Lupus Nephritis

Advanced sclerosis lupus nephritis. International Society of

Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-
eosin).
Background
Lupus Nephritis

Lupus nephritis, one of the most serious

manifestations of systemic lupus
erythematosus (SLE), usually arises within 5 years
of diagnosis; however, renal failure rarely occurs
before American College of Rheumatology
criteria for classification are met.
Lupus Nephritis

Evaluating renal function in patients with SLE to

detect any renal involvement early is important
because early detection and treatment can
significantly improve renal outcome. Renal
biopsy should be considered in any patient with
SLE who has clinical or laboratory evidence of
active nephritis, especially upon the first episode
of nephritis.
Lupus Nephritis

The principal goal of therapy in lupus nephritis is

to normalize renal function or, at least, to
prevent the progressive loss of renal function.
Therapy differs depending on the pathologic
lesion. With the advent of more aggressive
immunosuppressive and supportive therapy,
rates of renal involvement and patient survival
are improving.
Pathophysiology
The characteristics of the nephritogenic
autoantibodies associated with lupus nephritis are
as follows [1] :
Antigen specificity directed against nucleosome
or double-stranded DNA (dsDNA) - Some anti-
dsDNA antibodies cross-react with the
glomerular basement membrane
Higher-affinity autoantibodies may form
intravascular immune complexes, which are
deposited in glomeruli
Cationic autoantibodies have a higher affinity
for the anionic glomerular basement membrane
Autoantibodies of certain isotypes
(immunoglobulin [Ig] G1 and IgG3) readily
activate complement
Etiology
Genetic factors
Table 1. Genes Associated With Systemic Lupus
Erythematosus
Gene Locus Gene Name Gene Product
Lymphoid-specific
1p13.2 PTPN22 protein tyrosine
phosphatase

1q21-q23 CRP CRP

FcγRIIA (R131),
1q23 FCGR2A, FCGR2B
FcγRIIB

FcγRIIIA (V176),
1q23 FCGR3A, FCGR3B
FcγRIIIB

1q31-q32 IL10 IL-10

1q36.12 C1QB C1q deficiency

Genetic factors
Table 1. Genes Associated With Systemic Lupus
Erythematosus
Gene Locus Gene Name Gene Product
Signal transducer and
2q32.2-q32.3 STAT4 activator of transcription
4

Cytotoxic T-
2q33 CTLA4 lymphocyte-associated
protein 4 (CTLA-4)

HLA-DRB1:
DR2/*1501,
6p21.3 HLA-DRB1
DR3/*0301C1q
deficiency
Genetic factors
Table 1. Genes Associated With Systemic Lupus
Erythematosus
Gene Locus Gene Name Gene Product
6p21.3 C2, C4A, C4B C2, C4 deficiencies

6p21.3 TNF TNF-a (promoter, -308)

10q11.2-q21 MBL2 Mannose-binding lectin

CRP = C-reactive protein; HLA = human leukocyte antigen; IL =

interleukin; TNF = tumor necrosis factor.
 SLE is more common in first-degree relatives of patients
with SLE (familial prevalence, 10-12%). Concordance
rates are higher in monozygotic twins (24-58%) than in
dizygotic twins (2-5%), supporting an important role for
genetics in the development of SLE. However, the
concordance rate in monozygotic twins is not 100%,
suggesting that environmental factors trigger
development of clinical disease.
Human leukocyte antigen (HLA) class II
genes include the following:

HLA-DR2 and HLA-DR3 are associated with SLE

HLA-DR4 is associated with a lower prevalence
of SLE and appears to be protective
Complement genes include the following:

C1Q, C1R, and C1S deficiencies are associated

with SLE, lupus nephritis, and production of anti-
dsDNA
C2 and C4 deficiencies are associated with SLE
or lupus-like syndrome
C4A and C4B (possibly) gene deletions are
associated with SLE
FcγR genes include the following:

 These mediate the binding of IgG and IgG-containing

immune complexes to cells such as macrophages and
other mononuclear phagocytes
 FcγRIIa binds to IgG2 and is encoded by 2 codominant
alleles, H131 (or high affinity) and R131 (or low affinity);
the low-affinity phenotype (homozygous for R131 allele;
131R/R) is associated with lupus nephritis in African
Americans
FcγR genes include the following:

 FcγRIIIa binds to IgG1 and is encoded by 2 codominant

alleles, V158 (or high affinity) and F158 (or low affinity);
the low-affinity phenotype (homozygous for F158 allele;
158F/F) is associated with SLE
Other relevant genes include the following:

