Clin Exp Nephrol (2016) 20:1–13
DOI 10.1007/s10157-015-1179-y
REVIEW ARTICLE
Lupus nephritis: an update
Tasnim F. Imran1 • Frederick Yick1 • Suneet Verma1,2 • Christopher Estiverne1
Chinonye Ogbonnaya-Odor1 • Srikanth Thiruvarudsothy1 • Alluru S. Reddi1,2 •
Neil Kothari1
Received: 15 April 2015 / Accepted: 2 October 2015 / Published online: 16 October 2015
Ó Japanese Society of Nephrology 2015
Abstract Lupus nephritis (LN) is an inflammatory con-
dition of the kidneys that encompasses various patterns of
renal disease including glomerular and tubulointerstitial
pathology. It is a major predictor of poor prognosis in
patients with systemic lupus erythematosus (SLE). Genetic
factors, including several predisposing loci, and environ-
mental factors, such as EBV and ultraviolet light, have
been implicated in the pathogenesis. It carries a high
morbidity and mortality if left untreated. Renal biopsy
findings are utilized to guide treatment. Optimizing risk
factors such as proteinuria and hypertension with renin-
angiotensin receptor blockade is crucial. Immunosuppres-
sive therapy is recommended for patients with focal or
diffuse proliferative lupus nephritis (Class III or IV) dis-
ease, and certain patients with membranous LN (Class V)
disease. Over the past decade, immunosuppressive thera-
pies have significantly improved long-term outcomes, but
the optimal therapy for LN remains to be elucidated.
Cyclophosphamide-based regimens, given concomitantly
with corticosteroids, have improved survival significantly.
Even though many patients achieve remission, the risk of
relapse remains considerably high. Other treatments
include hydroxychloroquine, mycofenolate mofetil, and
biologic therapies such as Belimumab, Rituximab, and
Abatacept. In this paper, we provide a review of LN,
& Tasnim F. Imran
imranta@njms.rutgers.edu
1
Department of Medicine, New Jersey Medical School,
Rutgers, The State University of New Jersey, 185 South
Orange Avenue, Newark, NJ 07103, USA
2 major predictor of poor prognosis [8]. In about 5 % of the
Division of Nephrology, New Jersey Medical School,
Rutgers, The State University of New Jersey, 185 South
Orange Avenue, Newark, NJ 07103, USA
•
including pathogenesis, classification, and clinical mani-
festations. We will focus, though, on discussion of the
established as well as emerging therapies for patients with
proliferative and membranous lupus nephritis.
Keywords Lupus nephritis
Systemic lupus
erythematosus
Renal lupus
Introduction
Lupus nephritis (LN) refers to inflammation of the kidney
that encompasses diverse patterns of renal disease includ-
ing glomerular, tubulointerstitial and vascular pathology
[1]. Renal involvement in systemic lupus erythematosus
(SLE) may be present in approximately 60 % of adults,
with 25–50 % of patients presenting with clinical renal
disease at the time of diagnosis [2]. Most patients affected
are female, and younger than 50 years of age. However,
male patients tend to have more frequent renal involvement
and greater severity of disease [3, 4]. The prevalence of
SLE ranges from 1.4 to 21.9 %; incidence is estimated to
be 7.4–159.4 cases per 100,000 person-years. The inci-
dence varies depending on the studied population. The
cumulative incidence of LN is higher in people of Asian
(55 %), African (51 %), and Hispanic (43 %) ancestry as
compared with Caucasians (14 %) [5].
With the advent of advanced therapies, the 5-year renal
survival rate of LN patients has shown continuous
improvement from 44 % in 1953–1969, 82 % in
1990–1995, to nearly 96 % today [6, 7]. Lupus nephritis,
when occurring early in the course of SLE, is considered a
cases, LN may appear more than 5 years after the onset of
SLE (delayed LN). Delayed LN has a higher association
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2 Clin Exp Nephrol (2016) 20:1–13
with Sjogren syndrome (SS), lung involvement, and
antiphospholipid syndrome as compared with early LN [9].
Although the etiology remains unclear, genetic, hormonal
and environmental factors likely play a role in manifesta-
tion of disease and severity. Several genes have been
implicated in both SLE and lupus nephritis. Other factors,
such as a higher incidence of SLE in monozygotic twins,
and greater risk of developing the disease if family mem-
bers have SLE or other autoimmune conditions, suggest a
genetic predisposition.
Lupus nephritis is a severe complication of SLE that
carries a high morbidity and mortality if left untreated. An
abnormal urinalysis with or without elevated plasma cre-
atinine is present in many patients with LN and SLE, with
proteinuria being a characteristic feature of lupus nephritis
[6]. Several types of renal disease may be found in patients
with SLE, including immune complex mediated glomerular
disease. These types are differentiated based on
histopathology obtained via renal biopsy [10]. In a few
cases, patients may have ‘‘silent lupus nephritis,’’ which
refers to histopathologic disease in the absence of clinical
manifestations.
Even with treatment, renal involvement significantly
affects the survival and quality of life of patients with SLE
[11]. Although several clinical trials have evaluated the
efficacy of treatment options, the ideal regimen remains to
be elucidated. Controlled randomized trials on severe
proliferative and membranous lupus nephritis have aimed
to achieve long intervals of remission while attempting to
minimize side effects of therapy. However, some patients
have disease refractory to these treatments and may benefit
from new immunomodulatory agents that are currently
being studied [12]. In this paper, we review the patho-
genesis, classification, clinical manifestations, and the
current treatment options for lupus nephritis, including the
newer immunomodulatory agents and therapies.
Pathogenesis
The pathogenesis of systemic lupus erythematosus is roo-
ted in the formation of autoantibodies that target self DNA
or other self-nuclear antigens. Although not completely
understood, it is suggested that these autoantibodies are a
result of abnormalities in the clearance of cellular debris
that result from cellular apoptosis [13]. The formation of
autoantibodies will eventually cause a loss of immune
tolerance and further progression of disease [14]. Once a
source of immunogenic material, such as chromatin, is
utilized to form autoantibodies, a cascade of other
autoantibodies are created, and eventually autoantibodies
against dsDNA form.
123
Evidence suggests that nucleosomes from apoptotic
cells largely contribute to the immunogenic material tar-
geted by autoantibodies [15]. Initially, apoptosis was
described as the only mechanism through which the anti-
genic material would have a chance to be presented, but
recent studies have shown that other types of cell death
could also potentially contribute [16]. Usually, the rapid
clearance of a dead cell would prevent autoantibody for-
mation. However, in patients with SLE, it is possible that
either inappropriate clearance of cellular debris or an
abnormal increase in cell death provides ample opportunity
for nucleosomes to become antigenic material for autoan-
tibody formation [3, 13, 16]. These autoantibodies can
form immune complexes, which deposit in various organ
systems, leading to dysfunction. There is also a lower
threshold of immune response to the Type I interferon
pathway, which has been identified as a potential factor in
SLE [17, 18].
The role of long-lived memory plasma cells and B-cell
hyperactivity has been recently elucidated in the patho-
genesis of SLE [19, 20]. The loss of B-cell tolerance to
self-antigens and subsequent autoimmune responses lead to
the deposition of circulating immune complexes (CIC)
[21]. The size of immune complexes, charge, local hemo-
dynamic factors, and clearing mechanisms of the mesan-
gium all influence where the immune complexes localize
within the glomerulus. Renal deposition of autoantibodies
forms immune complexes, which is the source of renal
dysfunction in lupus nephritis. This causes the activation of
the complement system and subsequent release of cytoki-
nes, leading to renal injury [13, 22]. Studies have also
shown that direct binding of anti-DNA antibodies to
mesangial cells causes an inflammatory response as well as
further cellular proliferation [3]. Autoantibodies against
C1q have also been isolated. These autoantibodies have
been identified to cause functional C1 deficiency, con-
tributing to defective clearance of cellular debris from
apoptosis and immune complexes [13]. This may further
fuel the formation of more autoantibodies as nuclear rem-
nants are not adequately removed.
Genetic factors play a major role in the pathogenesis of
lupus nephritis. Predisposing loci include HLA-DR2,
HLA-DR3, HLA-DRB1 loci, HLA-DRB*0301, and HLA-
DRB1*1501. However, multiple genes are involved,
including those that regulate immunity and lymphocyte
signaling. In short, a single gene polymorphism that leads
to SLE has not been identified; rather a combination of
susceptibility genes and/or absence of protective genes are
necessary to lead to overt disease [23]. Environmental
factors have also been implicated in the pathogenesis of
SLE. These include viruses such as EBV, ultraviolet light,
silica, dust, and allergies to medications [24].
Clin Exp Nephrol (2016) 20:1–13 3

