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 <1 g/24 hr. 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

Children with SLE should be treated by pediatric specialists in medical centers where medical and psychologic support can be given to patients and their families. 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 1-2 mg/kg/day in divided doses followed by a slow steroid taper over 4-6 mo beginning 4-6 wk 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 500-1,000 mg/m² followed by additional infusions every 3 mo for 18 mo appears to reduce the risk of progressive renal dysfunction. Azathioprine at a single daily dose of 1.5-2.0 mg/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

Renal survival without the need for dialysis is seen in 80% of patients 10 years after the diagnosis of SLE nephritis. Patients with diffuse proliferative WHO class IV lupus nephritis exhibit the highest risk for progression to end-stage renal disease. Concerns regarding the side effects of chronic immunosuppressive therapy and the risk of recurrent disease are lifelong. Close monitoring for relapse of disease is imperative to ensure successful renal outcomes. 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 >20 g of cyclophosphamide or other immunosuppressant therapies.