REVIEWS

Diagnosis and treatment of lupus nephritis

flares—an update
Ben Sprangers, Marianne Monahan and Gerald B. Appel
Abstract | Relapses or flares of systemic lupus erythematosus (SLE) are frequent and observed in 27–66% of
patients. SLE flares are defined as an increase in disease activity, in general, requiring alternative treatment
or intensification of therapy. A renal flare is indicated by an increase in proteinuria and/or serum creatinine
concentration, abnormal urine sediment or a reduction in creatinine clearance rate as a result of active
disease. The morbidity associated with renal flares is derived from both the kidney damage due to lupus
nephritis and treatment-related toxic effects. Current induction treatment protocols achieve remission in the
majority of patients with lupus nephritis; however, few studies focus on treatment interventions for renal flares
in these patients. The available data, however, suggest that remission can be induced again in a substantial
percentage of patients experiencing a lupus nephritis flare. Lupus nephritis flares are independently
associated with an increased risk of deterioration in renal function; prevention of renal flares might, therefore,
also decrease long-term morbidity and mortality. Appropriate immunosuppressive maintenance therapy might
lead to a decrease in the occurrence of renal and extrarenal flares in patients with SLE, and monitoring for the
early detection and treatment of renal flares could improve their outcomes.
Sprangers, B. et al. Nat. Rev. Nephrol. 8, 709–717 (2012); published online 13 November 2012; doi:10.1038/nrneph.2012.220

Introduction
In patients with systemic lupus erythematosus (SLE),
lupus nephritis is a common and serious complica-
tion that often requires aggressive immunosuppressive
therapy.1 The results of randomized controlled trials
document that the majority of patients with severe lupus
nephritis achieve a complete or partial remission after
6 months of induction therapy with regimens based on
either mycophenolate mofetil or cyclophosphamide.
However, renal flares can still occur during mainte-
nance therapy, and contribute to morbidity in patients
with SLE.2–4
The reported incidence of renal flares in large clini-
cal trial cohorts of patients with lupus nephritis varies
substantially, both as a consequence of different defini-
tions of flares and because of the inclusion of hetero-
geneous populations of patients treated with different
regimens and follow-up. Use of prolonged durations of
maintenance therapy and careful monitoring has helped
to decrease the incidence and severity of renal flares
in patients with SLE over the past 8 years.5–8 Whether
measurement of new biomarkers of renal injury will
further reduce the incidence and severity of renal flares
in patients with lupus nephritis remains to be proven;
however, wide acceptance of new and precise defini-
tions, such as those by the European League Against
Competing interests
G. B. Appel declares associations with the following companies:
Aspreva–Vifor, Bristol–Myers Squibb, Genentech, La Jolla
Pharmaceuticals, Roche. See the article online for full details of
the relationships. The other authors declare no competing
interests.
Rheumatism (EULAR),9 might aid in the study of renal
flares in the future. Such definitions might also facili-
tate the development of more effective and less toxic
treatments for renal flares than are currently in use.10,11
In this Review, we discuss the definitions of renal flares
and describe advances in the diagnosis and treatment of
renal flares.
Definitions and types of renal flares
Many definitions for renal flares in patients with SLE
have been used in different populations and studies
(Table 1). In April 2009, EULAR published a consensus
statement on the terminology used in the management
of lupus nephritis, which provided definitions for both
SLE flares and renal flares.9 EULAR defines a flare or
relapse of SLE as an increase in disease activity requiring
more-intensive treatment, and a renal flare as an increase
Department of
in proteinuria or serum creatinine level, an abnormal Medicine, Division of
urinary sediment or a reduction in creatinine clearance Nephrology, University
Hospitals Leuven,
due to active disease.9 Renal flares can be subdivided into Leuven, Belgium
proteinuric or nephritic flares. The EULAR consensus (B. Sprangers).
statement also defines an extrarenal flare as those that Department of
Medicine, Room 2124
affect one or more nonrenal body systems in patients New York–Presbyterian
with SLE. Hospital, Columbia
University Medical
The definitions of SLE flares and renal flares pro- Center 622 West 168th
vided by the EULAR consensus statement 9 should Street, New York,
facilitate direct comparison of future treatment NY 10032, USA
(M. Monahan,
studies, as well as advance our understanding of the G. B. Appel).
incidence, detection, prevention and management of
Correspondence to:
lupus nephritis flares. However, these definitions have G. B. Appel
clear limitations. Serological markers, such as serum gba2@columbia.edu

