Glomerular Diseases

Cynthia G. Pan and Ellis D. Avner

PATHOGENESIS
 Glomerular injury may be a result of genetic, immunologic, perfusion, or coagulation disorders.
o Genetic disorders of the glomerulus may result from mutations in DNA exons encoding
proteins located within the glomerulus, interstitium, or tubular epithelium; mutations in
regulatory genes controlling DNA transcription; abnormal posttranscriptional modification of
RNA transcripts; or abnormal posttranslational modification of proteins.
o Immunologic injury to the glomerulus results in glomerulonephritis, which is a generic term
for several diseases, but more precisely a histopathologic term defining inflammation of the
glomerular capillaries.
 Evidence that glomerulonephritis is caused by immunologic injury includes
morphologic and immunopathologic similarities to experimental immune-mediated
glomerulonephritis; the demonstration of immune reactants (immunoglobulin,
complement) in glomeruli; abnormalities in serum complement; and the finding of
autoantibodies (anti-GBM) in some of these diseases.
 There appear to be 2 major mechanisms of immunologic injury: glomerular
deposition of circulating antigen–antibody immune complexes and interaction of
antibody with glomerular antigens in situ. In the latter circumstance, the antigen
may be a normal component of the glomerulus (the noncollagenous domain [NC-1]
of type IV collagen, a putative antigen in human anti-GBM nephritis) or an antigen
that has been deposited in the glomerulus.
 In immune complex–mediated diseases, antibody is produced against, and
combines with, a circulating antigen that is usually unrelated to the kidney (see Fig.
508-6). The immune complexes accumulate in GBMs and activate the complement
system, leading to immune injury. Acute serum sickness in rabbits is produced by a
single intravenous injection of bovine albumin. Within 1 wk after injection, a rabbit
produces antibody against bovine albumin, and the antigen remains in the blood in
high concentration. As antibody enters the circulation, it forms immune complexes
with antigen. Although the amount of antigen in the circulation exceeds that of
antibody (antigen excess), the complexes formed are small, remain soluble in the
circula- tion, and are deposited in glomeruli. The processes involved in glomerular
localization are not well understood but include characteristics of the complex
(concentration, charge, size) and/or the glomerulus (mesangial trapping, negatively
charged capillary wall); hydrodynamic forces; and the influence of various chemical
mediators (angiotensin II, prostaglandins).
 With deposition of immune complexes in glomeruli, rabbits develop an acute
proliferative glomerulonephritis. Immunofluorescence microscopy demonstrates
granular (“lumpy-bumpy”) deposits con- taining immunoglobulin and complement
in the glomerular capillary wall. Electron microscopic studies show these deposits to
be on the epithelial side of the GBM and in the mesangium. For the next few days,
as additional antibody enters the circulation, the antigen is ulti- mately removed
from the circulation and the glomerulonephritis subsides.
 An example of in situ antigen–antibody interaction is anti–GBM antibody disease, in
which antibody reacts with antigen(s) of the GBM. Immunopathologic studies reveal
linear deposition of immunoglobulin and complement along the GBM in
 Goodpasture syndrome (see Chapter 517) and certain types of rapidly progressive
glomerulo- nephritis (see Chapter 516).
 The inflammatory reaction that follows immunologic injury results from activation
of 1 or more mediator pathways. The most important of these is the complement
system, which has 2 initiating sequences: the classic pathway, which is activated by
antigen–antibody immune complexes, and the alternative or properdin pathway,
which is activated by polysaccharides and endotoxin. These pathways converge at
C3; from that point on, the same sequence leads to lysis of cell membranes (see
Chapter 133). The major noxious products of complement activation are produced
after activation of C3 and include anaphylatoxin (which stimulates contractile
proteins within vascular walls and increases vascular permeability) and chemotactic
factors (C5a) that recruit neutrophils and perhaps macrophages to the site of
complement activation, leading to consequent damage to vascular cells and
basement membranes. Therapeutic agents to block the antibody production and
components of the complement cascade are available and may provide additional
tools to treat immune-mediated kidney injury (see Chapters 514 and 518).
o The coagulation system may be activated directly, after endothelial cell injury that exposes
the thrombogenic subendothelial layer (thereby initiating the coagulation cascade), or it
may be activated indirectly, after complement activation. Consequently, fibrin is deposited
within glomerular capillaries or within Bowman’s space as crescents. Activation of the
coagulation cascade can also activate the kinin system, which produces additional
chemotactic and anaphylatoxin-like factors.

