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Lupus Nephritis: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.

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Lupus Nephritis
Updated: Sep 11, 2016
Author: Lawrence H Brent, MD; Chief Editor: Vecihi Batuman, MD, FASN more...

OVERVIEW

Practice Essentials
Lupus nephritis is histologically evident in most patients with systemic lupus erythematosus (SLE),
even those without clinical manifestations of renal disease. Evaluating renal function in SLE
patients is important because early detection and treatment of renal involvement can significantly
improve renal outcome. See the image below.

Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class
VI (100, hematoxylin-eosin).
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Signs and symptoms

Patients with lupus nephritis may report the following:

Other symptoms of active SLE (eg, fatigue, fever, rash, arthritis, serositis, or central nervous
system [CNS] disease); these are more common with focal proliferative and diffuse
proliferative lupus nephritis
Asymptomatic lupus nephritis During regular follow-up, laboratory abnormalities suggest
active lupus nephritis; this is more typical of mesangial or membranous lupus nephritis
Active nephritis Peripheral edema secondary to hypertension or hypoalbuminemia; extreme
peripheral edema is more common with diffuse or membranous lupus nephritis
Diffuse lupus nephritis Headache, dizziness, visual disturbances, or signs of cardiac
decompensation

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Lupus Nephritis: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.com/article/330369-overview#showall

Physical findings may include the following:

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

See Presentation for more detail.

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

See Workup for more detail.

Management

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.

Key points of American College of Rheumatology guidelines for managing lupus nephritis are as
follows:

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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

Patients with class V lupus nephritis are generally treated with prednisone for 1-3 months,
followed by tapering for 1-2 years if a response occurs. If no response occurs, the drug is
discontinued. Immunosuppressive drugs are generally not used unless renal function worsens or
a proliferative component is present on renal biopsy samples.

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-])

Patients with end-stage renal disease require dialysis and are good candidates for kidney
transplantation. Hemodialysis is preferred to peritoneal dialysis.

See Treatment and Medication for more detail.

Background
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 is histologically evident in most patients with SLE, even those without clinical
manifestations of renal disease. The symptoms of lupus nephritis are generally related to
hypertension, proteinuria, and renal failure. (See Presentation.)

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. (See Workup.)

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. (See Treatment.)

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Pathophysiology
Autoimmunity plays a major role in the pathogenesis of lupus nephritis. The immunologic
mechanisms include production of autoantibodies directed against nuclear elements. 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] G 1 and IgG 3) readily activate
complement

These autoantibodies form pathogenic immune complexes intravascularly, which are deposited in
glomeruli. Alternatively, autoantibodies may bind to antigens already located in the glomerular
basement membrane, forming immune complexes in situ. Immune complexes promote an
inflammatory response by activating complement and attracting inflammatory cells, including
lymphocytes, macrophages, and neutrophils. [2, 3]

The histologic type of lupus nephritis that develops depends on numerous factors, including the
antigen specificity and other properties of the autoantibodies and the type of inflammatory
response that is determined by other host factors. In more severe forms of lupus nephritis,
proliferation of endothelial, mesangial, and epithelial cells and the production of matrix proteins
lead to fibrosis. [4]

Glomerular thrombosis is another mechanism that may play a role in pathogenesis of lupus
nephritis, mainly in patients with antiphospholipid antibody syndrome, and is believed to be the
result of antibodies directed against negatively charged phospholipid-protein complexes. [2]

Etiology
Genetic factors

As with many autoimmune disorders, evidence suggests that genetic predisposition plays an
important role in the development of both SLE and lupus nephritis. Multiple genes, many of which
are not yet identified, mediate this genetic predisposition (see Table 1 below). [5, 6, 7, 8, 9, 10, 4, 11]

Table 1. Genes Associated With Systemic Lupus Erythematosus (Open Table in a new window)

Gene Locus Gene Name Gene Product

Lymphoid-specific protein
1p13.2 PTPN22
tyrosine phosphatase

1q21-q23 CRP CRP

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FCGR2A,
1q23 FcRIIA (R131), FcRIIB
FCGR2B

FCGR3A,
1q23 FcRIIIA (V176), FcRIIIB
FCGR3B

1q31-q32 IL10 IL-10

1q36.12 C1QB C1q deficiency

Signal transducer and


2q32.2-q32.3 STAT4
activator of transcription 4

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

HLA-DRB1: DR2/*1501,
6p21.3 HLA-DRB1
DR3/*0301C1q deficiency

C2, C4A,
6p21.3 C2, C4 deficiencies
C4B

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 lupuslike syndrome

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C4A and C4B (possibly) gene deletions are associated with SLE

