Minimal Mesangial and Mesangial Proliferative Lupus Nephritis (ISN/RPS Class I and II)

Agnes B. Fogo, MD,1 Mark A. Lusco, MD,1 Behzad Najafian, MD,2 and Charles E. Alpers, MD 2

AJKD Atlas of Renal Pathology

Microscopy Images

Figure 1
Figure 1. Minimal mesangial lupus nephritis ISN/RPS class I with no significant glomerular changes by light microscopy (Jones silver stain).
Figure 2
Figure 2. Mesangial proliferative lupus nephritis ISN/RPS class II with mild mesangial proliferation without endocapillary hypercellularity or glomerular scarring related to lupus nephritis (periodic acid–Schiff stain). Reproduced with permission from AJKD 32(1):e1-e2.1.
Figure 3
Figure 3. Mesangial proliferative lupus nephritis ISN/RPS class II with granular mesangial without capillary loop staining (immunofluorescence microscopy, IgM). Reproduced with permission from AJKD 32(1):e1-e2.1.
Figure 4
Figure 4. Mesangial proliferative lupus nephritis ISN/RPS class II with mesangial deposits (electron microscopy). Repro- duced with permission from AJKD 32(1):e1-e2.1. -

Clinical & Pathologic Features

Lupus nephritis (LN) is defined as a glomerular immune complex disease that occurs in patients who meet American College of Rheumatology criteria for diagnosis of systemic lupus erythematosus (SLE).

SLE is a systemic autoimmune disease, most commonly involving the skin, kidneys, joints, heart, and serosal surfaces. Women are affected more than men (9:1), and SLE is more common in African Americans. Onset usually is from teenage years to the third decade of life, but SLE may manifest at any age.

Kidney involvement is a major cause of morbidity and the most common cause of death in SLE patients.

The varying glomerular immune complex patterns are diagnosed according to the ISN/RPS classification.

These include predominantly mesangial deposits (classes I, II); subendothelial deposits with endocapillary hypercellularity or prominent duplication of glomerular basement membranes, often with necrotizing and crescentic lesions (classes III and IV, focal and diffuse LN), or membranous forms (class V). The mesangial forms are seen in up to 25% of biopsies of SLE patients, typically with mild clinical symptoms, with low-grade proteinuria and hematuria and usually preserved glomerular filtration rate. Class I minimal mesangial LN is rarely seen in kidney biopsies, which are unlikely to be prompted by symptoms. LN may precede other findings of SLE, or develop at any time in the disease course, and manifest initially with any class. Transformations between classes—spontaneously or in response to therapy—are common.

Light microscopy: Minimal mesangial LN (class I) shows unremarkable glomeruli without mesangial hypercellularity or other specific lesions. Mesangial proliferative LN (class II) shows mesangial hypercellularity and expanded mesangial areas, but absence of endocapillary hypercellularity, histologically evident immune deposits, crescents, or scarring related to such past active lesions.

Immunofluorescence microscopy: Both class I and II mesangial forms of LN have diffuse, often global granular mesangial staining which may be in a “fullhouse” polyclonal pattern, with IgG, IgA, IgM, C3, and C1q, with dominant or codominant IgG, or restricted to a single immunoglobulin class, typically IgG. Nuclear staining for IgG, reflecting positive ANA, may be present. Granular immune complex deposits may rarely involve peritubular capillaries.

Electron microscopy: Mesangial deposits are present in class I and II mesangial forms of LN, with only rare or occasional subepithelial or subendothelial deposits.

In cases with additional so-called lupus podocytopathy, there may be widespread foot process effacement, associated with nephrotic proteinuria.

Etiology / Pathogenesis

There are genetic predispositions to SLE. Inadequate clearance of nuclei from cells undergoing apoptosis (triggered by various environmental insults, including ultraviolet radiation) leads to excess nuclear antigens which, combined with additional abnormalities in B and T lymphocytes, ultimately results in autoantibody formation. The activation of Toll-like receptors and dendritic cells and high interferon a levels are additional elements postulated to perpetuate this process. Autoantibodies develop against a variety of nuclear materials, including DNA, RNA, and various histone and nonhistone proteins. Autoantibodies may bind to endogenous fixed antigens or exogenous antigens “planted”

Differential Diagnosis

Mesangial deposits may occur in chronic GN due to infection, cryoglobulinemia, C1q nephropathy, and IgA nephropathy, each with disease-specific findings.

Mixed connective tissue disease and lupus-like illnesses show a similar spectrum of glomerular lesions as seen in SLE, and are distinguished clinically and to some degree by laboratory testing.

Key Diagnostic Features

 Mesangial deposits by immunofluorescence and electron microscopy  Full-house staining by immunofluorescence with dominant or codominant IgG  Tubuloreticular aggregates in endothelial cells by electron microscopy  No mesangial proliferation or other active endocapillary, necrotizing, or crescentic lesions in ISN/ RPS class I minimal mesangial LN; mesangial proliferation only in ISN/RPS class II mesangial proliferative LN