POSTINFECTIOUS GLOMERULONEPHRITIS
Postinfectious glomerulonephritis (PIGN) is a
syndrome of glomerular injury that occurs as a result of the immune system’s
response to certain infections. The archetypal example is poststreptococcal
glomerulonephritis (PSGN), an acute nephritis that develops following
streptococcal infections of the skin or throat, and among the oldest described
nephrologic diseases. Many infections can cause PIGN, but the unifying feature
is immune complex depositi n in the glomerulus that triggers inflammatory
injury.
PATHOPHYSIOLOGY
A variety of bacteria, fungi,
viruses, and parasites have been specifically associated with certain patterns
of glomerular injury, including membranoproliferative glomerulonephritis (see
Plate 4-22) and membranous nephropathy (see Plate 4-12).
Most clinically evident PIGN,
however, results from bacterial infections. Classically, PIGN occurs in
children after infection of the skin or oropharynx with specific nephritogenic
strains of Group A Streptococcus (GAS). Although this picture remains
true in the developing world, recent series from developed countries show Staphylococcus
spp. now equaling or outnumbering Streptococcus spp. as the most
common cause of PIGN. In addition, as many as one third to one half of cases
are caused by Gram-negative organisms. Furthermore, those at risk are no longer
children but rather adults over the age of 40, often with medical comorbidities
such as diabetes and alcoholism. These epidemiologic shifts are most likely due
to widespread availability and use of antibiotics for the treatment and
prophylaxis of bacterial pharyngitis.
While the full pathogenesis of PIGN
is incompletely understood, it is known to occur in only a minority of patients
infected with recognized nephritogenic organisms. This observation implies that
host susceptibility factors play a crucial role, in addition to specific traits of
the infectious organisms themselves.
Fundamentally, nephritogenic
infections present certain pathogenic antigens to the immune system, which
responds by generating antibodies and forming immune complexes. These complexes
may either form in the circulation and then deposit in the glomerulus during
filtration, or they may form in the glomerulus in situ. Classically, immune
complex deposits are found in the subepithelial space. The complexes activate
complement (especially the alternative pathway) and lead to the recruitment of
inflammatory cells (such as macrophages) to the glomerulus, producing immunemediated
damage.
One postulated mechanism underlying
this process is molecular mimicry, in which the infectious organism presents
antigens that, by coincidence, are structurally similar to normal components of
the glomerular filtration barrier, such as laminin or collagen. Consequently,
the immune response against the organism becomes inadvertently directed against
the glomerulus as well.
Another potential mechanism for
immune complex formation is that the infectious organism produces specifically
nephritogenic antigens that bind to the glomerular capillary wall and activate
an immune response. In the case of PSGN, two proteins produced by streptococci
bear special mention: nephritis-associated streptococcal plasmin receptor
(NAPlr) and streptococcal cationic proteinase exotoxin B (SpeB). NAPlr is thought to bind to glomeruli, where
it captures plasmin and leads to activation of the alternative complement
pathway. SpeB, with its zymogen precursor zSpeB, is an exotoxin produced by Streptococcus
pyogenes that also binds plasmin and can activate leukocytes. One series of
patients with PSGN reported the presence of glomerular deposits containing SpeB
in 12 of 17 biopsies, and circulating antibodies to SpeB in all patients (53 of
53).
PRESENTATION AND DIAGNOSIS
The clinical manifestations of PIGN
are variable and depend on characteristics of both host and pathogen. Poststreptococcal disease (PSGN)
classically presents as a child aged 5 to 12 who develops gross hematuria 1020
days after a bout of pharyngitis or pyoderma. It typically causes an acute
nephritic syndrome, with microscopic or gross hematuria, proteinuria, and
hypertension. Often, facial edema and a mild decrease in renal function are seen as well.
Occasionally the proteinuria is severe enough to cause nephrotic syndrome. In
less than 1% of cases, rapidly progressive glomerulonephritis occurs, leading
to severe renal failure that requires dialysis. When confronted with a child
who has gross hematuria following an upper respiratory infection (URI), the
crucial differential is between PSGN and IgA nephropathy (IgAN), which can have
similar presentations. The key to diagnosis comes from the history and lies in
the latency period between pharyngitis and hematuria; for PSGN, it usually
takes 10 to 14 days for the hematuria to develop (or even 3 weeks following
skin infection), whereas in IgAN hematuria occurs within 5 days of URI.
