CHAPTER
Nephritic Syndrome
11 Patrick Niaudet
Nephritic syndrome is a clinical syndrome defined by the
association of hematuria, proteinuria, and often arterial
hypertension and renal failure. Nephritic syndrome is due to
glomerular injury with glomerular inflammation. Clinical
presentations of nephritic syndrome include acute nephritic
syndrome, syndrome of rapidly progressive glomerulonephri-
tis, syndrome of recurrent macroscopic hematuria, and syn-
drome of chronic glomerulonephritis. Each presentation can
be associated with several types of glomerulonephritis. Clin-
ical presentation, family history, presence of extrarenal symp-
toms, results of immunologic tests, and renal histology most
often identify the underlying disease. Patients with rapidly
progressive glomerulonephritis need urgent histologic diagno-
sis and treatment to prevent irreversible renal damage.
CLASSIFICATION OF
GLOMERULONEPHRITIS
Glomerulonephritis can be classified on histopathologic
grounds. By light microscopy, there is no histologic lesion
specific of a particular disease. The same morphologic appear-
ance may have different clinical presentations. Whether the
glomerulonephritis is primary or secondary to a systemic
disease, there is always a good correlation between the his-
tologic lesions and the prognosis. With the exception of
acute poststreptococcal glomerulonephritis, this is one
reason why renal biopsy is so important in a patient with
glomerulonephritis.
According to the absence or presence of proliferative
lesions, several disorders may be described. Membranous
glomerulonephritis is the most frequent form of glomeru-
lonephritis without cellular proliferation. It is characterized
by a diffuse thickening of the glomerular basement mem-
brane (GBM) due to the presence of deposits on the epithe-
lial side of the GBM. These deposits are separated by spike
projections of the basement membrane. There are three main
types of proliferative glomerulonephritis. Endocapillary pro-
liferative glomerulonephritis (or mesangial proliferative
glomerulonephritis) is characterized by endocapillary cell
proliferation without alteration of the GBM. The prolifera-
tion mainly involves mesangial cells with an increase of
mesangial matrix. In addition to mesangial cell proliferation,
in some cases endothelial cells may proliferate and circulating
polymporphonuclear cells, as well as monocytes and macro-
phages, may be present. This is characteristic of acute
poststreptococcal glomerulonephritis. The second type is
membranoproliferative glomerulonephritis (MPGN). In
addition to endocapillary cell proliferation, there is a diffuse
thickening of the GBM due to the interposition of mesangial
matrix between the basement membrane and the endothelial
cells. By electron microscopy these two types can be described
as type I with subendothelial deposits and type II with dense
deposits inside the basement membrane. The third type of
proliferative glomerulonephritis is endocapillary and extra-
capillary glomerulonephritis, where endocapillary cell prolif-
eration is accompanied by extracapillary cell proliferation or
crescents.
Immunofluorescence examination is most important for
the study of glomerulonephritis. Several types of deposits
may be present according to their appearance, their location,
and their composition (Table 11-1). There are two types of
glomerulonephritis that can only be diagnosed by immun-
ofluorescence examination. The first is anti-GBM glomeru-
lonephritis with linear deposits of IgG along the glomerular
basement membrane. By light microscopy, the lesions most
often consist of necrotizing and crescentic glomerulonephri-
tis. The second type is IgA nephropathy with the presence
of granular deposits in the mesangium that contain mainly
IgA but also frequently IgG and C3. The same appearance is
observed in Henoch-Schönlein purpura nephritis. By light
microscopy, there are several features that define the severity
of endocapillary and extracapillary cell proliferation.
In other types of glomerulonephritis, immunofluorescence
examination is also helpful to define disease. The presence of
humps that contain C3 on the external side of the GBM is
characteristic of postinfectious glomerulonephritis. Membra-
nous glomerulonephritis is characterized by the presence of
granular deposits on the external side of the GBM that
contain mainly IgG. In membranoproliferative glomerulone-
phritis type I, C3 deposits are found along the GBM and in
the mesangial areas, often in association with IgG deposits.
Voluminous deposits that only contain C3 are present in the
mesangium of patients with MPGN type II. Table 11-2 shows
the main types of glomerulonephritis.
ACUTE NEPHRITIC SYNDROME
The onset of acute nephritic syndrome may be sudden, with
fever, headache, and abdominal pain, or more progressive,
195
with peripheral edema, weight gain, and asthenia. Peripheral
 Chapter 11 Nephritic Syndrome