NATURE REVIEWS | NEPHROLOGY VOLUME 8  |  DECEMBER 2012  |  709

© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
■■ Renal flares are associated with impaired renal prognosis and increased
cumulative exposure of patients to drug toxic effects
■■ Proteinuric flare is defined as persistently increased proteinuria (>0.5–1.0 g
daily) after a complete response, or doubling of proteinuria (to >1.0 g daily)
after a partial response
■■ A nephritic flare is defined as an increase or recurrence of urinary sediment
with or without increased proteinuria, and is usually associated with a decline
in renal function
■■ Reappearance of urinary casts and increased titres of antibodies to double-
stranded DNA can predict renal flares
■■ Whether monitoring of novel urinary or serum biomarkers can be used to
predict lupus nephritis flares remains to be proven in prospective clinical trials
■■ Prolonging the duration of maintenance therapy and careful clinical monitoring
seem to decrease the incidence and severity of renal flares
complement levels and titres of antibodies to double-
stranded DNA (dsDNA) are not included in these defi-
nitions. Likewise, there has been no attempt to include
new biomarkers such as urinary monocyte chemo­
attractant protein‑1 (MCP‑1, also known as chemokine
[C-C motif] ligand 2), urinary neutrophil gelatinase-
associated lipo­calin (NGAL, also known as lipocalin-2),
or urinary TWEAK12–17 in these definitions. In the past,
a distinction was made between mild, moderate, and
severe nephritis; the EULAR definitions include only
severe and nonsevere nephritis. Findings of haematu-
ria and erythrocyte casts in urine have been useful in
diagnosing disease; however, the evaluation of urinary
sediment has been challenging and sometimes counter­
productive in controlled trials due to false-postive results
Table 1 | Definitions of renal flares
Study Nephritic flare
Moroni et al. Plasma creatinine concentration ≥30% above previous value; nephritic urinary
(1996)2 sediment; proteinuria
Moroni et al.
(2006)6
Ioannidis Presence of any of the following features on at least two occasions: proteinuria
et al. (2000)27 >2 g per day; serum creatinine concentration >30%; active urine sediment
Illei et al. Mild: reappearance of cellular casts or ≥10 RBC/HPF; proteinuria, ≤2 g per day
(2002)29* and stable serum creatinine levels
Moderate: reappearance of cellular casts or ≥10 RBC/HPF; proteinuria >2 g per
day and stable serum creatinine concentration
Severe: reappearance of cellular casts or ≥10 RBC/HPF; serum creatinine
concentration ≥30% increase above level at time of complete remission
Illei et al. Mild: cellular casts by at least one category (on a scale of 0–4) or ≥10 RBC/HPF if
(2002)29‡ baseline levels were <10 RBC/HPF; or at least twice as many RBC/HPF as at
baseline if baseline levels were ≥10 RBC/HPF; proteinuria ≤2 g per day; stable
serum creatinine concentration (<30% increase above level at time of stabilization)
Moderate: increase in number of cellular casts or RBC/HPF; proteinuria >2 g per
day; stable serum creatinine concentration
Severe: in number of cellular casts or RBC/HPF; serum creatinine concentration
≥30% increase above level at time of complete remission
Gordon et al. Proteinuria or serum creatinine concentration; abnormal urinary sediment or a
(2009)9§ reduction in creatinine clearance due to the presence of active disease; or
recurrence of active urinary sediment, with or without proteinuria; usually
associated with in renal function||
Severe: or recurrence of active urinary sediment with or without proteinuria;
≥25% serum creatinine concentration
*In patients with a complete response. ‡In patients with a partial response or stabilization. §Flare is defined as an increase in disease activity requiring more intensive treatment. ||Renal flare.
Abbreviations: NA, not applicable; RBC/HPF, red blood cells per high-power field.
710  |  DECEMBER 2012  |  VOLUME 8  www.nature.com/nrneph
© 2012 Macmillan Publishers Limited. All rights reserved
from urinary tract infections, vaginal infections and
laboratory inaccuracies.18–20
Increases in proteinuria of greater than 1.0 g per
day might indicate the onset of active proliferative
lupus nephritis, transformation to class V membra-
nous lupus nephritis (as defined by the International
Society of Nephrology), the onset of lupus podo­
cytopathy or chronic kidney damage.21 The distinc-
tion between flare-related glomerular disease or
non­i mmunological causes of increased proteinuria
can only be made by performing a renal biopsy and
is important as each of these diagnoses has a differ-
ent prognosis and requires different therapy. Changes
detectable in repeated renal biopsy specimens have not
yet been used by any research group to define renal
flare due to the biopsy-associated risk of bleeding or
kidney loss, although this technique would probably
provide the most accurate assessment of renal disease
activity and prognosis. 22 At present, the Glomerular
Center Group at Columbia University uses a modifi-
cation of the EULAR criteria and older classification
systems, 18 in which nephritic flares are defined as a
reappearance of cellular casts in urine or ≥10 red blood
cells per high-power microscopic field of view, with or
without proteinuria, and with or without a decrease in
renal function. Proteinuric flares are defined only as a
rise in protein­uria. A repeat renal biopsy is performed
in all patients with SLE experiencing renal flare associ-
ated with a rise in serum creatinine level or a persistent
increase in proteinuria of >1.0 g daily if subnephrotic
before the flare.
Proteinuric flare
Proteinuria (doubled if in the nephrotic range, or
increased by 2 g per day if <3.5 g per day at baseline);
no change in plasma creatinine concentration
NA
Proteinuria >2 g per day; stable serum creatinine
levels (<30% increase above level at time of
complete remission) and inactive urine sediment (no
cellular casts and <10 RBC/HPF)
Proteinuria >2 g per day; stable serum creatinine
concentration (<30% increase above level at time of
complete remission); no change in urine sediment
Persistent in proteinuria >0.5–1.0 g per day after
achieving complete remission; doubling to >1 g per
day after achieving partial remission
 REVIEWS

Table 2 | Reported incidence of renal flares

Study Patients Renal Duration of Incidence of relapse (%) Relapse rates in treatment subgroups
(n) histology* follow-up (months)
Donadio et al. (1978)23 50 IV 43 31.0 47% prednisone alone; 14% prednisone and oral
cyclophosphamide
Boumpas et al. (1992)24 65 III, IV, V 60 NR 10% long-term pulse cyclophosphamide§;
55% short-term pulse cyclophosphamide||
Ciruelo et al. (1996)25 48 II, III, IV 60 and 120 25.0 at 60 months; NR
46.0 at 120 months
Moroni et al. (1996)2 70 III, IV, V 127 66.0 NR
Gourley et al. (1996)26 82 III, IV 60 12.0 36% pulse methylprednisolone; 7% pulse
cyclophosphamide; 0% combined pulse
methylprednisolone and pulse cyclophosphamide
after 1 year
Ioannidis et al. (2000)27 85 III, IV NR 36.0 NR
Chan et al. (2000) 28
50 IV 12 13.0 15% mycophenolate mofetil;
11% cyclosphosphamide
Illei et al. (2002)29 145 III, IV 144 45.0 40% in complete responders; 63% in partial
responders; IV pulse cyclophosphamide, IV pulse
methylprednisolone or combination IV pulse
cyclophosphamide and methylprednisolone
Mok et al. (2002)30 55 IV 60 32.0 (6.0 at 12 months; NR
21.0 at 36 months)
Houssiau et al. (2002)31 90 III, IV, V 41 28.0 27% in low-dose group; 29% in high-dose group
Mosca et al. (2002)4 91 IV 95 54.0 NR
El Hachmi et al. (2003) 32
46 II, III, IV, V 60 37.0 NR
Contreras et al. (2004)5 59 III, IV, V 72 29.0 42% cyclophosphamide; 30% azathioprine;
15% mycophenolate mofetil
Chan et al. (2005)33 64 IV 63 31.0 33% mycophenolate mofetil;
29% cyclophosphamide and azathioprine
Moroni et al. (2006)34‡ 32 III, III + V, 203 53.0 NR
IV, IV + V
Moroni et al. (2007)3‡ 93 III, III + IV, 181 64.0 NR
IV, IV + V
Mok et al. (2009)35 38 Va, Vb 144 ± 69 36.8 (19.4 at 60 months; NR
32.0 at 120 months)
*WHO classification unless otherwise indicated. ‡International Society of Nephrology–Renal Pathology Society classification. 22 §Cyclophosphamide 0.5–1.0 g/m² pulse per month for 6 months.
||
Cyclophosphamide 0.5–1.0 g/m² pulse per month for 6 months with additional cyclophosphamide 0.5–1.0 g/m² pulse per quarter for 2 years. Abbreviations: IV, intravenous; NR, not reported.

