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Postinfectious glomerulonephritis
IGA NEPHROPATHY
PAUCI-IMMUNE GLOMERULONEPHRITIS
(ANCA-ASSOCIATED)
Poststreptococcal GN commonly follows streptococcal pharyngitis during cold-
weather months and streptococcal skin infections or pyoderma during warm-
weather months
(1) glomerular trapping of circulating immune complexes
(2) in situ immune antigen-antibody complex formation resulting from
antibodies reacting with either streptococcal components deposited in the
glomerulus or with components of the glomerulus itself, which has been
termed molecular mimicry.
Nephritogenic streptococci produce proteins with unique antigenic
determinants. These antigenic determinants have a particular affinity for sites
within the normal glomerulus. Following release into the circulation, the
antigens bind to these sites within the glomerulus. Once bound to the
glomerulus, they activate complement directly by interaction with properdin.
Glomerular-bound streptococcal antibodies also serve as fixed antigens and
bind to circulating antistreptococcal antibodies, forming immune complexes.
Complement fixation via the classic pathway leads to the generation of
additional inflammatory mediators and recruitment of inflammatory cells.
nephritis strainassociated protein (NSAP), and nephritis-associated plasmin
receptor (NAPlr),
IgA nephropathy (Berger disease) is a primary renal disease of IgA deposition in
the glomerular mesangium
IgA nephropathy can be a primary (renal-limited) disease, or it can be
secondary to hepatic cirrhosis, celiac disease, and infections such as HIV and
cytomegalovirus. Susceptibility to IgA nephropathy seems to be inheritable. IgA
nephropathy is the most common primary glomerular disease worldwide,
particularly in Asia. It is most commonly seen in children and young adults, with
males affected two to three times more commonly than females
is caused by the following systemic ANCA-associated small-vessel vasculitides:
granulomatosis with polyangiitis (formerly known as Wegener granulomatosis),
microscopic polyangiitis (no lungs) , and Churg-Strauss disease (history of
asthma or allergy
The pathogenesis of these entities appears to involve cytokine-primed
neutrophils presenting cytoplasmic antigens on their surfaces (proteinase 3 and
myeloperoxidase). Circulating
ANCAs then bind to these antigens and activate a neutrophil respiratory burst
with consequent vascular damage.
Putative environmental exposures that may encite the initial response include S
aureus and silica.
classic example of the acute nephritic syndrome characterized by the
sudden onset of gross hematuria, edema, hypertension, and renal
insufficiency
Poststreptococcal GN is most common in children ages 5-12 yr and
uncommon before the age of 3 yr.
The typical patient develops an acutebnephritic syndrome 1-2 wk after an
antecedent streptococcal pharyngitis or 3-6 wk after a streptococcal
pyoderma.
The severity of kidney involvement varies from asymptomatic microscopic
hematuria with normal renal function to gross hematuria with acute renal
failure.
Edema is the most frequent and sometimes the only clinical finding.
According to some investigators, edema is found in approximately 85% of
patients. Edema usually appears abruptly and first involves the periorbital
area, but it may be generalized. The degree of edema widely varies and
depends on a number of factors, including the severity of glomerular
involvement, the fluid intake, and the degree of hypoalbuminemia. The
triad of edema, hematuria, and hypertension is classic for APSGN.
If the nephritic syndrome is present, edema is first seen in regions of low
tissue pressure such as the periorbital and scrotal areas. Hypertension in
the nephritic syndrome is due to sodium retention resulting from acute
decrease in GFR. Heavy glomerular bleeding from inflammation may result
in gross hematuria (smoky or cola-colored urine)
An episode of gross hematuria is the most common presenting symptom.
Frequently, this is associated with a mucosal viral infection such as an
upper respiratory infection. The urine becomes red or smokey-colored 12
days after illness onseta so-called synpharyngitic presentation in
contradistinction to the latent period seen in
postinfectious glomerulonephritis.
Symptoms of a systemic inflammatory disease, including fever, malaise,