Classification patients may present with a membranous or proliferative

The deposition of immune complexes and subsequent
inflammation leads to the glomerulonephritis seen in lupus
nephritis patients. Glomerular injury has been classified
into three distinct patterns—mesangial, endothelial, and
epithelial [25]. As with other glomerular diseases, lupus
nephritis may encompass multiple areas of involvement
and the histopathology may be pleomorphic, which com-
plicates both clinical syndromes and the classifications of
severity for glomerular injury [13, 25]. Kidney biopsy
remains the gold standard for diagnosis of lupus nephritis.
The World Health Organization (WHO), the International
Society of Nephrology, and the Renal Pathology Society
(ISN/RPS) classify lupus nephritis based on glomerular
pathology [13]. Advances in technology and research have
allowed both classification systems to be revised on many
occasions and the most recent version of classification will
be reviewed. Classes I through VI are described in Table 1.
Silent lupus nephritis
Lupus nephritis can be classified as ‘‘silent’’ if the patient is
asymptomatic yet renal biopsy demonstrates evidence of
nephritis [26]. Despite no clinical signs of disease, a few
glomerulosclerosis [13]. In one study, kidney biopsy was
offered to SLE patients over an 11-year period; 86 out of
195 patients had no clinical renal disease. Of these 86
patients, 15 % were found to have Class III or IV LN, and
10 % had Class V disease on biopsy [28].
Tubulointerstitial disease
Some patients with SLE may have tubulointerstitial dis-
ease, manifested by immune deposits of immunoglobulins
or complements along the basement membranes of tubules
and interstitial capillaries [29]. This is more commonly
found in patients with Class III or IV LN, often concur-
rently with glomerular disease.
End-stage renal disease due to lupus nephritis
End-stage renal disease (ESRD) due to LN is characterized
by fibrosis on histology [13]. At this stage, dialysis is
necessary and ultimately, kidney transplantation is required
for continued survival [27]. The percentage of patients who
progress to end-stage LN varies from 5 to 50 % [29]. These
patients have increased mortality during the first several
months of dialysis due to increased rate of infections and

