Case study of tacrolimus as an effective treatment for idiopathic membranous glomerulonephritis in pregnancy

Introduction

Nephrotic syndrome is an uncommon but important condition in pregnancy, with complications related to renal protein loss including oedema, need for diuresis, thrombosis, hypogammaglobulinaemia and infection risk.^1,2 Idiopathic membranous glomerulonephritis (IMN) is a very uncommon cause of nephrotic syndrome in pregnancy with the literature limited to case reports and two case series.^2–7

We present a case of safe and efficacious use of tacrolimus monotherapy to treat IMN in pregnancy, thereby controlling nephrotic syndrome and enabling avoidance of glucocorticoids and cyclophosphamide.

Case

A 26-year-old Caucasian female with a background of morbid obesity and polycystic ovarian syndrome presented with nephrotic syndrome at 27 weeks’ gestation in her first pregnancy. Biochemistry results included a serum albumin of 17 g/L, protein:creatinine ratio of (PCR) 337 mg/mmol and serum creatinine 29 µmol/L. Figure 1 details the peripartum events and the trajectory of laboratory parameters. She had no clinical or biochemical markers suggestive of systemic lupus erythematosus. The pregnancy was complicated by gestational diabetes mellitus treated with dietary modification alone. Nephrotic syndrome was closely monitored rather than the empiric use of glucocorticosteroids prior to delivery due to clinical stability and the risk of exacerbating her diabetes. She did not develop hypertension or require diuresis. She received standard venous thromboembolic prophylaxis. She had a normal vaginal delivery at 38 weeks and 3 days, following induction of labour for chorioamnionitis. Fetal birth weight was 2700 g (7th centile). The placenta weight was below the 10th percentile with features of chorioamnionitis and acute funisitis.

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Figure 1.

Biochemical parameters over time.

A postpartum biopsy revealed membranous glomerulonephritis, stage 2 with no other abnormality. Secondary causes were excluded. Anti-phospholipase A2 antibody assay was not routinely available at the time. As proteinuria persisted six months postpartum, she was commenced on the angiotensin receptor blockade (ARB) agent irbesartan and titrated up to the maximum dose of 300 mg. Despite 12 months of treatment she had ongoing proteinuria of 6 g per day. Given her past history of obesity and gestational diabetes, the side effect profile of glucocorticoids was deemed unacceptable. She wanted to conceive once in remission, thus use of cyclophosphamide and mycophenolate mofetil for maintenance immunosuppression were avoided.

At 18 months postpartum tacrolimus was commenced. After one month of tacrolimus, the urine PCR decreased (487 to 78 mg/mmol) and blood albumin normalised (27 to 36 g/L). The trough level of tacrolimus, measured 12 h after a dose, ranged from 7.4–12.8 µg/L (measured by liquid chromatography mass spectrometry). The serum creatinine rose slightly but remained stable (Figure 1).

Three months after commencing tacrolimus she conceived and the ARB was stopped. Low-dose tacrolimus was continued (3–5 mg twice daily) although trough levels fell to 2.4–3.9 µg/L. Pregnancy complications included mild hypertension treated with labetolol and gestational diabetes mellitus with good glycaemic control achieved with dietary modification alone. Nephrotic syndrome remained in remission during pregnancy with stable urine PCR of 11–61 mg/mmol, albumin of 34–35 g/L in the first trimester and 28–29 g/L in the second and third trimesters. Fetal growth was satisfactory on ultrasound monitoring.

She underwent planned induction of labour by artificial rupture of membranes at 38 weeks’ gestation and had an uncomplicated vaginal delivery. Timing of delivery was due to her comorbid conditions of hypertension and diabetes rather than any renal indication. The placenta was normal. The male infant had a birth weight of 3250 g (42nd centile), with neonatal jaundice requiring phototherapy but no other complications.

Discussion

Data on primary glomerular disease show increased rates of adverse pregnancy outcomes particularly preterm delivery, low birth weight, preeclampsia and progression of renal dysfunction. ⁸ IMN specifically has been associated with adverse maternal and fetal outcomes.^3,7,9 In a review of 33 pregnancies with IMN only 2 of 10 of women with greater than 5 g/24 h proteinuria had a live infant born after 32 weeks’ gestation compared with 21 of 23 with less than 5 g/24 h. Though these data reflect practice from over 30 years ago, this still highlights that control of nephrotic syndrome in pregnancy is essential for better perinatal outcomes. ³

For the treatment of IMN, the Kidney Disease Improving Global Outcomes 2012 Guideline recommends calcineurin inhibition as a second-line option in those with a contraindication to first-line treatment with cyclical corticosteroid and alkylating agents. ¹⁰ In our patient, there was concern regarding the significant side effects of glucocorticoids including obesity and diabetes, and a reluctance to use cyclophosphamide due to potential impact on ovarian function. The increasing prevalence of diabetes and obesity highlights the need for treatment protocols with steroid minimisation.^11,12

Tacrolimus monotherapy has been used with success and safely in non-pregnant patients with IMN.^13,14 Tacrolimus has also been effectively used in pregnancy in the post-transplant period and in lupus nephritis.^15–17 Our patient rapidly achieved and maintained disease remission with tacrolimus monotherapy, thereby facilitating a better clinical situation for subsequent pregnancy with good maternal and fetal outcomes.

In this case, the tacrolimus dose was titrated to achieve trough levels of 3–5 ng/ml during pregnancy, and was well tolerated. Tacrolimus has complex pharmacokinetics, being highly bound to protein and erythrocytes. ¹⁸ Targeting whole blood levels in pregnancy may increase toxicity risk, as the unbound fraction rises due to altered haematocrit and hypoalbuminaemia. ¹⁹ Monitoring unbound concentrations during pregnancy maybe a better measure, however a routine clinical assay is not available as yet. We noted a small rise in serum creatinine from 43 µmol/L to 58 µmol/L after tacrolimus commencement, but an appropriate fall in pregnancy and return to baseline levels post-partum occurred.

As in the first pregnancy, gestational diabetes mellitus occurred. Despite the possible diabetogenic side effects of tacrolimus, this was managed successfully with dietary modification alone. Glucocorticoid therapy is particularly diabetogenic and if used, pharmacological treatment for the diabetes would probably have been required.

Conclusion

IMN during pregnancy can be successfully and safely managed with tacrolimus monotherapy. This has been used widely in pregnancy in other settings and provides an alternative immunosuppressive option for women wishing to avoid the side-effects of first-line therapies for IMN. The treatment options for IMN in pregnancy require further research though given the rarity of this situation, this is likely to be through case reports and observational studies.