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Recent progress in the treatment of lupus nephritis

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Mod Rheumatol
DOI 10.1007/s10165-012-0655-4
REVIEW ARTICLE
Recent progress in the treatment of lupus nephritis
Antonis Fanouriakis • Eleni Krasoudaki •
Michail Tzanakakis • Dimitrios T. Boumpas
Received: 31 January 2012 / Accepted: 18 April 2012
Ó Japan College of Rheumatology 2012
Abstract The treatment of lupus nephritis has seen sig-
nificant advances during the past decade mainly due to the
publication of well-designed randomized clinical trials
(RCTs). The choice of treatment is guided by the histo-
pathologic classification but is also influenced by demo-
graphic, clinical, and laboratory characteristics that allow
for the identification of patients at risk for more aggressive
disease. For the induction arm, low-dose cyclophospha-
mide regimens and mycophenolate mofetil have been
validated as alternatives to the established National Insti-
tutes of Health regimen of high-dose cyclophosphamide;
for the maintenance phase, azathioprine and mycopheno-
late compete for treatment of first choice. Rituximab is
efficacious in real-life clinical practice but ineffective in
clinical trials. The role of recently approved belimumab in
lupus nephritis eagerly awaits further documentation.
Aggressive management of comorbid conditions, such as
hypertension and dyslipidemia, is of utmost importance.
Here, we review the latest advances in lupus nephritis
A. Fanouriakis (&)
D. T. Boumpas
Department of Rheumatology, Clinical Immunology and
Allergy, University Hospital of Heraklion, University of Crete
Medical School, 71003 Heraklion, Greece
e-mail: afanouriakis@edu.med.uoc.gr
E. Krasoudaki
Department of Nephrology, Venizeleion Hospital of Heraklion,
Heraklion, Greece
M. Tzanakakis
Department of Nephrology, University Hospital of Heraklion,
University of Crete Medical School, Heraklion, Greece
D. T. Boumpas
Institute of Molecular Biology and Biotechnology (FORTH),
Heraklion, Greece
therapy with a focus on recent RCTs as well as new bio-
logic agents under development. Furthermore, we propose
a therapeutic algorithm in an effort to facilitate clinical
decision-making in this gradually changing landscape.
Upcoming European and American recommendations
should provide further clarification.
Keywords Biologics
Controlled trials
Lupus nephritis
Introduction
During the course of the disease, a patient with systemic
lupus erythematosus (SLE) will face up to a 60 % risk of
developing glomerulonephritis (LN), a manifestation with
a significant impact on the quality of life and survival [1].
Of these patients, 10–30 % will progress to end-stage renal
disease (ESRD) within 15 years of diagnosis [2]. Despite
considerable advances in treatment in recent years, recent
studies in adult and pediatric SLE patients have found that
the incidence of LN-associated ESRD has increased and
outcomes have not improved [3, 4].
For physicians providing care for lupus patients, the last
decade has been intriguing. Various immunosuppressive
agents have been studied in an effort to achieve clinical
efficacy in terms of remission of nephritis while minimiz-
ing the deleterious side effects of treatment. In this review,
we highlight the most important recent advances in the
field with a focus on (1) induction and maintenance therapy
of proliferative LN, (2) treatment options in membranous
LN, and (3) randomized controlled trials (RCTs) of new
biologic agents.
The treatment of severe LN involves a period of inten-
sive immunosuppressive therapy to prevent immunological
injury (induction therapy), followed by a period of less
123