Incidence of flares respectively.35 The majority of these renal flares were

The reported incidence of renal flares ranges from 27%
to 66% (Table 2).2–5,23–35 Values are influenced by the pop-
ulations studied, the distribution of histological classes of
renal disease in each cohort, the treatments administered
and definitions of renal flare used, making direct com-
parisons difficult. Before 2004, and the introduction of
long-term maintenance therapy as standard care, up to
50% of patients with proliferative lupus nephritis relapsed
after the reduction or cessation of intensive immuno­
suppressive therapy, with relapse rates of 5–15 events
per 100 patient-years (mean 8 relapses per 100 years of
follow-up).36 Clinical trials published in the past 7 years
using more intensive induction therapy, longer dura-
tions of therapy and more intensive maintenance therapy
have reported a decreased incidence of flares.5,33,34,37–39
For example, in patients with SLE who have pure mem-
branous nephropathy treated with glucocorticoids and
azathioprine, the cumulative incidence of lupus nephritis
flares at 5, 10 and 15 years was 19.4%, 32.0% and 36.8%,
nephrotic (Table 1). The Aspreva Lupus Management
Study (ALMS)7 and the MAINTAIN Nephritis trial8
also found a low incidence of renal flares; 19% in the
mycophenolate mofetil and 25% in the azathio­prine
treatment groups in the MAINTAIN study, and 21.6%
in mycophenolate mofetil versus 36% in the azathio-
prine treatment groups in ALMS. The design of these
trials is crucial to interpreting the reported differences
in the incidence of renal flare, as described below.
Prediction and diagnosis of flare
Intensive monitoring of patients with lupus nephritis
after they have achieved remission is advocated, as early
diagnosis and the initiation of appropriate immuno­
suppressive therapy is central to the management of renal
flares. The measurement of glomerular filtration rate
(GFR) alone is not adequate to monitor patients with SLE
for the occurrence of renal flares, as substantial increases
in the number of sclerotic glomeruli can occur despite a

NATURE REVIEWS | NEPHROLOGY VOLUME 8  |  DECEMBER 2012  |  711

© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
Box 1 | Risk factors for renal flare in patients with SLE
■■ Young age at onset of SLE (<30 years)
■■ Male sex
■■ African American ethnicity
■■ Delay in initiation of treatment
■■ Long time to reach remission
■■ Low serum levels of complement C4 at the time of
response
■■ Partial response or stabilization
■■ High SLE disease activity score
■■ The presence of arterial hypertension
■■ Signs of severe SLE (CNS involvement and leukopenia)
■■ Treatment with low-dose immunosuppression
Abbreviations: CNS, central nervous system; SLE, systemic lupus
erythematosus.
stable GFR,40,41 especially in patients who have been in
prolonged remission. Although monitoring of protein­
uria by measurement of the protein:creatinine ratio in a
spot urine test is widely performed in clinical practice,
including in our institution (owing to the convenience
of sample collection), the results of a study comparing
protein:creatinine ratios derived from bimonthly paired
spot urine testing versus 24 h urine collections suggested
that the use of spot urinary protein:creatinine ratios
might be associated with an increased number of false-
positive and false-negative diagnoses of renal flare.18–20
This finding requires corroboration by further studies.
Various factors have been associated with an increased
risk of renal flares (Box 1). In one study, cellular casts
were present in urine before or at the onset of renal
relapse in 35 of 43 patients, with a mean interval of
10 ± 2 weeks between the appearance of cellular casts
and onset of renal relapse.42 A number of novel markers
in serum, such as antibodies to complement C1q43 or the
peptide adrenomedullin,44,45 nitrate and nitrite levels,46
and in urine, such as urinary NGAL, IL‑6, IL‑8, IL‑10,
macrophage inflammatory protein‑1 (α‑MIP‑1), and
TWEAK;12,14,46–52 as well as urinary proteomic profiles,
have been proposed as markers for renal flares.47,53–56
Promising results have been reported for measure-
ment of urinary NGAL as a predictor of renal flares in
patients with SLE.57 Circulating levels of complement C4
in serum have also been suggested to be predictive of
renal flares; however, complement C4 levels remain sup-
pressed long after the onset of clinical remission, making
a drop in complement C4 level a more appropriate pre-
dictor of flare than the absolute complement C4 concen-
tration.58 A rise in titres of antibodies to dsDNA and/
or complement C1q is also associated with an increased
likelihood of subsequent clinical relapse.43,59,60 Although
potentially interesting, the clinical utility of these sero-
logical markers needs to be determined in prospective
random­ized trials and validated in controlled studies
before they can be widely used in a clinical setting.
Changes in levels of serological parameters might be
helpful in diagnosing renal flares, but these tests should
only be used in the context of the entire spectrum of
clinical and renal features of the patient. The adminis-
tration of prednisone at the point in time when a rise
712  |  DECEMBER 2012  |  VOLUME 8  www.nature.com/nrneph
© 2012 Macmillan Publishers Limited. All rights reserved
in the titre of antibodies to dsDNA occurs has been
investigated prospectively as a way to prevent relapse.61
A rise in the level of dsDNA antibodies was detected in
46 patients, of whom 24 received conventional treatment
for relapse plus additional prednisone and 22 received
conventional treatment for relapse without additional
prednisone.61 The relapse rate was significantly higher
in the group receiving conventional treatment than in
the additional-prednisone group (20 patients versus two
patients). The cumulative oral dose of prednisone did not
differ significantly between the two groups, and cyto-
toxic therapy was required by more patients in the group
receiving conventional therapy than in the group receiv-
ing additional prednisone (seven versus two patients).61
Although these results are interesting, we do not recom-
mend that prednisone is administered when an isolated
rise in dsDNA antibody titres is detected, as this solitary
trial included only a limited number of white patients.
Instead, we would recommend increasing the intensity
of monitoring of urinary sediment and renal function for
such patients, to enable prompt identification of relapse
and renal flare.
If detectable serological activity persists, and the
clinical and renal findings described below are equivo-
cal, a renal biopsy can be performed to detect whether
active lupus nephritis is present. Renal biopsy remains
the gold standard for the diagnosis of renal flares. Renal
biopsy is also generally performed in all patients with
SLE who experience a severe renal flare (defined as a
rise in serum creatinine concentration or a persistent
increase in proteinuria of >1 g per day if subnephrotic
at baseline, Table 1), and in those in whom it is unclear
whether the clinical features truly indicate an active
flare. For example, in patients who apparently develop
a recurrence after prolonged remission of lupus nephri-
tis, analysis of biopsy samples is important to distin-
guish between active lupus nephritis (which should be
treated with immunosuppressive therapy) or scarring
and non­immunological damage resulting from previ-
ous inflammatory injury, which would not improve with
further immunosuppressive therapy.62 A renal biopsy is
also helpful in patients in whom there is discordance
between clinical findings, such as negative serological
test results and the absence of active urine sediment, but
with increasing proteinuria and/or declining renal func-
tion. Renal biopsy in these patients would help to estab-
lish whether these features are caused by atypical flare
or progression to a higher class of lupus nephritis, focal
segmental glomerulosclerosis or lupus vasculopathy.
Treatment of renal flares
The risks associated with renal flares include both cumu-
lative drug toxic effects related to treatment and cumu-
lative renal damage; therefore, prompt and appropriate
therapeutic intervention could potentially improve these
patients’ outcomes.
Induction therapy
Data on the optimal treatment of renal flares in patients
with SLE are scarce. Despite the lack of data, most