Table 1 Histopathological and glomerular classification of lupus nephritis

Class Primary location of Microscopy
immunocomplexes

I: Minimal Mesangium Minimal deposition of mesangium and often appears normal on light microscopy. Diagnosed
Mesangial based on immunofluorescence or electron microscopy (EM)
Weening et al.
[25]
II: Mesangial Mesangium Defined by mesangial hypercellularity. Deposition visualized through light microscopy. May
Proliferative have minimal deposition of subendothelium or subepithelium on EM
Weening et al.
[25]
III: Focal Subendothelium Endocapillary or extracapillary glomerulonephritis comprising \ 50 % of glomeruli.
Weening et al. Characterized by focal subendothelial deposits, with variable involvement of the mesangium.
[25] Further subdivision based on whether lesions are active (A) or chronic (C)
IV: Diffuse Subendothelium Endocapillary or extracapillary glomerulonephritis comprising [50 % of glomeruli.
Weening et al. Characterized by diffuse subendothelial deposits, with variable involvement of the
[25] mesangium. Subdivision of class based on percentage of lesions that are segmental (involving
less than 50 % of glomerular tuft) or global (involving more than 50 % of glomerular tuft).
Further subdivision based on active (A) or chronic (C) lesions, as seen in class III
V: Membranous Subepithelium Subepithelial immune deposits seen on light microscopy. Can be present with Class III or IV
Weening et al. disease
[25]
VI: Advanced Variable [90 % of glomeruli globally sclerosed due to advancement of Class III, IV, or V disease. No
Sclerosing active inflammation
Weening et al.
[25]

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4 Clin Exp Nephrol (2016) 20:1–13
underlying immunosuppression from immunosuppressant
medications. Long-term outcomes for SLE patients with
ESRD due to LN are similar to other patients with chronic
kidney disease (CKD) stage V [29].
Clinical manifestations
Renal involvement in SLE patients often develops con-
currently or soon after diagnosis. Patients may experience
periods of remissions and exacerbations. Clinical involve-
ment often correlates with glomerular involvement of dis-
ease. Class I patients have almost no, or minimal evidence
of kidney disease, and Class II patients may have minimal
clinical involvement. Class III disease, focal proliferative
LN, is often associated with active lupus disease and
serologies. These patients tend to have hypertension, pro-
teinuria more than 1 g/day, elevated creatinine, and/or
nephrotic syndrome. Patients with Class IV disease, diffuse
proliferative LN, tend to present with the most active and
severe clinical manifestations. In addition to findings
associated with Class III disease, they typically present
with high anti-DNA antibody titers, low serum comple-
ment levels, active urinary sediment with erythrocytes and
cellular casts, and nephrotic syndrome [29]. Patients with
Class V disease, membranous LN, usually present with
nephrotic syndrome and have an increased risk of throm-
bosis. Patients with Class VI disease, end-stage LN, have
hypertension, a decreased glomerular filtration rate, and
have often had years of lupus flares leading to renal
sclerosis.
Treatment
Although there have been several randomized controlled
trials comparing various therapies (Table 2), the optimal
treatment of patients with LN remains to be elucidated [21,
30–39].
Lupus nephritis progresses to end-stage kidney disease
in 5–10 % of patients 10 years after diagnosis [38].
Without treatment, the overall prognosis is very poor,
especially for proliferative LN. Patients with WHO Class
IV lupus nephritis have a reported 5-year survival of 17 %
without intensive immunosuppressive treatment [6]. Cur-
rent immunosuppressive therapies have substantially
improved outcomes; cyclophosphamide-based regimens,
usually given with concomitant corticosteroids, have
improved survival to 90 % in many cases [6, 40, 41]. Even
though remission is induced in a significant proportion of
patients, risk of relapse remains considerably high and has
been reported to range from 18 to 46 % [42].
According to the 2012 American College of Rheuma-
tology guidelines for the management of lupus nephritis,
123
there is no expert consensus on what constitutes remission,
flare, and response [43]. In some studies, remission has
been defined as less than 10 red blood cells/high-power
field and less than 1 g protein in a 24-h urine sample, in the
absence of doubling of serum creatinine level [11]. This is
further discussed in the treatment section under therapies
for specific classes of lupus nephritis.
Renal biopsy findings are essential in guiding treatment.
Immunosuppressive therapy is recommended for patients
with focal or diffuse proliferative lupus nephritis, and in
certain patients with membranous LN, especially those
with nephrotic syndrome, an elevated serum creatinine and
concurrent proliferative disease [43]. Progression of lupus
nephritis, like chronic kidney disease in general, is partly
related to intra-glomerular hypertension. Hypertension
should be aggressively managed and patients with pro-
teinuria should receive renin-angiotensin system blockade
therapy (angiotensin-converting enzyme inhibitor or
angiotensin receptor II blocker), and lipid-lowering therapy
[43]. In particular, all patients with proteinuria of more
than or equal to 0.5 g in 24 h should receive renin-an-
giotensin system blockade [13]. With regards to lipid
lowering, therapy, the SHARP (Study of Heart and Renal
Protection) trial did not reveal a risk reduction of pro-
gression to ESRD with simvastatin/ezetimibe therapy [45].
However, lipid-lowering therapy should be considered in
patients with lupus nephritis because of its significant
cardiovascular benefit.
Treatment of class I and II lupus nephritis
Patients with class I and II LN generally have a very good
prognosis. The treatment strategy consists of regular
monitoring for disease activity and optimal blood pressure
control. Treatment for Class II LN (mesangial-proliferative
LN) patients with proteinuria \1 g/days is dictated by the
extra-renal clinical manifestations of lupus [43, 44]. Those
with proteinuria [3 g/days are treated with corticosteroids
or calcineurin inhibitors, similar to patients with minimal
change disease. The lowest risk for CKD progression was
found in patients whose systolic blood pressure was
maintained in a range of 110–129 mmHg, especially in
those individuals with proteinuria [1 g/days [45]. An
increase in relative risk for CKD progression at pressures
above 130 mmHg has been noted [45]. These patients do
well with angiotensin-converting enzyme (ACE) inhibitors
or angiotensin receptor blockers (ARB), as these agents not
only help maintain a blood pressure less than
130/80 mmHg, but also reduce proteinuria and may even
prevent the development of biopsy proven glomeru-
lonephritis [46, 47]. As per the eighth Joint National
Commission guidelines, which synthesized data from three
main trials (MDRD, AASK, and REIN 2), the optimal
 Table 2 Randomized controlled trials on therapies for lupus nephritis
Authors Trial Age sample Diagnostic criteria Exclusion criteria Comparison Outcome
(year) type criteria size