TABLE 11-1 Immunofluorescence Microscopy in Glomerulonephritis

Deposits Deposits Location Main protein Disease

Linear Continuous GBM IgG Anti-GBM disease
Granular Disseminated Extramembranous C3 Postinfectious GN
Granular Contiguous Extramembranous IgG Membranous GN
Granular Irregular Endomembranous C3 MPGN type I
Granular Nodular Mesangial C3 MPGN type II
Granular Arborized pattern Mesangial IgA IgA nephropathy
Granular Irregular Mesangial and peripheral IgG, IgA, IgM, C3 SLE

TABLE 11-2 Classification of Glomerulonephritis TABLE 11-3 Investigations in a Child with

Primary Membranous glomerulonephritis
glomerulonephritis Membranoproliferative glomerulonephritis
type I
Membranoproliferative glomerulonephritis
type II (dense deposit disease)
IgA nephropathy
Anti-GBM disease
Idiopathic crescentic glomerulonephritis
Secondary Poststreptococcal glomerulonephritis
glomerulonephritis Other infections
Henoch-Schönlein purpura
Systemic lupus erythematosus
Microscopic polyangiitis
Wegener granulomatosus
Churg-Strauss syndrome
Cryoglobulinemia
Rheumatic fever
edema is often moderate but may be more pronounced with
anasarca. Edema and systemic hypertension are secondary to
extracellular volume expansion, including vascular volume
expansion. Pulmonary or cerebral oedema may complicate
acute nephritic syndrome. Hypertension is often severe and
may be responsible for hypertensive encephalopathy with
headaches, seizures, coma, and blindness. Congestive heart
failure may develop due to fluid retention and hypertension,
in which case echocardiography should be performed. Oligu-
ria is accompanied by brown urine. Proteinuria is often prom-
inent, more than 2 g per day, and nonselective. Hematuria is
constant, either microscopic or macroscopic, and higher than
200.000 per minute. There are red blood cell casts and dys-
morphic red blood cells, typical of their glomerular origin.
Renal blood flow and glomerular filtration rate fall, resulting
in a moderate or severe increase in serum creatinine that
usually normalizes within a few days.
Sometimes the clinical presentation is atypical. For
instance, when patients present with oligoanuria, the differ-
ential diagnosis from acute tubular necrosis is not obvious.
The diagnosis may be suspected because the patient is hyper-
tensive and has peripheral edema, and because hematuria
preceded renal failure. Renal histology shows the glomerular
lesions. Other patients may have isolated macroscopic hema-
196
turia, isolated proteinuria, or isolated hypertension.
Acute Nephritic Syndrome or Rapidly
Progressive Glomerulonephritis
Complement levels (CH50, C3, C4)
Antistreptolysin O, anti-DNAse B, antistreptokinase, anti-NADase,
antihyaluronidase antibodies
IgA
Antinuclear antibodies, anti-DNA antibodies
ANCA
Anti-GBM antibodies
Serology for EBV and hepatitis B and C
Renal biopsy with light microscopy and immunofluorescence
The pathologic correlate of acute nephritic syndrome is
proliferative glomerulonephritis. Proliferation is initially due
to the presence of neutrophils and monocytes and later to an
increase in resident glomerular cells, namely endothelial cells
and mesangial cells. This inflammation may involve most
glomeruli (diffuse proliferative glomerulonephritis) or may
be less extensive (focal proliferative glomerulonephritis).1
Clinical, biologic, and histologic evaluations are necessary
to identify the precise glomerular disease, and early diagnosis
is important because many of the disorders respond to
therapy. The clinical history and physical examination may
provide evidence of a systemic disease. A recent skin or
throat infection suggest poststreptococcal glomerulonephri-
tis, whereas a facial rash and arthritis favor systemic lupus
erythematosus. Laboratory investigations are also needed and
can be extensive (Table 11-3). Serum complement measure-
ment, including total hemolytic complement and C3, pro-
vides useful information for classification and follow-up of
acute nephritic syndrome.
Renal biopsy is often required, and immunofluorescence
microscopy examination is particularly helpful in that it may
show granular deposits of immunoglobulins that define
immune-complex glomerulonephritis. Linear deposition of
immunoglobulins along the glomerular basement membrane
is characteristic of anti-GBM disease. The absence of signifi-
cant deposits of immunoglobulins defines a pauci-immune
glomerulonephritis (Figure 11-1).
Most often, at least in children, acute nephritic syndrome
is secondary to acute postinfectious glomerulonephritis.
Acute nephritic syndrome may also be secondary to a primary
 Chapter 11 Nephritic Syndrome

