REVIEWS

Redefining lupus nephritis: clinical

1
Renal Division, Department of
Medicine, Peking University
First Hospital, Institute of
Nephrology, Peking University,
Key Laboratory of Renal
Disease, Ministry of Health
of China, Beijing 100034,
P. R. China.
2
Department of Nephrology,
Peking University International
Hospital, 1 Zhongguancun Life
and Science Street, Changping
District, Beijing 102206,
P. R. China.
3
Department of Pathology and
Laboratory Medicine, Cedars
Sinai Medical Center, Los
Angeles, 90048 California,
USA.
4
Department of Medicine,
David Geffen School of
Medicine at UCLA, 8 Bethany,
Laguna Niguel, 92677
California, USA.
5
Peking-Tsinghua Center for
Life Sciences, 5 Summer
Palace Street, Haidian District,
Beijing 100871, P. R. China.
Correspondence to M.-H.Z.
mhzhao@bjmu.edu.cn
doi:10.1038/nrneph.2017.85
Published online 3 Jul 2017
implications of pathophysiologic
subtypes
Feng Yu1,2, Mark Haas3, Richard Glassock4 and Ming-Hui Zhao1,5
Abstract | Systemic lupus erythematosus (SLE) is associated with a broad spectrum of clinical and
immunologic manifestations, of which lupus nephritis is the most common cause of morbidity
and mortality. The development of nephritis in patients with SLE involves multiple pathogenic
pathways including aberrant apoptosis, autoantibody production, immune complex deposition
and complement activation. The 2003 International Society of Nephrology/Renal Pathology
Society (ISN/RPS) classification system for lupus nephritis was widely accepted with high
intraobserver and interobserver concordance to guide therapeutic strategy and provide
prognostic information. However, this classification system is not based on the underlying disease
pathophysiology. Some additional lesions that contribute to disease presentation, including
glomerular crescents, podocyte injury, tubulointerstitial lesions and vascular injury, should be
recognized. Although outcomes for patients with lupus nephritis have improved over the past
30 years, treatment of this disease remains challenging and is best approached on the basis of
the underlying pathogenesis, which is only partially represented by the various pathological
phenotypes defined by the ISN/RPS classification. Here, we discuss the heterogeneous
mechanisms involved in the pathogenesis of lupus nephritis and how improved understanding
of underlying disease mechanisms might help guide therapeutic strategies.
Systemic lupus erythematosus (SLE) is a chronic auto- on the 2003 International Society of Nephrology/
immune disease that affects multiple organs and tis- Renal Pathology Society (ISN/RPS) classification
sues, of which the development of kidney disease is system1–4 (BOX 1).
the most important predictor of morbidity and mor- Despite the availability of these guidelines, remission
tality. Renal involvement is indicated by the presence is achieved in only 50–70% of patients and 10–20% of
of haematuria, proteinuria or decreased renal func- patients will progress to ESRD within 5 years of diag-
tion, and requires confirmation by renal biopsy. The nosis1–3. These poor outcomes represent an enormous
purpose of renal biopsy is to confirm the diagnosis of challenge to the use of therapeutic strategies based on
lupus nephritis, establish pathologic patterns, activity the current classification system5–9. Moreover, several
and chronicity of renal injury, guide therapeutic strat- clinical trials of immunomodulatory therapies, includ-
egy, and provide prognostic information including the ing trials of mycophenolate mofetil10, ciclosporin11, and
likelihood of response to treatment and of progression rituximab12, failed to demonstrate superiority over con-
to end-stage renal disease (ESRD). A well-established ventional therapies. Although the failure of these trials
histopathologic classification system that is predic- might be in part attributable to the selection of incorrect
tive of therapeutic response and outcomes is therefore end points13, their failure might be also partly attributed
required. Three major guidelines for the management to the molecular heterogeneity and complex nature of
of lupus nephritis exist — the American College of the disease, suggesting that targeted approaches might be
Rheumatology (ACR) guideline, the Kidney Disease: needed to improve therapeutic efficiency in lupus nephri-
Improving Global Outcomes (KDIGO) guideline, tis. In support of this notion, a 2016 study that profiled
and the Joint European League Against Rheumatism/ the blood transcriptome of 158 paediatric patients with
European Renal Association–European Dialysis SLE confirmed a common type I interferon signature
and Transplant Association (EULAR/ERA–EDTA) and identified a plasmablast signature as the most robust
­guideline — all of which base their recommendations biomarkers of disease activity. Importantly, gradual

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Key points
• The main purposes of renal biopsy in patients with systemic lupus erythematosus are
to confirm the diagnosis of lupus nephritis, to assess disease activity and/or chronicity,
guide therapeutic strategy, and provide prognostic information
• Although the 2003 International Society of Nephrology/Renal Pathology Society
(ISN/RPS) lupus nephritis classification system has been widely accepted, some
additional lesions reflect the underlying disease pathogenesis and should be included
or otherwise recognized
• The ISN/RPS classification system is based on histology and not necessarily on the
underlying pathogenesis, which needs to be the focus of treatment
• The presence of glomerular crescents, podocyte injury, tubulointerstitial lesions
and thrombotic microangiopathy, in particular, are indicative of underlying disease
processes and should be considered when assessing patients with lupus nephritis
• The current management of lupus nephritis is based on steroids and non-selective
immunosuppressive drugs; novel agents that specifically interfere with the underlying
pathophysiologic mechanisms of lupus nephritis are needed to improve disease
outcomes
enrichment of neutrophil transcripts was detected dur-
ing the development of active nephritis and distinct sig-
natures in response to treatment were identified based
on different pathological subtypes, enabling stratification
of the patients into seven groups according to disease
activity and the underlying molecular signature14. This
study indicates that the pathologic classification of lupus
nephritis could be improved by incorporating immuno­
pathological and/or molecular markers of disease pro-
cesses with the currently used histological parameters15,16,
a suggestion that is supported by other researchers17,18.
A good association between clinical indices and patho-
logical features is needed to evaluate the treatment
response of patients with lupus nephritis19.
In this Review, we summarize potential approaches
by which the ISN/RPS classification system could be
improved through consideration of underlying disease
processes characterized by the presence of glomerular
crescents, podocyte injury, tubulointerstitial lesions and
vascular injury. Particular emphasis is given to discus-
sion of the potential clinical relevance of histopathologic
findings in predicting disease outcome and in facilitating
the choice of therapeutic interventions.
Classification of lupus nephritis
The value of renal biopsy
Renal biopsy is crucial to the diagnosis and management
of lupus nephritis. The KDIGO, ACR and EULAR/ERA–
EDTA guidelines recommend that a renal biopsy is per-
formed to confirm the diagnosis, assess disease activity
and/or chronicity and guide treatment 1–3. A repeat renal
biopsy should be considered in some circumstances such
as in patients who relapse, or to reconcile discordance
among clinical parameters such as persisting immuno-
logical activity despite complete or partial remission of
proteinuria or renal function3,4,20. In general, renal biopsy
should be considered when a patient with SLE develops
proteinuria (>500 mg per day or >3+ on urine dipstick),
active urine sediments or evidence of renal insufficiency
(defined by an estimated glomerular filtration rate
<60 ml/min/1.73 m2). Some clinical analyses have also
demonstrated histological variants in patients with lupus
nephritis and acute kidney injury (AKI), which might
influence clinical decision making 1–3. For example, a
2011 analysis of a large cohort of patients with lupus
nephritis found evidence of pathological changes — such
as endocapillary proliferative glomerulonephritis, extra-
capillary proliferative glomerulonephritis (also known as
crescentic glomerulonephritis), membranoproliferative
glomerulonephritis, thrombotic microangiopathy and
acute tubular–interstitial nephritis — in renal biopsy
samples from patients with AKI21. More importantly,
the different renal histopathologic injuries associated
closely with clinical implications and long-term out-
comes beyond serum creatinine level, highlighting the
importance of renal biopsy.
The above clinical studies illustrate the value of renal
biopsy in providing insights into disease processes that
are not apparent by clinical or laboratory data alone.
A valuable histopathologic classification system for
lupus nephritis should have certain features: it should
have clear and precise definitions of disease pathology,
have reproducible criteria with low intraobserver and
interobserver variation, and should provide prognostic
information for response to therapy and renal outcomes.
The 2003 ISN/RPS classification
The aim of the 2003 ISN/RPS classification of lupus
nephritis 4 was to accommodate new insights into
pathologic lesions and pathogenesis of lupus nephritis
and eliminate inconsistencies and ambiguities present in
the 1995 WHO classification22. Updates included a new
definition for class I lupus nephritis, an emphasis on the
diagnosis of combinations of membranous and prolif-
erative glomerulonephritis (class III and V, or class IV
and V), the separation of class IV lupus nephritis into
segmental (IV‑S) and global (IV‑G) variants, and clearer
definitions for all classes4 (BOX 1).
Since its publication multiple validation studies have
compared the ISN/RPS classification with the older WHO
classification. One comparative study reported higher
reproducibility using the ISN/RPS classification, but
noted that the interobserver agreement was far from ideal
and that reproducibility of the assessment of activity and
chronicity scores was disappointing 23. Similarly, a 2008
study reported that intraobserver and inter­observer
agreement was higher using the ISN/RPS classification
than the WHO classification, although interobserver
agreement was found to be low for both classification sys-
tems24. Studies have also evaluated the prognostic value
of the 2003 classification system; for instance, one retro-
spective study of long-term outcomes of 60 patients with
lupus nephritis reported good correlation between disease
classification according to the ISN/RPS system and long-
term renal outcomes in terms of predicting response to
therapy, and progression to ESRD and/or death25. Many
other studies since 2005 have further documented the
importance of renal biopsy and the ISN/RPS system in
managing patients with lupus nephritis19,26–32.
Although the ISN/RPS classification is an improve-
ment on previous systems and has been widely accepted
by renal pathologists and clinicians, it relies heavily on
pathology as observed by light microscopy, and not the

