SLE

Glomerulonephritis Associated with

Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is characterized by
fever, weight loss, dermatitis, hematologic abnormalities,
arthritis, and involvement of the heart, lungs, central
nervous system, and kidneys.
Glomerulonephritis is the most important cause of
morbidity and mortality in SLE.
Renal disease in childhood SLE is present in up 80%
patients and is more active than that seen in adults.
Occasionally, renal disease is the only presenting clinical
manifestation.

Pathogenesis and Pathology

The clinical manifestations of SLE are mediated by immune complexes.
The classification of lupus nephritis of the World Health Organization
(WHO) is based on a combination of light microscopy,
immunofluorescence, and electron microscopy features.
In patients with WHO class I nephritis (minimal mesangial lupus
nephritis), no histologic abnormalities are detected on light microscopy
but mesangial immune deposits are present on immunofluorescence or
electron microscopy.
In WHO class II nephritis (mesangial proliferative nephritis), light
microscopy shows both mesangial hypercellularity and increased matrix
along with mesangial deposits containing immunoglobulin and
complement.

 WHO class III nephritis and WHO class IV nephritis

are interrelated lesions characterized by both mesangial
and endocapillary lesions.
Class III nephritis is defined by <50% glomeruli with
involvement and class IV has 50% glomerular
involvement.
Immune deposits are present in both the mesangium and
subendothelial areas.
A subclassification scheme helps grade severity of the
proliferative lesion based on whether the glomerular
lesions are segmental (<50% glomerular tuft involved) or
global (50% glomerular tuft involved).

 The WHO classification scheme also delineates whether

there is a predominance of chronic disease versus active
disease.
Chronic injury results in glomerular sclerosis and is felt to be
the consequence of significant proliferative disease seen in
class III and IV.
Other signs of active disease include capillary walls that are
thickened secondary to subendothelial deposits (creating
the wire-loop lesion), necrosis, and crescent formation.
WHO class IV nephritis is associated with poorer outcomes
but can be successfully treated with aggressive
immunosuppressive therapy.

 WHO class V nephritis (membranous lupus nephritis), is less

commonly seen as an isolated lesion and resembles idiopathic
membranous nephropathy with subepithelial immune deposits.
This lesion is often seen in combination with class III or IV
proliferative nephritis, and if the membranous lesion is present in
>50% glomeruli, both classes are noted in designation.
This classification scheme also identifies cases with combinations
of mixed class III, IV, and V lesions, resulting in more appropriate
treatment for such patients.
Transformation of the histologic lesion from one class to another is
common.
This is more likely to occur among inadequately treated patients
and usually results in progression to a more severe histologic
lesion.

Clinical Manifestations
The majority of children with SLE are adolescent girls.
The clinical findings in patients having milder forms of lupus nephritis
(all class I-II, some class III) include hematuria, normal renal function,
and proteinuria <1g/24hr.
Some patients with class III and all patients with class IV nephritis
have hematuria and proteinuria, reduced renal function, nephrotic
syndrome, or acute renal failure.
The urinalysis may be normal on rare occasions in patients with
proliferative lupus nephritis.
Patients with class V nephritis commonly present with nephrotic
syndrome.

Diagnosis
The diagnosis of SLE is confirmed by the detection of
circulating antinuclear antibodies and by demonstrating
antibodies that react with native double-stranded DNA.
In most patients with active disease, C3 and C4 levels are
depressed.
In view of the lack of a clear correlation between the clinical
manifestations and the severity of the renal involvement,
renal biopsy should be performed in all patients with SLE.
These results are used to guide the selection of
immunosuppressive therapies.

Treatment
The goal of immunosuppressive therapy in
lupus nephritis is producing a clinical and
serologic remission, defined as normalization of
anti-DNA antibody, C3, and C4 levels.
Therapy is initiated in all patients with
prednisone at a dose of 1-2mg/kg/day in
divided doses followed by a slow steroid taper
over 4-6mo beginning 4-6wk after achieving a
serologic remission.

 For patients having more severe forms of nephritis (WHO classes III and
IV), 6 consecutive monthly intravenous infusions of cyclophosphamide at
a dose of 500-1,000mg/m2 followed by additional infusions every 3mo
for 18mo appears to reduce the risk of progressive renal dysfunction.
Azathioprine at a single daily dose of 1.5-2.0mg/kg may be used as a
steroid-sparing agent in patients with WHO class I or II lupus nephritis.
Single-center clinical trials also suggest the potential benefit of
mycophenolate mofetil in patients with lupus nephritis, although results
of long-term therapy, particularly compared with standard therapy, has
not been systematically evaluated.
Rituximab, a chimeric monoclonal antibody specific for human CD20,
may be effective in patients with WHO type IV lupus nephritis resistant to
conventional immunosuppressive therapies.

Prognosis
Patients with diffuse proliferative WHO class IV lupus
nephritis exhibit the highest risk for progression to endstage renal disease.
Special care must be taken to minimize the risks of
infection, osteoporosis, obesity, poor growth, hypertension,
and diabetes mellitus associated with chronic steroid
therapy.
Patients require counseling regarding the risk of
malignancy or infertility, which may be increased in those
receiving a cumulative dose of >20g of cyclophosphamide
or other immunosuppressant therapies.