aggressive maintenance therapy to maintain the response
and prevent flares and damage accrual. The pioneering
studies of the National Institutes of Health (NIH) in the
1980s established intravenous (IV) cyclophosphamide
(CY) in combination with steroids as the ‘‘gold standard’’
for the treatment of proliferative LN. These RCTs in
patients with severe, proliferative LN established that six
pulses of IV CY (0.5–1 g/m2) and methylprednisolone
(MP) on consecutive months, followed by quarterly follow-
up pulses for 2 years, represented a superior treatment
regimen and prevented relapses better than a shorter regi-
men limited to six doses alone [5, 6]. Extension of the
follow-up to a total of 11 years provided further docu-
mentation of the higher efficacy of the IV CY–IV MP
combination in the long-term outcome of LN [7]. The same
set of studies clearly showed that oral CY provides no
additional benefit over IV CY, while contributing to the
toxicity of the treatment [8]. Therefore, oral administration
has been practically abandoned.
The significant toxicity accompanying long-term high-
dose CY therapy and the inadequate response of almost
one-third of the patients has stimulated an intense effort to
find alternative therapies for severe proliferative LN.
Indeed, although rates were comparable between treatment
arms in the NIH trials, bacterial infections (often necessi-
tating hospitalization) and premature amenorrhea are seri-
ous potential side effects of prolonged CY therapy. Given
the fact that the majority of patients are women of child-
bearing age, gonadal toxicity in particular poses a serious
issue [rates of sustained amenorrhea in young (B30 years
old) females treated with IV CY range from 12 to 43 %] [7].
Alternative choices for induction therapy
Low-dose IV CY and the Euro-Lupus project
The aforementioned toxicity concerns, together with the
common belief that the disease may be less severe in
Caucasians, led investigators mainly from Europe to seek
alternative, less toxic IV CY protocols. In the Euro-Lupus
project, 90 patients with diffuse or focal proliferative LN
(or membranous plus proliferative), but generally mild
disease [mean serum creatinine (SCr) 1.2 mg/dl, mean
proteinuria 3.0 g/day], were randomized to receive either
(1) standard 6 monthly pulses of CY (0.5–1 g/m2) followed
by infusions every third month or (2) a shorter treatment
course consisting of 500 mg of IV CY every 2 weeks for
six doses (cumulative CY dose, 3 g), followed by azathi-
oprine (AZA) maintenance therapy (2 mg/kg/day) [9].
Both groups received three pulses of 750 mg IV MP in the
start of induction therapy, followed by oral doses of ste-
roids with gradual tapering. Primary end-points, such as
123
Mod Rheumatol
ESRD and doubling of SCr rates, did not differ between the
two groups, with a median time to remission of 9 months.
More importantly, albeit not statistically significant, there
was a difference in the rate of severe infections in favor of
the low-dose group. Outcomes in both groups were also
comparable after 10 years of follow-up, with a mean sur-
vival rate of 92 % for both treatment arms [10]. To the
investigators’ credit, only six patients were lost to follow-
up during the 10-year period. The same study elegantly
showed that early response to therapy (expressed as a drop
in proteinuria at 6 months) is a reliable predictor of good
renal outcome even in the long-term [11]. Consequently,
low-dose IV CY may serve as a reasonable alternative
therapy for selected, white European patients with mild to
moderately severe LN; whether this can be extrapolated to
patients of different origin or with more severe disease
remains to be seen.
The pro-mycophenolate mofetil movement: pros
and cons
Three RCTs in the last decade have evaluated the efficacy
of mycophenolate mofetil (MMF), a potent inhibitor of
inosine monophosphate dehydrogenase, in comparison to
standard NIH IV CY regimens as an induction treatment in
proliferative LN. A common finding from these studies,
confirmed by subsequent meta-analyses, is that MMF has
at least comparable—if not superior—efficacy to CY
together with a better safety profile. These observations
generated an ‘‘enthusiastic movement’’ in favor of MMF,
with some proclaiming ‘‘the end of the CY era’’. This
enthusiasm overlooked specific shortcomings of the MMF
trials, such as the lack of long-term follow-up as well as the
failure to achieve remission in a significant percentage of
patients.
Chan et al. [12] first compared MMF (2 g/day for
6 months followed by 1 g/day for 6 months) to oral CY
(2.5 mg/kg for 6 months) followed by AZA (1.5 mg/kg/day
for 6 months) in a Chinese population with diffuse prolif-
erative LN. At 12 months, the two treatments had achieved
a similar efficacy, with more than 90 % of the patients of
both treatment groups showing complete or partial remis-
sion; amenorrhea, leukopenia, and death occurred only in
the CY group. Comparable relapse rates and SCr levels,
accompanied by fewer infections in the MMF group, were
found at the 5-year follow-up (with an additional 22
patients) [13]. In a subsequent 6-month study from the
USA involving racially diverse patients with either prolif-
erative or membranous LN, MMF was found to be superior
to monthly IV CY in terms of complete remission (22.5 vs.
5.8 %; of note, the study was designed as a non-inferiority
trial), with fewer severe infections and vomiting but more
frequent diarrheal symptoms [14].
Mod Rheumatol
Following these encouraging results, the Aspreva Lupus