clinicians treat patients with lupus nephritis flares
according to the severity of the renal flare to avoid either
undertreatment or overtreatment. Most clinicians
agree that severe nephritic flares (biopsy-proven lupus
nephritis class III or IV) require treatment,63 but whether
patients with mild proteinuric flares should receive
intensive immunosuppressive therapy is less clear. In
patients experiencing nephritic flares, although some
data support the use of cyclophosphamide to induce or
re-establish remission, the cumulative toxic effects asso-
ciated with prolonged exposure to this alkylating agent
are of concern. One study included 85 patients with pro-
liferative lupus nephritis who were treated with monthly
intravenous pulse cyclophosphamide and prednisone.
During follow-up, 23 patients experienced a relapse
after a median of 79 months.27 After a further course
of induction treatment (involving monthly intravenous
cyclophosphamide), 15 of the 23 patients (65%) entered
a second remission after a median of 32 months. Adverse
events were reported in 15 patients and included irrevers-
ible kidney damage, peripheral neuropathy and recurrent
infection.27 Several alternative induction regimens have
been developed to avoid these cumulative toxic effects,
including the low-dose protocol used in the Euro-Lupus
Nephritis Trial for the treatment of glomerulonephritis:
500 mg of intravenous cyclophosphamide fortnightly for
up to six doses,64 and the use of mycophenolate mofetil.26
No data are available to support low-dose cyclophospha-
mide in combination with mycophenolate mofetil as an
approach for the treatment of renal flares. Nonetheless,
many clinicians prefer to use standard or increased
doses of mycophenolate mofetil to treat nephritic flares.
For example, in our experience a patient who experi-
ences a nephritic flare while taking 500 mg or 750 mg of
mycophenolate mofetil twice daily could be treated with
2–3 g of mycophenolate mofetil per day to induce remis-
sion. In patients with nephrotic flares, or who experience
an increase in proteinuria, initiation of treatment also
seems reasonable; the regimen used might be similar to
that used to treat a nephritic flare or might just require
the addition of a calcineurin inhibitor.65,66 In patients
with pure membranous lupus nephropathy experiencing
renal flares, re-treatment with an increased dose of pred-
nisolone, with or without another immuno­suppressive
agent (mycophenolate mofetil, cyclophosphamide or
tacrolimus), resulted in complete or partial remission in
79% and 21% of patients, respectively.35
Although biologic agents such as rituximab, beli-
mumab and abatacept have been used to treat patients
with resistant lupus nephritis, scant data are available
on their effects in relapsing disease. A small number of
studies have evaluated the use of rituximab in the treat-
ment of lupus nephritis flares.67–69 One group studied a
combination of daily mycophenolate mofetil and pred-
nisone plus a once-weekly dose of rituximab for 4 weeks
in 10 women who developed biopsy-proven relapse of
proliferative lupus nephritis during maintenance therapy
with mycophenolate mofetil or azathioprine.69 Complete
remission was achieved in six patients by the end of fol-
low-up, and this protocol seemed to be most effective
NATURE REVIEWS | NEPHROLOGY VOLUME 8  |  DECEMBER 2012  |  713
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
in patients with limited proteinuria.69 Although ritux­
imab has not been shown to add benefit to a standard
induction regimen consisting of steroids in combination
with mycophenolate mofetil in the treatment of lupus
nephritis, this B‑cell-depleting agent might have a role in
the treatment and prevention of renal flares in patients
with SLE experiencing frequent relapses or refractory
disease.70 More studies are necessary to establish the
optimal dose of mycophenolate mofetil and the role of
rituximab in the treatment of lupus nephritis flares and
to compare their cost-effectiveness.
Maintenance therapy
Recognition that renal flares most frequently occur after
a decrease or discontinuation of immunosuppressive
therapy has been a major factor in establishing immuno-
suppressive maintenance therapy regimens for patients
with lupus nephritis (Table 3). In the absence of specific
contraindications, virtually all patients receiving induc-
tion therapy for lupus nephritis should subsequently be
given some form of maintenance therapy.5 The optimal
choice of agent and duration of maintenance therapy
remain unclear. Maintenance therapy consisting of
intravenous pulse cyclophosphamide every 3 months is
effective in patients with proliferative lupus nephritis.71
However, when this maintenance regimen was directly
compared with oral azathioprine or mycophenolate
mofetil,5 event-free survival was significantly decreased
in the cyclophosphamide-treated patients, owing to an
increase in sepsis-related deaths.5 Relapse-free survival
was also significantly worse in the cyclophosphamide-
treated patients than in patients treated with myco­
phenolate mofetil and azathioprine. 5 Maintenance
therapy with daily use of oral agents is, therefore,
preferred over cyclophosphamide-based treatment.
Maintenance therapy with azathioprine or myco­
phenolate mofetil for at least 12–24 months has been
evaluated in three studies.7,8,64 Data from the Euro-Lupus
Nephritis Trial show that maintenance therapy with
azathioprine is not sufficient to prevent renal flare in all
patients.31,32 In ALMS, maintenance therapy with either
oral azathioprine (2 mg/kg) or myco­phenolate mofetil
(2 g per day) for 3 years was compared in patients with
SLE after 6 months of induction treatment with either
oral mycophenolate mofetil or intravenous cyclophos-
phamide, both in combination with oral steroids. 7
Mycophenolate mofetil was significantly more success-
ful than azathioprine in extending the time to treatment
failure and in decreasing the number of treatment fail-
ures (defined as a composite of end-stage renal disease,
doubling of the serum creatinine level, renal flare, or ini-
tiation of rescue therapy), and the results were similar
in all ethnic and geographic subgroups of patients.7
Renal flares occurred in 24% of the azathioprine-treated
group and 12% of the myco­phenolate mofetil-treated
group. 7 The European MAINTAIN trial compared
the efficacy and safety of mycophenolate mofetil and
azathio­prine given as maintenance therapy to patients
with proliferative lupus glomerulo­nephritis.8 The data
from MAINTAIN show no significant difference in
REVIEWS

Table 3 | Prospective randomized trials of maintenance therapy in patients with lupus nephritis
Study Participants n Histologic Induction therapy Maintenance therapy Outcomes
(proportion of subtype (patients n)
women and ethnicity)
Moroni et al. 75, 90% women, NR 87% IV* Intravenous cyclophosphamide Azathioprine 1.5–2.0 mg/kg Similar in both groups: decreased
(2006)6 13% Vc or pulse once a month for daily (33) proteinuria
Vd* 3 months (0.5 g for patients Ciclosporin 2.5–4.0mg/kg Azathioprine group: 8 renal flares
≤50 kg, 1.0 g for patients daily (36) Ciclosporin group: 7 renal flares
>50 kg); oral
cyclophosphamide 1.0–
2.0 mg/kg daily for 3 months
Contreras et al. 59, 95% women 20% III* Intravenous cyclophosphamide Azathioprine 1.0–3.0 mg/kg Mycofenolate mofetil (95%) and
(2004)5 White: 8% 78% IV* 0.5–1.0 g/m² for 6 months§ daily (111) azathioprine (80%) both more
Black: 46% 2% Vb* Mycophenolate mofetil effective and safer than long-term
Hispanic or other: 46% 0.5–3.0 g daily (116) intravenous cyclophosphamide
Intravenous (44%); event-free survival: 4
cyclophosphamide patients died and 3 developed
0.5–1.0 g/m² once every end-stage renal disease in
3 months cyclophosphamide group
Houssiau et al. 105, 91% women 31% III* Intravenous cyclophosphamide Azathioprine 2.0 mg/kg Incidence of renal flares 25% in
(2010)8 White: 79% 58% IV* 0.5 g every 2 weeks for daily (52) azathioprine group vs 19% in
(MAINTAIN) Black: 12% 3% Vc* 3 months§ Mycophenolate mofetil mycophenolate mofetil group (NS);
Asian: 9% 8% Vd* 2.0 g daily (53) serum creatinine concentration,
serum complement C3 level and
global disease activity scores also
similar in both groups
Dooley et al. 227, 86% women 13% III or Intravenous cyclophosphamide Azathioprine 2.0 mg/kg Mycophenolate mofetil superior to
(2011)7 (ALMS White: 44% IV + V‡ 0.5–1.0 g/m² once a month daily (111) azathioprine in reducing primary
MAINTENANCE) Black: 10% 72% IV or for 6 months, or Mycophenolate mofetil end points: time to treatment
Asian: 33% IV + V‡ mycophenolate mofetil 3.0 g 2.0 g daily (116) failure, time to renal flare and time
Other: 13% 15% V‡ daily§|| to rescue therapy
Treatment failure rates 32.4% in
azathioprine group vs 16.4% in
mycophenolate mofetil group
*WHO classification unless otherwise indicated. ‡International Society of Nephrology–Renal Pathology Society classification. §All patients randomly allocated to maintenance therapy at
initiation of induction therapy. ||All patients randomly allocated to maintenance therapy after achieving remission with induction therapy. Abbreviations: NR, not reported; NS, not significant.

