C h a p t e r 2 5
Disorders of Renal Function
627
Glomerular Lesions Associated with
Systemic Disease
Many systemic diseases (e.g., systemic lupus erythema-
tosus, diabetes mellitus) are associated with glomerular
injury. In some diseases the glomerular involvement may
be the major clinical manifestation.
Systemic Lupus Erythematosus Glomerulonephritis.
Renal involvement is one of the most common compli-
cations of SLE.
5,18
The pathogenesis of SLE (see Chapter
44) is uncertain, but appears to be related to dysregu-
lated B-cell immunity with production of autoantibod-
ies to a variety of nuclear, cytoplasmic, extracellular
matrix, and cell membrane components. Most glomer-
ular injury is triggered by the deposition of immune
complexes within the glomerular wall. Immune com-
plexes may derive from the circulation, develop locally,
or both.
The clinical manifestations of SLE glomerulonephri-
tis, commonly referred to as
lupus nephritis
, depend on
the site of immune complex–mediated injury. Immune
complexes confined to the mesangium cause less
inflammation than subendothelial immune complexes,
which have greater exposure to inflammatory cells and
mediators in the blood and therefore are more likely
to produce inflammation.
5,18
Immune complexes may
also localize in the renal interstitium, walls of inter-
stitial vessels, and basement membranes, causing the
tubulointerstitial inflammation that occurs in persons
with SLE.
5
Because of the high risk for kidney disease, all per-
sons with SLE should undergo routine urinalysis to
monitor for the appearance of hematuria or proteinuria.
If urinary abnormalities are noted, renal biopsy is often
performed. Treatment depends on the extent of glomer-
ular involvement. Oral corticosteroids and angiotensin-
converting enzyme (ACE) inhibitors are the mainstays
of treatment. Persons with more advanced disease may
require treatment with immunosuppressive agents (e.g.,
intravenous cyclophosphamide or oral mycophenolate
mofetil). Clinical trials using other immunosuppressant
agents are ongoing.
Diabetic Glomerulosclerosis.
Diabetic nephropathy
is a major cause of chronic kidney disease and the most
common cause of kidney failure treated by renal replace-
ment therapy in the United States.
4,5,19,20
It occurs in both
type 1 and type 2 diabetes mellitus.
The lesions of diabetic nephropathy most commonly
involve the glomeruli and are associated with three glo-
merular syndromes: nonnephrotic proteinuria, nephrotic
syndrome, and chronic renal failure. Widespread thick-
ening of the glomerular capillary basement membrane
occurs in almost all persons with diabetes and can occur
without evidence of proteinuria. This is followed by a
diffuse increase in mesangial matrix, with mild prolif-
eration of mesangial cells. As the disease progresses, the
mesangial cells impinge on the capillary lumen, reduc-
ing the surface area for glomerular filtration. In nodular
glomerulosclerosis, also known as
Kimmelstiel-Wilson
syndrome,
there is nodular deposition of hyaline in the
mesangial portion of the glomerulus. As the sclerotic
process progresses in the diffuse and nodular forms of
glomerulosclerosis, there is complete obliteration of the
glomerulus, with impairment of renal function.
Although the mechanisms of glomerular change
in diabetes are uncertain, they are thought to repre-
sent enhanced or defective synthesis of the glomeru-
lar basement membrane and mesangial matrix with
inappropriate incorporation of glucose into the non-
cellular components of these glomerular structures.
20
Alternatively, hemodynamic changes that occur sec-
ondary to elevated blood glucose levels may con-
tribute to the initiation and progression of diabetic
glomerulosclerosis.
4
It has been hypothesized that
elevations in blood glucose produce an increase in
GFR and glomerular pressure that leads to enlarge-
ment of glomerular capillary pores by a mechanism
that is, at least partly, mediated by angiotensin II. This
enlargement results in an increase in the protein con-
tent of the glomerular filtrate, which in turn requires
increased endocytosis of the filtered proteins by tubu-
lar endothelial cells, a process that ultimately leads to
nephron destruction and progressive deterioration of
renal function.
The clinical manifestations of diabetic glomerulo-
sclerosis are closely linked to those of diabetes. The
increased GFR that occurs in persons with early altera-
tions in renal function is associated with
microalbu-
minuria,
defined as urinary albumin excretion of 30 to
300 mg in 24 hours.
5
Microalbuminuria is an impor-
tant predictor of future diabetic nephropathies.
4,19
In
many cases, these early changes in glomerular func-
tion can be reversed by careful control of blood glu-
cose levels (see Chapter 33). Inhibition of angiotensin
by ACE inhibitors or ARBs has been shown to have a
beneficial effect, possibly by reversing increased glo-
merular pressure. Hypertension and cigarette smok-
ing have been implicated in the progression of diabetic
nephropathy. Thus, control of blood pressure (to levels
of 130/80 mm Hg or less) and smoking cessation are
recommended as primary and secondary prevention
strategies in persons with diabetes.
SUMMARY CONCEPTS
■■
Glomerulonephritis represents a group of kidney
diseases that result from inflammation and injury
of the glomerulus. It may occur as a primary
condition in which the glomerular abnormality
is the only disease present, or as a secondary
condition in which the glomerular abnormality
results from another disease, such as diabetes
mellitus or SLE. Most cases of primary and many
cases of secondary glomerular disease probably
have an immune origin.
(continued)