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Box 1 | The 2003 ISN/RPS lupus nephritis classification system4
Class I: Minimal mesangial lupus nephritis
• Normal glomeruli by light microscopy, but mesangial immune deposits by
immunofluorescence.
Class II: Mesangial proliferative lupus nephritis
• Purely mesangial hypercellularity of any degree or mesangial matrix expansion by
light microscopy, with mesangial immune deposits.
• A few isolated subepithelial or subendothelial deposits may be visible by
immunofluorescence or electron microscopy, but not by light microscopy.
Class III: Focal lupus nephritis*
• Active or inactive focal, segmental or global endocapillary or extracapillary
glomerulonephritis involving <50% of all glomeruli, typically with focal
subendothelial immune deposits, with or without mesangial alterations.
Class IV: Diffuse lupus nephritis‡
• Active or inactive diffuse, segmental or global endocapillary or extracapillary
glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse
subendothelial immune deposits, with or without mesangial alterations.
• This class is divided into diffuse segmental (IV‑S) lupus nephritis when ≥50% of the
involved glomeruli have segmental lesions, and diffuse global (IV‑G) lupus nephritis
when ≥50% of the involved glomeruli have global lesions. Segmental is defined as a
glomerular lesion that involves less than half of the glomerular tuft. This class includes
cases with diffuse wire loop deposits but with little or no glomerular proliferation.
Class V: Membranous lupus nephritis
• Global or segmental subepithelial immune deposits or their morphologic sequelae by
light microscopy and by immunofluorescence or electron microscopy, with or without
mesangial alterations.
• Class V lupus nephritis may occur in combination with class III or IV in which case both
will be diagnosed.
• Class V lupus nephritis may show advanced sclerosis.
Class VI: Advanced sclerotic lupus nephritis
• ≥90% of glomeruli globally sclerosed without residual activity.
Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and
fibrosis, severity of arteriosclerosis or other vascular lesions. *Indicate the proportion of
glomeruli with active and with sclerotic lesions. ‡Indicate the proportion of glomeruli with
active and with sclerotic lesions, and the proportion of glomeruli with fibrinoid necrosis and/or
cellular crescents. Modified with permission from the International Society of Nephrology ©
Weening, J. J. et al. Kidney Int. 65, 521–530 (2004).
underlying disease pathophysiology. Although small
studies are available, whether the classification system
can accurately predict clinical outcomes and thera-
peutic responses when combined with clinical and
laboratory data has not been thoroughly assessed17.
Prospective, evidence-based validation studies similar
to those used to validate the Oxford MEST system for
IgA ­nephropathy 33–41 are still needed.
Proposed modifications
In 2015, a group of nephropathologists highlighted
some difficulties with the ISN/RPS classification, mostly
relating to uncertainties in the evaluation of particular
disease classes and inconsistencies in the definitions of
Segmental lesions histologic parameters16. The researchers also suggested
A lesion that involves less than ways in which the classification could be improved, in
half the glomerular tuft. particular, by including thrombotic microangiopathy
and glomerular crescents in the classification system
Global lesions
A glomerular lesion that affects
because these lesions might adversely affect renal out-
more than 50% of the comes16. Other researchers have suggested incorporat-
glomerular tuft. ing components of the complement system, such as C1q,
C4d, C3 and the membrane attack complex, in the classi-
fication17,18, given evidence for the involvement of com-
plement in disease pathogenesis. Here, we outline some
of the key issues with the current classification system
and suggest additional lesions that should be considered
in any new classification system of lupus nephritis.
Cut-off thresholds for segmental versus global d ­ iffuse
nephritis. The ISN/RPS classification divides class IV
lupus nephritis into IV‑S and IV‑G subclasses, depend-
ing on whether the glomerular lesions are primarily
segmental or global4. This subclassification of class IV
lupus nephritis was initially proposed on the basis of
findings showing that diffuse segmental lesions had
more vasculitic–like features than global lesions and
were associated with a worse renal prognosis42. However,
subsequent validation studies that have compared fea-
tures of IV‑S with IV‑G have failed to show statistically
significant differences in renal outcomes between the
two subclasses24,25,43–46, a finding supported by a 2012
­meta-analysis of eight studies47.
The subclassification of ISN/RPS class IV nephritis,
which includes all biopsy samples with ≥50% glomeru-
lar involvement, into IV‑S and IV‑G lesions differs from
the original 1982 WHO classification of lupus nephritis,
which classified biopsy samples according to the type of
lesion: those with severe segmental glomerulonephri-
tis with ≥50% glomerular involvement were classed as
WHO class III ≥50%, and those with diffuse global glo-
merulonephritis were classed as WHO class IV48. A 2008
study in which biopsy samples with WHO class IV or
class III >50% lupus nephritis were reclassified accord-
ing to ISN/RPS criteria led to the reclassification of 39
WHO class IV samples as ISN/RPS class IV-G46. Of the
44 samples originally classified as WHO class III >50%,
22 were reclassified as ISN/RPS IV‑S. The remaining 22
were considered to be ISN/RPS class IV‑G lupus nephri-
tis, but were categorized separately as class IV‑query
(IV‑Q). Of the 61 patients with class IV‑G, renal sur-
vival was worse for those with class IV‑Q (that is, those
who had been reclassified from the WHO class III >50%
category) than for those originally classified as WHO
class IV (33% versus 77% at 10 years, P = 0.001). 10‑year
renal survival was almost twice as high for patients in
class IV‑S than for those with class IV‑Q, but did not quite
reach statistical significance (62% versus 33%, P = 0.057).
The researchers concluded that although the ISN/RPS
IV‑S and IV‑G categories were created to be analogous
to severe segmental and diffuse glomerulonephritis in
the WHO classification and are considered to be equiva-
lent by some pathologists, clearly they are not. Grouping
patients who were originally classified as having WHO
class III >50% (that is, those with IV‑Q) together with
those with the best prognosis (WHO class IV) within
subclass IV‑G, obscures prognostic and pathogenic dif-
ferences, and explains the lack of difference in outcomes
between ISN/RPS IV‑S and IV‑G lesions in the studies
mentioned above.
The threshold of 50% glomerular involvement to
define classes III and IV and the use of segmental and
global lesions to subdivide class IV lupus nephritis in the