Pauci-immune GN Anti-GBM disease Immune complex GN

Serology ANCA Anti-GBM antibodies Low C3 Normal C3

IF No deposits Linear IgG Granular Ig and C3 Granular Ig and C3

Microscopic polyangiitis Anti-GBM disease Post infectious GN IgA nephropathy

Diseases Wegener Goodpasture MPGN SHP nephritis
SLE
Shunt nephritis

Figure 11-1 Evaluation and diagnosis of acute nephritic syndrome.

TABLE 11-4 Causes of Nephritic Syndrome

in Children

Primary renal diseases IgA nephropathy

Membranoproliferative glomerulonephritis
type I or type II
Anti-GBM disease
Idiopathic crescentic glomerulonephritis
Secondary renal diseases Postinfectious glomerulonephritis
(poststreptococcal, endocarditis,
shunt nephritis)
Henoch-Schönlein purpura nephritis
Systemic lupus erythematosus
Wegener’s granulomatosis
Microscopic polyangiitis

Figure 11-2 Poststreptococcal glomerulonephritis. Endocapillary prolif-

glomerulonephritis such as IgA nephropathy, anti-GBM
disease, MPGN, or pauci-immune glomerulonephritis. Some-
times extrarenal symptoms indicate a secondary glomeru-
lonephritis, such as Henoch-Schönlein purpura nephritis or
lupus nephritis (Table 11-4).
The main cause of acute nephritic syndrome is acute
postinfectious glomerulonephritis, which usually follows a
streptococcal infection.2 It occurs most often after an upper
respiratory tract or a skin infection with a nephritogenic
strain of group A2 β-hemolytic streptococcus. In a child with
acute nephritic syndrome, several features suggest a diagnosis
of acute poststreptococcal glomerulonephritis: a throat or
skin infection in previous weeks, an increase in the antistrep-
tolysin O and anti-DNAse antibody titers, and a marked but
transient reduction of C3 and C4. The diagnosis is usually
made on clinical and serologic grounds. When a renal biopsy
is performed, it shows a diffuse endocapillary proliferative
glomerulonephritis with numerous polynuclear cells and the
eration and numerous red (fibrinous) extramembranous deposits
(humps).
presence of humps on the external side of the GBM (Figure
11-2). In most cases the prognosis is good, with complete
recovery. Early complications include hypertensive encepha-
lopathy, cardiac failure, and pulmonary edema where there
is fluid overload. Except in rare cases with extensive crescent
formation, serum creatinine is moderately elevated and nor-
malizes within a few days, whereas proteinuria disappears
within a few days or weeks and hematuria may last longer.
Complement returns to normal within 6 to 8 weeks. In chil-
dren, a renal biopsy is indicated if the infectious context is
not obvious, the child presents with extrarenal symptoms,
renal failure persists for more than 10 days, C3 remains low
for more than 2 months, and proteinuria does not disappear
197
after 3 to 6 months. Other infectious agents (bacterial, viral,
 Chapter 11 Nephritic Syndrome
TABLE 11-5 Acute Glomerulonephritis
and Infections
Bacterial infections Skin or throat (Streptococcus group A)
Endocarditis (Staphylococcus aureus, Streptococcus
viridans)
Visceral abscess (S. aureus, Escherichia coli,
Pseudomonas, Proteus mirabilis)
Shunt nephritis (S. aureus, Staphylococcus albus,
S. viridans)
Pneumonia (Diplococcus pneumoniae, Mycoplasma)
Typhoid fever (Salmonella typhi)
Viral infections Epstein-Barr virus
Parvovirus B19
Varicella
CMV
Coxsackie
Rubella
Mumps
Hepatitis B
Parasitic infections Schistosoma mansoni
Plasmodium falciparum
Toxoplasma gondii
Filaria
fungal, or parasitic) may also trigger the development of
acute glomerulonephritis (Table 11-5).
Acute nephritic syndrome may be secondary to MPGN.3
Indeed, the clinical presentation of MPGN may mimic acute
postinfectious glomerulonephritis and may show following an
infection. However, with MPGN, proteinuria persists, as well
as a low C3. The C3 and C4 levels are decreased in MPGN
type I due to the activation of both complement pathways.
In MPGN type II or dense deposit disease, C3 is low but C4
is not decreased because only the alternative pathway of
complement activation is involved. An IgG autoantibody (C3
nephritic factor) that binds to the C3 convertase and pro-
motes permanent activation of the alternative pathway is
present in most cases.
Few patients with IgA nephropathy present with acute
nephritic syndrome. Acute nephritic syndrome may also be