Management Study (ALMS), one of the largest [n = 370
patients, 27 % of whom had renal impairment with an
estimated glomerular filtration rate (GFR) of \60 ml/min/
1.73 m2] and most racially diverse RCTs performed in LN,
sought to demonstrate the potential superiority of MMF
over IV CY [15]. The response rates at 6 months were
similar for both groups (56 % for MMF, 53 % for IV CY),
and there were no differences in the frequency of adverse
events (total events 96 % for MMF, 95 % for IV CY). Of
note, however, the response to MMF was better in certain
race/ethnic groups, such as Blacks and mixed Latin
American (Hispanic) patients. Following the publication of
the results from these RCTs, three recent meta-analyses
have concluded that MMF is as effective as CY [pooled
relative risk (RR) for complete remission ranging from
1.60 to 1.61, P value = non-significant (NS)] and tends to
have a better safety profile (pooled RR: 0.17 for amenor-
rhea, 0.41–0.65 for leukopenia, 0.77–0.83 for infections) as
induction therapy for proliferative LN [16–18].
Where do these data leave us regarding the use of MMF
in proliferative LN? Most certainly, it cannot be believed
that we are now beyond the CY ‘‘era’’—especially in cases
of severe LN, for which only CY has exhibited beneficial
long-term effects, i.e., beyond 5 years. On the other hand,
MMF is a valid option for induction therapy in moderately
severe cases of proliferative LN, especially in Black and
Hispanic patients or when gonadal toxicity is an issue (see
also section on Maintenance therapy).
Any room for AZA in the induction phase?
The 10-year follow-up data of the Dutch Lupus Nephritis
Study Group have recently been published. This study
originally tested the efficacy of AZA as induction–main-
tenance regimen in 87 European patients with proliferative
LN who were randomized to receive pulse IV CY (totally
13 pulses in 2 years) ? oral prednisone versus IV MP ?
AZA ? a tapering dose of oral prednisone [19]. After a
median follow-up duration of 5.7 years, the rates of dou-
bling of baseline SCr and renal relapses were higher in the
AZA than the IV CY group. Repeat renal biopsy after
2 years of treatment in a subset of patients (n = 39)
showed a significant increase in the chronicity index in the
AZA arm; however, these histological variables could not
predict long-term renal outcomes, potentially due to the
relatively limited number of repeat biopsies [20]. In the
10-year extension of the follow-up, the results were not
much different [21]. Renal relapses were significantly more
common in the AZA ? MP group (38 vs. 10 % in the IV
CY group, with a HR of 4.5), as was the sustained doubling
of SCr (16 vs. 8 %, although the latter parameter did not
reach statistical significance due to the lack of power of the
study). Of note, non-Caucasian race (almost 25 % of study
patients) was an independent strong predictor for deterio-
ration of renal function irrespective of type of therapy.
Together, these data suggest that AZA should be
reserved preferably for young white—but not Black or
Hispanic—female patients with mild proliferative or
membranous LN who strongly wish to conceive and avoid
the gonadal toxicity of CY [22].
Rituximab: good in real-life, poor in clinical trials
The use of rituximab (RTX) in LN has generated
ambivalent feelings in clinicians caring for SLE patients.
Multiple small, uncontrolled observational studies over
the past decade have demonstrated the clear efficacy of
this agent usually in patients with refractory nephritis who
have failed conventional immunosuppressive regimens,
including CY and MMF. A meta-analysis of seven
observational studies found a complete or partial response
rate of 69 %, with the lowest rates of complete response
observed in patients with membranous (type V) LN [23].
More recently, pooled data from centers in the UK and
Spain demonstrate complete or partial response rates in
about two-thirds (67 %) of 164 patients with LN treated
with RTX, which was used in the majority of cases as the
second-line option in refractory disease or flares [24];
76 % of these patients also received concomitant CY or
MMF. Not surprisingly, the presence of NS or renal
failure at the time of RTX administration was a predictor
of poor prognosis and non-response.
Contrary to the promising results of open-label trials,
the LUNAR trial—a randomized, double-blind, phase III,
multi-center trial comparing RTX and placebo on top of
standard of care (MMF ? tapering doses of steroids) in
144 SLE patients with proliferative LN (types III/IV)—
failed to meet its primary end-point [25]. By week 52, no
statistically significant differences were observed between
the two groups in terms of complete or partial renal
response [defined by SCr, normalization of urinary sedi-
ment, and urine protein-to-creatinine (Pr/Cr) ratio]; of
note, there were numerically more responders in the RTX
group (57 vs. 46 %). Along with EXPLORER, the coun-
terpart trial in nonrenal lupus, the LUNAR trial has
received considerable criticism not only for its lack of
power to prove superiority but also for the use of full,
effective doses of established background therapies that
may have potentially diluted any effect attributable to
RTX. Until more data are available, most experts agree
that RTX constitutes a valid therapeutic option in patients
with aggressive disease refractory to conventional treat-
ment regimens (as was the case in most open-label trials
as opposed to the milder forms included in the trials) or in
the prevention of flares.
123