the incidence of renal flares, time to renal flare, renal
outcome, or the incidence of adverse events between
the two treatment groups.8 However, several key dif-
ferences exist between MAINTAIN and the 2011
mycophenolate mofetil versus azathioprine mainte-
nance trial, which was a continuation of ALMS. 7 For
example, the study populations differed greatly: in
MAINTAIN the majority of the 105 participants were
white, whereas the ALMS MAINTENANCE trial was
an international study that included 227 patients of
different ethnic groups from various geographic loca-
tions.7 A major difference in study design was that the
azathioprine versus myco­phenolate mofetil mainte-
nance study included only patients who had achieved
a renal response after 6 months of induction therapy,
whereas in the MAINTAIN trial all patients were ran-
domly allocated to receive one of the two maintenance
therapies at the start of induction treatment. Although
in the MAINTAIN trial 25% of patients experienced
renal flares in the azathio­prine arm versus 19% in the
mycophenolate mofetil arm, this difference was not sta-
tistically significant.8 However, the incidence of renal
flares in both studies is low compared with that in studies
from before 2004 and prior to the introduction of main-
tenance therapy as standard care. No data are currently
available regarding the outcome of these patients after
discontinuation of maintenance therapy (Table 3).
Other immunosuppressive agents evaluated in main-
tenance therapy to prevent renal flares include ciclo-
sporin,6 tacrolimus72,73 and rituximab;74 however, none
of these agents has been studied in large numbers of
patients.6,74 The optimal maintenance treatment regimen
to prevent renal flares in a given patient depends not only
on drug efficacy, but also on its adverse effects and cost.
Azathioprine is effective, cheap and can be used during
pregnancy.75 Mycophenolate mofetil is also highly effec-
tive, but considerably more expensive than azathioprine
and is a known teratogen.76
The role of serial biopsy in surveillance
It is clear that the comparison of serial biopsy specimens
can provide important prognostic information and
confirm or refute the suitability and efficacy of therapy
in patients with lupus nephritis.77,78 Reasons to carry
out a repeat renal biopsy include the ability to discover
associated nonimmune-mediated glomerular lesions
(podocytopathies) and lupus-associated thrombotic
angiopathies,79–82 and to assess prognostic indicators
such as interstitial fibrosis.62,77,83,84 However, no strict
guidelines are available on the use of repeat biopsy to
guide treatment decision-making in patients with lupus
nephritis, and at present it is not known whether serial
biopsy is superior as a guide to appropriate therapy or
prognosis compared with clinical data alone.

714  |  DECEMBER 2012  |  VOLUME 8  www.nature.com/nrneph

© 2012 Macmillan Publishers Limited. All rights reserved
 REVIEWS

Some clinicians have recommended using serial kidney
biopsies to detect which patients with lupus nephritis will
relapse or respond poorly to induction therapy.62,83 In nine
of 10 Chinese patients diagnosed as having mesangial
lupus nephritis on initial biopsy who failed to respond
to induction therapy or relapsed, a repeat biopsy sample
showed progression to a higher class of nephritis.85 In
another study, an increase in protein­uria predicted pro-
gression to a more severe class of lupus nephritis.86 In this
Review we recommend that repeat renal biopsy samples
should be obtained from patients with proliferative lupus
nephritis (class III or IV) who do not have complete reso-
lution of serological markers and have concomitant renal
symptoms suggesting an increased risk of flare. Persistent
urine sediment changes, proteinuria >1 g per day or
failure of serum creatinine concentration to normalize
in a patient in whom serum levels of complement factors
or anti-dsDNA titres have also not normalized would also
indicate the need for biopsy.
Renal flares are often particularly difficult to detect
in patients with membranous lupus nephritis, in whom
they frequently manifest as high levels of protein­uria
and an inactive urine sediment unaccompanied by
extrarenal symptoms. Interestingly, repeat renal biopsy
specimens showed pure membranous lesions in only
four of 10 patients initially diagnosed as having pure
membranous nephropathy.30 The other six patients had
features of proliferative lupus nephritis: either diffuse
proliferative nephritis (class IV in two patients); or mixed
membranous and proliferative nephritis (class V + III in
three patients; class V + IV in one patient).35 In patients
with membranous lupus nephritis, therefore, periodic
measurement of urine protein content is essential. A
progressive increase in proteinuria in a patient with
biopsy-proven membranous lupus nephritis warrants a
further biopsy.
Furthermore we recommend repeat renal biopsy in
patients with biopsy-proven lupus nephritis class I or
II who have failed to respond to treatment or experi-
ence a relapse (to rule out transformation to a higher
grade nephritis), who have systemic symptoms, negative
findings on serology and inactive urine sediment, but
with increased proteinuria and/or decreased renal func-
tion (to establish whether it is an atypical renal flare or
transformation to another class of lupus nephritis, focal
segmental glomerulosclerosis or lupus vasculopathy).
Conclusions
Renal flares in patients with lupus nephritis are asso-
ciated with impaired renal survival. Close monitoring
for urinary sediment changes, increases in proteinuria
and changes in serological markers such as antibodies
to dsDNA are necessary to enable the early recogni-
tion and prompt treatment of renal flares (particularly
protein­uric flares). Such monitoring is especially impor-
tant in the period following the initial induction of
remission, and during tapering or withdrawal of
immuno­suppressive therapy.
Data regarding optimal treatment regimens are cur-
rently limited, and multicentre, prospective studies
comparing intravenous cyclophosphamide with oral
mycophenolate mofetil and evaluating rituximab and
other biological agents are needed. To prevent renal
flares, maintenance therapy with adequate doses of
azathio­prine or mycophenolate mofetil should be admin-
istered for a prolonged period of time. The optimal
duration of maintenance therapy remains to be deter-
mined, but for most patients with severe lupus nephritis,
maintenance therapy is likely to be needed for at least
3–4 years. To reduce the risk of possible adverse effects
of long-term immunosuppressive treatment, we propose
that the doses used for maintenance therapy should be
reduced slowly after this time period in patients who
have achieved complete remission. Further studies are
also necessary to determine the optimal combination of
markers for monitoring disease activity and diagnosing
renal flares without relying on sequential biopsies.
Careful monitoring of patients in remission, expertise
of the clinicians and a good patient–physician relation-
ship to reduce nonadherence to therapy are pre­requisites
for obtaining optimal survival and renal function in
patients with lupus nephritis. We hope that with earlier
and more effective treatment of patients with renal
flares, the morbidity and mortality associated with lupus
nephritis will be further reduced.
Review criteria
PubMed was searched for English-language articles
published before January 2012 using the terms “lupus
nephritis”, “SLE”, “systemic lupus erythematosus”,
“flares”, “relapse”, “cyclophosphamide”, “MMF”,
“mycophenolate mofetil” and “rituximab”. Relevant
references published after this date were also included.
The reference lists from key articles were searched to
identify additional papers. Abstracts from the American
Society of Nephrology and International Society of
Nephrology annual meetings were considered. Relevant
articles were selected for inclusion on the basis of the
authors’ knowledge of the clinical treatment of lupus
nephritis flares.