observed in children with anti-GBM disease and in children
with vasculitis associated with ANCA, although a clinical
presentation of rapidly progressive glomerulonephritis is
more frequent (see later).
Acute nephritic syndrome may occur in patients with
systemic disease such as Henoch-Schönlein purpura or sys-
temic lupus erythematosus. The clinical manifestations of
Henoch-Schönlein purpura include a classic tetrad of rash,
arthralgias, abdominal pain, and renal disease that can occur
in any order and at any time over several days to several
weeks. Renal disease is usually noted within a few days to 4
weeks after the onset of systemic symptoms.4 Urinalysis in
affected patients reveals mild proteinuria with an active sed-
iment characterized by microscopic (or macroscopic) hema-
turia with red cell and other cellular casts. Most patients have
relatively mild disease characterized by asymptomatic hema-
turia and proteinuria with a normal or only slightly elevated
plasma creatinine concentration. However, more marked
198
findings may occur, including nephrotic syndrome, hyperten-
sion, and acute renal failure. On renal biopsy, the disease is
characterized by the diffuse presence of granular deposits
that always contain predominant IgA localized within the
mesangium. By light microscopy, four patterns may be
described: mesangiopathic glomerulonephritis, focal and seg-
mental glomerulonephritis, diffuse proliferative endocapil-
lary glomerulonephritis, and endocapillary and extracapillary
glomerulonephritis.
Clinical symptoms and signs of renal involvement, which
usually appear during the first years, are noted in 40% to 80%
of patients with systemic lupus erythematosus.5 Proteinuria
is the most frequent abnormality. It may be moderate, but
more often it is abundant when accompanied by nephrotic
syndrome. Microscopic hematuria is mostly associated with
proteinuria. The urinary sediment contains granular casts,
often with red cells. Patients with severe nephritis are often
hypertensive and have reduced renal function with an
increased plasma creatinine. This occurs in up to 50% of
children with lupus nephritis. Anti-double-stranded DNA
antibodies are more specific to systemic lupus erythematosus
(SLE) than are antinuclear antibodies. Hypocomplementemia
is observed in 75% of cases at presentation. Decreased levels
of CH50, C1q, and C4 are related to the activation of the
classical pathway of the complement system. Renal biopsy in
patients with acute nephritic syndrome commonly shows
class III or class IV nephropathy (focal proliferative glomeru-
lonephritis or diffuse proliferative glomerulonephritis) with
immune deposits where IgG, mainly IgG1 and IgG3, is
dominant. IgA and IgM are also present, as well as early
complement components C1q and C4, along with C3. Such
positivity for the three Ig classes and C1q, C4, and C3
is called full house and is only found in lupus nephritis.
Fibrin deposits are also found, particularly in class IV
biopsies.
SYNDROME OF RAPIDLY PROGRESSIVE
GLOMERULONEPHRITIS
The syndrome of rapidly progressive glomerulonephritis is
characterized by a subacute nephritic syndrome with dete-
rioration of renal function.6 Patients often have macroscopic
hematuria with red blood cell casts and heavy proteinuria
with nephrotic syndrome and edema. Hypertension may be
less pronounced than in patients with acute nephritic syn-
drome. Renal failure persists, and patients may develop oli-
goanuria within a few days. The same biologic tests as for
acute nephritic syndrome should be performed, including
detection of anti-GBM antibodies, ANCA, anti-DNA anti-
bodies, and measurement of complement fractions. Renal
biopsy should be performed quickly.
The pathologic correlate of rapidly progressive glomeru-
lonephritis is crescentic glomerulonephritis, where extracap-
illary proliferation involves the majority of glomeruli. The
crescents are composed of monocytes and parietal epithelial
cells that proliferate in the Bowman’s space (Figure 11-3).
Crescents may be segmental or circumferential and are
initially cellular but may rapidly progress to fibrosis. The
prognosis is related to the proportion of crescents, their
extent (segmental or circumferential), and their content (cel-
lular, fibrocellular, or fibrous). An immediate diagnosis and

