Lupus (2014) 23, 11921196

http://lup.sagepub.com

CONCISE REPORT

Tacrolimus is an effective treatment for lupus nephritis

in pregnancy
P Webster1, A Wardle1, K Bramham2, L Webster2, C Nelson-Piercy2 and L Lightstone1
1

Imperial College Healthcare NHS Trust Lupus Centre, Hammersmith Hospital, London, UK; and 2Division of Womens Healthy, Womens
Health Academic Centre, Kings College London, UK

Lupus nephritis during pregnancy increases morbidity and mortality for mother and baby.
Flares are difficult to treat as many therapeutic options are teratogenic or fetotoxic. Steroids
alone may be unable to control disease activity and are associated with higher rates of preterm
delivery, sepsis and gestational diabetes. Reports of using tacrolimus to treat lupus nephritis in
pregnancy are limited. We describe the pregnancies of nine women in whom tacrolimus was
successfully used to treat lupus nephritis flare (six patients) or maintain stable disease (three
patients). Introduction or dose escalation of oral steroids was avoided in five of the patients
who developed active disease and steroid dose was rapidly reduced in the sixth patient. All
women with disease flare attained partial or complete remission after starting tacrolimus.
None of the women on maintenance treatment developed active disease. We propose tacrolimus as an effective adjuvant or alternative therapy to steroids for treating lupus nephritis
flare or maintaining stable disease during pregnancy. Lupus (2014) 23, 11921196.
Key words: Lupus nephritis; tacrolimus; pregnancy

Introduction
Systemic lupus erythematosus (SLE) frequently
aects women of childbearing age without aecting
fertility, therefore pregnancy is not uncommon, but
both maternal and neonatal complications are
higher than background, particularly for women
with lupus nephritis. In a recent meta-analysis of
2751 pregnancies of patients with SLE, lupus nephritis (LN) was associated with preterm birth and
maternal hypertensive disorders in women with
active, compared with quiescent disease.1 Disease
are, high initial creatinine and proteinuria at conception are predictive of worse outcomes; a 6month period of quiescence prior to pregnancy is
currently recommended.2
LN ares may be more common in pregnancy
due to an altered maternal immune state to establish fetal tolerance increasing disease activity.3
Flares may cause a decline in renal function, accelerating progression to end-stage renal disease.
Correspondence to: Philip Webster, Imperial College Healthcare NHS
Trust Lupus Centre, Hammersmith Hospital, Du Cane Road, London,
UK. W12 0HS.
Email: p.webster@imperial.ac.uk
Received 12 March 2014; accepted 28 May 2014
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

Management of LN in pregnancy remains challenging because of limited therapeutic options.

Cyclophosphamide and mycophenolate mofetil
(MMF) are teratogenic and safety data in later
pregnancy limited.4 Hydroxychloroquine and
azathioprine are eective for maintaining stable
disease rather than to treat ares.5,6 Safety data
regarding rituximab therapy in pregnancy suggest
placental transfer, and use is not recommended.7
Steroids alone are unlikely to control disease activity and are associated with reduced birth weight,
preterm rupture of membranes, preterm delivery
and increased rates of maternal sepsis and gestational diabetes.8
Tacrolimus is a calcineurin inhibitor (CNI) that
causes immunosuppression by preventing T-cell
activation
and
interleukin-2
transcription.
Calcineurin may cause damage to podocytes by
dephosphorylation of the actin-organizing synaptopodin. CNIs may inhibit the action of calcineurin
on the actin cytoskeleton of podocytes, restoring
normal structure and thus controlling proteinuria.9
Evidence supporting the use of tacrolimus to treat
LN ares in pregnancy is limited to one case
report.10 We present nine patients in whom tacrolimus was successfully used to maintain stable disease or treat disease are during pregnancy.
10.1177/0961203314540353

Tacrolimus is an effective treatment for lupus nephritis in pregnancy

P Webster et al.

1193

Methodology
All pregnant women with LN in our local obstetricrenal clinic database between 19972012 with at
least one tacrolimus concentration measured
between their last menstrual period and date of
delivery were included. The most recent renal
biopsy was reported for each case. Tacrolimus
dose was titrated to achieve trough levels of
58 ng/ml. Complete remission is dened as a
urine protein/creatinine ratio <50 mg/mmol.
Partial remission is dened as a non-nephrotic
PCR (<300 mg/mmol) with >50% fall from peak
at time of are.