Lewis RCTa C16 86 Lupus diagnosed by ARAb Pregnancy Prednisone and cyclophosphamide vs Addition of plasmapheresis did not
et al. criteria Creatinine Prednisone and improve prognosis of patients with
[30] WHO Class III, IV, V based concentration [6 mg/dl cyclophosphamide ? plasmapheresis SLE
on renal biopsy Previous treatment with
plasmapheresis
History of myocardial
Clin Exp Nephrol (2016) 20:1–13

disease
History of malignancy
Peptic ulcer disease and
active liver disease
Chan RCT N/A 42 Lupus diagnosed by ARA Serum creatinine MMFc ? prednisolone vs MMF ? prednisolone has same
et al. criteria concentration [3.4 mg/ Prednisolone ? cyclophosphamide then efficacy as
[31] WHO Class IV based on renal dl changed to AZAd Prednisolone ? cyclophosphamide
biopsy Severe infection or then changed to AZA
cerebral lupus
Poor compliance
Pregnancy
Treatment with
cyclophosphamide
within last 6 months
Treatment with
prednisolone at 0.8 mg/
kg/day for [2 weeks
Houssiau RCT C14 90 Lupus diagnosed by ACRe Take cyclophosphamide High-dose IV cyclophosphamide ? AZA vs No statistical significance between
et al. criteria or AZA during previous Low dose IV cyclophosphamide ? AZA the two modalities; good clinical
[32] WHO Class III, IV, Vc, Vd year results may be possible with just
Renal thrombotic low dose treatment
microangiopathy
Preexisting chronic renal
failure
Pregnancy
Previous malignancy
Diabetes mellitus
Poor compliance
5

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 6

Table 2 continued
Authors Trial Age sample Diagnostic criteria Exclusion criteria Comparison Outcome
(year) type criteria size