Cytokine genes - Certain polymorphisms of

the IL10 gene (high producers) and possibly
the IL1RN and TNFA genes (low producers) are
associated with SLE
Mannose-binding lectin genes - These gene
polymorphisms are associated with an
increased risk of SLE
Other relevant genes include the following:

Apoptosis genes - Defects of several apoptosis

genes are associated with lupuslike syndromes in
mice and, rarely, SLE in humans,
including CD95 (Fas) and CD178 (FasL)
Immunologic factors

The initial autoantibody response appears to be

directed against the nucleosome, which arises
from apoptotic cells.
Patients with SLE have poor clearance
mechanisms for cellular debris. Nuclear debris
from apoptotic cells induces plasmacytoid
dendritic cells to produce interferon-α, which is
a potent inducer of the immune system and
autoimmunity.
Immunologic factors

 Autoreactive B lymphocytes, which are normally

inactive, become active in SLE because of a
malfunction of normal homeostatic mechanisms,
resulting in escape from tolerance. This leads to the
production of autoantibodies. Other autoantibodies,
including anti-dsDNA antibodies, develop through a
process of epitope spreading. These autoantibodies
develop over time, in an orderly fashion, months to years
before the onset of clinical SLE. [
Signs and symptoms
Asymptomatic lupus nephritis

During regular follow-up, laboratory

abnormalities suggesting active lupus nephritis
include hematuria or proteinuria; this is more
typical of mesangial or membranous lupus
nephritis
Active nephritis

Nephritic symptoms related to hypertension and

poor renal function (typical of diffuse lupus
nephritis):
Peripheral edema
Headache and dizziness
Nausea and vomiting
Active nephritis

Nephrotic symptoms related to proteinuria (typical

of membranous lupus nephritis):
Peripheral or periorbital edema
Coagulopathy
Physical findings

 Focal and diffuse lupus nephritis – Generalized

active SLE with the presence of a rash, oral or nasal
ulcers, synovitis, or serositis; signs of active nephritis
 Active lupus nephritis – Hypertension, peripheral
edema, and, occasionally, cardiac
decompensation
 Membranous lupus nephritis – Peripheral edema,
ascites, and pleural and pericardial effusions
without hypertension
Diagnosis
Laboratory tests to evaluate renal function
in SLE patients include the following:

Blood urea nitrogen (BUN) testing

Serum creatinine assessment
Urinalysis (to check for protein, red blood cells
[RBCs], and cellular casts)
Spot urine test for creatinine and protein
concentration
24-hour urine test for creatinine clearance and
protein excretion
Laboratory tests for SLE disease activity
include the following:

Antibodies to double-stranded DNA (dsDNA)

Complement (C3, C4, and CH50)
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)
Renal biopsy should be considered in any
patient with SLE who has clinical or laboratory
evidence of active nephritis, especially upon
the first episode of nephritis
Lupus nephritis is staged according to the classification
revised by the International Society of Nephrology (ISN)
and the Renal Pathology Society (RPS) in 2003, as follows:

 Class I – Minimal mesangial lupus nephritis

 Class II – Mesangial proliferative lupus nephritis
 Class III – Focal lupus nephritis (active and chronic;
proliferative and sclerosing)
 Class IV – Diffuse lupus nephritis (active and chronic;
proliferative and sclerosing; segmental and global)
 Class V – Membranous lupus nephritis
 Class VI – Advanced sclerosis lupus nephritis
Management
Key points of American College of Rheumatology
guidelines for managing lupus nephritis are as
follows:
Patients with clinical evidence of active,
previously untreated lupus nephritis should have
a renal biopsy to classify the disease according
to ISN/RPS criteria
All patients with lupus nephritis should receive
background therapy with hydroxychloroquine,
unless contraindicated
Glucocorticoids plus either cyclophosphamide
intravenously or mycophenolate mofetil orally
should be administered to patients with class
III/IV disease; patients with class I/II nephritis do
not require immunosuppressive therapy
Angiotensin-converting enzyme inhibitors or
angiotensin-receptor blockers should be
administered if proteinuria reaches or exceeds
0.5 g/day
Blood pressure should be maintained at or
below 130/80 mm Hg
Investigational therapies for lupus
nephritis and SLE include the following:
Rituximab
Other anti-CD20 monoclonal antibodies (eg,
ocrelizumab, ofatumumab, epratuzumab, and
TRU-015)
Belimumab
Atacicept
Abetimus
Anticytokine therapies (eg, monoclonal
antibodies directed against interferon alfa,
interleukin [IL]-1, IL-6, IL-10, and tumor necrosis
factor alpha [TNF-α])