prompt treatment are necessary to prevent development of
irreversible renal failure.
Rapidly progressive glomerulonephritis can occur as a
primary renal disease without any sign of systemic disease.
The classification is based on the results of immunofluores-
cence microscopy that shows the presence or absence of
immune deposits. Linear deposition of IgG along the glomer-
ular basement membrane is characteristic of anti-GBM
disease. Granular deposits are observed in different primary
glomerular diseases where crescents are superimposed, such
as MPGN, IgA nephropathy, and membranous nephropathy.
Some cases do not show immune deposits and are referred
to as pauci-immune glomerulonephritis. These cases are
frequently associated with antineutrophil cytoplasmic
antibodies.7
Figure 11-3 Crescentic glomerulonephritis. Circumferential fibrocellular
crescent.
C-ANCA
Figure 11-4 Pattern of immunofluorescence of C-ANCA and P-ANCA.
Chapter 11 Nephritic Syndrome
Anti-GBM disease is an autoimmune disease caused by
circulating autoantibodies directed against the α3 chain of
type IV collagen.8,9 This is a rare disorder that may be associ-
ated with pulmonary hemorrhage (Goodpasture syndrome)
or limited to the kidney. Antibodies are bound to the GBM,
accompanied by complement activation, leukocyte infiltra-
tion, ruptures of the GBM, and necrotizing proliferative
glomerulonephritis with crescents. Patients have hematuria,
proteinuria, and rapid deterioration of renal function. Circu-
lating anti-GBM antibodies can be detected with indirect
immunofluorescence by incubating the patient’s serum with
a frozen section of a normal human kidney. The antibody
titer may be measured by radioimmunoassay or by enzyme-
linked immunosorbent assay (ELISA). Renal biopsy shows
crescentic necrotizing glomerulonephritis and linear deposi-
tion of IgG along the GBM, often with C3 deposition.
The presence of circulating antineutrophil cytoplasmic
antibodies (ANCAs) is an important diagnostic clue when the
renal biopsy shows pauci-immune glomerulonephritis.10
These antibodies are detected by indirect immunofluores-
cence and by ELISA (Figure 11-4). A diffuse cytoplasmic
staining by immunofluorescence (C-ANCA) correlates with
the presence of antiproteinase-3 antibodies, whereas a peri-
nuclear staining (P-ANCA) is observed with antimyeloper-
oxidase antibodies. ANCAs are observed in Wegener’s
granulomatosis, microscopic polyangiitis, and idiopathic
necrotizing glomerulonephritis. C-ANCAs are associated
with Wegener’s granulomatosus with a specificity of 95%.
Patients with microscopic polyangiitis may have either C-
ANCAs or P-ANCAs, whereas the majority of those with
necrotizing glomerulonephritis have P-ANCAs.11 ANCAs
may also be found in the serum of patients with SLE, Henoch-
Schönlein purpura, or anti-GBM disease.
Rapidly progressive glomerulonephritis can also result
from immune complex glomerulonephritis, which includes
SLE, Henoch-Schönlein purpura nephritis, poststreptococcal
glomerulonephritis, or endocarditis.
P-ANCA
199
 Chapter 11 Nephritic Syndrome
SYNDROME OF RECURRENT
MACROSCOPIC HEMATURIA
This syndrome is characterized by transient episodes of mac-
roscopic hematuria of 1 to 3 or more days. It often occurs 1
or 2 days following an upper respiratory tract infection. It
can be accompanied by proteinuria, which may or may not
persist after macroscopic hematuria has resolved. Blood pres-
sure is usually normal.
This syndrome is often observed in children with IgA
nephropathy. However, renal biopsy is necessary to confirm
this diagnosis. Recurrent episodes of macroscopic hematuria
may also be observed in children with Alport syndrome.
SYNDROME OF CHRONIC
GLOMERULONEPHRITIS
Most human glomerulonephritis progresses at variable rates
relative to chronic renal failure. Although clinical symptoms
may have developed earlier and brought the child to medical
attention, some children are diagnosed at a late stage of the
disease with hypertension, proteinuria with or without hema-
turia, and progressive renal insufficiency. Renal biopsy at this
stage may show nonspecific lesions of end-stage kidney
disease, and it may not be possible to identify the glomerular
disease that initiated the glomerular lesions. Immunofluores-
cence is often more helpful.
DIFFERENTIAL DIAGNOSIS
Acute nephritic syndrome secondary to acute glomerular
inflammation can mimic other diseases. Children with hemo-
lytic uremic syndrome often have macroscopic hematuria,
proteinuria, hypertension, and acute renal failure but also
show hemolytic anemia with schizocytes and thrombocyto-