1. Appel, G. B. & Jayne, D. Lupus nephritis in
Comprehensive Clinical Nephrology (eds
Floege, J., Johnson, R. J. & Feehaly, J.) 308–321
(Saunders Elsevier, St. Louis, 2010).
2. Moroni, G., Quaglini, S., Maccario, M., Banfi, G. &
Ponticelli, C. “Nephritic flares” are predictors of
bad long-term renal outcome in lupus nephritis.
Kidney Int. 50, 2047–2053 (1996).
3. Moroni, G. et al. The long-term outcome of 93
patients with proliferative lupus nephritis.
Nephrol. Dial. Transplant. 22, 2531–2539 (2007).
4. Mosca, M. et al. Renal flares in 91 SLE patients
with diffuse proliferative glomerulonephritis.
Kidney Int. 61, 1502–1509 (2002).
5. Contreras, G. et al. Sequential therapies for
proliferative lupus nephritis. N. Engl. J. Med. 350,
971–980 (2004).
6. Moroni, G. et al. A randomized pilot trial
comparing cyclosporine and azathioprine for
maintenance therapy in diffuse lupus nephritis
over four years. Clin. J. Am. Soc. Nephrol. 1,
925–932 (2006).
7. Dooley, M. A. et al. Mycophenolate versus
azathioprine as maintenance therapy for lupus
nephritis. N. Engl. J. Med. 365, 1886–1895
(2011).
8. Houssiau, F. A. et al. Azathioprine versus
mycophenolate mofetil for long-term
immunosuppression in lupus nephritis:
results from the MAINTAIN Nephritis Trial. Ann.
Rheum. Dis. 69, 2083–2089, (2010).
9. Gordon, C. et al. European consensus statement
on the terminology used in the management of