123
Yee et al. RCT 16–65 32 Lupus diagnosed by ACR Treatment with Intermittent pulse cyclophosphamide and No significant difference in efficacy
[33] criteria cyclophosphamide or methylprednisolone vs. Oral continuous between two treatment modalities
WHO Class III, IV based on AZA 3 weeks prior cyclophosphamide and prednisolone for tested
renal biopsy Pure mesangial or pure 3 months followed by continuous AZA and
membranous- prednisolone
proliferative
glomerulonephritis on
biopsy
Previous treatment with
cyclophosphamide
for [3 months
Previous malignancy
Non-lupus renal disease
Contreras RCT C18 59 Lupus diagnosed by ARA Creatinine IV cyclophosphamide followed by oral MMF vs. Maintenance with oral AZA or oral
et al. criteria clearance \20 ml/min IV cyclophosphamide followed by oral AZA MMF were more efficacious than
[34] WHO Class III, IV, or Vb Significant infection vs. long-term IV cyclophosphamide long-term IV cyclophosphamide
based on renal biopsy therapy
Pregnancy
[7 doses of IV
cyclophosphamide
Treatment with
AZA [8 weeks
Chan RCT N/A 62 Lupus diagnosed by ARA Serum creatinine MMF vs CTX-AZA as continuous induction- MMF has same efficacy as CTX-
et al. criteria concentration [4.52 mg/ maintenance treatment AZA as continuous induction-
[35] WHO Class IV based on renal dl maintenance treatment
biopsy Severe infection or
cerebral lupus
Treatment with CTX or
MMF within 6 months
prior to study
Treatment with
prednisolone at
doses [0.4 mg/kg per
day for [2 weeks
Clin Exp Nephrol (2016) 20:1–13
 Table 2 continued
Authors Trial Age sample Diagnostic criteria Exclusion criteria Comparison Outcome
(year) type criteria size

Moroni RCT C16 75 Lupus diagnosed by ACR Silent nephritis Cyclosporine vs. AZA in maintenance therapy No significant difference in efficacy
et al. criteria Renal diseases unrelated between two treatment modalities
[36] WHO Class IV, Vc, or Vd to lupus tested
based on renal biopsy Treatment with
cyclosporine or AZA
6 months prior to
Clin Exp Nephrol (2016) 20:1–13

screening visit
Cumulative
cyclophosphamide dose
of [200 mg/kg
-Previous malignancy
Appel RCT 12–75 370 Lupus diagnosed by ACR Insufficient proteinuria MMF vs IV cyclophosphamide as induction MMF was not statistically superior to
et al. criteria Serious infection or illness treatment IV cyclophosphamide as induction
[37] WHO Class III, IV, V based Prohibited concurrent
on renal biopsy medication
Pregnancy
Leukopenia
Renal biopsy not met time
criteria
Houssiau RSTf C14 105 Lupus diagnosed by ACR Treatment with AZA vs MMF as long-term immunosuppressive MMF was not statistically superior to
et al. criteria glucocorticoids in the treatment of LN AZA
[38] WHO Class III, IV, Vc, Vd month prior
based on renal biopsy Treatment with
cyclophosphamide,
AZA, MMF, or
cyclosporin A in
previous year
Non-lupus renal disease
Dooley RCT 12–75 227 Active class III, IV, or V LN N/A Oral MMF vs Oral AZA ? placebo MMF superior to AZA in maintaining
et al. with prior response to oral renal response and in preventing
[39] MMF or IV relapse
cyclophophamide during
induction study
7

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8 Clin Exp Nephrol (2016) 20:1–13

blood pressure goal for all ages with CKD is \140/90 and

Adding rituximab is not superior to

use of ACE inhibitors and ARBs is essential to achieve this
goal, unless a contraindication is present [48–50]. How-

just MMF ? corticosteroids

ever, recent studies have warned against the use of ACE
inhibitors and ARBs in combination due to a higher risk of
complications.

Hydroxychloroquine
Outcome

Antimalarials, such as hydroxychloroquine, have long been

used as a treatment modality for lupus and recent evidence
suggests that they may have a role in the treatment of lupus
Adding rituximab to MMF ? corticosteroids vs
Adding placebo to MMF ? corticosteroids

nephritis. The Hopkins lupus cohort [51], a prospective

database, found that hydroxycholoroquine increases the
chance for complete renal response in conjunction with
mycophenolate mofetil (MMF) therapy for membranous
lupus nephritis. Of patients on hydroxycholoroquine, 64 %
achieved remission within a year compared with only
22 % of those not on hydroxychloroquine (p = 0.036, log-
rank test) [52]. In a Canadian study, hydroxycholoroquine
reduced lupus nephritis flare incidence by 74 %, but did
not reach statistical significance (p = 0.25) [49, 53].
Comparison

Fessler et al. have reported that hydroxychloroquine may

delay or prevent renal damage [52]. All patients with LN
of any class are treated with hydroxychloroquine (maxi-
mum daily dose of 6–6.5 mg/kg ideal body weight) unless
eGFR \ 25 ml/minute/

there is a specific contraindication to the drug. There is

some evidence that hydroxychloroquine may protect
[50 % glomerular

Interstitial fibrosis
Exclusion criteria

against the onset of LN, relapses of LN, and ESRD [54].