penia. In addition, hemolytic uremic syndrome often follows
an episode of diarrhea secondary to a verotoxin-producing
strain of Escherichia coli. Some patients with Alport syn-
drome have macroscopic hematuria and proteinuria, mimick-
ing acute nephritic syndrome. A family history, an association
with hearing defects, and a renal biopsy will confirm the
diagnosis.
PATHOGENESIS
Nephritic syndrome is secondary to glomerular inflammation.
Several immunologic events may initiate glomerular injury.12
The role of antibodies has been clearly demonstrated. The
interaction of antibodies with antigens in situ in the glomer-
ulus, which may or may not lead to the formation of immune
complexes, is the main mechanism of glomular injury, whereas
the glomerular deposition of circulating immune complexes
is probably much less frequent. A cellular immune response
mediated by T lymphocytes has been shown to induce
glomerular injury in experimental models with an infiltration
of glomeruli by circulating inflammatory cells. However, in
most types of glomerulonephritis, both humoral and cellular
events are involved.
Once these events have started, secondary mechanisms of
200
glomerular injury begin with a cascade of inflammatory medi-
ators. These mediators are responsible for an increased per-
meability to proteins and a decreased glomerular filtration
rate. They are also responsible for structural alterations of
the glomeruli with hypercellularity, thrombosis, necrosis, and
crescent formation.13,14
Humoral Immunity
Humoral immunity is involved in many forms of glomeru-
lonephritis, with deposition of antibodies within the kidney
being the initiating event. Indeed, immunoglobulin deposi-
tion is observed in the glomeruli in many forms of glomeru-
lonephritis. These immunoglobulins are presumed to be part
of immune complexes. Circulating immune complexes may
localize in the glomeruli by simple deposition. Normally, fol-
lowing complement activation, circulating immune com-
plexes are cleared when they bind to the C3b receptor on
erythrocytes that are then removed by the liver and spleen.
In some instances circulating immune complexes may bind
to the Fc receptors of mesangial cells and deposit in the
glomeruli. This mechanism is probably less frequent than in
situ formation of immune complexes where antibodies bind
to structural components of the glomerulus or to antigens
that have been trapped or planted within the glomerulus.15
For example, autoantibodies may develop against compo-
nents of the GBM and result in anti-GBM disease. These
autoantibodies have been shown to be directed against an
epitope located in the noncollagenous domain of the α3 chain
of type IV collagen (the Goodpasture antigen).9 The same
antigen is also present in the alveolar basement membrane,
which explains why some patients also develop pulmonary
hemorrhage. Binding of the antibodies to the GBM triggers
the inflammatory response, resulting in glomerulonephritis.
Autoantibodies may be directed against glomerular cell
surface antigens. In the animal model of Heyman nephritis
that resembles human membranous nephropathy, antibodies
are directed against megalin, a member of the low-density
lipoprotein receptor gene family, expressed on epithelial cells
such as podocytes and the brush border of proximal tubular
cells.16,17 The rat Thy 1 model is another example of glomer-
ulonephritis induced by antibodies directed against mesangial
cell antigens.18 Glomerular damage may also result from the
interaction of antibodies directed against endothelial cell
surface antigens. Exogenous antigens trapped or planted in
the glomerulus may bind antibodies, resulting in the in situ
formation of immune complexes. There is increasing evi-
dence that in most types of human glomerulonephritis,
immune complexes are formed in situ and do not result from
the deposition of immune complexes preformed in the cir-
culation.12 Such mechanism may well explain glomerulone-
phritis related to drugs, infectious agents, or endogenous
antigens such as nucleic acids or tumor antigens. These in situ
formed immune complexes tend to disappear unless they
enlarge and stabilize. This occurs when the immune response,
which consists of a polyclonal B-cell activation, induces the
formation of different antibodies such as rheumatoid factors
IgM anti-IgG or anti-idiotypic antibodies that bind to the
complexes. These immune complexes activate the comple-
ment cascade and trigger glomerular inflammation.
In IgA nephropathy, recent studies have shown that IgA
deposition in the glomerular mesangium may be the result of