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Pauci-immune
A pattern associated with
minimal evidence of staining
for immunoglobulins on
glomeruli by
immunofluorescence.
ISN/RPS system were predominantly selected to bring
the classification in line with traditional pathology ter-
minology, rather than based on actual data relating to
the clinical relevance of these features; however, some
studies published since publication of the 2003 ISN/RPS
classification support the notion that pathological dif-
ferences exist between IV‑G and IV‑S lesions. A 2005
study demonstrated that class IV‑S lesions had more glo-
merular fibrinoid necrosis and fewer immune deposits
than IV‑G lesions, whereas IV‑G lesions behaved as a
typical immune complex-mediated glomerulonephri-
tis, suggesting pathogenic differences44. A study of auto­
antibodies supports this hypothesis. We demonstrated
a higher prevalence of anti-neutrophil cytoplasmic
antibodies (ANCA) in sera of patients with class IV‑S
lupus nephritis than in those with class IV‑G nephri-
tis and a higher prevalence of anti‑C1q IgG1 and IgG3
subclasses in sera of patients with class IV‑G nephri-
tis45. Together, these data suggest that some forms of
lupus nephritis might resemble ANCA-associated
­ auci-­i mmune necrotizing and crescentic glomeru-
p ease or focal segmental glomerulosclerosis (FSGS), and
lonephritis (as is discussed in further detail below).
However, ­studies27,43,44 have also shown that class IV‑S
and IV‑G lupus nephritis can transform between each
other, potentially challenging the concept that different
pathogenic mechanisms underlie the two subclasses.
Re‑evaluation of the ISN/RPS classification should con-
sider a more evidence-based approach to define cut-off
thresholds for focal versus diffuse lesions as well as the
pathophysiological and clinical relevance of segmental
versus global forms of lupus nephritis.
Crescentic lupus nephritis in class IV‑G. Rapidly pro-
gressive glomerulonephritis (RPGN) is characterized
by pathological features of crescentic glomerulonephri-
tis and is a severe clinical syndrome associated with
progressive loss of renal function. Crescents can be
observed in association with a number of different renal
pathologies, and are fairly common in biopsy samples
from patients with lupus nephritis49. In one cohort of 62
patients with RPGN and biopsy-proven crescentic glo-
merulonephritis, 32 patients (51.6%) had lupus nephri-
tis50. The clinical relevance of these crescents is, however,
unclear as no studies have examined the clinical rele-
vance of extensive (or true) crescentic lupus nephritis
(which we define as the presence of crescents in ≥50%
of glomeruli). In a cohort of 152 Chinese patients with
class  IV‑G lupus nephritis, we found that patients
with extensive crescents (affecting ≥50% of glomeruli)
have worse outcomes than those of other patients with
class IV‑G lupus nephritis51.
Although biopsy samples with true crescentic glo-
merulonephritis are classified as diffuse class IV lupus
nephritis according to the ISN/RPS schema, in our histo-
pathological evaluations51, we found that biopsy samples
with crescentic IV‑G lesions have significantly higher
levels of interstitial inflammation, interstitial fibrosis and
necrosis than IV‑G biopsy samples without crescentic
glomerulonephritis51. More interestingly, we identi-
fied lower levels of IgG, IgA, IgM, C3, C1q and fibrin
in crescentic biopsy samples than in non-crescentic
biopsy samples, suggesting further similarities between
crescentic IV‑G samples and ANCA vasculitis. These
findings suggest that differences in underlying patho-
genic mechanisms and disease outcomes might exist
within the same subclass of lupus nephritis, and leads
us to recommend that the presence of true crescentic
glomerulonephritis (defined as the presence of crescents
in ≥50% of glomeruli) is included as part of a new lupus
nephritis classification system (FIG. 1).
Podocyte injury. Renal biopsy samples from patients
with lupus nephritis can demonstrate injury to nearly
any cell type, including the podocyte. Evidence for the
clinical relevance of podocyte injury comes from several
studies that have described patients with lupus nephritis,
nephrotic-range proteinuria and extensive effacement of
podocyte foot processes, without evidence of immune
complex deposition in peripheral glomerular capillar-
ies or endocapillary proliferation52,53. Morphologically,
these podocyte lesions resemble minimal change dis-
researchers involved in these studies have proposed
using the term ‘lupus podocytopathy’ to describe this
entity 54–56. A retrospective study of 19 patients with col-
lapsing glomerulopathy and SLE or SLE-like disease
reported massive proteinuria in 95% of patients; seg-
mental and/or global collapsing glomerulopathy was
seen in 11–77% of glomeruli, and extensive foot pro-
cess effacement was seen in 82% of patients. Seven of
13 patients with follow‑up data progressed to ESRD57.
A large Chinese study of 3,750 biopsy samples from
patients with lupus nephritis identified 50 cases (1.33%)
of lupus podocytopathy, including 13 cases of minimal
change disease, 28 instances with evidence of mesangial
proliferation, and nine cases of FSGS58. Extensive foot
process effacement was evident in all 50 biopsy sam-
ples and electron-dense deposits present exclusively in
mesangial cells were evident in 47 biopsy samples. All
50 patients presented with nephrotic syndrome, and
34% had AKI. Most notably, patients with FSGS had a
higher risk of AKI and severe tubulointerstitial injury
and a lower remission rate than patients with minimal
change disease or mesangial proliferation, although
no patient died or developed ESRD over a median fol-
low‑up of 62 months. On the basis of the differences in
AKI incidence, severity of tubular injury and response
to treatment, the researchers proposed that lupus podo­
cytopathy is divided into two different subtypes: m­ inimal
change/mesangial proliferation and FSGS58.
A 2014 study 59 of renal biopsy samples from patients
with lupus nephritis and proteinuria found that
immuno­histochemical staining for podocyte markers
was generally preserved in patients with membranous
(class V) lupus nephritis. By contrast, <10% of prolifer-
ative forms of lupus nephritis (class III or IV) showed
preserved expression of podocyte markers, suggesting
the presence of structural podocyte damage in prolif-
erative forms of lupus nephritis. This loss of podocyte
integrity in patients with proliferative forms of lupus
nephritis might account for the worse prognosis of
these patients compared to those with membranous

