Transcript ACUTE POSTSTREPTOCOCCAL GLOMERULONEPHRITIS

ACUTE POSTSTREPTOCOCCAL
GLOMERULONEPHRITIS
A.R.Merrikhi.MD.
PediatricNephrologist
INTRODUCTION
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Poststreptococcal glomerulonephritis (PSGN) is caused
by prior infection with specific nephritogenic strains of
group A beta-hemolytic streptococcus.
The clinical presentation of PSGN varies from
asymptomatic, microscopic hematuria to the full-blown
acute nephritic syndrome, characterized by red to brown
urine, proteinuria (which can reach the nephrotic range),
edema, hypertension, and acute kidney injury.
The prognosis is generally favorable, especially in
children, but in some cases, the long-term prognosis is
not benign.
*Diffuse Intracapillary GN
*Diffuse Endocapillary GN
*Acute Postinfection GN
EPIDEMIOLOGY
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Although PSGN continues to be the most common
cause of acute nephritis globally, it primarily
occurs in developing countries.
Of the estimated 470,000 new annual cases of
PSGN worldwide, 97 percent occur in developing
countries, with an annual incidence that ranges
from 9.5 to 28.5 per 100,000 individuals.
In more developed and industrialized countries,
the incidence has decreased over the past three
decades.
EPIDEMIOLOGY
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Based upon data from the Italian Biopsy registry, the
estimated annual incidence was 0.3 per 100,000
individuals between 1992 and 1994.
The risk of PSGN is increased in older patients (greater
than 60 years of age) and in children between 5 and 12
years of age.
PSGN is uncommon in children less than three years of
age.
The incidence of clinically detectable PSGN in children
infected during a GAS epidemic is about 5 to 10 percent
with pharyngitis and 25 percent with skin infections.
Host factors
Age: (2-12 years , 5%< 2 yrs)
 Sex: (M:F→2:1)
 Socioeconomic background
 Genetic predisposition (HLA-DR1 & DRW4)
(HLA –DRW48 & DRW8 less susceptible)
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PATHOGENESIS
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PSGN appears to be caused by glomerular immune
complex disease induced by specific nephritogenic
strains of group A beta-hemolytic streptococcus
(GAS).
The resulting glomerular immune complex disease
triggers complement activation and inflammation.
Pathogenesis of APSGN
A.
B.
C.
D.
Trapping of circulating immune Complexes in
the glomeruli
Molecular mimicry between streptococcal &
renal antigen
Insitu immune complex formation between
antistreptococcal antibodies & glomerular
planted Ags
Direct complement activation by streptococcal
Ags deposited in the glomeruli
PATHOGENESIS
The mechanisms for the immunologic glomerular injury
induced by GAS infection:
 Deposition of circulating immune complexes with
streptococcal antigenic components
 In situ immune complex formation resulting from deposition
of streptococcal antigens within the glomerular basement
membrane (GBM) and subsequent antibody binding
 In situ glomerular immune complex formation promoted by
antibodies to streptococcal antigens that cross-react with
glomerular components (molecular mimicry)
 Alteration of a normal renal antigen that elicits autoimmune
reactivity
Nephritogenic Antigens
Endostreptosin → Early phase of APSGN
 Cationic Antigens → Later phase of the disease
 Streptococcal pyrogenic Exotoxin B (SpeB)
Ab titers to SpeB are markedly elevated in APSGN
(Acute rheumatic fever, scarlet fever or healthy subjects)
 SpeB→ 67% APSGN biopsy specimens
 Streptokinase
 Neuraminidase
 Nephritis – Associated plasmin Receptor (NAPlr)→ Early
stage
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Nephritogenic Antigens
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There are two leading candidates for the putative
streptococcal antigen(s) responsible for PSGN:
Nephritis-associated plasmin receptor (NAPlr), a
glycolytic enzyme, which has glyceraldehyde-3phosphate dehydrogenase (GAPDH) activity
Streptococcal pyrogenic exotoxin B (SPE B), a cationic
cysteine proteinase
Nephritogenic antigens
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In a study of Japanese patients with PSGN, NAPlr was present in
renal biopsy samples obtained within the first 14 days of their
disease.