Results
There were 55 women with LN managed by our
obstetric-renal clinic, which included 14 women
for pre-conception counselling and 41 pregnancies.
Out of the 41 pregnancies, nine (22%) received
tacrolimus during pregnancy to treat LN (Table 1).
Cases 18 had stable/quiescent disease for at
least 12 months prior to pregnancy and case 9
had no prior history of LN. Cases 13 took tacrolimus before conception and had stable disease
throughout their pregnancies. Cases 49 all experienced disease are; for 5 out of 6 women this
occurred in the rst trimester. All women were
normotensive and had nephrotic range proteinuria
at the time of are. In cases 5, 8 and 9 tacrolimus
replaced azathioprine in their treatment regimens.
Tacrolimus was added to a regimen including
azathioprine in cases 4, 6 and 7. Cases 4 and 7
also received single doses of IV methylprednisolone
at the time of are. Initiating or increasing the dose
of oral prednisolone was avoided in cases 59. Case
4 received escalated oral prednisolone at the time of
are, although a reducing regimen began within 1
month and initiation of induction of remission
occurred despite reducing steroids. All six patients
who ared began induction of remission during
pregnancy and achieved partial or complete remission by 6 months postpartum (Figure 1(a), 1(b)).
All six were in complete remission by 12 months
postpartum regardless of their stage of chronic
kidney disease entering pregnancy. Creatinine concentrations declined during pregnancy in cases 5, 6
and 8, but returned to pre-pregnancy concentrations by 6 months postpartum. Case 9 had a sustained rise in serum creatinine post-partum but
with no previous values recorded prior to pregnancy; creatinine at her rst visit may have only

represented the physiological rst trimester fall

rather than a pre-pregnancy value. There were
nine live births with weights appropriate for gestational age and no congenital abnormalities.

Discussion
Tacrolimus has been used to treat LN in the nonpregnant population for disease maintenance,11
management of disease ares,12 and to treat disease
refractory to traditional treatments.13 Tacrolimus is
considered to be safe during pregnancy14 and
during breastfeeding.15 The safety prole of CNIs
during pregnancy has mainly been established in
the solid organ transplant population. However,
both tacrolimus and ciclosporin are associated
with preterm delivery and low birth weight,16 complications that are also more common in women
with LN. Steroids are an established, eective and
safe therapy during pregnancy, and are not teratogenic, unlike conventional treatments for LN such
as cyclophosphamide and MMF. They therefore
remain important in the treatment of LN are,
although in the high and sustained doses required
to treat LN ares cause signicant side eects.
Recent evidence showing the success of minimal
steroid regimes has been reported in non-pregnant
patients, including a rituximab/MMF protocol
with no oral steroids17 and cyclophosphamide
with reduced oral steroids and then a rapid
taper.18 However, data are lacking in pregnant
women with LN.
Tacrolimus was titrated to a trough level of
58 ng/ml and increases in doses were frequently
required. Tacrolimus is highly bound to both
plasma proteins and erythrocytes, with complex
pharmacokinetics which dier depending on
whether whole blood, plasma or serum is examined.
This is further complicated in pregnancy due to
normal physiological changes such as alteration of
activity of drug-metabolizing enzymes, increased
creatinine clearance, anaemia and hypoalbuminaemia. Maintaining whole-blood tacrolimus concentrations during pregnancy runs the risk of toxicity
due to higher unbound fractions, whilst no dosage
adjustment may result in under-treatment.
Monitoring unbound trough concentrations, also
in the context of patients disease activity, may be
a better measure during pregnancy.19 In this series
tacrolimus was well tolerated, and we propose its
use as either an adjuvant or alternative therapy to
steroids in treating stable LN and disease are
during pregnancy, particularly due to the risk of
Lupus