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lupus nephritis, despite similar levels of proteinuria, at
least in the patients in this cohort. Our study measured
foot process width (FPW) to assess the podocyte foot
process effacement and studied correlations between
podocyte damage and clinico-pathological parameters
in 202 Chinese patients with lupus nephritis. FPW cor-
related with proteinuria, and a threshold FPW was iden-
tified that could differentiate nephrotic proteinuria from
non-nephrotic proteinuria60. On the basis of these stud-
ies, we suggest that the presence of lupus podocytopathy,

a b Podocyte injury

Crescentric
glomerulonephritis

c Mesangial hypercellularity

Podocyte

Mesangial
cell

d Diffuse lupus
Endothelial nephritis
cell

Parietal Bowman
epithelial capsule IV-G IV-S
cell

e Vascular lesions

Blood
vessel

Blood clot Plaque ICDs

Plaque
f Tubulointerstital ICDs Interstitial Tubulitis Arteriosclerosis TMA
lesions inflammation

T cell

Macrophage

Figure 1 | Pathological features of lupus nephritis subtypes. a | The
proliferation of extracapillary epithelial cells and infiltration of inflammatory
cells leads to the formation of cellular crescents. Periodic acid–silver
methenamine staining (PASM) ×400. b | Podocyte injury and foot process
effacement can also occur in lupus nephritis. Original magnification of
electron microscope image ×6,000. c | Mesangial hypercellularity is defined
by the proliferation of mesangial cells, matrix expansion and mesangial
deposition of immune complexes. Periodic acid–Schiff (PAS) staining ×400.
d | Diffuse (class IV) lupus nephritis can be subsclassified into segmental
(IV‑S) and global (IV‑G) subclasses. Class IV‑S exhibits segmental fibrinoid
necrosis with segmental endocapillary hypercellularity (Masson trichrome
staining ×400). Class IV‑G exhibits global endocapillary and mesangial
hypercellularity with infiltration of inflammatory cellsReviews
Nature (PAS staining ×400).
| Nephrology
e | Vascular lesions include the presence of immune complex deposits (ICDs)
in the vasculature, demonstrated by granular staining for IgG along
arteriolar walls (immunofluorescence ×400), arteriosclerosis characterized
by arterial intimal fibrosis (PASM staining ×400), and thrombotic
microangiopathy (TMA) with arteriolar thrombi and swelling of endothelial
cells (PASM staining ×400). f | Tubulointerstitial lesions include ICDs in the
tubular basement membrane demonstrated by granular staining for IgG
(immunofluorescence ×400), interstitial inflammation with severe interstitial
infiltration of mononuclear inflammatory cells (haematoxylin and eosin
staining ×400), and tubulitis with infiltration of lymphocytes between
tubular epithelial cells (PAS staining ×400).

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Renal flares
Defined by an increase in urine
sediment, protein excretion,
and serum creatinine value
from baseline.
defined by the presence of nephrotic-range protein­uria
and podocyte lesions, might represent an extreme form
of podocyte damage. We propose that the degree of
podocyte injury in different types of lupus nephritis
should be given more attention (FIG. 1), as the presence
of specific injuries might have t­ herapeutic implications.
Tubulointerstitial lesions. The ISN/RPS classification
focuses primarily on glomerular pathology, although it
indicates that the biopsy report should include a descrip-
tion of tubulointerstitial injuries. An increasing body
of evidence, however, suggests that the importance of
tubulo­interstitial damage requires greater emphasis than
is given in the current classification. We investigated the
impact of tubulointerstitial damage in a multicentre
cohort of 313 lupus nephritis patients from North China,
and found that glomerular and tubulointerstitial lesions
do not always coexist, and that tubulointerstitial inflam-
mation, tubular atrophy, and interstitial fibrosis were
independent risk factors for renal outcomes61. In another
cohort of 68 patients from the USA, Hsieh et al. found
that 72% of biopsy samples had evidence of moderate or
severe tubulointerstitial inflammation62. The research-
ers found that severity of tubulointerstitial inflamma-
tion, but not severity of glomerular injury, identified
patients at greatest risk of ESRD. Similar results have
been reported by several other studies63–67. Hsieh et al.
also suggested that patients with lupus nephritis and
tubulointerstitial inflammation should receive inten-
sive therapeutic intervention62. To this end, a 2013
cohort study of 73 patients with lupus nephritis iden-
tified a correlation between interstitial inflammation at
repeat biopsy and renal survival (P = 0.005), despite the
absence of a correlation between interstitial inflamma-
tion at the baseline biopsy and worsening of renal func-
tion (P = 0.17)63. Furthermore, resolution of interstitial
inflammation in lupus nephritis as evident on the repeat
biopsy correlated with a favourable outcome in patients
with interstitial inflammation at baseline (P = 0.047).
Thus, thorough assessment of tubulointerstitial dam-
age provides information about disease prognosis and
should be included in the lupus nephritis classification
system (FIG. 1).
Renal vascular lesions. The ISN/RPS classification
requests that pathologists indicate the severity of arterio­
sclerosis or other vascular lesions, but overall pays very
little attention to vascular lesions, although these are
common in biopsy samples from patients with lupus
nephritis68. Two studies from 2012 and 2013 showed
that adding an assessment of vascular damage to the
ISN/RPS classification increased its prognostic value69,70.
At least five renal vascular lesions are commonly
observed in biopsy samples from patients with lupus
nephritis: vascular immune complex deposits (ICDs),
arteriosclerosis, thrombotic microangiopathy (TMA),
non-inflammatory necrotizing vasculopathy and true
renal vasculitis68 (FIG. 1). In a cohort of 341 patients with
stable lupus nephritis, we found renal vascular lesions
in 81.8% of samples, including vascular ICDs (74.3%),
arteriosclerosis (24.0%), TMA (17.6%), necrotizing
vasculopathy (3.8%), and true renal vasculitis (0.6%);
37.6% of the patients presented with more than two
types of vascular lesions69. Patients with TMA had the
poorest renal outcome; surprisingly, those with purely
vascular ICDs (that is, with no other vascular lesion)
had the second-to‑worst outcomes, although vascular
ICDs are traditionally thought to be a benign pheno-
type69. A series of other studies indicate that renal vas-
cular lesions are closely associated with clinical disease
activity and renal outcomes, and that renal TMA is an
independent risk factor for long-term renal outcomes
in patients with lupus nephritis69,71–74. The presence of
TMA lesions in renal biopsy samples from patients with
lupus nephritis might not always be associated with
haematological features of microangiopathy, such as
haemolytic anaemia, schistocytosis and thrombocyto-
paenia). Thus, we propose that concise descriptions and
grades of different renal vascular lesions are added to the
classification system.
In another study of 79 patients with biopsy-proven
lupus nephritis, we found that 50 (63.3%) had arterio-
sclerosis lesions on renal biopsy whereas 29 patients had
no evidence of vascular changes75. Patients with arterio-
sclerosis presented with more severe echocardiographic
indices, including larger left atrial diameter, left ven-
tricular end-diastolic diameter and interventricular sep-
tum thickness, than patients without vascular changes,
highlighting the clinical relevance of vascular lesions75.
Disease pathogenesis and treatment
Despite the use of histopathology to guide therapeutic
decisions, the morbidity and mortality of lupus nephritis
remains high. The current approach to the management
of lupus nephritis is based on steroids and other non-
specific immunosuppressive drugs. Dysregulation of
the immune system is fundamental to the pathogenesis
of lupus nephritis, and targeting multiple aspects of the
immune response through the combined use of multiple
immunosuppressants (multitarget therapy) proved supe-
rior to a standard regimen of steroids and cyclophos-
phamide (intravenous or oral) as induction therapy for
lupus nephritis in a 2015 Chinese study 76. Nonselective
immuno­suppressants are, however, associated with
potentially life-threatening complications including an
increased risk of infection. In addition, they are often
associated with incomplete renal remission and a high
rate of renal flares, which might be more prominent in
patients with features such as vasculopathy, crescentic
glomerulonephritis, and tubulointerstitial lesions1–3.
Thus, treatment of lupus nephritis remains a challenge
and we propose that it should target the pathogenesis
of the disease, as determined by the assessment of the
histopathological disease phenotypes.
Novel drugs that interfere specifically with the patho-
genic mechanisms of lupus nephritis, with fewer adverse
effects and higher efficacy than nonspecific immuno-
suppressive agents, are needed. Here, we briefly dis-
cuss traditional therapeutic approaches guided by the
ISN/RPS classification system, and how consideration
of additional lesions might facilitate the identification of
more targeted therapies77–83.