Antibodies to NAPlr were present in the sera of 92 percent of
patients with PSGN, and 60 percent of patients with
uncomplicated group A streptococcal infections.
In another report that included patients from Latin America and
Switzerland, SPE B was found in 12 of 17 biopsies. SPE B
deposition colocalized with complement deposition and within
the subepithelial electron dense deposits (humps) that are
characteristic of PSGN.
Antibodies to SPE B were detected in the convalescent sera in all
53 patients who were tested.
In contrast, circulating antibodies to NAPlr were found in only 5
of 47 tested sera, and in only one biopsy sample.
PATHOLOGY
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Light microscopy
Light microscopy shows a diffuse proliferative
glomerulonephritis with prominent endocapillary
proliferation and numerous neutrophils.
Trichrome stain may show small subepithelial humpshaped deposits.
The severity of involvement varies and usually
correlates with the clinical findings.
Crescent formation is uncommon and is associated
with a poor prognosis.
Pathologic changes
Light microscopic findings
Early stage → glomerular hypercellularity
Later stage → Proliferation of intrinsic endothelial
& mesangial cells
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PATHOLOGY
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Immunofluorescence microscopy
Immunofluorescence (IF) microscopy reveals a
characteristic pattern of deposits of immunoglobulin
(IgG) and C3 distributed in a diffuse granular pattern
within the mesangium, and glomerular capillary
walls.
Other immune reactants (eg, IgM, IgA, fibrin, and
other complement components) may also be detected.
IF microscopy
Coarse granular staining for IgG & C3 can be
detected in GCW
IgM→ less frequently
IgA & C1 & C4 → absent
Garland , starry sky & mesangial patterns
PATHOLOGY
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Electron microscopy
The dome-shaped subepithelial electron-dense
deposits that are referred to as humps.
Subendothelial immune deposits and subsequent
complement activation are responsible for the local
influx of inflammatory cells, leading to a proliferative
glomerulonephritis, an active urine sediment, and a
variable decline in glomerular filtration rate.
Subepithelial "humps" are responsible for epithelial
cell damage and proteinuria, similar to that seen in
membranous nephropathy
Electron microscopy
Swelling of glomerular endothelial & mesangial cells
Humps (disappear 6 wks after the clinicalonset of dx)
CLINICAL MANIFESTATIONS
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The clinical presentation varies from asymptomatic,
microscopic hematuria to the full-blown acute nephritic
syndrome, characterized by red to brown urine, proteinuria
(which can reach the nephrotic range), edema,
hypertension, and an elevation in serum creatinine.
There is usually an antecedent history of a group A betahemolytic streptococcal (GAS) skin or throat infection.
The latent period between GAS infection and PSGN is
dependent upon the site of infection: between one and three
weeks following GAS pharyngitis and between three and
six weeks following GAS skin infection.
CLINICAL MANIFESTATIONS
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The most common presenting signs in children:
Edema — Generalized edema is present in about two-thirds of
patients due to sodium and water retention. In severe cases, fluid
overload leads to respiratory distress due to pulmonary edema.
Gross hematuria — Gross hematuria is present in about 30 to 50
percent of patients. The urine looks smoky, and tea or coca colacolored.
Hypertension — Hypertension is present in 50 to 90 percent of
patients and varies from mild to severe. It is primarily caused by
fluid retention. Hypertensive encephalopathy was an uncommon
but serious complication.
Subclinical cases of PSGN are primarily characterized by
microscopic hematuria .