PATHOLOGY
The glomerulus may be injured by several mechanisms, but it has only a limited number of
histopathologic responses; different disease states can produce similar microscopic change

Proliferation of glomerular cells occurs in most forms of glomeru- lonephritis and may be generalized
(involving all glomeruli) or focal (involving only some glomeruli and sparing others). Within a single
glomerulus, proliferation may be diffuse (involving all parts of the glomerulus) or segmental (involving
only 1 or more tufts, but not others). Proliferation commonly involves the endothelial and mesan- gial
cells and is often associated with an increase in the mesangial matrix (see Fig. 508-6). Mesangial
proliferation can result from deposi- tion of immune complex within the mesangium. The resultant
increase in cell size and number, and production of mesangial matrix, can increase glomerular size and
narrow the lumens of glomerular capil- laries, leading to renal insufficiency.
Crescent formation in Bowman’s space (capsule) is a result of pro- liferation of parietal epithelial cells
and is often associated with clinical signs of renal dysfunction. Crescents develop in several forms of
glomerulonephritis (termed rapidly progressive or crescentic; see Chapter 516) and are a characteristic
response to deposition of fibrin in Bowman’s space. Newly formed crescents contain fibrin, the prolif-
erating epithelial cells of Bowman’s space, basement membrane–like material produced by these cells,
and macrophages that might have a role in the genesis of glomerular injury. Over the subsequent days
to weeks, the crescent is invaded by connective tissue and becomes a fibroepithelial crescent. This
process generally results in glomerular obsolescence and the clinical development of chronic renal
failure. Crescent formation is often associated with glomerular cell death. The necrotic glomerulus has a
characteristic eosinophilic appearance and usually contains nuclear remnants. Crescent formation is
usually asso- ciated with generalized proliferation of the mesangial cells and with either immune
complex or anti-GBM antibody deposition in the glo- merular capillary wall.
Certain forms of acute glomerulonephritis show glomerular exuda- tion of blood cells, including
neutrophils, eosinophils, basophils, and mononuclear cells. The thickened appearance of GBM can result
from a true increase in the width of the membrane (as seen in mem- branous glomerulopathy; see
Chapter 512), from massive deposition of immune complexes that have staining characteristics similar to
the membrane (as seen in systemic lupus erythematosus; see Chapter 514), or from the interposition of
mesangial cells and matrix into the sub- endothelial space between the endothelial cells and the GBM.
The last can give the basement membrane a split appearance, as seen in type I membranoproliferative
glomerulonephritis (see Chapter 513) and other diseases.
Sclerosis refers to the presence of scar tissue within the glomerulus. Occasionally, pathologists use this
term to refer to an increase in mesangial matrix.
Tubulointerstitial fibrosis is present in all patients who have glo- merular disease and who develop
progressive renal injury. This fibrosis is initiated by injury to either the glomeruli, which, if severe, may
secondarily involve the tubules, or direct injury to the tubules themselves. Tubular injury recruits
mononuclear cell infiltrate, which releases a variety of soluble factors that have fibrosis-promoting
effects. Matrix proteins of the renal interstitium begin to accumulate, leading to even- tual destruction
of renal tubules and peritubular capillaries. The actual transformation of tubular epithelium to
mesenchymal tissue can con- tribute to progressive tubulointerstitial fibrosis, a process termed
epithelial-mesenchymal transformation.

Cellular location of injury during glomerulonephritis.

A. Mesangial cell disease
a. IgA nephropathy,
b. IgM nephropathy,
c. Mesangioproliferative glomerulonephritis
d. Class II lupus nephritis,
e. Diabetic nephropathy
B. Epithelial cell injury
a. Membranous nephropathy,
b. Minimal change disease,
c. Focal segmental glomerulosclerosis,
d. Class V lupus nephritis,
e. Diabetic nephropathy
A. Endothelial cell injury
a. Infection-associated glomerulonephritis
b. Mesangiocapillary glomerulonephritis,
c. Class III and IV lupus nephritis,
d. Anti–glomerular basement membrane disease,
e. Vasculitis and cryoglobulinemia,
f. Hemolytic-uremic syndrome

Mesangial cells are directly exposed to the circulation. Deposition of immune complexes within these
cells is typically seen in disorders such as immunoglobulin A (IgA) nephropathy; it results in proliferation
and expansion of the cells, leading to hematuria, proteinuria, and renal impairment.
Epithelial cells, in conjunction with basement membrane, allow filtration of plasma solutes but retard
passage of cells and plasma proteins. Disease related to these cells is typified by the presence of
subepithelial deposits and flattening of the foot processes that engage the basement membrane,
resulting in disruption of the filtration barrier and proteinuria.
Endothelial cell disease can result from deposition of immune complex (as occurs in mesangiocapillary
glomerulonephritis), attachment of antibody to the basement membrane (Goodpasture disease), or
trauma and activation of coagulation (hemolytic-uremic syndrome). Endothelial cell proliferation and
necrosis are accompanied by leukocyte accumulation, and rupture of the basement membrane, crescent
formation, and disruption of glomerular architecture can develop. A nephritic or rapidly progressive
presentation ensues. (From Chadban SJ, Atkins RC: Glomerulonephritis, Lancet 365:1797–1806, 2005.)