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Tertiary lymphoid organs Current therapeutic approaches of these three guidelines, the general recommendations
Highly organized lymph As mentioned earlier, the three major guidelines, are outlined below along with brief discussion of the
node-like structures. ACR, KDIGO and EULAR/ERA–EDTA1–3, base their underlying pathogenesis of the different subtypes.
recommendations primarily on the underlying histo-
logic lesions as defined by the ISN/RPS classification. Class I and Class II lupus nephritis. Class I and Class II
Although some differences exist in the recommendations lupus nephritis result from immune complexes that
form within the mesangium by binding of antibodies to
Immunostimulatory autoantigens or following the release of antigens from
Dendritic cell nucleic acids mesangial cells84.
BAFF
The deposition of immune complexes in the mesan-
BAFF-R CD40 CD40L gium and expansion of the mesangial matrix do not
usually cause irreversible glomerulosclerosis, possibly
CD19 MHC class II IL-23 owing to the regenerative capacity of mesangial cells84.
B cell T cell TH17 Thus, Class I and Class II lupus nephritis might imply
TCR IL-17 a more favourable prognosis than other classes of lupus
IL-6
B7 CD28 nephritis, and aggressive immunosuppressive therapy is
CTLA4
CD20 not indicated unless the proteinuria is >3 g per day or
CD22
HMGB1 extrarenal clinical manifestations are prominent.
Plasma Macrophage histones Treg
cell Class III and IV lupus nephritis. Class III and Class IV
Immune Neutrophil lupus nephritis result from the deposition of immune
Autoantibodies complexes
complexes in the subendothelial space of the glomeru-
Autoantigen- lar capillaries, which causes endothelial cell activation
Autoantigens TLR specific T cell via the same complement Fc receptor and nucleic acid
Endothelial cell sensing mechanisms that operate in mesangial cells
GBM (FIG. 2). The development of tertiary lymphoid organs in
the tubulointerstitium leads to clonal expansion and
ongoing somatic hypermutation of B cells and plasma
cells that can lead to intrarenal autoantibody production,
Podocyte C4d
TH17 local inflammation, and tissue pathology, implying that
Complement B cell-targeted therapies with heightened tissue penetra-
TNF tion might be beneficial for patients with class III and IV
Epithelial cell IFNα lupus nephritis85,86.
The recommended therapy for class III and IV lupus
nephritis includes a sequence of induction and main­ten­
Interstitial
ance phases. Induction therapy usually involves a combi-
endothelial cell nation of high-dose parenteral and oral corticosteroids
with either cyclophosphamide (oral or intravenous) or
Antiphospholipid
mycophenolate mofetil (MMF), whereas maintenance
Tubular
Anti-dsDNA epithelial cell antibodies therapy involves azathioprine or MMF and low-dose oral
antibodies
corticosteroids. Studies have reported average remission
BCL-2 T cell (complete and partial) rates of nearly 70% after 6 months
Blood vessel initial therapy 10,87,88, but higher remission rates can be
achieved with more prolonged treatment.
Figure 2 | Cell-mediated disease mechanisms of lupus nephritis. The sensing of A 2012 systematic review found that MMF in
Nature Reviews
immunostimulatory nucleic acids by dendritic cells drives B lymphocyte and | Nephrology
combination with corticosteroids was as effective as
T lymphocyte activation and the production of autoantibodies and autoantigen-
specific T cells, leading to glomerular endothelium, podocyte, tubulointerstitial and cyclophosphamide plus corticosteroids in achieving
vascular injury. Specific leukocyte subsets, including IL‑17‑producing T helper type 17 remission in patients with proliferative lupus nephritis.
(TH17) cells, drive inflammation and contribute to renal immunopathology. B‑cell- However, these standard treatments are all associated
activating factor (BAFF) might increase the generation of new autoreactive B cells, with considerable adverse effects, therapy failure and
inhibitB cell apoptosis and stimulate the differentiation of B cells into immunoglobulin- relapse, highlighting the need for more effective, less
producing plasma cells. Infiltrating leukocytes might also provide a source of nuclear toxic options. Interest is growing in the potential use
antigens and cytokines, such as interferon (IFN) α, tumour necrosis factor (TNF), IL‑1 and of calcineurin inhibitors (CNIs) in severe class III and
IL‑6. High mobility group box 1 (HMGB1), biglycan and histones released from immune IV lupus nephritis1–3. A 2015 meta-analysis reported
cells can bind Toll-like receptors (TLRs) expressed by endothelial cells, leading to an that tacrolimus was more effective than cyclophospha-
inflammatory response. Inaddition, anti-double-stranded DNA (anti-dsDNA) antibodies
mide at inducing complete remission in patients with
can induce fibronectin secretion in proximal renal tubular epithelial cells, leading to
TGFβ activation and collagen synthesis. Activation of the apoptosis regulator BCL‑2 class III and IV lupus nephritis, but was not more effec-
might also contribute to the development of tubulointerstital inflammation, whereas tive than MMF89. However, randomized clinical trials of
antiphospholipid antibody-induced thrombosis might contribute to the development of tacrolimus in lupus nephritis have so far been small90,91.
interstitial vascular inflammation. GBM, glomerular basement membrane; TCR, T‑cell Extended follow‑­­up of the CYCLOFA-LUNE trial
receptor; Treg, regulatory T cell. (median 7.7 years) indicated that the CNI ciclosporin

NATURE REVIEWS | NEPHROLOGY VOLUME 13 | AUGUST 2017 | 489

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with regard to the use of CNIs in patients with lupus

Tabalumab BAFF
nephritis, especially in those with renal vascular lesions
such as TMA, which has been attributed to the use of
Belimumab BAFF-R CD40 CD40L drugs such as CNIs. Large-scale, multicentre clinical
Nonselective immunosuppressants

