OVERVIEW OF GLOMERULONEPHRITIS
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.
PRESENTATION
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.
DIAGNOSIS
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.
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.
Immunofluorescence
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.
