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Renal involvement is a frequent and potentially serious manifestation of systemic lupus erythematosus (SLE).1-4 It contributes to both morbidity and mortality, in part directly and in part through complications of therapy.
There has been recent progress in treating patients with SLE and renal involvement. This treatment is based on the use of a uniform histologic classification system (the International Society of Nephrology [ISN] classification), better understanding of the clinical course of different patterns of renal involvement, and through the use of information obtained from large randomized trials to treat lupus nephropathy.
LN epidemiology and pathogenesis
While the incidence of SLE and lupus nephritis (LN) varies considerably among studies,5 in general, females outnumber males approximately 10:1, and the peak average age is 15-45 years. Renal disease may be more severe in children and males and affects 25%-50% of SLE patients at onset and up to 60% during their disease course. LN is more common and more severe in minorities—including African Americans and Hispanic Americans—than in Caucasians, and in those with lower socioeconomic status regardless of racial background.
Genetics and environmental, and hormonal factors all play a role in the predilection to lupus and perhaps to LN.3,5-7 A number of spontaneous and inducible models of SLE and LN have been well studied in mice, including the NZB B/W F1 hybrid, the BXSB/yaa, and the MRL/lpr models.3,6 Autoimmunity is important in the pathogenesis of SLE,6-9 the disease process, including a breakdown in self tolerance, polyclonal hyperactivity of B cells along with defective auto-regulation of T cells that leads to autoantibody production, and deposition of immune deposits with a subsequent inflammatory responses.3,6-9
The failure of apoptotic mechanisms to delete or silence autoreactive cells (tolerance) may allow clonal expansion of such cells later in life, leading to auto-reactive cells and auto-antibody production. The deposition of circulating immune complexes, the in situ formation of others and the activation of complement are major components of glomerular involvement in LN.
Although most investigators believe mesangial and subendothelial immune complex deposits are derived from deposition of circulating immune complexes while subepithelial complexes found in membranous LN are often formed in situ, many factors influence the localization of glomerular immune complexes.
These include the size, charge, and avidity of the immune complexes, as well as the clearing ability by the mesangium and local hemodynamics.3,4 The glomerular localization of immune complexes activates complement-mediated damage, procoagulant factors, leukocyte chemoattraction, and release of cytokines associated with cellular proliferation and matrix formation. In some patients, vascular and tubulointerstitial damage are prominent.
Both the course of SLE and LN is characterized by episodes of illness (flares) followed by episodes of relative quiescence (remissions). From 30%-50% of SLE patients have clinically evident renal disease at presentation,1-4 but renal involvement occurs in as many as 60% of patients during the disease course. LN is manifested by proteinuria, microhematuria with dysmorphic erythrocytes, erythrocyte casts, and hypertension.
In some, development of nephritic syndrome is associated with proliferative glomerulonephritis and a decline in glomerular filtration rate (GFR). Other patients, including those with proliferative disease and some with membranous lupus nephropathy, develop the nephrotic syndrome. Clinical features generally correlate well with histologic findings on renal biopsy.