe proteinuria, hypoalbuminemia, edema, and hyperlipidemia.
Volume overload or discomfort from edema of the extremities may require the use of diuretic therapy during pregnancy. In such cases, diuretic therapy should be used cautiously with close monitoring of volume status, renal function, and electrolytes. As diuretic use during pregnancy can lead to development of oligohydramnios, close fetal surveillance is recommended.
Both pregnancy and nephrotic syndrome are considered hypercoagulable states, thereby significantly increasing the risk of venous thrombosis. Hence, prophylactic anticoagulation needs to be considered in pregnant women who develop heavy proteinuria (>5 g/day) especially in the presence of severe hypoalbuminemia (<2.0 mg/dl). Prophylactic anticoagulation also needs to be considered in patients who have nephrotic syndrome from underlying MN as this glomerular disease is more commonly observed to cause venous thrombosis . Warfarin is contraindicated in pregnancy as it is teratogenic and can cause fetal loss. Both unfractionated and low-molecular-weight heparin are considered to be safe during pregnancy as they do not cross the placenta. Prophylactic anticoagulation may need to be continued or resumed after delivery (for up to at least 6 weeks postpartum) as the risk for venous thrombosis remains increased during this period.
As discussed above, RAAS inhibitors including ACE-Is and ARBs are commonly used for antiproteinuric and antihypertensive effects in nonpregnant patients with glomerular diseases. Due to the teratogenic effects of these agents, they are contraindicated during pregnancy. Hyperlipidemia is usually not treated during pregnancy as hydroxymethylglutaryl coenzyme A reductase inhibitors are also contraindicated in pregnancy.