an abnormal structure.19-21 The glomerular deposits are com-
posed of monomeric IgA1, and it has been shown that the
amount of O-galactose residues in the hinge region is signifi-
cantly decreased in patients with the disease. This structural
anomaly may be responsible for delayed clearance of IgA1
and an increased binding of IgA1 to the mesangial cells.
Cell-Mediated Immunity
The generation of nephritogenic antibodies that initiate
glomerulonephritis requires the presence of T lymphocytes.
T lymphocytes may also cause glomerulonephritis in the
absence of antibodies, although this mechanism is much less
common, occurring in the experimental model of glomeru-
lonephritis when CD4+ T lymphocytes from an animal
immunized with GBM are transferred to a normal animal.22
Secondary Mediators of Glomerulonephritis
Once the primary immunologic event has taken place, a
number of mediators are activated that produce the inflam-
matory response and lead to glomerulonephritis.23,24
Complement
Activation of the complement system contributes to the
inflammatory response as has been demonstrated in several
forms of experimental glomerulonephritis.25,26 Also, deposi-
tion of complement components is a frequent feature of
human glomerulonephritis. Complement activation generates
C3b and C5a, which are small chemoattractant peptides that
stimulate the release of vasoactive amines and chemotactic
factors from basophils and mast cells. C5b fragments also
attract neutrophils, eosinophils, and basophils to the site of
injury.18 The terminal complement components formed by
C5b-C9 constitute the membrane attack complex (MAC)
that can directly injure resident glomerular cells without the
participation of inflammatory cells.27 MAC can also activate
the production of interleukin (IL)-8 and macrophage chemo-
tactic protein-1 (MCP-1) by endothelial cells28 and the pro-
duction of IL-1, reactive oxygen species (ROS), and
prostaglandins by mesangial cells. It also mediates endothelial
cell apoptosis.29 In contrast, the complement system allows
the elimination of circulating immune complexes, preventing
their deposition in the glomeruli. Complement components
maintain the circulating immune complexes as soluble so they
can be cleared by phagocytic cells.
Coagulation System
Activation of the coagulation cascade in the glomeruli is trig-
gered by tissue factor and leads to the formation of thrombi.
Fibrin deposition is frequently observed in necrotizing
glomerulonephritis and crescentic glomerulonephritis. Intra-
glomerular thrombi also have proinflammatory actions. In
several experimental models of glomerulonephritis, fibrino-
lytic agents such as ancrod or streptokinase have a beneficial
effect. The role of fibrin deposition is also demonstrated in
the experimental model of fibrinogen-deficient mice that are
resistant to the induction of anti-GBM disease.30
Recruitment of Leukocytes
Infiltration of glomeruli by leukocytes is a constant feature of
glomerulonephritis. Monocytes and macrophages play a major
Chapter 11 Nephritic Syndrome
role in the inflammatory lesions. Renal injury due to these cells
occurs via the release of proinflammatory cytokines such as
TNFα, the recruitment of leukocytes via the release of chem-
okines such as MCP-1, macrophage inflammatory protein-1α
and Rantes, cell proliferation via the release of macrophage
colony-stimulating factor, cell death via the release of ROS,31
and proteases that may also damage the GBM.32,33 Circulating
monocytes and macrophages are recruited in the kidney
through chemokines produced locally during the inflamma-
tory reaction.34 Experimentally, blockade of chemokines such
as macrophage chemotactic protein-1 or its receptor CCR2,
or RANTES,35-37 prevent leukocyte accumulation in the kidney.
Then, macrophages migrate into the renal tissue following the
interaction between cell surface adhesion molecules and their
ligands on the endothelial cells.38 This migration is regulated
by chemoattractant molecules, especially chemokines.39 Two
families of chemokines have been more extensively investi-