NATURE REVIEWS | NEPHROLOGY VOLUME 8  |  DECEMBER 2012  |  715

© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
lupus glomerulonephritis. Lupus 18, 257–263
(2009).
10. Fiehn, C. et al. Improved clinical outcome of
lupus nephritis during the past decade:
importance of early diagnosis and treatment.
Ann. Rheum. Dis. 62, 435–439 (2003).
11. Houssiau, F. A. et al. Early response to
immunosuppressive therapy predicts good renal
outcome in lupus nephritis: lessons from long-
term followup of patients in the Euro-Lupus
Nephritis Trial. Arthritis Rheum. 50, 3934–3940
(2004).
12. Brunner, H. I. et al. Urinary neutrophil gelatinase-
associated lipocalin as a biomarker of nephritis
in childhood-onset systemic lupus
erythematosus. Arthritis Rheum. 54,
2577–2584 (2006).
13. Brunner, H. I. et al. Association of noninvasively
measured renal protein biomarkers with
histologic features of lupus nephritis. Arthritis
Rheum. 64, 2687–2697 (2012).
14. Rovin, B. H., Song, H., Birmingham, D. J.,
Hebert, L. A., Yu, C. Y. & Nagaraja, H. N. Urine
chemokines as biomarkers of human systemic
lupus erythematosus activity. J. Am. Soc. Nephrol.
16, 467–473 (2005).
15. Zhang, X. et al. Biomarkers of lupus nephritis
determined by serial urine proteomics. Kidney
Int. 74, 799–807 (2008).
16. Schwartz, N. et al. Urinary TWEAK as a
biomarker of lupus nephritis: a multicenter
cohort study. Arthritis Res. Ther. 11, R143
(2009).
17. Satoskar, A. A. et al. Discrepancies in glomerular
and tubulointerstitial/vascular immune complex
IgG subclasses in lupus nephritis. Lupus 20,
1396–1403 (2011).
18. Fine, D. M. et al. A prospective study of protein
excretion using short-interval timed urine
collections in patients with lupus nephritis.
Kidney Int. 76, 1284–1288 (2009).
19. Birmingham, D. J. et al. Spot urine protein/
creatinine ratios are unreliable estimates of
24 h proteinuria in most systemic lupus
erythematosus nephritis flares. Kidney Int. 72,
865–870 (2007).
20. Hebert, L. A. et al. Random spot urine protein/
creatinine ratio is unreliable for estimating 24-
hour proteinuria in individual systemic lupus
erythematosus nephritis patients. Nephron Clin.
Pract. 113, c177–c182 (2009).
21. Kraft, S. W., Schwartz, M. M., Korbet, S. M. &
Lewis, E. J. Glomerular podocytopathy in
patients with systemic lupus erythematosus.
J. Am. Soc. Nephrol. 16, 175–179 (2005).
22. Weening, J. J. et al. The classification of
glomerulonephritis in systemic lupus
erythematosus revisited. J. Am. Soc. Nephrol. 15,
241–250 (2004).
23. Donadio, J. V. Jr, Holley, K. E., Ferguson, R. H. &
Ilstrup, D. M. Treatment of diffuse proliferative
lupus nephritis with prednisone and combined
prednisone and cyclophosphamide. N. Engl. J.
Med. 299, 1151–1155 (1978).
24. Boumpas, D. T. et al. Controlled trial of pulse
methylprednisolone versus two regimens of
pulse cyclophosphamide in severe lupus
nephritis. Lancet 340, 741–745 (1992).
25. Ciruelo, E., de la, Cruz, J., Lopez, I. & Gomez-
Reino, J. J. Cumulative rate of relapse of lupus
nephritis after successful treatment with
cyclophosphamide. Arthritis Rheum. 39,
2028–2034 (1996).
26. Gourley, M. F. et al. Methylprednisolone and
cyclophosphamide, alone or in combination, in
patients with lupus nephritis. A randomized,
controlled trial. Ann. Intern. Med. 125, 549–557
(1996).
716  |  DECEMBER 2012  |  VOLUME 8  www.nature.com/nrneph
27. Ioannidis, J. P. & Moutsopoulos, H. M.
Remission, relapse, and re-remission of
proliferative lupus nephritis treated with
cyclophosphamide. Kidney Int. 57, 258–264
(2000).
28. Chan, T. M. et al. Efficacy of mycophenolate
mofetil in patients with diffuse proliferative lupus
nephritis. Hong Kong-Guangzhou Nephrology
Study Group. N. Engl. J. Med. 343, 1156–1162
(2000).
29. Illei, G. G. et al. Renal flares are common in
patients with severe proliferative lupus nephritis
treated with pulse immunosuppressive therapy:
long-term followup of a cohort of 145 patients
participating in randomized controlled studies.
Arthritis Rheum. 46, 995–1002 (2002).
30. Mok, C. C., Ho, C. T., Chan, K. W., Lau, C. S. &
Wong, R. W. Outcome and prognostic indicators
of diffuse proliferative lupus glomerulonephritis
treated with sequential oral cyclophosphamide
and azathioprine. Arthritis Rheum. 46,
1003–1013 (2002).
31. Houssiau, F. A. et al. Immunosuppressive
therapy in lupus nephritis: the Euro-Lupus
Nephritis Trial, a randomized trial of low-dose
versus high-dose intravenous
cyclophosphamide. Arthritis Rheum. 46,
2121–2131 (2002).
32. El Hachmi, M., Jadoul, M., Lefebvre, C.,
Depresseux, G. & Houssiau, F. A. Relapses of
lupus nephritis: incidence, risk factors, serology
and impact on outcome. Lupus 12, 692–696
(2003).
33. Chan, T. M., Tse, K. C., Tang, C. S., Mok, M. Y. &
Li, F. K. Long-term study of mycophenolate
mofetil as continuous induction and
maintenance treatment for diffuse proliferative
lupus nephritis. J. Am. Soc. Nephrol. 16,
1076–1084 (2005).
34. Moroni, G. et al. Withdrawal of therapy in
patients with proliferative lupus nephritis:
long-term follow-up. Nephrol. Dial. Transplant. 21,
1541–1548 (2006).
35. Mok, C. C., Ying, K. Y., Yim, C. W., Ng, W. L. &
Wong, W. S. Very long-term outcome of pure
lupus membranous nephropathy treated with
glucocorticoid and azathioprine. Lupus 18,
1091–1095 (2009).
36. Grootscholten, C. & Berden, J. H.
Discontinuation of immunosuppression in
proliferative lupus nephritis: is it possible?
Nephrol. Dial. Transplant. 21, 1465–1469
(2006).
37. Ginzler, E. M. et al. Mycophenolate mofetil or
intravenous cyclophosphamide for lupus
nephritis. N. Engl. J. Med. 353, 2219–2228
(2005).
38. Contreras, G., Tozman, E., Nahar, N. & Metz, D.
Maintenance therapies for proliferative lupus
nephritis: mycophenolate mofetil, azathioprine
and intravenous cyclophosphamide. Lupus
14 (Suppl. 1), s33–s38 (2005).
39. Sinclair, A. et al. Mycophenolate mofetil as
induction and maintenance therapy for lupus
nephritis: rationale and protocol for the
randomized, controlled Aspreva Lupus
Management Study (ALMS). Lupus 16, 972–980
(2007).
40. Chagnac, A. et al. Outcome of the acute
glomerular injury in proliferative lupus nephritis.
J. Clin. Invest. 84, 922–930 (1989).
41. Valeri, A. et al. Intravenous pulse
cyclophosphamide treatment of severe lupus
nephritis: a prospective five-year study. Clin.
Nephrol. 42, 71–78 (1994).
42. Hebert, L. A., Dillon, J. J., Middendorf, D. F.,
Lewis, E. J. & Peter, J. B. Relationship between
appearance of urinary red blood cell/white blood
© 2012 Macmillan Publishers Limited. All rights reserved
cell casts and the onset of renal relapse in
systemic lupus erythematosus. Am. J. Kidney
Dis. 26, 432–438 (1995).
43. Marto, N., Bertolaccini, M. L., Calabuig, E.,
Hughes, G. R. & Khamashta, M. A. Anti‑C1q
antibodies in nephritis: correlation between
titres and renal disease activity and positive
predictive value in systemic lupus
erythematosus. Ann. Rheum. Dis. 64, 444–448
(2005).
44. Matrat, A. et al. Simultaneous detection of
anti‑C1q and anti-double stranded DNA
autoantibodies in lupus nephritis: predictive
value for renal flares. Lupus 20, 28–34 (2011).
45. Mak, A., Cheung, B. M., Mok, C. C., Leung, R. &
Lau, C. S. Adrenomedullin—a potential disease
activity marker and suppressor of nephritis
activity in systemic lupus erythematosus.
Rheumatology (Oxford) 45, 1266–1272 (2006).
46. Oates, J. C., Shaftman, S. R., Self, S. E. &
Gilkeson, G. S. Association of serum nitrate and
nitrite levels with longitudinal assessments of
disease activity and damage in systemic lupus
erythematosus and lupus nephritis. Arthritis
Rheum. 58, 263–272 (2008).
47. Mosley, K. et al. Urinary proteomic profiles
distinguish between active and inactive lupus
nephritis. Rheumatology (Oxford) 45,
1497–1504 (2006).
48. Chan, R. W. et al. Expression of T‑bet, a type 1
T‑helper cell transcription factor, in the urinary
sediment of lupus patients predicts disease
flare. Rheumatology (Oxford) 46, 44–48 (2007).
49. Pitashny, M. et al. Urinary lipocalin‑2 is
associated with renal disease activity in human
lupus nephritis. Arthritis Rheum. 56,
1894–1903 (2007).
50. Xuejing, Z. et al. Urinary TWEAK level as a
marker of lupus nephritis activity in 46 cases.
J. Biomed. Biotechnol. http://dx.doi.org/
10.1155/2012/359647 (2012).
51. Schwartz, N. et al. Urinary TWEAK as a
biomarker of lupus nephritis: a multicenter
cohort study. Arthritis Res. Ther. 11, R143
(2009).
52. Schwartz, N. et al. Urinary TWEAK and the
activity of lupus nephritis. J. Autoimmun. 27,
242–250 (2006).
53. Feng, X. et al. Association of increased
interferon-inducible gene expression with
disease activity and lupus nephritis in patients
with systemic lupus erythematosus. Arthritis
Rheum. 54, 2951–2962 (2006).
54. Oates, J. C. et al. Prediction of urinary protein
markers in lupus nephritis. Kidney Int. 68,
2588–2592 (2005).
55. Varghese, S. A. et al. Urine biomarkers predict
the cause of glomerular disease. J. Am. Soc.
Nephrol. 18, 913–922 (2007).
56. Suzuki, M. et al. Identification of a urinary
proteomic signature for lupus nephritis in
children. Pediatr. Nephrol. 22, 2047–2057
(2007).
57. Rubinstein, T. et al. Urinary neutrophil
gelatinase-associated lipocalin as a novel
biomarker for disease activity in lupus nephritis.
Rheumatology (Oxford) 49, 960–971 (2010).
58. West, C. D. Relative value of serum C3 and C4
levels in predicting relapse in systemic lupus
erythematosus. Am. J. Kidney Dis. 18, 686–688
(1991).
59. ter Borg, E. J., Horst, G., Hummel, E. J.,
Limburg, P. C. & Kallenberg C. G. Measurement
of increases in anti‑double‑stranded DNA
antibody levels as a predictor of disease
exacerbation in systemic lupus erythematosus.
A long-term, prospective study. Arthritis Rheum.
33, 634–643 (1990).