Other therapeutic agents
Tacrolimus and multi-target therapy
Tacrolimus, a more potent calcineurin inhibitor than
cyclosporine A (CsA), has also shown efficacy in LN with
a generally favorable toxicity profile. Initial open-label
trials and an RCT exhibited the beneficial effects of ta-
crolimus as induction therapy in both proliferative and
membranous LN [26, 27]. More recently, in a head-to-head
comparison with IV CY, Chen et al. [28] randomized 81
Chinese patients with mild active LN (mostly class IV,
mean proteinuria approx. 400 mg/24 h, mean SCr\1 mg/dl)
to receive either tacrolimus (started at 0.05 mg/kg/day and
titrated to trough levels of 5–10 ng/ml) or six pulses of IV
CY (0.75 g/m2 in the first pulse, adjusted to 0.5–1 g/m2
thereafter). Designed as a noninferiority trial, the study
showed higher, although not statistically significant, rates
of complete remission and response for the tacrolimus
group (52.4 vs. 38.5 % and 90.5 vs. 82.1 %, respectively)
after 6 months. However, this difference was entirely
accounted for by the subset of patients with pure mem-
branous (class V) LN. In terms of safety, tacrolimus was
better tolerated than IV CY, with significantly less frequent
leukopenia and gastrointestinal disturbance. In a similar
6-month open-label trial with 60 Chinese patients com-
paring both tacrolimus and MMF to standard IV CY
therapy, the rates of complete and partial remission were
comparable, with tacrolimus showing a trend towards fas-
ter resolution of proteinuria [29]. While providing proof of
concept for the efficacy of tacrolimus as induction therapy
for LN, these studies are limited by their short duration of
follow-up (6 months) and relatively small sample size.
Mixed class IV ? V LN (proliferative lesions superim-
posed on membranous LN) represents a high-risk histolog-
ical subtype with lower remission rates [30]. Tacrolimus has
been used in this subgroup of patients as part of a ‘‘multi-
target’’ combination therapeutic regimen. Combination
therapy (tacrolimus 4 mg/day ? MMF 1 g/day) was com-
pared against IV CY (6–9 pulses of 1 g/m2), both used in
combination with corticosteroids (three daily pulses IV MP
0.5 g/day followed by oral prednisone) [31]. Enrolled
patients (n = 40) had normal renal function (estimated
GFR 98 ml/min) and a mean urinary protein excretion of
4.4 g/24 h. After 6 months, ten patients in the ‘‘multi-tar-
get’’ group versus one patient in the IV CY group achieved
complete remission. The combination therapy was well
tolerated and no major effects were observed. These data
need to be examined cautiously in view of the limited
follow-up period (9 months), which does not allow for
solid conclusions to be drawn mainly in terms of long-term
calcineurin inhibitor nephrotoxicity. In this regard, a recent
study reported considerable toxicity in five of seven
123
Mod Rheumatol
patients with LN who received MMF (mean dose 2.8 g) and
tacrolimus (mean trough level 4.7 ng/dl) for 2–54 months
[32]. Overall, well-designed randomized studies with a large
number of patients and long-term follow-up are essential in
order to allow generalizability of such results and to be able to
draw definite conclusions regarding the use of tacrolimus
either alone or as part of a combination regimen in the
induction therapy of LN.
Cyclosporine A
Uncontrolled studies including a small number of patients
have demonstrated the efficacy of CsA, the prototypical
calcineurin inhibitor, when used in combination with cor-
ticosteroids in refractory-to-conventional treatment prolif-
erative LN. Initially, a group of Czech investigators
prospectively studied 31 LN patients, 13 of whom were
intolerant or refractory to CY, who were treated with CsA
(dose adjusted to trough level 80–120 ng/ml) either as first-
or second-line treatment together with prednisone (20 mg/
day and tapered to B10 mg/day) [33]. With a mean follow-
up of 85 months, more than 90 % of patients achieved
complete remission (proteinuria \1 g/day and improved or
stabilized renal function); nearly half of these patients
experienced a renal flare after CsA was withdrawn. Given
the considerable concern associated with CsA nephrotoxi-
city, long-term therapy with this agent warrants further
validation.
In a subsequent randomized study from the same group,
40 patients with newly diagnosed proliferative LN and
mild renal insufficiency were assigned to sequential
induction and maintenance therapy with either CY or CsA
[34]. The CY regimen included eight pulses of IV CY
(10 mg/kg) administered within 9 months, followed by
four to five oral CY boluses (10 mg/day in 6- to 8-week
intervals), while CsA was given orally (4–5 mg/kg/day) for
9 months and then tapered to 3.75–1.25 mg/kg/day within
the next 9 months. Oral steroids were started at 0.8 mg/kg
with gradual tapering. In the induction part of the regimen,
the same number of patients (5; 24 % for CY and 26 % for
CsA, respectively) met the criteria for complete response/
remission at 9 months (defined as normal urinary sediment,
proteinuria \0.3 g/24 h and stable serum creatinine level).
Partial response rates also did not differ. At the end of the
maintenance phase (18 months), 14 % patients in the CY
group compared to 37 % of patients in the CsA group were
in remission; another eight (38 %) and 11 (58 %) patients,
respectively, fulfilled the partial response criteria. How-
ever, this difference in response rates in favor of CsA was
largely attributed to the higher proportion of patients
achieving a urinary protein excretion rate of \0.3 g/24 h
(response criterion of proteinuria; 38 % in CY group vs.