Clinical presentation
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Abrupt onset of hemutaria (100%)
Proteinuria (80%)
Edema (90%)
HTN (60-80%)
Mild to moderate renal insufficiency (25-40%)
Latent period → (1-2 wks, throat infection , 3-6
wks skin infection)
Subclinical to clinically overt dx → 4-5:1
Clinical presentation
Gross hematuria (24-40%) (2wks)
 Urine: smoky or coke – colored
 Dysuria , frequency & abdominal
discomfort
 Transient oliguria (50%) , anuria (rare)
 Edema
 CHF
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Clinical presentation
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Hypertension
 Volume
dependent
 ↑ peripheral vascular resistance
Hypertensive emergency
Hypertensive urgency
Nausea/ vomiting /malaise/ anorexia/ lumbarpain/
weakness
Laboratory findings
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Urinalysis
The urinalysis in patients with PSGN reveal hematuria
(some of the red cells are typically dysmorphic) with
or without red blood cell casts, varying degrees of
proteinuria and often pyuria.
Nephrotic range proteinuria is uncommon and occurs
in about 5 percent of cases at presentation.
Laboratory findings
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Complement
In about 90 percent of patients, C3 and CH50 (total
complement activity) are significantly depressed in the
first two weeks of the disease course.
In comparison, C4 and C2 levels are usually normal or
only mildly decreased.
The C3 and CH 50 return to normal within four to eight
weeks after presentation.
The combination of a low C3 level and a normal or only
slightly decreased C4 level indicates activation of the
alternative pathway of complement.
Laboratory findings
Culture
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Because PSGN presents weeks after an antecedent
GAS infection, only about 25 percent of patients will
have either a positive throat or skin culture.
In patients with impetigo, there is an increased
likelihood of obtaining a positive skin culture.
Laboratory findings
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Serology
The streptozyme test, which measures five different
streptococcal antibodies, is positive in more than 95
percent of patients with PSGN due to pharyngitis and
about 80 percent of those with skin infections.
It includes the following antibodies:
Anti-streptolysin (ASO)
Anti-hyaluronidase (AHase)
Anti-streptokinase (ASKase)
Anti-nicotinamide-adenine dinucleotidase (anti-NAD)
Anti-DNAse B antibodies
Serology
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After a pharyngeal infection, the ASO, anti-DNAse B,
anti-NAD, and AHase titers are commonly elevated.
In comparison, only the anti-DNAse B and AHase titers
are typically increased after a skin infection.
If only the ASO titer is used to screen for GAS infection,
it may be falsely low or negative in patients with skin
infections.
DIAGNOSIS
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PSGN is usually diagnosed based upon clinical findings of
acute nephritis and demonstration of a recent group A betahemolytic streptococcal (GAS) infection.
The clinical findings of acute nephritis include hematuria
with or without red blood cell casts, variable degrees of
proteinuria, edema, and hypertension.
Documentation of a recent GAS infection includes either a
positive throat or skin culture or serologic tests (eg, ASO or
streptozyme test).
DIAGNOSIS
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Although a low C3 and/or CH 50 (total complement)
level are consistent with a diagnosis of PSGN, these
complement components may also be decreased in
other forms of glomerulonephritis, including
membranoproliferative glomerulonephritis.
A delay in the diagnosis of PSGN is more common in
children who do not have a history of an antecedent
GAS infection and have microscopic hematuria.
In most of the patients, presenting findings were due to
volume overload and included hypertension, edema,
and pulmonary edema.
Diagnostic Evaluation
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U/A: dysmorphic or crenated RBCs & RBC casts
Proteinuria (5-10% nephrotic range)
 WBC, hyaline & granular casts
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↑ BUN , Cr
↑ ASO , Anti- NADase (80% postpharyngitis
nephritis)
Antihyaluronidase & Anti- DNase B (80-90%) skin
infections)
↑ Antibody titers → 1-5 wks after infections
C3, C4 , CH50
↓C3 , CH50(90%)
ANCA (9%)
Renal biopsy
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A biopsy is usually performed in patients in whom other
glomerular disorders are being considered because they
deviate from the natural course of the PSGN or they
present late without a clear history of prior streptococcal
infection.