CD19 MHC class II trials are needed to further confirm the safety and effi-
cacy of CNIs in lupus nephritis: the ongoing AURA‑LV
B cell T cell
TCR study 92 will hopefully provide insights into the safety and
efficacy of the new CNI, voclosporin in patients with
B7 CD28 class III and IV lupus nephritis93.
CD20 CD22 CTLA4
IL-23 Of note, and as discussed in further detail below,
lupus nephritis remission is largely defined on the basis
Rituximab Epratuzumab Abatacept Anti-IL-23 of a decline in proteinuria, and all CNIs act directly on
Plasma cell IL-6 podocytes to reduce proteinuria independent of their
Autoantibodies Immune complexes immunosuppressive effects2 (FIG. 3). Thus, whether the
Sirukumab
disease remissions observed with CNI therapy result
Autoantigens from true remission of the immunological disease pro-
Endothelial cell cesses or are the result of the antiproteinuric effects of
GBM CNIs is not clear. Repeat renal biopsies are needed to
make this distinction.
Podocyte
Class V lupus nephritis. Class V lupus nephritis (also
C4d IL-17 known as membranous lupus nephritis) is caused by
TH17
Eculizumab/ the deposition of immune complexes in the subepithe-
CNIs

Neutrophil
CCX-168 lial compartment of the glomerular tuft, which leads to
Complement
Macrophage
complement activation and ultimately podocyte injury 94
Infliximab TNF (FIG. 2). Patients with class V lupus nephritis are usually
Autoantigen- treated with antiproteinuric and antihypertensive med-
Anti-IFN-γ IFNα specific T cell ications such as renin–angiotensin system blockers,
and can receive corticosteroids and immunosuppres-
sants as required depending on the presence of persis-
Epithelial cell tent nephrotic proteinuria or extrarenal manifestations
T cell BCL-2 ABT-199
of SLE.
As noted above, CNIs can reduce proteinuria through
Figure 3 | Therapeutic targets in systemic lupus erythematosus Nature(SLE)
Reviews Nephrology
and |lupus direct actions on podocytes. CNIs inhibit dephosphoryl-
nephritis. Greater understanding of the pathogenic processes underlying lupus nephritis ation and degradation of the actin-associated podocyte
has led to the identification of new therapeutic targets. B cells have a critical role in the
protein, synaptopodin, and thus help to stabilize the
pathogenesis of SLE, and B‑cell depletion therapy therefore remains an attractive
therapeutic option. The anti‑CD20 antibody, rituximab, can deplete autoreactive
podocyte actin cytoskeleton. Preliminary data indi-
B cells and thereby attenuate the production of autoantibodies involved in disease cate that combination CNI and corticosteroid therapy
manifestations. The B‑cell-activating factor (BAFF)-neutralizing antibody, belimumab, is effective in the treatment of class V lupus nephri-
was shown to reduce renal flares and proteinuria in patients with SLE. Other promising tis, especially in reducing proteinuria89,94–97; however,
B cell-depleting monoclonal antibodies, such as tabalumab and epratuzumab, require the initiation and duration of CNI therapy remains
further testing. Abatacept is a co-stimulatory inhibitor that targets B7‑1 (CD80) on the a matter of debate, as relapses are very common once
surface of dendritic cells or B cells, and blocks co-stimulation of CD28 on T cells. CNIs are stopped2. Moreover, CNIs are associated with
Inhibitors of the complement system, such as eculizumab and CCX‑168 could have an increased risk of TMA, indicating that alternative
therapeutic value in patients with concurrent thrombotic microangiopathy or ­therapeutic approaches are required.
anti-neutrophil cytoplasmic antibody-associated vasculitis. Calcineurin inhibitors (CNIs)
have immune modulatory effects but also direct effects on podocytes, and might be
useful in patients with lupus-associated podocyte injury. Inhibition of the apoptosis
Class VI lupus nephritis. The development of sclerotic
regulator BCL‑2 prevented the development of tubulointerstital inflammation in a mouse lesions in lupus nephritis results mainly from insuffi-
model of lupus nephritis. IL‑23 activation might have a role in the development of cient cellular regeneration following the injury and loss
glomerular crescents, suggesting that anti‑IL‑23 antibodies might be beneficial. Other of epithelial cells98, and leads to irreversible glomerulo­
promising therapies that need further exploration include infliximab, which targets the sclerosis and nephron loss. Vascular rarefaction, tubulo­
inflammatory tumour necrosis factor (TNF), sirukumab, which targets inflammatory IL‑6, interstitial ischaemia, and inflammation all contribute
and monoclonal antibodies to interferon (IFN). GBM, glomerular basement membrane; to the progression of renal fibrosis and sclerosis, which
TH17, T helper type 17 cell. is usually associated with a progressive decline in glo-
merular filtration rate and ultimately the development
of ESRD.
achieved similar results to those achieved with cyclo- Patients with class VI lupus nephritis should be
phosphamide in patients with class III and IV lupus treated with renin–angiotensin system blockers.
nephritis11. Although these small trials did not find any Corticosteroids and immunosuppressive agents should
Vascular rarefaction obvious evidence of acute or chronic nephrotoxicity be used only as dictated by the presence of extrarenal
Loss of capillaries. with use of tacrolimus or ciclosporin, concerns still exist manifestations.