Lupus

>12

>12

>12

>12

New diagnosis
in pregnancy

6 IV

7 V

8 IV-G (C)

9 V

V
>12
IV-G (A/C) >12
IV-G (A/C)
0
IV-G (A/C) >12

5 IV-G (C)

1
2
3
4

Class LN

No CKD

1
3
2
2

12

10

No Flare
No flare
No flare
18

1116

570

769

602

384

1514

Pred
Aza
Pred
Aza
HCQ

Aza
Pred
Aza
HCQ
Nil

No Flare
No flare
No flare
Aza
Pred

Pred
HCQ

21

20

10

Aza
HCQ
MPred
Aza
HCQ
Pred

Aza
Aza
Pred
Aza
Pred
MPred
Pred

30

Pre-conception
Pre-conception
Pre-conception
18

35

38

30

37

39
36
39
37

1400/M

2912/M

3320/F

1130/F

2988/M

3460/F
2512/F
2786/F
2476/F

29

7591

75

25

50

5075
2550
925
25

Gestation at
Birth Weight Birth Weight
delivery (wks) (g)/Sex
Centile

PR 6/12 PP 33
CR 12/12 PP

PR 1/12 PP

PR 19/40
CR 30/40

PR 1/12 PP
CR 8/12 PP
CR 3/12 PP

N/A
N/A
CR 12/12 PP
PR 32/40
CR 5/12 PP

Length of disease
quiescence prior to
Stage of CKD
Gestation at
Urine PCR Treatment at Gestation Tac
Treatment concurrent Gestation at
pregnancy (months) entering pregnancy flare (wks/40) at flare
time of flare started (wks/40) with Tac
Remission

Table 1 Clinical details of nine patients with lupus nephritis in whom tacrolimus was used during pregnancy to maintain stable disease or treat disease flare. Birth weight
centiles determined and plotted using Royal College of Paediatrics and Child Health UK-WHO Neonatal and Infant Close Monitoring Charts (baby is reported as on a
centile if within space of the line, centile range reported if not on or within space of line). Aza: azathioprine, HCQ: hydroxychloroquine; MPred: methylprednisolone;
Pred: prednisolone; Tac: tacrolimus; PR: partial remission; CR: complete remission; PP: postpartum; CKD: chronic kidney disease; PCR: protein/creatinine ratio; wks:
weeks; M: male; F: female; x/40: x weeks of gestation; x/12: x months

Tacrolimus is an effective treatment for lupus nephritis in pregnancy

P Webster et al.

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Tacrolimus is an effective treatment for lupus nephritis in pregnancy

P Webster et al.

1195

Figure 1 (a) Urine protein creatinine ratio over time of nine patients with lupus nephritis in whom tacrolimus was used during
pregnancy to maintain stable disease or treat disease flare. (b) Serum albumin over time of nine patients with lupus nephritis in
whom tacrolimus was used during pregnancy to maintain stable disease or treat disease flare.
Gestation Tac started: Patients 1, 2, 3 prior to pregnancy; Patient 4 18/40, Patient 5 30/40; Patient 6 8/40; Patient 7 10/40;
Patient 8 20/40; Patient 9 21/40.
Booking 12/40 (approximately); Midterm 20/40 (approximately); Term 33 39/40 (see Table 1).

harm to the fetus from conventional therapies.

Although this is an observational study of a heterogeneous group of women, a controlled trial in this
cohort of patients would be extremely dicult to
establish.

Conclusion
This novel case series demonstrates the safety and
ecacy of tacrolimus in treating LN and controlling proteinuria in pregnancy. We propose tacrolimus as an adjuvant or alternative therapy to
steroids for treating LN are or maintaining
stable disease during pregnancy, and would support its inclusion as another potential safe therapy
in the treatment of LN during pregnancy by the
UK Registry for Rare Kidney Diseases (RaDaR).

Funding
This research received no specic grant from any
funding agency in the public, commercial, or notfor-prot sectors.

Conflict of interest statement

The authors have no conicts of interest to declare.

Acknowledgements
Floria Cheng, specialist midwife in maternal medicine, Queen Charlottes & Chelsea Hospital,
Imperial College Healthcare NHS Trust, London,
UK.
Dr. Janet Lee and her colleagues in the Leslie
Brent Laboratory, Imperial College Healthcare
NHS Trust, London, UK.

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