Another interesting observation from the Hopkins lupus
sclerosis

1.73 m2

cohort included reduction in thrombosis with hydroxy-

chloroquine usage, particularly for antiphospholipid anti-
body-positive patients [51]. Hydroxychloroquine also has a
favorable impact on lipid profiles [54]. However, it is
supported by renal biopsy

known to be associated with retinal toxicity; thus, patients

Lupus diagnosed by ACR

ISN/RPS Class III or IV

taking Hydroxychloroquine should receive annual eye

exams.
Diagnostic criteria

ANA positivity

Treatment of Class III and IV or proliferative lupus

criteria

nephritis

Proliferative glomerulonephritis (Class III and IV) rep-

American College of Rheumatology

resents the most severe form of lupus nephritis and

sample

American rheumatism association

requires aggressive treatment to prevent progressive loss

size

144

of renal function and to minimize associated morbidity

Randomized-superiority trial
Randomized-controlled trial
criteria

and mortality. Treatment consists of an induction and

16–75

Mycophenolate mofetil
Age

maintenance phase. Partial response to therapy is defined

as a 25 % increase in estimated glomerular filtration rate
Table 2 continued
Trial

RCT
type

(eGFR) from baseline abnormal GFR prior to initiation

Azathioprine

of treatment, a 50 % reduction in urinary proteinuria or

urinary protein creatinine ratio of 0.2–2.0, and a change
Authors

et al.
Rovin
(year)

[21]