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Perinuclear-ANCA
A category of ANCA originally
described on the basis of their
immunofluorescence patterns
around the nucleus.
In situ adaptive immunity
A process in which infiltrate
organizes into well-
circumscribed aggregates of
B cells and T cells (in germinal
centres). These germinal
centres contain follicular
dendritic cells and enable
intrarenal B cells to undergo
clonal expansion and somatic
hypermutation.
Plasmablast foci
Plasmablast aggregates in
an organ.
NATURE REVIEWS | NEPHROLOGY VOLUME 13 | AUGUST 2017 | 491
REVIEWS
Treatments guided by additional lesions nephritis and severe podocyte effacement, we found that
As described above, the presence of features beyond those who received CNIs had better remission rates and
those included in the current classification system of long-term renal outcomes than those treated with other
lupus nephritis — including the presence of glomerular regimens, suggesting that therapies that facilitate podo-
crescents, podocyte injury, vasculopathy and tubulo­ cyte stability might be beneficial in a subgroup of patients
interstitial changes — provide insights into the under­ with lupus nephritis60 (FIGS 3,4).
lying pathogenic mechanisms of lupus nephritis and
might aid the identification of new therapeutic targets. Tubulointerstitial lesions. The mechanisms underlying
Here we discuss the underlying pathogenic mechan­ the development of tubulointerstitial lesions in lupus
isms of each of these lesions and how they might be nephritis remain unclear, and thus no specific treat-
targeted therapeutically. ment options exist. Severe tubulointerstitial inflamma-
tion is associated with in situ adaptive immunity and the
Crescentic lupus nephritis. The mechanisms that drive development of tertiary lymphoid organ–like structures
the formation of crescents in lupus nephritis are not with aggregates of T cells and B cells, plasmablast foci,
fully understood. A 2009 study showed that depletion and germinal centres110. Vimentin, an antigenic feature
of immature invariant natural killer T cells accentuated of inflammation, has been identified as a dominant
disease severity in a model of crescentic glomerulo­ autoantigen that drives clonal B-cell selection in lupus
nephritis99. Thus, targeting CX3CL1/CX3CR1 pathway, tubulointerstitial inflammation, suggesting that vimen-
which regulates the activation of invariant natural killer tin might represent a therapeutic target for tubulointer-
T cells, might represent a promising treatment approach stitial lesions in lupus nephritis111. Anti-double-stranded
with fewer adverse effects than general immunosuppres- DNA (anti-dsDNA) antibodies can induce fibronectin
sive therapies (FIG. 3). Animal models studies have also secretion in proximal renal tubular epithelial cells, lead-
demonstrated that the IL‑23/IL‑17 pathway contributes ing to TGFβ activation and collagen synthesis, again
to renal injury in experimental glomerulonephritis100; highlighting potential therapeutic targets112. Thus, explo-
thus, blocking IL‑23 production and/or the subsequent rations into the pathogenesis of tubulointerstitial lesions
recruitment of IL‑17A‑producing effector γδT cell-­ in lupus nephritis will likely identify targeted therapeutic
receptor-expressing CD3+CD4−CD8− NK1.1 T cells, interventions for future study 113.
which are thought to have a role in crescent formation, This point is illustrated by a study that used novel
might also prove beneficial in limiting glomerular dam- computational approaches to quantify the expression
age in part through limiting the recruitment of myeloid of apoptosis regulators in infiltrating lymphocytes in
cells. Cell lineage-tracing studies indicate that podocytes biopsy samples from patients with lupus nephritis and
and parietal epithelial cells also participate in crescent tubulointerstital inflammation. The apoptosis regulator,
formation101,102. BCL‑2, was frequently expressed in these biopsy sam-
Importantly, in one study of 10 patients with ples, indicating a role for dysregulated apoptosis in the
lupus nephritis and glomerular crescents, all patients immune response. Moreover, treatment of NZB/WF1
were posi­t ive for serum ANCA and five had anti-­ lupus nephritis mice with a selective oral inhibitor of
myeloperoxidase (MPO) antibodies103. Similarly, another BCL‑2 prevented the development of tubulointerstitial
study reported that 10 of 33 Chinese patients with lupus inflammation114.
nephritis and crescents in ≥50% glomeruli were ANCA-
positive and seven had MPO-ANCA51. In fact, one study Renal vascular lesions. Vascular lesions are a common
reported a correlation between the serum ANCA sta- feature of SLE, and renal vasculopathy might repre-
tus and the presence of crescents in patients with lupus sent an extreme form of such lesions. Key pathogenic
nephritis104, and others have reported an association mechanisms include endothelial cell activation and
between atypical perinuclear ANCA, such as anti-cathepsin dysfunction, and dysregulation of the immune system,
G antibodies, and the development of crescentic lupus particularly through immune complex-induced vascular
nephritis105,106. These findings provide strong evidence inflammation and antiphospholipid antibody-induced
for a role of ANCA in crescentic lupus nephritis, and thrombosis74,115 (FIG. 2). In addition to antiphospholipid
suggest that therapeutic approaches that are used to antibodies, renal TMA in lupus nephritis can be caused
treat vasculitis, including intensive plasmapheresis and by thrombotic thrombocytopenic purpura, malignant
the new anti‑C5aR antibody, should be assessed in this hypertension, pregnancy, scleroderma or drugs.
subgroup of patients51,103,107,108 (FIGS 3,4). Interestingly, studies have demonstrated a strong
relationship between the intensity of glomerular C4d
Podocyte injury. Proteinuria is a common feature of lupus staining and the presence of renal microthrombi in lupus
nephritis and reflects podocyte injury. Furthermore, the nephritis116,117. This finding suggests a role for the classical
presence of nephrotic-range proteinuria in patients with complement pathway in lupus nephritis-­associated renal
lupus membranous nephropathy might represent the TMA, similar to the mechanisms involved in antiphos-
presence of podocyte dysfunction. Decreased expres- pholipid antibody-induced thrombosis and humoral
sion of the slit diaphragm proteins, nephrin and podo- rejection in transplanted kidneys116,117. We have demon-
cin, in kidneys of mice and patients with lupus nephritis strated that the presence of glomerular C4d deposits and
suggests that immune-mediated processes contribute to decreased serum levels of the complement control pro-
disruption of the slit diaphragm109. In patients with lupus tein, factor H are associated with poor renal outcomes in
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Class I • Supportive therapy

and II • Immunosuppressive therapy (proteinuria >3g per day)

• Maintenance
• Initial treatment
Class III • Treatment Refractory Add-on rituximab or
• H+CYC
and IV • H+MMF cases calcineurin inhibitor
• H+MMF
Classical • H+AZA
subtypes
• Anti-proteinuric and anti-hypertensive medications
Class V
• Immunosuppressive therapy H+CYC/MMF/AZA (persistent nephrotic proteinuria)

• Supportive therapy
Pathological Class VI
• Immunosuppressive therapy (external manifestations)
classification
of lupus
nephritis
Crescentic • PE/MP • CCX-168? (CD88 inhibitor)
GN • Rituximab (anti-CD20 Abs) • Abatacept? (CD80 inhibitor)
• Eculizumab? (Anti-C5 Abs)
Tubulo-
interstitial • Rituximab? (Anti-CD20 Abs)
Additional lesions • Abatacept? (CD80 inhibitor)
subtypes
Renal • PE/MP
vascular TMA • Eculizumab? (Anti-C5 Abs)
lesions • Thrombomodulin?

Podocyte • Abatacept? (CD80 inhibitor)

injury • Rituximab? (Anti-CD20 Abs)
• CNIs

Figure 4 | Proposed treatment algorithm for various pathological subtypes of lupus nephritis. Nature We propose
Reviews that the
| Nephrology
choice of treatment should depend on the pathological class of lupus nephritis as defined by the International Society of
Nephrology/Renal Pathology Society (ISN/RPS) classification system, and the presence of additional pathogenic subtypes
described in this Review. The treatment of ISN/RPS class I–VI lupus nephritis should follow basic therapeutic strategies
according to the three major guidelines1–3. For the treatment of the additional subtypes based on the various
pathogenesis, including crescentic lupus nephritis, podocyte injury, renal vascular lesions and tubulointerstitial lesions,
a series of therapeutic intervention recommendations are proposed. For patients with crescentic lupus nephritis (which
we define as the presence of crescents in ≥50% of glomeruli), we recommend first treating with plasma exchange (PE)
and methlyprednisolone pulse (MP), combined with cyclophosphamide or rituximab. Additional treatment options that
require further investigation include anti-complement agents (CCX‑168 and eculizumab) and the CD80 inhibitor
abatacept. Patients with severe tubulointerstitial lesions might be treated with rituximab or abatacept, although quality
clinical trials are lacking. For patients with renal vascular changes, especially those with thrombotic microangiopathy
(TMA), we suggest PE and MP as the first choice therapy. Eculizumab or recombinant thrombomodulin might also have
potential but require further exploration. Rituximab or abatacept might have a role in the treatment of patients with
prominent podocyte injury but further evidence of efficacy is required. In particular, the Kidney Disease: Improving Global
Outcome guideline suggests that steroids and calcineurin inhibitors (CNIs) should be used in lupus podocytopathy2.
Abs, antibodies; AZA, azathioprine; CYC, cyclophosphamide; GN, glomerulonephritis; H, corticosteroids;
MMF, mycophenolate mofetil.