FcR genes include the following:

These mediate the binding of IgG and IgG-containing immune complexes to cells such as
macrophages and other mononuclear phagocytes
FcRIIa binds to IgG 2 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
FcRIIIa binds to IgG 1 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
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. [4, 12, 13]

Patients with SLE have poor clearance mechanisms for cellular debris. Nuclear debris from
apoptotic cells induces plasmacytoid dendritic cells to produce interferon-, which is a potent
inducer of the immune system and autoimmunity. [14, 15, 16]

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. [17]

Epidemiology
Frequency

In a multi-ethnic international cohort of patients enrolled within 15 months (mean, 6 months) after
SLE diagnosis and assessed annually, lupus nephritis occurred in 700 of 1827 patients (38.3%).
Lupus nephritis was frequently the initial presentation of SLE; it was identified at enrollment in
80.9% of cases. Patients with nephritis were younger, more frequently men and of African, Asian,
and Hispanic race/ethnicity. [18]

In a study of a large Spanish registry, lupus nephritis was histologically confirmed in 1092 of 3575
patients with SLE (30.5%). The mean age at lupus nephritis diagnosis was 28.4 years. The risk for
lupus nephritis development was significantly higher in men, in younger individuals, and in

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Lupus Nephritis: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.com/article/330369-overview#showall

Hispanics. Patients receiving antimalarials had a significantly lower risk of developing lupus
nephritis. [19]

Age-related demographics

Most patients with SLE develop lupus nephritis early in their disease course. SLE is more common
among women in the third decade of life, and lupus nephritis typically occurs in patients aged
20-40 years. [20] Children with SLE are at a higher risk of renal disease than adults and tend to
sustain more disease damage secondary to more aggressive disease and treatment-associated
toxicity. [21, 22, 23]

Sex-related demographics

Because the overall prevalence of SLE is higher in females (ie, female-to-male ratio of 9:1), lupus
nephritis is also more common in females; however, clinical renal disease has a worse prognosis
and is more common in males with SLE. [20]

Race-related demographics

SLE is more common in African Americans and Hispanics than in white people. Particularly severe
lupus nephritis may be more common in African Americans and Asians than in other ethnic
groups. [20]

Prognosis
Over the past 4 decades, changes in the treatment of lupus nephritis and general medical care
have greatly improved both renal involvement and overall survival. During the 1950s, the 5-year
survival rate among patients with lupus nephritis was close to 0%. The subsequent addition of
immunosuppressive agents such as intravenous (IV) pulse cyclophosphamide has led to
documented 5- and 10-year survival rates as high as 85% and 73%, respectively. [24]

Morbidity associated with lupus nephritis is related to the renal disease itself, as well as to
treatment-related complications and comorbidities, including cardiovascular disease and
thrombotic events. Progressive renal failure leads to anemia, uremia, and electrolyte and
acid-based abnormalities. Hypertension may lead to an increased risk of coronary artery disease
and cerebrovascular accident.

Nephrotic syndrome may lead to edema, ascites, and hyperlipidemia, adding to the risk of
coronary artery disease and the potential for thrombosis. The findings from one study indicate that
patients with lupus nephritis, particularly early-onset lupus nephritis, are at increased risk for
morbidity from ischemic heart disease. [25]

In a study of 56 children (<18 years) with either global or segmental diffuse proliferative lupus
nephritis, long-term renal outcomes were similar. Most patients reached adulthood but sustained
significant renal damage. Complete remission rates were 50% and 60% in the global and
segmental groups, respectively. Renal survival rates, defined as an estimated glomerular filtration
rate of 60 mL/min/1.73 m2, were 93%, 78%, and 64 % at 1, 5, and 10 years, respectively, and
corresponding patient survival rates were 98%, 96%, and 91%, respectively, with similar rates in

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the global and segmental groups. [26]

Therapy with corticosteroids, cyclophosphamide, and other immunosuppressive agents increases


the risk of infection. Long-term corticosteroid therapy may lead to osteoporosis, avascular necrosis,
diabetes mellitus, and hypertension, among other complications. Cyclophosphamide therapy may
cause cytopenias, hemorrhagic cystitis, infertility, and an increased risk of malignancy.

Clinical Presentation

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