from active to inactive urinary sediment. Complete

response is defined as eGFR [90 ml/min/1.73 m2,
b

d
a

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Clin Exp Nephrol (2016) 20:1–13
a [ 50 % reduction in urinary protein-to-creatinine ratio
of \0.2 and inactive urinary sediment [55]. The key
components for both phases include corticosteroids and
immunosuppressive agents. The average duration of
induction phase in most clinical trials has been
3–6 months with varying maintenance phase durations
ranging 2–3 years (MAINTAIN and ALMS trial) [38,
39]. The median time to remission is approximately
10 months [56].
Induction therapy
Induction therapy consists of potent immunosuppressive
treatment regimens to achieve remission. This is indicated
for patients with diffuse or moderate to severe focal pro-
liferative lupus nephritis. The Kidney Disease: Improving
Global Outcomes and the joint European League Against
Rheumatism and European Renal Association-European
Dialysis and Transplant Association (KDIGO, EULAR/
ERA-EDTA) guidelines suggest that induction therapy
should include glucocorticoids and either cyclophos-
phamide or mycophenolate mofetil (MMF) [43, 44, 57].
Within the first 3 months, patients are closely monitored. If
there are signs of disease progression such as worsening
serum creatinine or proteinuria, the immunosuppressive
agent may be changed (cyclophosphamide to MMF or vice
versa).
Glucocorticoid therapy when used alone is not as
effective as combined therapy with an immunomodulator.
A meta-analysis found that cyclophosphamide plus gluco-
corticoids compared to glucocorticoids alone reduced the
risk of renal progression as measured by creatinine dou-
bling, but also increased the risk of ovarian failure in some
trials [58].
There are no set guidelines on oral dosing of steroids but
most studies used the following regimen for induction: in
severe disease, intravenous methylprednisolone
500–1000 mg given over 30 min daily for 3 days was used,
then transitioned to oral prednisone tapered from an initial
dose of 0.5–1 mg/kg to a maintenance level of
5–10 mg/day, as per NIH protocol [59].
Cyclophosphamide may be given as a high-dose regi-
men (NIH protocol) or lower-dose (Euro-lupus protocol).
The higher-dose regimen includes intravenous cyclophos-
phamide 0.5–1 g/m2 monthly for 6–7 months followed by
quarterly administration of the same dose. Alternatively, a
lower-dose regimen, which consists of intravenous
cyclophosphamide 0.5 g/m2 (six biweekly pulses) for
10 weeks followed by azathioprine, has been can be used.
The Euro-Lupus trial found that Caucasian patients with
mild to moderate renal disease (mean serum creatinine of
1.15) had similar 10-year outcomes with the lower-dose
regimen [32].
9
Mycophenolate mofetil (MMF) has been found to be at
least equivalent to cyclophosphamide for induction ther-
apy. The Aspreva Lupus Management Study (ALMS) trial
compared MMF to cyclophosphamide in 370 patients with
lupus nephritis. At 24 weeks, no difference was found
between the groups with the endpoint of reduction in urine
protein-to-creatinine ratio to less than three, improvement
in creatinine or reduction of proteinuria [37]. MMF was
associated with a higher response rate in Black and His-
panic patients, and a lower incidence of ovarian failure and
alopecia [37].
Although the guidelines list that either cyclophos-
phamide or MMF may be used, some evidence suggests
that one particular agent might be a better option depend-
ing on race, disease activity, and patient preference. Black
and Hispanic patients may have higher success in achiev-
ing remission with MMF and may require higher induction
doses than patients of other racial/ethnic groups [37, 60].
Asian patients demonstrated significant intolerance when
given high daily doses of MMF and thus had higher
withdrawal rates in the MMF arm. However, when given
lower doses, these patients had better response rates [61].
In patients with rapidly rising creatinine and/or crescents
on renal biopsy indicative of severe LN, cyclophosphamide
is preferred, as it is one of the few drugs that has been
studied in a randomized control trial and proven to be
effective [62]. Furthermore, it is important for both patient
preference and drug toxicities to be taken into account. For
example, a woman desiring children would want to avoid
cyclophosphamide given its side effect of ovarian toxicity.
Patients on cyclophosphamide should also be monitored for
malignancies, particularly bladder cancer. A yearly Pap
smear test for cervical cancer screening is recommended,
along with periodic urine studies, serum creatinine, and
complete blood counts [63]. For patients on glucocorti-
coids, checking serum and urine glucose levels as well as
cholesterol levels is recommended [63].
Calcineurin inhibitors such as tacrolimus may be used
when patients cannot tolerate standard therapies. In a meta-
analysis performed by Deng et al. in Chinese populations,
several studies revealed that tacrolimus appears to be a
safer, more efficacious alternative to cyclophosphamide
when used in the induction phase of treatment. Tacrolimus
was found to be superior in causing complete remission,
while having a more tolerable side effect profile [64].
Rituximab, an anti-CD20 B-cell agent, has been used in the
past for induction therapy. The LUNAR (Lupus Nephritis
Assessment with Rituximab) trial, a multinational study in
2012, primarily assessed the efficacy of Rituximab when
added to MMF and steroids. However, there was no sta-
tistically significant response with regards to complete
remission [21]. Further studies may be needed to elucidate
Rituximab’s role in induction therapy.
123
10
Multi-targeted Drug Induction Therapy
The multi-targeted drug therapy (MDI) approach, as
demonstrated by a recent trial performed in China,
attempted to target different aspects of inflammation
implicated in LN. The population studied included patients
with biopsy proven LN. Tacrolimus, an inhibitor of T-cell
activation, in addition to MMF, an inhibitor of B-cell
activation, and steroids (these constituted the MDI arm)
were directly compared to cyclophosphamide and steroids.
The study found that at low doses, the MDI group achieved
complete remission within 24 weeks as compared to the
cyclophosphamide group. However, there was an increased
rate of serious adverse effects in the MDI arm. These
adverse effects included pneumonia, varicella zoster
infection, upper respiratory tract infection, skin and soft
tissue infections, epilepsy, septicemia and doubling of
creatinine. Moreover, the efficacy and side effect profile in
people of other ethnicities remains to be determined, as the
study was performed only in Chinese patients [65].
Maintenance therapy
Approximately 50 % of LN patients may experience
relapse after induction therapy, which makes maintenance
therapy essential for patients with severe LN [44].
Cyclophosphamide was previously the treatment of choice,
based on results of the initial NIH trial. It is however
associated with significant adverse events including infer-
tility, alopecia, and bladder malignancy [66].
In 2004, Contreras et al. evaluated patients treated with
induction therapy using cyclophosphamide, followed by
maintenance therapy with intravenous cyclophosphamide,
oral azathioprine or oral mycophenolate. The study enrol-
led fifty-nine patients with lupus nephritis (WHO Class III,
IV) who received induction therapy consisting of a maxi-
mum of 7 monthly boluses of intravenous cyclophos-
phamide plus corticosteroids and subsequently were
randomized to one of three maintenance therapies: quar-
terly intravenous injections of cyclophosphamide, oral
azathioprine (1–3 mg/kg of body weight/day), or oral
mycophenolate mofetil (500–3000 mg/day) for one to
3 years [34]. The results showed that the 72-month event-