and weight loss may be present and usually precede initial presentation by
In addition to hematuria and proteinuria from glomerular inflammation,
some patients exhibit purpura from dermal capillary involvement and
mononeuritis multiplex from nerve arteriolar involvement.
Ninety percent of patients with granulomatosis with polyangiitis have
upper (especially sinus)
or lower respiratory tract symptoms with nodular lesions that can cavitate
and bleed. Hemoptysis is a concerning sign and usually warrants
hospitalization and aggressive immunosuppression
Immunofluorescence microscopy reveals a pattern of lumpy-bumpy
deposits of immunoglobulin and complement on the glomerular
basement membrane and in the
mesangium. On electron microscopy, electron-dense deposits, or
humps, are observed on the epithelial side of the glomerular basement
membrane
Serum complement levels are low
Postinfectious glomerulonephritis due to group A streptococcal
infection,anti-streptolysin O (ASO) titers can be high unless theimmune
response has been blunted with previous antibiotictreatment.
Urinalysis demonstrates red blood cells, often in association with red
blood cell casts, proteinuria, and polymorphonuclear leukocytes.
mild normochromic anemia may be present from hemodilution and
low-grade hemolysis. The serum C3 level is significantly reduced in
>90% of patients in the acute phase, and returns to normal 6-8 wk after
onset. Although serum CH50 is commonly depressed, C4 is most often
normal in APSGN, or only mildly depressed.
There are no serologic tests that aid in this diagnosis;
serum IgA subclass 1 testing may be a possibility in the
future. Serum complements are normal. The typical pattern of injury seen
on kidney biopsy is a focal glomerulonephritis with mesangial
proliferation; immunofluorescence
demonstrates diffuse mesangial IgA and C3 deposits
Serologically, ANCA subtype analysis is done to determine whether
antiproteinase-3 antibodies (PR3-ANCA) or antimyeloperoxidase
antibodies (MPO-ANCA) are present.
Most patients with granulomatosis with polyangiitis are PR3 positive; the
remainder are MPO positive or, more rarely, do not demonstrate ANCA
serologically. Microscopic angiitis is generally associated with MPO ANCA.
Renal biopsy demonstrates necrotizing lesions and crescents on light
microscopy; immunofluorescence is negative
for immune complex deposition.
ANTI-GLOMERULAR BASEMENT
MEMBRANE GLOMERULONEPHRITIS &
GOODPASTURE SYNDROME
SYSTEMIC LUPUS ERYTHEMATOSUS
Minimal Change Disease
Goodpasture syndrome is defined by the clinical constellation of
glomerulonephritis and pulmonary hemorrhage; injury to both is mediated by
antibodies to epitopes in the
GBM
Renal involvement in SLE is very common, with estimates
ranging from 35% to 90%the higher estimates encompassing subclinical
disease.
Rates of lupus nephritis are
highest in non-whites.
The pathogenesis may be dysregulated cellular apoptosis resulting in
autoantibodies against nucleosomes; antibody/nucleosome complexes then
bind to components of the glomerulus to form immune complex glomerular
disease.
The majority of children with SLE are adolescent females. Lupus
nephritis affects most pediatric patients, and although commonly
presenting within the first year of diagnosis, may occur at any time
during the course of the disease.
is the most common cause of proteinuric renal disease in children, accounting
for about 80%
of cases. It often remits upon treatment with a course of
corticosteroids
The idiopathic nephrotic syndrome is more common in boys than in
girls (2 : 1) and most commonly appears between the ages of 2 and 6 y
The initial episode of idiopathic nephrotic syndrome, as well as
subsequent relapses, usually follows minor infections and, uncommonly,
reactions to insect bites, beestings, or poison ivy.
In children, the following:
Sudden onset of unexplained nephrotic-range proteinuria that is
mainly albumin
Normal renal function
Non-nephritic urine sediment
Renal biopsy in atypical cases
Renal biopsy is required in atypical cases and in adults. Electron microscopy
The onset of disease may be preceded by an upper respiratory tract
infection; hemoptysis, dyspnea, and possible respiratory failure may ensue.
Other findings are consistent with an RPGN, although some cases may
present with much milder forms of the nephritic spectrum of disease