74 % in CsA group; p = 0.02). In terms of adverse effects,
Mod Rheumatol
the frequency of infection-related adverse events were
similar, but treatment with CsA was associated with a
transient increase in blood pressure and decrease in GFR.
Until more data are available, current evidence suggests
that CsA may be considered as a therapeutic alternative to
CY in Caucasian patients with mild-to-moderate pro-
teinuric proliferative LN—but with diligent monitoring for
hypertension and nephrotoxicity.
Maintenance therapy
The need for maintenance treatment to decrease the num-
ber of flares and accrual of renal damage was demonstrated
in the early NIH trials. In these studies, prolonged
administration of quarterly pulses of IV CY for 2 years
decreased the rate of relapses compared to a shorter
6-month regimen [5]. Although the optimal duration of
maintenance therapy has yet to be elucidated, most clini-
cians will keep their patients on immunosuppression for at
least 2 years after remission has been achieved. For such a
long period, CY does not represent a viable option due to
its long-term toxicities of alopecia, hemorrhagic cystitis,
bladder cancer, gonadal damage, and early menopause.
Consequently, other agents have been extensively studied
in the last decade in an effort to minimize toxicity without
sacrificing efficacy.
The long-awaited recent publication of the maintenance
part of the ALMS trial marks the completion of a series of
studies comparing the two main agents currently used for
maintenance therapy in LN—MMF and AZA. Contreras
et al. [35] initially compared MMF (0.5–3 g/day) and AZA
(1–3 mg/kg/day) or quarterly pulses of IV CY as mainte-
nance therapy in proliferative LN following remission with
seven IV CY pulses. The study population (59 patients in
total) mostly comprised patients of Black and Hispanic
origin. Over 6 years of follow-up, the rate of survival
without death or chronic renal failure was significantly
higher in the MMF and AZA groups than in the CY group.
Equally important, MMF- or AZA-treated patients devel-
oped significantly less amenorrhea, infections, and gastro-
intestinal toxicity. The limitations of this study were the
relatively small number of patients and the use of lower
doses of IV CY together with higher doses of corticoste-
roids, which may have decreased efficacy and increased the
risk for infections.
The MAINTAIN Nephritis Trial included 105 European
patients (approx. 80 % Caucasian origin) with moderately
severe class III–IV LN who received induction therapy
with three daily 750 mg IV MP pulses followed by oral
prednizolone, and six IV CY pulses of 500 mg at 2-week
intervals (the Euro-Lupus regimen) [36]. After 3 months,
all patients were randomized to receive either AZA or
MMF, irrespective of the magnitude of the renal response
at the end of the induction period. After a minimum of
3 years, the two groups did not differ in terms of time-to-
renal flare (the primary end-point), number of severe flares,
renal remission, or doubling of SCr. Hematological cy-
topenias were more common in the AZA group. On the
contrary, the ALMS study included a total of 227 patients
(more than 50 % non-whites) who achieved a clinical
response to either MMF or IV CY in the induction phase, a
pivotal difference from the MAINTAIN study which did
not need response as a prerequisite [37]. These patients
were randomized to receive either MMF (target dose
2 g/day) or AZA (target dose 2 mg/kg/day) and were moni-
tored for 3 years. A composite index of treatment failure
(defined as either death, ESRD, renal flare, sustained
doubling of SCr, or need for rescue therapy) was used as
the primary end-point. In the intention-to-treat analysis,
MMF was superior to AZA with a hazard ratio for treat-
ment failure of 0.44 (p = 0.003) and a failure rate of 16 %
as compared to 32 % in the AZA group at 3 years. Of note,
Black patients and those who received IV CY during the
induction phase were less likely to experience treatment
failure if treated with MMF for maintenance. Similar to the
MAINTAIN study, leukopenia was more common in the
AZA group, as were side effects that led to therapy with-
drawal. Table 1 summarizes the similarities and differ-
ences of the main head-to-head maintenance studies of
MMF and AZA.
The discrepancy in the results of these two previous
studies may be partly explained by differences in the
induction protocol, the number and ethnicity of the
included patients (smaller size, with White patients
in MAINTAIN, racially diverse large trial in ALMS),
the prerequisite for response to induction treatment (in
ALMS), and the outcome measures used (single in
MAINTAIN, composite in ALMS). Instead of trying to
establish the superiority of one agent over the other, the
main conclusion to be drawn is that both AZA and MMF
constitute reasonable efficient options for maintenance
therapy of LN. Race, potential for pregnancy (MMF is
associated with an increased risk of spontaneous abortion
and fetal malformations), cost, and availability must be
considered in the individual patient to guide selection of
one drug over the other. As an example, white patients
of childbearing age with mild to moderate LN may be
initially treated with AZA, while non-Caucasian older
patients may be candidates for MMF. Contraindications
or intolerance to one agent may dictate switching to the
alternative.
All of these data are summarized in Fig. 1, which sug-
gests a step-by-step treatment algorithm and choice of
agents for proliferative LN based on baseline risk stratifi-
cation (low-risk vs. high-risk patients)
123
 Mod Rheumatol