Persistently low C3 levels beyond six weeks are
suggestive of a diagnosis of membranoproliferative
glomerulonephritis.
Recurrent episodes of hematuria are suggestive of IgA
nephropathy and are rare in PSGN.
A progressive increase in serum creatinine is
uncharacteristic of PSGN, but there are occasional
patients who do not recover from the acute episode.
Indications of kidney Biopsy
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Nephrotic – range proteinuria in the acute stage
Nl serum complement
Progressively increasing serum Cr
Prolonged hypocomplementemia for more than 3 mo
Ongoing macroscopic hematuria
Long standing proteinuria
DIFFERENTIAL DIAGNOSIS
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Membranoproliferative glomerulonephritis (MPGN)
IgA nephropathy
Secondary causes of glomerulonephritis —
Lupus nephritis and Henoch-Schönlein purpura nephritis
share similar features to PSGN.
Both hepatitis B and endocarditis-associated
glomerulonephritis share common features with PSGN
and also will present with reductions in C3 and C4.
Postinfectious GN due to other microbial agents
MANAGEMENT
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The patients with more than 30 percent crescents on
renal biopsy are often treated with
methylprednisolone pulses.
Management is supportive and is focused on treating
the clinical manifestations of the disease, particularly
complications due to volume overload.
These include hypertension and, less commonly,
pulmonary edema.
General measures include sodium and water restriction
and loop diuretics.
MANAGEMENT
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Loop diuretics generally provide a prompt diuresis
with reduction of blood pressure and edema.
In our practice, intravenous furosemide is given at
an initial dose of 1 mg/kg (maximum 40 mg).
Patients with PSGN have variable reductions in renal
function, and some patients require dialysis during
the acute episode.
Patients with evidence of persistent group A
streptococcal infection should be given a course of
antibiotic therapy.
COURSE
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Resolution of the clinical manifestations of PSGN is generally
quite rapid, assuming concurrent resolution of the infection.
A diuresis typically begins within one week, and the serum
creatinine returns to the previous baseline by three to four
weeks.
The urinary abnormalities disappear at differing rates.
Hematuria usually resolves within three to six months.
Proteinuria also falls during recovery, but at a much slower rate.
A mild increase in protein excretion is still present in 15 percent
at 3 years, and 2 percent at 7 to 10 years.
In severe cases with nephrotic range proteinuria, this degree of
proteinuria may persist for six months or more, long after the
hematuria has disappeared.
Recurrence
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Recurrent episodes of PSGN are rare.
This may be due to the long-term persistence of
antibodies to nephritis-associated streptococcal
antigen.
PROGNOSIS
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Most patients, particularly children, have an excellent
outcome.
This is true even in patients who present with acute renal
failure and may have crescents on the initial renal biopsy.
A review of three case series of 229 children with PSGN
found that approximately 20 percent had an abnormal
urinalysis (proteinuria and/or hematuria), but almost all
(92 to 99 percent) had normal or only modestly reduced
renal function 5 to 18 years after presentation.
However, the long-term prognosis of PSGN is not always
benign.
PROGNOSIS
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Some patients, particularly adults, develop
hypertension, recurrent proteinuria (with a relatively
normal urine sediment), and renal insufficiency as long
as 10 to 40 years after the initial illness.
These late renal complications are associated with
glomerulosclerosis on renal biopsy, which is thought to
be hemodynamically-mediated.
According to this hypothesis, some glomeruli are
irreversibly damaged during the acute episode and
compensatory hyperfiltration in the remaining glomeruli
maintains a relatively normal glomerular filtration rate.
Prognosis & clinical outcome
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Early mortality rate:<1%
Complete remission
Hypertension & gross hematuria → several weeks
Proteinuria → several months
Microscopic hematuria → persist for years
ESRD → 0.7- 7.0% (NAplr protein)
ESRD →2%
Recurrence APSGN →0.7-7.0%(NAplr protein)