(eg, glomerular hematuria and proteinuria with minimal renal dysfunction)
Nonglomerular syndromes include tubulointerstitial nephritis and
vasculitis.
All patients with SLE should have routine urinalyses to
monitor for the appearance of hematuria or proteinuria. If
urinary abnormalities are detected, kidney biopsy is often
performed.
In most patients with active disease, C3
and C4 levels are depressed. In view of the lack of a clear correlation
between the clinical manifestations and the severity of the renal
involvement, renal biopsy should be performed in all patients withSLE.
Histopathologic findings are used to determine the selection of
specific immunosuppressive therapies.
Patients may be asymptomatic or may have edema or
frothy urine. Venous thrombosis, such as an unprovoked
deep venous thrombosis may be an initial sign. There may
be symptoms or signs of an underlying infection or neoplasm (especially
lung, stomach, breast, and colon cancers)
in secondary membranous nephropathy.
Children usually present with mild edema, which is initially noted
around the eyes and in the lower extremities. Nephrotic syndrome can
initially be misdiagnosed as an allergic disorder because of the periorbital
swelling that decreases throughout the day. With time, the edema
becomes generalized, with the development of ascites, pleural effusions,
and genital edema. Anorexia, irritability, abdominal pain, and diarrhea are
common. Important features of minimal change idiopathic nephrotic
syndrome are the absence of hypertension and gross hematuria (the so-
called nephritic features).
Chest radiographs may demonstrate pulmonary infiltrates if pulmonary
hemorrhage is present.
Serum complement levels are normal. Circulating anti-GBM antibodies
are present in over 90% of patients. A small percentage of patients also
have elevated ANCA titers; these patients should be treated with plasma
exchange as for anti-GBM disease. Kidney biopsy typically shows crescent
formation on light microscopy, with linear IgG staining along the GBM on
immunofluorescence
class I, minimal mesangial
nephritis; class II, mesangial proliferative nephritis; class
III, focal (< 50% of glomeruli affected with capillary
involvement) proliferative nephritis; class IV, diffuse
(> 50% of glomeruli affected with capillary involvement)
proliferative nephritis; class V, membranous nephropathy;
and class VI, advanced sclerosis without residual disease
activity. Classes III and IV, the most severe forms of lupus
nephritis, are further classified as active or chronic, and
global or segmental, which confers additional prognostic
value
Serum evaluation for circulating PLA2R antibodies to
assess for idiopathic membranous nephropathy may be
available in the future. By light microscopy, capillary wall
thickness is increased without inflammatory changes or
cellular proliferation; when stained with silver methenamine, a spike
and dome pattern results from to projections of excess GBM between
the subepithelial deposits.
Immunofluorescence shows IgG and C3 staining along
capillary loops. Electron microscopy shows a discontinuous pattern of
dense deposits along the subepithelial surface of the basement
membrane
 demonstrates edema with diffuse swelling (effacement) of foot processes of
the epithelial podocytes (see see Figure: Electron microscopic features in
immunologic glomerular disorders.). Complement and Ig deposits are absent on
immunofluorescence. Although effacement is not observed in the absence of
proteinuria, heavy proteinuria may occur with normal foot processes.
FOCAL SEGMENTAL This is a relatively common renal pattern of injury resulting from damage to
GLOMERULOSCLEROSIS podocytes.
The list of possible causes
of podocyte injury is long and diverse and includes primary renal disease due to
(1) heritable abnormalities in any of several podocyte proteins,
(2) polymorphisms in the APOL1 gene in those of African descent, or (3)
increased levels of soluble urokinase receptors or increased
expression of CD80 (B7-1) on podocytes
Secondary FSGS may result from overwork injury, obesity, hypertension,
chronic urinary reflux, HIV infection, or analgesic
or bisphosphonate exposure
Dm nephropathy s glomerular sclerosis and fibrosis caused by the metabolic and hemodynamic
changes of diabetes mellitus. It manifests as slowly progressive albuminuria