SCr serum creatinine, Pr protein, WHO World Health Organization, ISN/RPS International Society of Nephrology/Renal Pathology Society, IV intravenous, CY cyclophosphamide, MMF mycophenolate mofetil, AZA azathioprine, HR
Membranous (class V) LN

MMF 15 %–AZA 20 %

MMF 15 %–AZA 32 %

MMF 19 %–AZA 25 %

MMF 16 %–AZA 32 %
HR 0.44 P = 0.003
Class V LN represents a unique subtype of LN. Immune
Treatment failure

HR 0.75 P = ns)
deposits are limited to the subepithelial space and renal
Renal flares

Renal flares

Renal flares
(6 years)

(3 years)

(3 years)
survival rates vary widely, partly owing to caveats in the
Results

original World Health Organization (WHO) classification

of LN, which included biopsies with superimposed prolif-

flare, ESRD, sustained doubling

of SCr, need for rescue therapy,
erative lesions (classes Vc and Vd) along with pure

Time to treatment failure (renal

(sustained doubling of SCr,

membranous changes (Va and Vb) into the same group—

Patient and renal survival

class V LN [38].
Table 1 Major randomized controlled trials comparing mycophenolate mofetil and azathioprine as maintenance therapies in proliferative lupus nephritis

For patients with membranous LN and low-grade pro-

Time to renal flare
Primary end point

ESRD, death)

teinuria (\2 g/day), although there is no consensus, most

experts agree that specific immunosuppressive treatment

death)
may not be necessary and that blockade of the renin–
angiotensin axis (RAAS) is sufficient to prevent progres-
sion to ESRD (risk of approximately 20 % at 10 years). By
monthly for 6 months) or MMF
NIH protocol (0.5–1 g/m2 IV CY

NIH protocol (0.5–1 g/m2 IV CY

Responders only re-randomized

contrast, the presence of significant proteinuria ([2 g/day),

Euro-Lupus (500 mg IV CY
All patients randomized for

All patients randomized for

NS, decreased GFR, or proliferative lesions in the renal

monthly for 6 months)

biweekly for 3 months

for maintenance phase

maintenance phase

maintenance phase

biopsy usually mandate the institution of immunosuppres-

Induction therapy

sive treatment. Unfortunately, the optimal therapeutic regi-

men remains far from certain. Small-sized, open-label
3 g/day

studies have indicated that tacrolimus has beneficial effects

in combination with steroids in membranous LN with
persistent proteinuria [39–41], but these results have to be
Mean proteinuria

validated in larger, more racially diverse randomized trials.

As mentioned above, the ‘‘multitarget’’ therapy with the
combination of prednisone, MMF, and tacrolimus as
(Pr/Cr)

induction therapy for mixed IV ? V LN showed promising

5.2

3.3

4.1

results and could be considered as an alternative regimen

for this subclass of patients, although close monitoring for
Mean SCr

side effects is warranted.

(mg/dl)

In a randomized controlled study, Austin et al. com-

1.7

1.0

1.1

pared CsA (5 mg/kg/day, then adjusted according to

Histologic subtype

changes in SCr), alternate-monthly IV CY (0.5–1 g/m2 9

72 % IV/IV ? V
13 % III/III ? V
classification)

classification)

classification)

6 doses), and glucocorticoids alone in 42 patients with

(ISN/RPS
78 % IV

58 % IV

membranous LN (median GFR 83 ml/min/1.73 m2,

20 % III

31 % III

15 % V
2 % Vb

8 % Vd
3 % Vc
(WHO

(WHO

median proteinuria 5.4 g/day). All patients received

alternate-day oral prednisone (1 mg/kg every other day
79 % white, 12 % Black

44 % white, 10 % Black

for 8 weeks, then tapered to 0.25 mg/kg every other day).

Hispanic/other, 8 %

33 % Asian 13 %
46 % Black, 46 %

Remission rates at 1 year were 27 % with prednisone,

60 % with IV CY, and 83 % with CsA. However, NS
9 % Asian

Hispanic

relapses were significantly less in the IV CY group than in

white

the CsA group (0.2 vs. 2.0/100 patient-months, respec-

Race

hazard ratio, ESRD End-stage renal disease,

tively; P = 0.02). Of note, patients with impaired renal

59 (95 % female)

105 (91 % female)

227 (86 % female)

Number of patients

function at baseline were not randomly assigned to the

CsA arm due to concerns for CsA-induced nephrotoxicity.
This, together with the small number of patients and the
relatively short follow-up limit the generalization of
conclusions. However, apart from the superiority of both
CsA and IV CY over steroid monotherapy for class V LN,
Contreras et al.

Houssiau et al.

Dooley et al.

this study indicates that CsA may require some form of

maintenance therapy (lower CsA doses or other immu-
[35]

[36]

[37]
Study

nosuppressive agent) to prevent relapses.