gated, α-chemokines and β-chemokines. α-chemokines have
a common CXC structure and recruit polymorphonuclear
cells. CC or β-chemokines recruit monocytes through their
receptors, CCR. Proliferation of monocytes and macrophages
that increases the inflammatory reaction occurs following the
local production of growth factors such as the monocyte
colony stimulating factor (MCSF).40 Macrophages are impor-
tant effector cells in glomerular lesions following humoral or
cell-mediated immune injury.41 They also release tissue factor
that induces fibrin deposition, crescent formation, and growth
factors such as transforming growth factor beta (TGFβ) and
IL-1 that promote fibrosis.42
The main chemotactic factors for the accumulation of
neutrophils in glomerulonephritis are C5a and other chem-
okines such as IL-8. The migration of neutrophils follows the
interaction of adhesion molecules on these neutrophils with
endothelial cells (selectins, integrins, ICAM-1, and VCAM).
The adhesion molecules are induced following the production
of cytokines and mediators of inflammation. Neutrophils may
then release ROS, particularly H2O2, and proteolytic enzymes
that contribute to glomerular damage.
Endothelial and Mesangial Cells
Glomerular endothelial cell injury occurs following antibody
deposition. This injury induces cell proliferation, expression
of adhesion molecules, and release of vasoctive molecules,
and finally causes necrosis, apoptosis, and thrombosis.43,44
Mesangial cell proliferation occurs in a variety of human
glomerulonephritides, including IgA nephropathy and lupus
nephritis. Activation and proliferation of mesangial cells is
triggered by a variety of mediators such as cytokines, growth
factors, immune complexes, antibodies, and C5b. Activated
mesangial cells produce proinflammatory mediators including
chemokines, cytokines, ROS, prostaglandins, growth factors,
and extracellular matrix components.
Role of Small Peptides
Many growth factors and cytokines are produced by both
glomerular and inflammatory cells.39,45 They bind to specific
cell surface receptors and may either promote or prevent
renal injury. Growth factors such as platelet-derived growth
factor (PDGF), TGFβ, and vascular endothelial growth factor
201
(VEGF) have important roles in glomerular injury, including
 Chapter 11 Nephritic Syndrome
glomerular cell proliferation, extracellular matrix deposition,
and sclerosis. PDGF has a mitogenic effect on mesangial cells
and is a chemoattractant that also promotes tissue repair.46
TGFβ has an antiproliferative effect on glomerular cells and
a proapoptotic action.
Interleukins are known to play an important role in the
inflammatory response. IL-1, IL-8, and IL-18 have a proin-
flammatory action in glomerulonephritis.47 IL-1 induces
mesangial cell proliferation and promotes the synthesis of
several substances. IL-8 is produced by mesangial cells and is
a chemoattractant for granulocytes. Other interleukins such
as IL-4, IL-10, and IL-11 have an anti-inflammatory and
protective effect.
TREATMENT
Most children with acute nephritic syndrome need to be
hospitalized. There is no reason to prescribe rest unless the
child prefers to stay in bed. Dietary recommendations include
restricting water and sodium intake. The amount of water is
calculated according to weight gain and diuresis. In case of
renal failure, potassium intake should also be restricted.
In case of oliguria with weight gain, loop diuretics should
be prescribed. They often induce effective diuresis and con-
sequently reduce blood volume. Furosemide at a dose of
2 mg/kgBW may be given orally or intravenously and repeated
twice a day if needed.
Hypertension should be treated with antihypertensive
drugs. Nifedipine may be given orally at a dose of 0.5 mg/
kgBW every 6 hours. If blood pressure is not well controlled
with nifedipine, the use of nicardipine as a continuous intra-
venous infusion at a dose of 0.5 to 2 μg/kgBW per minute is
recommended.
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