patients with lupus nephritis and renal TMA, suggesting
that activation of both the classical and alterative path-
ways of complement might be involved in the develop-
ment of TMA in these patients71,116,117. In the past few
years reports have emerged describing the successful use
of the anti‑C5 monoclonal antibody, eculizumab, and
the anti-inflammatory, anticoagulant agent recombinant
human soluble thrombo­modulin, in patients with lupus
­nephritis-­associated TMA and diffuse proliferative
lupus nephritis resistant to conventional therapy, sug-
gesting that direct targeting of the underlying pathogenic
­mechanism is a promising approach118–121 (FIGS 3,4).
Advances in novel therapies
Improved understanding of the pathogenesis of different
lupus nephritis subtypes suggests that various novel bio-
logic agents and small molecules might be appropriate
therapies for specific types of lupus nephritis.
B cell-directed therapies. B cells have a critical role in
the pathogenesis of SLE beyond antibody production,
and B cell-depletion therapy has remained an attrac-
tive therapeutic option for nearly 10 years. Rituximab
and ocrelizumab are humanized chimeric monoclonal
anti‑CD20 antibodies that deplete autoreactive B cells
and thereby have the potential to attenuate the pro-
duction of ­autoantibodies that contribute to disease
manifestations.
The EXPLORER study of patients with class III or
IV lupus nephritis, however, failed to demonstrate a
benefit of adding rituximab to immunosuppressant
and cortico­steroid therapy 12. The subsequent LUNAR
study of 144 patients with class III or IV lupus nephri-
tis showed that the addition of rituximab to MMF and
corticosteroids led to greater reductions in levels of
anti-dsDNA and in levels of the complement compo-
nents C3 and C4, but did not improve clinical outcomes

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after 1 year of treatment 122. The BELONG trial showed
a numerically but not statistically significant difference
in renal response rate with addition of ocrelizumab to
standard therapy; however, this study was stopped early
owing to a higher rate of serious infections123. Although
anti‑B‑cell therapies will eventually decrease inflamma-
tion by abrogating the generation of immune complexes
and intrarenal tertiary lymphoid organs, the failure of the
above trials indicate that the effects of B‑cell depletion
are not immediate nor direct and that anti‑B‑cell therapy
might be more effective for maintenance of remission
than for induction of remission in patients with lupus
nephritis12,122,123. Contributing features that might have
led to the failure of anti‑B‑cell therapy to demonstrate
superiority over standard treatment regimens probably
also include the concomitant use of high-dose steroids,
the use of stringent and nonorgan-specific criteria for
clinical response, short follow‑up periods, small sample
sizes and a lack of an effect on critical non-circulating
pools of long-lived B cells. Nevertheless, the trials con-
firmed the safety of repeated treatment with rituximab124.
A small study of patients with severe lupus nephritis with
mean follow‑up of nearly 4 years suggests that rituximab
shows promise as part of an intensified induction ther-
apy protocol for patients who want to avoid or minimize
immunosuppressive maintenance therapy and oral ster-
oids125. The ongoing RITUXILUP study aims to demon-
strate whether the addition of rituximab to MMF therapy
is useful in treating lupus nephritis flares and whether
it has a long lasting steroid-sparing beneficial effect 126.
Preliminary findings suggest that rituximab can ena-
ble oral steroids to be safely avoided in the treatment of
lupus nephritis127. Ongoing studies with obinutuzumab128
and ofatumumab129 — monoclonal anti‑CD20 antibodies
with greater capacity for B‑cell depletion than rituximab
— are in progress130, and along with RITUXILUP, will
hopefully answer the remaining questions regarding the
efficacy of anti‑B‑cell therapy in lupus nephritis.
Of note, as B cells become depleted in response to
anti‑CD20 antibodies, levels of B‑cell-activating factor
(BAFF; also known as TNFSF13B or BLyS) increase,
which might increase the generation of new autore-
active B cells, inhibit B-cell apoptosis and stimulate
the differentiation of B cells into immunoglobulin-­
producing plasma cells (FIG. 2). A phase III trial of beli-
mumab, a monoclonal antibody that neutralizes BAFF,
in patients with SLE and renal involvement showed
that patients who received belimumab tended to have
fewer renal flares and significantly greater reductions
in proteinuria than those treated with placebo, pro-
viding support for the use of B cell–directed therapies
in maintenance protocols for lupus nephritis131 (FIG. 3).
A systematic review of 2,004 patients with SLE pro-
vides further support for targeting BAFF to induce or
­maintain a renal response132.
Neither rituximab nor belimumab deplete antibody-­
producing plasma cells. Thus, inhibition of anti-
body production by plasma cells by the proteasome
inhibitor, bortezomib, remains a promising therapeutic
strategy as has been demonstrated in mouse models of
lupus nephritis133–135.
T‑cell-directed therapies. Abatacept is a c­ o-stimulatory
inhibitor that targets B7‑1 (CD80) on the surface of
dendritic cells and B cells, blocking co-stimulatory
interaction between B7‑1 or B7‑2 and CD28 on T cells.
Unfortunately, abatacept as an add‑on to low-dose
cyclophosphamide or MMF failed to improve complete
renal response rates in clinical trials136–138. The failure of
these trials might be due to the strict definitions of renal
response; a revised global multi-centre trial of abatacept
in lupus nephritis is ongoing 139.
Other therapeutics under development. Various other
anti-inflammatory and/or immune regulatory agents are
under development and warrant investigation in lupus
nephritis140 (FIG. 3). Allogeneic mesenchymal stem cell
transplantation was used to successfully treat a small
group of patients with lupus nephritis who were refrac-
tory to conventional therapies141. Other therapies, such
as immuno-adsorption of anti-dsDNA antibodies and
immuno-adsorption with a C1q column, have been
reported to be useful in SLE and might also be useful
for the treatment of lupus nephritis142–145.
As our understanding of the pathogenic mechanisms
of lupus nephritis continues to expand, more accurate
therapeutic targets will undoubtedly be identified (FIG. 4).
Conclusions
Although the 2003 ISN/RPS lupus nephritis classifi-
cation system has gained international recognition,
intriguing controversies require further exploration
and new insights into disease pathogenesis need to be
incorporated16. The identification of lesions — namely
crescentic glomerulonephritis, podocyte injury, vascu-
lopathy and tubulointerstitial changes — that were not
included in the original classification but are increasingly
recognized as being important in their contribution
to the pathogenesis of disease, should be incorporated
into the classification to improve its clinical value and aid
therapeutic decision making. We propose that targeting
these pathogenic pathways might enable a more person-
alized approach to the treatment of disease and lead to
improved outcomes for patients with lupus nephritis.

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Acknowledgements
We gratefully acknowledge the contributions of Hong Chu,
Ying Tan, Chen Wang and Su‑xia Wang, Peking University First
Hospital, Beijing, for collecting data discussed in this Review.
This work is supported by grants of National Natural Science
Foundation of China to Innovation Research Group
(No. 81621092) and National Natural Science Foundation of
China (No. 81470932, No.81500526, No. 81670640 and
No. 81670639).
Author contributions
All authors researched data for the article, provided substan-
tial contributions to discussions of its content, wrote the arti-
cle, and reviewed and/or edited of the manuscript before
submission.
Competing interests statement
R.G. consults for Genentech. The other authors declare no
competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

NATURE REVIEWS | NEPHROLOGY VOLUME 13 | AUGUST 2017 | 495

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