with worsening hypertension and renal insufficiency. Diagnosis is based on
history, physical examination, urinalysis, and urine albumin/creatinine ratio.
Treatment is strict glucose control, angiotensin inhibition (using ACE inhibitors
or angiotensin II receptor blockers), and control of BP and lipids.
Hyperglycemia causes glycosylation of glomerular proteins, which may be
responsible for mesangial cell proliferation and matrix expansion and vascular
endothelial damage. The glomerular basement membrane classically becomes
thickened
Lesions of diffuse or nodular intercapillary glomerulosclerosis are distinctive;
areas of nodular glomerulosclerosis may be referred to as Kimmelstiel-Wilson
lesions . There is marked hyalinosis of afferent and efferent arterioles as well as
arteriosclerosis; interstitial fibrosis and tubular atrophy may be present. Only
mesangial matrix expansion appears to correlate with progression to end-stage
renal disease
Clinically, patients present
with proteinuria; 80% of children and 50% of adults have
overt nephrotic syndrome in primary FSGS. Decreased
GFR is present in 2550% at time of diagnosis. Patients
with FSGS and nephrotic syndrome typically progress to
ESRD in 68 years
Some people with FSGS develop swelling (edema) of the eyelids in the
morning and edema of the legs and body late in the day due to retention of
fluid and this is what leads them to seek medical attention. Some notice
foamy or bubbly urine when they urinate (due to the protein in the urine).
Because symptoms may develop gradually, the disorder may first be
discovered when there is an abnormal urine test (with protein and blood)
or blood test (abnormal kidney function) done for a routine physical exam
or on exam for an unrelated disorder. Many patients will have high blood
pressure at the time of diagnosis.
FSGS patients commonly present with heavy proteinuria, hypertension,
renal dysfunction, edema, or a combination; however, asymptomatic, non-
nephroticrange proteinuria is sometimes the only sign. Microscopic
hematuria is occasionally present.
Diabetic nephropathy develops about 10 years after the
onset of diabetes mellitus. It may be present at the time
type 2 diabetes mellitus is diagnosed. The first stage of
diabetic nephropathy is hyperfiltration with an increase in
GFR, followed by the development of microalbuminuria
(30300 mg/d). With progression, albuminuria increases
to > 300 mg/d and can be detected on a urine dipstick as
overt proteinuria; the GFR subsequently declines over
time. Yearly screening for microalbuminuria is recommended for all
diabetic patients to detect disease at its
earliest stage; however, diabetic nephropathy can, less commonly result in
nonproteinuric CKD.
Diagnosis requires kidney biopsy. Light microscopy
shows sclerosis of portions (or segments) of some, but not
all glomeruli (thus, focal and not diffuse disease). IgM and
C3 are seen in the sclerotic lesions on immunofluorescence, although it is
presumed that these immune components are simply trapped in the
sclerotic glomeruli and are
not pathogenic. Electron microscopy shows fusion of epithelial foot
processes as seen in minimal change disease.
Manifestations of nephrotic syndrome
BUN in 20-40%
Normal complement levels
LM
Focal and segmental sclerosis
Hyalinosis
Adhesions to Bowman's Capsule
Hypercellular mesangium
Thick B.M.
F.M. = IgM, C3
E.M. = Loss of foot processes, detachment of epithelium from B.M.
The most common lesion in diabetic nephropathy is
diffuse glomerulosclerosis, but nodular glomerulosclerosis
(Kimmelstiel-Wilson nodules) is pathognomonic. The
kidneys are usually enlarged as a result of cellular hypertrophy and
proliferation. Kidney biopsy is not required in
most patients, though, unless atypical findings are present,
such as sudden onset of proteinuria, nephritic spectrum
features (see above), massive proteinuria (>10 g/d), urinary
cellular casts, or rapid decline in GFR.
DN is asymptomatic in early stages. Sustained microalbuminuria is the
earliest warning sign. Hypertension and some measure of dependent
edema eventually develop in most untreated patients. In later stages,
patients may develop symptoms and signs of uremia (eg, nausea,
vomiting, anorexia) earlier (ie, with higher GFR) than do patients without
DN, possibly because the combination of end-organ damage due to