free survival rate for the composite end point of death or
chronic renal failure was higher in the MMF and azathio-
prine groups than in the cyclophosphamide group
(p = 0.05 and p = 0.009, respectively). Since then, these
two drugs have often been used in maintenance protocols.
A meta-analysis, comparing azathioprine to MMF for
maintenance therapy showed no significant difference in
mortality or progression to ESRD. MMF was however
found to have a lower rate of renal relapse [67]. For
patients with diffuse proliferative lupus nephritis, a
123
Clin Exp Nephrol (2016) 20:1–13
mycophenolate mofetil and prednisolone combination was
found to be just as effective as a regimen of cyclophos-
phamide and prednisolone, each followed by azathioprine
and prednisolone [31]. Azathioprine is the preferred choice
for women in complete remission who desire to become
pregnant in the future. Low dose prednisone is continued in
patients who are on maintenance therapy, with the goal of
achieving symptomatic control with the lowest possible
dose. Although cyclosporine was found to result in a robust
reduction in proteinuria, creatinine clearance post-treat-
ment was lower when compared to that of patients treated
with cyclophosphamide [67].
Treatment of Class V or membranous lupus
nephritis
Patients with sub-nephrotic proteinuria and pure membra-
nous lupus nephritis have a good prognosis regardless of
treatment options. Pure membranous LN is rare and thus
randomized control trials to evaluate superiority of treat-
ment modalities are limited. No consensus of management
has yet emerged for this group of patients who may not
require any specific therapy beyond renin-angiotensin
system blockade [68]. Patients with membranous LN with
nephrotic range proteinuria do well with use of steroids and
addition of immunosuppression. In one randomized con-
trolled trial, the remission rates were 27 % with prednisone
alone, 60 % with addition of cyclophosphamide and 83 %
with addition of cyclosporine [69]. The response of the
cyclosporine group in contrast to the cyclophosphamide
group was faster in terms of reduction in proteinuria but the
latter group had fewer relapses. Subsequent studies have
also demonstrated the efficacy of oral MMF as compared to
intravenous cyclophosphamide induction therapy. The
remission rates, relapses, and overall clinical courses were
similar with these two agents [70].
Biologic therapies
Biologic therapies have recently gained more momentum
in the treatment of lupus nephritis. The use of rituximab as
an off- label treatment for LN is increasing and while
clinical experience is lacking in the use of Belimumab,
clinical trials have shown favorable response [60, 71].
Biologics may lead to significant changes in the manage-
ment of SLE in the future.
Belimumab
Belimumab is a monoclonal antibody against B-Cell acti-
vating factor/B-lymphocyte stimulator (Blys), a cytokine
that releases survival signals for B cells and is often
overproduced in SLE patients. Inhibition of this cytokine
Clin Exp Nephrol (2016) 20:1–13
results in reduced CD20?B lymphocytes and a shorter life
of plasma cells. Belimumab was found to be effective in
reducing flares, disease severity and proteinuria in SLE
patients [13, 71].
Rituximab
Rituximab is a chimeric monoclonal antibody to CD20. As
mentioned above, Rituximab was not found to be as
effective as other traditional therapies for induction or
maintenance. It may however have a role in the treatment
of patients with refractory disease. A pooled data analysis
of patients with refractory disease showed that Rituximab
was particularly effective in patients with mixed mem-
branous-proliferative lupus nephritis and Class III LN. Of
note, there have been a few reported cases of progressive
multifocal leukoencephalopathy, a fatal demyelinating
disease, with the use of Rituximab [13].
Abatacept and other biologics
Abatacept is a soluble Fc:CTLA-4 fusion protein that
competes with CD28 to prevent T-cell activation. A
phase II/III study with Abatacept plus MMF and corti-
costeroids was terminated prematurely due to inefficacy
[13]. Other trials analyzing the use of biologics in SLE
patients have excluded patients with lupus nephritis.
Newer trials like RING, a European based randomized
controlled trial on Rituximab as a treatment for patients
with refractory LN, are underway [72]. Tabalumab, an
anti-Blys monoclonal antibody, is also being studied in
phase II/III trials [71]. Given that the interferon pathway
may also be involved in the pathogenesis of SLE, a few
studies with anti-interferon agents have been undertaken.
Unfortunately, none have shown clinical efficacy as of
yet [71].
Clinical course and prognosis
The clinical course of patients with LN varies, with up to
60 % of patients developing progressive kidney failure.
Prognosis has improved over the years with the advent of
new therapies. Patients with kidney injury limited to the
renal mesangium have a good prognosis and are less likely
to develop progressive renal failure. Those with minimal
and limited glomerular injury generally have adequate
response to therapy, and less than 5 % of these patients
progress to renal failure [29]. Class III patients may
advance to Class IV disease. Those patients with more
proliferation, necrotizing features on histopathology, or
crescent formation have a worse prognosis. The least
11
favorable outcomes have been noted in patients with dif-
fuse proliferative disease. Improvement in survival
regardless of diagnosis and class has been achieved with
modern immunosuppressive therapies and better supportive
care [29].
Lupus nephritis tends to occur more frequently in
African Americans and overall less favorable prognosis is
also notable within this population. This may relate to
genetic and/or socioeconomic factors. Other factors asso-
ciated with poor outcomes included age, gender, duration
of SLE diagnosis, uncontrolled hypertension, anemia, ele-
vated serum creatinine, high rate of decline in GFR, and
chronic renal scarring [29]. Retrospective studies have
shown that 5-year survival rate of these patients depends on
whether there is membranous involvement only, or if
proliferative lesions are also present. Those with prolifer-
ative lesions in addition to membranous ones had about
20–48 % 10-year survival in one study, while those with
only membranous disease had a 72 % survival [29].
Other factors that may affect clinical course include
adherence to treatment and suboptimal care [72]. Several
interventions have been proposed to improve adherence
such as repeated explanations regarding why each treat-
ment is prescribed, an overall treatment plan outlined from
therapy initiation, and the use of pill counters and aids [72].
Suboptimal care may arise if a multidisciplinary approach
to patient care is not achieved.
Conclusion
Over the past decade, advances in immunosuppressive
therapies have led to substantial improvement in overall
survival rates of patients with lupus nephritis. This review
describes established and new therapies for LN. Table 2
highlights the major trials assessing various therapies
including cyclophosphamide, azathioprine, mycofenolate
mofetil, and dosing regimens.
For all patients with LN, it is crucial to optimize risk
factors such as proteinuria and hypertension with renin-
angiotensin-receptor blockade therapy. When deciding on a
particular therapy, it is important to consider potential
adverse effects such as atherosclerosis, infertility, and bone
disease. Treatment should be individualized based on the
patient’s clinical presentation, biopsy findings, tolerability
and long-term goals. Future studies, some of which are
underway, may help shed light on new and refined thera-
pies for this condition.
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest. No
funding was received.
123
12
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