Page 540 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

526 C H A P T E R 13 Kidney and Its Collecting System
Figure 13–7 High-power view of focal and segmental glomerulosclero-
sis (periodic acid–Schiff stain), seen as a mass of scarred, obliterated
capillary lumens with accumulations of matrix material that has replaced
a portion of the glomerulus.
(Courtesy of Dr. H. Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, antigens. An endogenous podocyte antigen, the phospholi-
Massachusetts.)
in the areas of hyalinosis. On electron microscopy, the podo-
cytes exhibit effacement of foot processes, as in minimal-
change disease.
In time, progression of the disease leads to global sclerosis
of the glomeruli with pronounced tubular atrophy and inter-
stitial fibrosis. This advanced picture is difficult to differentiate
from other forms of chronic glomerular disease, described
later on.
A morphologic variant called collapsing glomerulopa-
thy is being increasingly reported. It is characterized by col-
lapse of the glomerular tuft and podocyte hyperplasia. This
is a more severe manifestation of FSGS that may be idiopathic
or associated with HIV infection, drug-induced toxicities, and
some microvascular injuries. It carries a particularly poor
prognosis.
Clinical Course
In children it is important to distinguish FSGS as a cause of the
nephrotic syndrome from minimal-change disease, because the
clinical courses are markedly different. The incidence of
hematuria and hypertension is higher in persons with
FSGS than in those with minimal-change disease; the FSGS-
associated proteinuria is nonselective; and in general the
response to corticosteroid therapy is poor. At least 50% of
patients with FSGS develop end-stage kidney disease
within 10 years of diagnosis. Adults typically fare even less
well than children.
Membranous Nephropathy
Membranous nephropathy is a slowly progressive disease,
most common between 30 and 60 years of age. It is char­
acterized morphologically by the presence of subepithelial
immunoglobulin-containing deposits along the GBM. Early in
the disease, the glomeruli may appear normal by light
microscopy, but well-developed cases show diffuse thicken-
ing of the capillary wall.
In about 85% of cases, membranous nephropathy is
caused by autoantibodies that cross-react with antigens
expressed by podocytes. In the remainder (secondary
membranous nephropathy), it occurs secondary to other
disorders, including
• Infections (chronic hepatitis B, syphilis, schistosomiasis,
malaria)
• Malignant tumors, particularly carcinoma of the lung
and colon and melanoma
• Systemic lupus erythematosus and other autoimmune
conditions
• Exposure to inorganic salts (gold, mercury)
• Drugs (penicillamine, captopril, nonsteroidal anti-
inflammatory agents)
PAT H O G E N E S I S
Membranous nephropathy is a form of chronic
immune complex glomerulonephritis induced by anti-
bodies reacting in situ to endogenous or planted glomerular
pase A2 receptor, is the antigen that is most often recognized
by the causative autoantibodies.
The experimental model of membranous nephropathy is
Heymann nephritis, which is induced in animals by immuniza-
tion with renal tubular brush border proteins that also are
present on podocytes. The antibodies that are produced
react with an antigen located in the glomerular capillary wall,
resulting in granular deposits (in situ immune complex
formation) and proteinuria without severe inflammation.
A puzzling aspect of the disease is how antigen-antibody
complexes cause capillary damage despite the absence of
inflammatory cells. The likely answer is by activating comple-
ment, which is uniformly present in the lesions of membra-
nous nephropathy. It is hypothesized that complement
activation leads to assembly of the C5b-C9 membrane attack
complex, which damages mesangial cells and podocytes
directly, setting in motion events that cause the loss of slit
filter integrity and proteinuria.
MORPHOLOGY
Histologically, the main feature in membranous nephropathy
is diffuse thickening of the capillary wall (Fig. 13–8, A).
Electron microscopy reveals that this thickening is caused in
part by subepithelial deposits, which nestle against the
GBM and are separated from each other by small, spikelike
protrusions of GBM matrix that form in reaction to the
deposits (spike and dome pattern) (Fig. 13–8, B). As the
disease progresses, these spikes close over the deposits,
incorporating them into the GBM. In addition, as in other
causes of nephrotic syndrome, the podocytes show efface-
ment of foot processes. Later in the disease, the incor-
porated deposits may be broken down and eventually
disappear, leaving cavities within the GBM. Continued deposi-
tion of basement membrane matrix leads to progressive
thickening of basement membranes. With further progres-
sion, the glomeruli can become sclerosed. Immunofluores-
cence microscopy shows typical granular deposits
of immunoglobulins and complement along the GBM
(Fig. 13–4, A).