diabetes (eg, neuropathy) and renal failure worsens symptoms.
Membranous Nephropathy is deposition of immune complexes on the glomerular basement membrane
(GBM) with GBM thickening. Cause is usually unknown, although secondary
causes include drugs, infections, autoimmune disorders, and cancer.
Manifestations include insidious onset of edema and heavy proteinuria with
benign urinary sediment, normal renal function, and normal or elevated BP.
Diagnosis is by renal biopsy. Spontaneous remission is common. Treatment of
patients at high risk of progression is usually with corticosteroids
andcyclophosphamide or chlorambucil.
Acute tubulointerstitial nephritis
Acute tubulointerstitial nephritis (ATIN) involves an inflammatory infiltrate and
edema affecting the renal interstitium that often develops over days to months.
Over 95% of cases result from infection or an allergic drug reaction.
ATIN causes acute kidney injury; severe cases, delayed therapy, or continuance
of an offending drug can lead to permanent injury and chronic kidney disease.
Patients typically present with edema and nephrotic-range proteinuria
MN is usually idiopathic but may be secondary to any of the following: and occasionally with microscopic hematuria and hypertension.
Symptoms and signs of a disorder causing MN (eg, a cancer) may be
Drugs (eg, gold, penicillamine, NSAIDs) present initially.
Infections (eg, hepatitis B or C virus infection, syphilis, HIV)
Autoimmune disorders (eg, SLE)
Thyroiditis
Cancer
Parasitic diseases (eg, malaria, schistosomiasis, leishmaniasis)
Depending on the patients age, 4 to 20% have an underlying cancer,
including solid cancers of the lung, colon, stomach, breast, or kidney;
Hodgkin or non-Hodgkin lymphoma; chronic lymphocytic leukemia; and
melanoma. MN is rare in children and, when it occurs, is usually due to
hepatitis B virus infection or SLE. Renal vein thrombosis is more frequent in
MN and is usually asymptomatic, but may manifest with flank pain,
hematuria, and hypertension. It may progress to pulmonary embolism
Symptoms and signs of ATIN may be nonspecific and are often absent Urinalysis that shows signs of active kidney inflammation (active urinary
unless symptoms and signs of renal failure develop. Many patients develop sediment), including RBCs, WBCs, and WBC casts, and absence of bacteria
polyuria and nocturia (due to a defect in urinary concentration and sodium on culture (sterile pyuria) is typical; marked hematuria and dysmorphic
reabsorption). RBCs are uncommon. Eosinophiluria has traditionally been thought to
suggest ATIN; however, the presence or absence of urinary eosinophils is
ATIN symptom onset may be as long as several weeks after initial toxic not particularly useful diagnostically. Proteinuria is usually minimal but
exposure or as soon as 3 to 5 days after a 2nd exposure; extremes in may reach nephrotic range with combined ATIN-glomerular disease
latency range from 1 day with rifampin to 18 mo with an NSAID. Fever and induced by NSAIDs, ampicillin, rifampin, interferon alfa, or ranitidine.
urticarial rash are characteristic early manifestations of drug-induced ATIN,
but the classically described triad of fever, rash, and eosinophilia is present Blood test findings of tubular dysfunction include hypokalemia (caused by
in < 10% of patients with drug-induced ATIN. Abdominal pain, weight loss, a defect in potassium reabsorption) and a nonanion gap metabolic
and bilateral renal enlargement (caused by interstitial edema) may also acidosis (caused by a defect in proximal tubular bicarbonate reabsorption
occur in ATIN and with fever may mistakenly suggest renal cancer or or in distal tubular acid excretion).

polycystic kidney disease. Peripheral edema and hypertension are

uncommon unless renal failure occurs. Ultrasonography, radionuclide scanning, or both may be needed to

differentiate ATIN from other causes of acute kidney injury, such as acute

tubular necrosis. In ATIN, ultrasonography may show kidneys that are

greatly enlarged and echogenic because of interstitial inflammatory cells

and edema. Radionuclide scans may show kidneys avidly taking up

radioactive gallium-67 or radionuclide-labeled WBCs. Positive scans

strongly suggest ATIN (and indicate that acute tubular necrosis is less

likely), but a negative scan does not exclude ATIN.

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