A case of minimal change disease during pregnancy – benefits of early diagnosis and use of corticosteroids

Background

Nephrotic syndrome occurs in only 0.01–0.03% of all pregnancies and is rarely caused by primary glomerulopathies.^1–3 Nevertheless, prompt diagnosis and treatment of primary glomerular conditions are vital to prevent poor outcomes such as maternal renal failure, fetal growth restriction and fetal death. ⁴

Case report

A 34-year-old woman, 10 weeks into her third pregnancy, was referred to obstetric medical services with a two-week history of intermittent cloudy urine. Similar, occasional episodes since childhood had never been investigated. In her first pregnancy, she had a miscarriage at 15 weeks and in her second pregnancy, she had insulin-requiring gestational diabetes. She had been subsequently diagnosed with type 2 diabetes mellitus (which was diet-controlled) and hypercholesterolemia. She was euvolemic and normotensive (blood pressure 120/69 mmHg). Urine dipstick showed 1+ protein and no blood. On presentation, she had normal renal function (creatinine 42 µmol/L), mildly low albumin (28 g/L, normal range 35–50 g/L). She had a speckled anti-nuclear antibody at a titre of 1:80, and otherwise unremarkable glomerulonephritis screen. Her 24-h urine protein was 0.38 g/24 h (creatinine excretion of 8.05 mmol/24 h). At 11 weeks of gestation, she was commenced on insulin for management of her gestational diabetes. At 12 weeks of gestation, her urinary protein excretion increased to 5.0 g/24 h (creatinine excretion of 8.62 mmol/24 h) and serum albumin was 27 g/L. Given these changes, a renal biopsy was performed at 12 weeks and 6 days of gestation. There were no complications from the biopsy. Light microscopy showed normal glomeruli with mild acute tubular injury, and no deposition on immunofluorescence. Electron microscopy showed thin glomerular basement membrane with a mean thickness of 226 nm (range 117–518 nm) with 10% podocyte foot processes effacement. The consensus was that she had minimal change disease or unsampled focal segmental glomerulosclerosis and the minimal foot process effacement could be due to sampling error. At 14 weeks of gestation, she was commenced on prednisone 50 mg per day for 4 weeks, followed by 5 mg taper every second week. She was also commenced on sulfamethoxazole and trimethoprim, a H2-receptor antagonist, calcium and vitamin D to limit steroid adverse effects. To prevent venous thromboembolism (VTE), she received low-molecular weight heparin (LMWH) and aspirin to reduce the risk of pre-eclampsia. Her proteinuria started to reduce by week 16, and was undetectable by week 18 (albumin 30 g/L), which she maintained post-partum. Her responsiveness to steroids was also consistent with a diagnosis of minimal change disease. Steroid therapy likely increased her required insulin dosage throughout her pregnancy. She delivered a baby boy at 37 weeks and 4 days of gestation via caesarean section following spontaneous rupture of membranes (SROM), given her history of previous caesarean section and comorbidities. The baby had trisomy 21 and weighed 2.6 kg. She required insulin to manage her diabetes until one month post-partum, after which her diabetes was controlled with diet. There were no other adverse effects related to immunosuppression.

Discussion

Nephrotic syndrome is characterised by proteinuria greater than 3.5 g/24 h, peripheral oedema, hypoalbuminemia and often hyperlipidaemia. The differentials for proteinuria in pregnancy are wide and include pregnancy-related conditions (e.g. preeclampsia), primary renal conditions and systemic diseases (e.g. diabetes mellitus), making early diagnosis challenging. Low-level proteinuria of up to 0.3 g/24 h can be normal in pregnancy. ⁵ Severe proteinuria, even without uncontrolled hypertension and significant renal impairment, can precipitate preeclampsia, acute kidney injury and fetal complications including intrauterine growth restriction, prematurity, polyhydramnios, anasarca and fetal death. ⁶ Early diagnosis of nephrotic syndrome due to primary glomerular diseases allows initiation of supportive and disease-modifying treatment, which is crucial in improving maternal and fetal outcomes.^2,6–8

In this case, though glomerular disease was most likely, renal biopsy was essential for exact diagnosis and to guide treatment. The benefits of early diagnosis were weighed against the risks of miscarriage associated with renal biopsy. A recent systematic review, including 243 renal biopsies across five studies, found a 7% risk of any complication during pregnancy, compared with 1% risk post-partum, likely related to hormonal changes to renal blood supply in pregnancy. ⁹ The risk of major complications to mother and fetus was 2%, compared to 0.1% in young, non-pregnant women.^9–11 There was a 5% risk of minor complications such as macroscopic haematuria and loin pain as compared with 1.3% risk in post-natal biopsies. ⁹ The highest risk period was 25 weeks’ gestational age (range 23–26 weeks). ⁹ The increased complication rate contributes to the reluctance amongst nephrologists to perform renal biopsy in pregnancy, but two-thirds of physicians across four studies changed their treatment based on the biopsy results. ⁹ There is an argument to delay biopsy and trial empirical therapy until delivery, and there is a case of MCD that has been successfully managed thus. ¹ The decision and timing of renal biopsy in pregnancy need to be an individualised decision made with a woman who has been well informed of the associated risks.

The treatment guidelines for MCD in the non-pregnant woman recommend the use of high-dose corticosteroids to induce remission, and cyclophosphamide, calcineurin inhibitors or rituximab for steroid-intolerant, steroid-dependent or frequently relapsing MCD.^12,13 There are two published case reports of MCD diagnosed and treated during pregnancy.^14,15 Treating frequently relapsing MCD in the pregnant woman is more difficult as the recommended treatments have a high risk of spontaneous pregnancy loss, congenital malformations, fetal growth restriction and preterm delivery. ¹³

Corticosteroids have been used safely in pregnancy in lupus nephritis and renal transplant; however, women must be monitored for adverse effects. ⁶ , ¹⁶ Maternal to cord blood ratio of corticosteroids is approximately 8–10 to 1. ⁹ Older studies report a 2.6–3.4-fold increased risk of infant oral cleft lip or cleft palate with use in early pregnancy; however, newer evidence suggests that this risk may be overstated.^17–20 Pooled studies have not identified an increased risk of major congenital birth defects, though there is an association with chronic steroid use and newborn hypoadrenalism.^17,21 Pregnancy has a four- to sixfold increased risk of VTE and prophylactic,^22,23 anti-coagulation with LMWH can mitigate this effect.^24,25 While there is an increased risk of pregnancy-induced hypertension, there does not appear to be an increased risk of preeclampsia from steroid use alone, but rather an increased risk from underlying renal or systemic disease activity.^{20,24,26–28} Managing renal disease early in pregnancy is essential to prevent preeclampsia and chronic kidney disease post-partum.^29,30

In conclusion, while MCD in pregnancy can pose a diagnostic and therapeutic challenge, the evidence supports early diagnosis and use of disease-altering immunosuppression, which can have considerable benefits and relatively low risks to mother and fetus.