123
Mod Rheumatol
Fig. 1 Recommended management of proliferative lupus nephritis
based on risk stratification. LN lupus nephritis, SCr serum creatinine,
Pr/Cr protein-to-creatinine ratio measured in random urine sample (g/g),
MMF constitutes yet another therapeutic option for
membranous LN, as it has been shown to exert anti-pro-
teinuric effects in this subgroup of patients [42]. Recently,
a pooled analysis of 84 patients with pure class V LN from
two aforementioned prospective RCTs comparing MMF to
IV CY as induction therapy in LN (the ALMS and a pre-
vious study by Ginzler et al. [14]) demonstrated that,
irrespective of the initial level of proteinuria (nephrotic or
subnephrotic), there was no difference between MMF- and
IV CY-treated patients in terms of percentage change in
urine protein and change in SCr [43]. To complicate mat-
ters, MMF monotherapy failed to demonstrate efficacy in a
randomized trial for idiopathic membranous nephropathy
[44].
A subset of LN patients treated with rituximab in open-
label trials over the last decade had class V LN (20 in
total). In the previous pooled analysis from European
cohorts, complete and partial response rates were seen in
two-thirds of patients, albeit complete response was sig-
nificantly less common than that in mixed membranous-
proliferative LN (18 vs. 50 %) [24]. Of note, NS at the time
of rituximab administration predicted a worse response. On
AZA azathioprine, CY cyclophosphamide, MP methylprednisolone,
MMF mycophenolate mofetil, IS immunosuppressives, IV intravenous,
NR/PR no remission/partial remission
the contrary, a recent study demonstrated that the RTX–IV
CY combination markedly improved proteinuria and led to
resorption of subepithelial electron-dense deposits in the
basal membrane in six patients with refractory membra-
nous LN [45]. Recent data also suggest that RTX might
preserve renal podocytes and provide protection from
recurrent focal segmental glomerulosclerosis [46]; the
ultimate role of RTX in proteinuric membranous LN awaits
further characterization in a larger number of patients.
Collectively, when immunosuppressive therapy is
required in class V LN, the combination of IV CY with IV
MP, MMF, a course of oral CsA, or tacrolimus, and even
AZA all constitute acceptable therapeutic options. The
choice should be individualized and depend on various
factors, including age, race, planning of pregnancy, and
cost. In therapy-resistant cases, a course of RTX may be
considered. On the contrary, for patients with proteinuria
of \2 g/day, a combination of angiotensin converting
enzyme inhibitors (ACEIs) to minimize urine protein
excretion with statins and low-dose aspirin may be suffi-
cient. Vigilant monitoring to detect evolution to a more
aggressive type of nephritis requiring immunosuppressive
123

