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Glomerulonephritis (GN) is a general term used to indicate glomerular inflammation, which may occur secondary to many different disease processes. The specific pattern of inflammation, as dictated by the under-lying process, generally determines the major signs and symptoms, which may include microscopic or gross hematuria, proteinuria, hypertension, edema, and/or renal insufficiency.

Glomerulonephritis may present as any of the following clinical syndromes:
Asymptomatic Hematuria with or Without Proteinuria. Adults with IgA nephropathy (see Plate 4-16) often present in this manner. Their urinary abnormalities are commonly discovered on routine physical examination and urine dipstick.
Recurrent Gross Hematuria. Children with IgA nephropathy often present in this manner, developing gross hematuria several days after an upper respiratory infection (“synpharyngitic nephritis”).
Acute GN. Patients have “nephritic syndrome,” which includes variable degrees of renal insufficiency; oliguria; hypertension; edema; proteinuria; and gross or microscopic hematuria. Poststreptococcal GN (Plate 4-19), membranoproliferative GN (Plate 4-22), and lupus nephritis (Plate 4-49) often present in this manner. Rapidly Progressive Glomerulonephritis (RPGN). Patients experience a rapid deterioration of renal function over days, weeks, or months that invariably progresses to end-stage renal disease (ESRD) if untreated. Any form of glomerulonephritis may cause RPGN, although vasculitic glomerulonephritis and antiglomerular basement membrane disease frequently cause this severe phenotype.
Chronic GN. Patients have minimal symptoms and are often discovered to have hypertension, renal impairment, and proteinuria on routine physical examination and laboratory assessment. IgA nephropathy frequently presents in this manner after years of preceding asymptomatic hematuria/proteinuria, which may have gone unnoticed.

Glomerulonephritis should be suspected in any patient with one of the above clinical presentations. Proteinuria should be quantified using either a 24-hour collection or, more often, a spot urine protein : creatinine ratio. Glomerular hematuria can be distinguished from other causes of urinary tract bleeding by the presence of either dysmorphic red blood cells (RBCs) or RBC casts on urine microscopy. RBCs become dysmorphic upon passing through the damaged GBM. An acanthocyte, characterized by its protruding blebs, is an example of a dysmorphic RBC. A large number of dysmorphic RBCs (often defined as 50% to 80% of RBCs seen on urine microscopy) indicates glomerular bleeding. Meanwhile, some of the RBCs in the tubules become bound together by the Tamm-Horsfall mucoprotein, forming RBC casts, which are thus also characteristic of glomerular bleeding.
The different causes of glomerulonephritis are distinguished based on history, clinical findings, serologic tests, and renal biopsy findings. The characteristic features of each disease process are described later in this section. Some general terms, however, are often used to describe the patterns of glomerular inflammation seen on light microscopy and immunofluorescence.
Light Microscopy
With light microscopy, the pattern of glomerular inflammation is often described as mesangial, endocapillary, and/or extracapillary (crescentic); focal or diffuse; and segmental or global.
Mesangial/Endocapillary/Extracapillary (Crescentic). Inflammation can occur in several different regions of the glomerulus, leading to characteristic structural changes.
Mesangial involvement can manifest as mesangial hypercellularity (defined as more than three mesangial cells per mesangial area) and/or mesangial matrix expansion. These structural changes are often associated with microscopic hematuria and/or mild proteinuria, with preservation of normal filtration function. Common causes include IgA nephropathy and class II lupus nephritis.
Endocapillary involvement can manifest as occlusion of glomerular capillaries by endothelial and mesangial cell proliferation, as well as by leukocyte infiltration. These changes are often associated with hematuria, proteinuria, and reduction of filtration function.
Common causes include postinfectious GN and class III or IV lupus nephritis.
Extracapillary involvement, more commonly known as crescentic disease, manifests as thickening of the parietal epithelium of Bowman’s capsule to more than two cell layers, which causes it to resemble a crescent. The formation of such crescents occurs secondary to the rupture of glomerular capillaries, which permits cells and proteins to leak into and accumulate along Bowman’s space. Cellular crescents are the defining lesion of rapidly-progressive glomerulonephritis (RPGN, see Plate 4-25).
Focal/Diffuse. In focal GN, fewer than half of the glomeruli appear abnormal. Common causes of focal disease include IgA nephropathy and class III lupus nephritis.
In diffuse GN, more than half of the glomeruli appear abnormal. Common causes include postinfectious GN, class IV lupus nephritis, and membranoproliferative GN.
Segmental/Global. In segmental lesions, fewer than half of the capillaries within most affected glomerular tufts appear abnormal. In global lesions, more than half of the capillaries within most affected glomerular tufts appear abnormal.

The pattern observed on immunofluorescent staining of the glomerulus for antibodies and/or complement proteins can often be described as granular, linear, or pauci-immune. These patterns offer clues into the underlying disease process.
Granular. A pattern of patchy, granular staining for antibodies and complement proteins suggests immune complex deposition. The deposited complexes fix complement, leading to direct complement-mediated damage and, frequently, endocapillary proliferation.
IgA nephropathy is the most common cause of immune complex GN and the most common cause of GN in general. Other causes of immune complex GN include lupus nephritis, membranoproliferative GN, and postinfectious GN. These diseases are typically associated with depressed complement levels, reflecting their mechanism of inflammation; however, complement levels may remain normal in IgA nephropathy because of the slow rate at which the various components are consumed.
Linear. A pattern of continuous, linear staining for antibodies and complement proteins along the capillary walls suggests direct binding of antibodies to the glomerular basement membrane (GBM). Such binding occurs in the anti-GBM diseases, in which autoantibodies form against the noncollagenous 1 (NC1) domain of the α-3 chain of type IV collagen (α-3 IV). The resulting inflammation almost invariably leads to RPGN.
In the spectrum of anti-GBM disease, one third of patients have renal-limited disease, whereas the remainder have the combined pulmonary-renal syndrome named for Goodpasture. Goodpasture syndrome occurs when the anti-GBM autoantibodies bind to the alveolar basement membrane, causing pulmonary hemorrhage. This syndrome occurs almost exclusively in smokers and others exposed to hydrocarbons, suggesting that environmental factors play a key role in determining the susceptibility of the pulmonary capillaries to circulating anti-GBM autoantibodies.
Pauci-immune. A general lack (or, as the name suggests, paucity) of staining for antibodies or complement proteins suggests vasculitic GN. In such cases, inflammation generally reflects the presence of circulating antineutrophil cytoplasmic antibodies (ANCAs), which are believed to directly activate neutrophils. The ensuing glomerular inflammation often leads to RPGN, and it may be either isolated or part of a systemic vasculitis. Other common histologic findings include fibrinoid glomerular necrosis, periglomerular inflammation, and arteritis.
ANCAs can be subdivided into those with a cytoplasmic staining pattern (c-ANCA) and those with a perinuclear staining pattern (p-ANCA). c-ANCAs almost always target proteinase-3 antigens (PR3- ANCA) and are often associated with Wegener granulomatosis. p-ANCAs almost always target myeloperoxidase antigens (MPO-ANCA) and are often associated with Churg-Strauss disease and microscopic polyangiitis. The ANCA-positive systemic vasculitides all feature a propensity toward multiple organ involvement. Specifically, Wegener granulomatosis and microscopic polyangiitis are associated with pulmonary hemorrhage, whereas Churg-Strauss features asthma and eosinophilia.

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