60. Akhter, E., Burlingame, R. W., Seaman, A. L.,
Magder, L. & Petri, M. Anti‑C1q antibodies have
higher correlation with flares of lupus nephritis
than other serum markers. Lupus 20,
1267–1274 (2011).
61. Bootsma, H. et al. Prevention of relapses in
systemic lupus erythematosus. Lancet 345,
1595–1599 (1995).
62. Moroni, G. et al. Clinical and prognostic value of
serial renal biopsies in lupus nephritis. Am. J.
Kidney Dis. 34, 530–539 (1999).
63. Bertsias, G. & Boumpas, D. T. Update on the
management of lupus nephritis: let the
treatment fit the patient. Nat. Clin. Pract.
Rheumatol. 4, 464–472 (2008).
64. Houssiau, F. A. et al. Immunosuppressive
therapy in lupus nephritis: the Euro-Lupus
Nephritis Trial, a randomized trial of low-dose
versus high-dose intravenous
cyclophosphamide. Arthritis Rheum. 46,
2121–2131 (2002).
65. Alsuwaida, A. Successful management of
systemic lupus erythematosus nephritis flare-up
during pregnancy with tacrolimus. Mod.
Rheumatol. 21, 73–75 (2011).
66. Szeto, C. C. et al. Tacrolimus for the treatment of
systemic lupus erythematosus with pure class V
nephritis. Rheumatology (Oxford) 47,
1678–1681 (2008).
67. Melander, C. et al. Rituximab in severe lupus
nephritis: early B‑cell depletion affects long-term
renal outcome. Clin. J. Am. Soc. Nephrol. 4,
579–587 (2009).
68. Moroni, G. et al. Rituximab versus oral
cyclophosphamide for treatment of relapses of
proliferative lupus nephritis: a clinical
observational study. Ann. Rheum. Dis. 71,
1751–1752 (2012).
69. Boletis, J. N. et al. Rituximab and mycophenolate
mofetil for relapsing proliferative lupus nephritis:
a long-term prospective study. Nephrol. Dial.
Transplant. 24, 2157–2160 (2009).
NATURE REVIEWS | NEPHROLOGY VOLUME 8  |  DECEMBER 2012  |  717
70. Houssiau, F. A. & Ginzler E. M. Current treatment
of lupus nephritis. Lupus 17, 426–430 (2008).
71. Austin, H. A. & Balow J. E. Natural history and
treatment of lupus nephritis. Semin. Nephrol. 19,
2–11 (1999).
72. Chen, W. et al. Outcomes of maintenance
therapy with tacrolimus versus azathioprine for
active lupus nephritis: a multicenter randomized
clinical trial. Lupus 21, 944–952 (2012).
73. Uchino, A. et al. Tacrolimus is effective for lupus
nephritis patients with persistent proteinuria.
Clin. Exp. Rheumatol. 28, 6–12 (2010).
74. Camous, L. et al. Complete remission of lupus
nephritis with rituximab and steroids for
induction and rituximab alone for maintenance
therapy. Am. J. Kidney Dis. 52, 346–352 (2008).
75. Nguyen, T., Vacek, P. M., O’Neill, P., Colletti, R. B.
& Finette, B. A. Mutagenicity and potential
carcinogenicity of thiopurine treatment in
patients with inflammatory bowel disease.
Cancer Res. 69, 7004–7012 (2009).
76. Anderka, M. T., Lin, A. E., Abuelo, D. N.,
Mitchell, A. A. & Rasmussen S. A. Reviewing the
evidence for mycophenolate mofetil as a new
teratogen: case report and review of the
literature. Am. J. Med. Genet. 149A, 1241–1248
(2009).
77. Hill, G. S. et al. Predictive power of the second
renal biopsy in lupus nephritis: significance of
macrophages. Kidney Int. 59, 304–316 (2001).
78. Hill, G. S. et al. Outcome of relapse in lupus
nephritis: roles of reversal of renal fibrosis and
response of inflammation to therapy. Kidney Int.
61, 2176–2186 (2002).
79. Baranowska-Daca, E. et al. Nonlupus nephritides
in patients with systemic lupus erythematosus:
a comprehensive clinicopathologic study and
review of the literature. Hum. Pathol. 32,
1125–1135 (2001).
80. Daugas, E. et al. Antiphospholipid syndrome
nephropathy in systemic lupus erythematosus.
J. Am. Soc. Nephrol. 13, 42–52 (2002).
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
81. Tektonidou, M. G., Sotsiou, F., Nakopoulou, L.,
Vlachoyiannopoulos, P. G. &
Moutsopoulos H. M. Antiphospholipid
syndrome nephropathy in patients with
systemic lupus erythematosus and
antiphospholipid antibodies: prevalence,
clinical associations, and long-term outcome.
Arthritis Rheum. 50, 2569–2579 (2004).
82. Cheunsuchon, B., Rungkaew, P.,
Chawanasuntorapoj, R., Pattaragarn, A. &
Parichatikanond, P. Prevalence and
clinicopathologic findings of antiphospholipid
syndrome nephropathy in Thai systemic lupus
erythematosus patients who underwent renal
biopsies. Nephrology (Carlton) 12, 474–480
(2007).
83. Bajaj, S. et al. Serial renal biopsy in systemic
lupus erythematosus. J. Rheumatol. 27,
2822–2826 (2000).
84. Gunnarsson, I. et al. Repeated renal biopsy in
proliferative lupus nephritis—predictive role of
serum C1q and albuminuria. J. Rheumatol. 29,
693–699 (2002).
85. Tam, L. S., Li, E. K., Lai, F. M., Chan, Y. K. &
Szeto, C. C. Mesangial lupus nephritis in
Chinese is associated with a high rate of
transformation to higher grade nephritis. Lupus
12, 665–671 (2003).
86. Appel, G. B., Cohen, D. J., Pirani, C. L.,
Meltzer, J. I. & Estes, D. Long-term follow-up of
patients with lupus nephritis. A study based on
the classification of the World Health
Organization. Am. J. Med. 83, 877–885 (1987).
Author contributions
B. Sprangers and G. Appel researched the data for
the article. B. Sprangers wrote the article.
B. Sprangers, G. Appel and M. Monahan provided
substantial contributions to discussion of the content
and to review and/or editing of the manuscript before
submission.