treatment (severe membranous or mixed membranous with
proliferative LN) is mandatory.
Novel therapies
Biologics and tolerogens: promises and failures
The recently approved belimumab (anti-BLyS; B lym-
phocyte stimulator) has not been formally tested in LN.
However, approximately 15 % of patients participating in
two recent phase III studies leading to drug approval (more
than 1,500 study participants in total) had renal involve-
ment at baseline. Pooled data in this subgroup of patients
showed a positive trend for belimumab in reducing renal
flares (1.4 vs. 2.8 % for placebo) and proteinuria [47].
Although far from conclusive, these results lend support to
the future evaluation of BLyS blockade as a therapeutic
option for LN, possibly as add-on therapy in patients with
incomplete response.
Abatacept (CTLA4-Ig), a T-cell costimulation modula-
tor, has been shown to halt disease progression in lupus-
prone mice, especially when combined with CY [48].
Following an initial phase IIb trial that failed to show
efficacy in non-renal SLE (although again on a background
therapy of high-dose steroids) [49], two RCTs were laun-
ched to evaluate abatacept in combination with background
immunosuppression in the treatment of LN. The results of
the first RCT, a 12-month phase II/III trial with MMF ?
steroids as the comparator arm, were recently reported in
abstract form [50]. In 298 patients with proliferative LN,
two different doses of abatacept failed to increase the rates
of complete response (normalization of GFR, protein
excretion, and urinary sediment) over placebo, although a
greater reduction in proteinuria was noted in patients pre-
senting with NS at baseline. Of note, if less stringent cri-
teria for response were applied [as in the ACCESS study
(Abatacept and Cyclophosphamide Combination Therapy
for Lupus Nephritis), still recruiting participants], complete
response rates would be higher and significant differences
would be noted among the different arms (34.8 and 29.3 % for
the two dosing regimens of abatacept vs. 21 % in the placebo
group) [51]. As is common in lupus trials, this discrepancy
connotes the ‘‘rocky path’’ of choosing clinically meaningful
outcome measures in LN. The full-text report of both RCTs is
needed in order to draw more solid conclusions for the role of
T-cell costimulation modulation in renal SLE.
Finally, atacicept (TACI-Ig) and ocrelizumab (anti-CD
22)—both targeting B-cells—as well as synthetic tolero-
gens (such as abetimus sodium or spliceosomal peptide
P140) represent notable recent failures as therapeutic
options in LN either due to unexpected rates of infectious
complications or to a lack of efficacy [52, 53].
123
Mod Rheumatol
Adjunct therapy in LN
Patients with lupus have an increased risk of developing
atherosclerotic cardiovascular events, attributable not only
to traditional risk factors but also to disease-specific
parameters and the effects of medications [52, 53]. Con-
sequently, strict control of hypertension, dyslipidemia, and
hyperglycemia is of utmost importance for patients with
LN.
Hypertension remains a clinically important issue as it
has been associated with a worse renal prognosis [54].
Most experts recommend that blood pressure must be kept
below 130/80 mmHg for patients with minimal proteinuria
(\0.5 g/day) and below 120/75 mmHg for patients with
significant proteinuria ([1 g/day). Nephritis per se con-
tributes to hypertension through the RAAS. Consequently,
ACEis or angiotensin receptor blockers are the antihyper-
tensive agents of choice in patients with chronic kidney
disease owing to their additional antiproteinuric effects;
additionally, in patients with lupus these agents seem to
delay the development of renal involvement and to be
associated with an overall lower disease activity [55].
Aggressive treatment of dyslipidemia (target low-den-
sity lipoprotein \100 mg/dl and triglycerides \150 mg/dl)
is recommended for patients with LN, similar to the high-
risk population for cardiovascular disease. Akin to non-
SLE patients, statins remain the cornerstone of therapy for
dyslipidemia in the context of LN. Apart from changing the
lipid profile and decreasing overall cardiovascular risk
(even in kidney transplant recipients due to LN [56]), there
is evidence that statins also exhibit anti-inflammatory and
immunomodulatory actions [57]. Pravastatin in particular,
when given in combination with RAAS blockade, has also
been shown to reduce proteinuria, alleviate renal disease,
and prolong survival in a mouse model of SLE [58].
Hydroxychloroquine (HCQ) constitutes a sine qua non
for SLE patients. Although usually prescribed to treat
musculoskeletal, cutaneous or serosal manifestations of
lupus, antimalarials are gaining ground as an essential
component of LN therapy [59]. Early data from Canada
showed a 74 % reduction in risk for nephritic flare in
patients who continued treatment with HCQ as compared
to those who withdrew from treatment [60]. An observa-
tional study in a multi-ethnic cohort showed a reduced
cumulative probability of renal damage in LN patients
receiving HCQ [61]. Although the study was criticized for
potentially overestimating the protective effects of HCQ, it
did provide proof-of-concept for the role of the latter in
LN. In a small trial (n = 29 patients) of MMF in mem-
branous LN, concurrent use of HCQ led to a statistically
significant improvement in the rate of renal remission at
12 months [62]. The results of cross-sectional studies
advocate for a beneficial effect of HCQ on serum lipid
Mod Rheumatol
levels, but the data are inconsistent and thus the potential
role of antimalarials in dyslipidemia require further vali-
dation [63].
Despite optimal therapy, at least 20 % of patients with
LN still progress to ESRD. Recent data show that younger
patients, African Americans, or Native Americans with LN
receive renal replacement therapy relatively more often;
notably, this does not translate into improved survival rates
during the first years of treatment [3]. Clinically important
risk factors for the development of ESRD include abnormal
SCr values at presentation, delay in treatment initiation,
failure to achieve remission, and uncontrolled systolic
hypertension [64, 65]. For renal replacement therapy in
lupus patients, retrospective studies carried out during the
last decade support hemodialysis (HD) over continuous
ambulatory peritoneal dialysis (CAPD) due to the lower
incidence of infectious complications (most commonly
peritonitis) and the beneficial effect on disease activity,
although long-term survival rates are similar [66, 67].
Kidney transplantation is a viable alternative option for
SLE patients with ESRD. In a recent retrospective study
from Korea, patients who underwent kidney transplantation
after 3 years of renal replacement therapy had lower
complication rates than patients receiving HD and CAPD
[68]. Overall patient survival was better in kidney trans-
plantation than in HD.
Conclusion
In recent years, potent drugs, such as MMF, have definitely
enriched our armamentarium in LN, and the future holds
great promise with the development of new biologic drugs.
The lupus community is struggling to design optimal ran-
domized trials with clinically meaningful end-points in an
effort to maximize efficacy and minimize toxicity. Ideally,
advances in our understanding of pathogenesis and phar-
macogenomics as well as the identification of valid bio-
markers for monitoring response to treatment will
eventually lead to more targeted, individualized therapies.
Conflict of interest None.
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