Patients with IgAN may also report having similar hematuric episodes in the
past.
As opposed to “classic” PSGN, PIGN
in the developed world most commonly occurs in older individuals with subacute
or chronic infections (acute and subacute bacterial endocarditis, pulmonary
infections, visceral abscesses, infected ventriculoatrial shunts) who have
significant medical comorbidities, especially those causing immune compromise
(such as diabetes, malignancy, and substance abuse). These infections
frequently require prolonged courses of treatment, and renal abnormalities
often develop before the infection is entirely eradicated. Microscopic hematuria
is present in up to 90%, with greater than 1 g/day proteinuria in roughly 4 of
5 patients, and the full nephrotic syndrome in about a quarter of patients.
Unlike in PSGN, however, gross hematuria is rare.
Further laboratory testing can help
narrow the diagnosis to PIGN. PIGN is one of the glomerulonephritides, for
example, in which serum complement levels are low (the others being lupus
nephritis, MPGN, and cryoglobulinemic GN). Hypocomplementemia is present in 60%
to 70% of patients with PIGN, and closer to 90% of patients with PSGN.
Typically C3 is significantly depressed, whereas C4 is only slightly depressed
or normal, which suggests activation of the alternate complement pathway. Of
note, a child with presumed PSGN and hypocomplementemia whose complement levels
do not return to normal within 8 to 12 weeks should be evaluated for MPGN.
The specific diagnosis of PSGN is
supported by serologic evidence of recent streptococcal infection. Several
different antistreptococcal antibodies can be measured. The most common is the
antistreptolysin O titer (ASO). Although this assay is highly sensitive for
recent streptococcal pharyngitis, it will be negative following 50% of
streptococcal skin infections. Anti-DNAse B antibody, in contrast, is less
sensitive for pharyngeal infections but is 90% sensitive for recent
streptococcal skin infections. The diagnosis of PSGN can often be made
clinically without a kidney biopsy, especially in children with a typical
course. Indications for biopsy might include repeated negative testing for
antistreptococcal serologies, persistent renal insufficiency, persistent
proteinuria, or hypocomplementemia beyond 8 to 12 weeks.
In adults with suspected PIGN,
however, the picture is often clouded by the presence of medical comorbidities,
comorbid renal disease, and medication or antibiotic use. Many other types of
glomerular disease may be possible depending on the history, such as diabetic
nephropathy, membranous nephropathy related to malignancy, or reactive
amyloidosis. Older patients with atheroemboli may also have depressed complement
levels and hematuria. Antibiotics used to treat active infections may cause
acute interstitial nephritis or toxic tubular injury. For these reasons, a
kidney biopsy becomes invaluable for elucidating the diagnosis.
Several different histologic
findings may be present in PIGN, and the diagnosis can usually be made using
light microscopy and immunofluorescence. On light microscopy, PIGN classically
causes diffuse hypercellularity involving all of the glomeruli, with the
capillary lumina obscured by endothelial proliferation,
mesangial proliferation, and infiltration by monocytes and neutrophils. Silver
stain may reveal characteristic postinfectious humps in the subepithelial
space. These humps represent deposits of immune complexes that include
complement and immunoglobulins. Immunofluorescence usually shows granular
deposition of C3 and IgG, and occasionally IgM. This staining may follow the
capillary wall (“garland”) or it may be more diffuse (“starry sky.”) Electron
microscopy will show large
dome-shaped humps in the subepithelium, and it may also show small immune
complexes in the mesangium and subendothelium.
In the rare cases when acute PIGN
leads to rapidly progressive glomerulonephritis, histology will show disruption
of the glomerular basement membrane and the formation of cellular crescents.
This presentation appears to occur more frequently with Staphylococcus
aureus infections.
It must be noted that many people
experience asymptomatic or subclinical urinary abnormalities (low-level
proteinuria, pyuria, and microscopic hematuria) following trivial or
self-limited bacterial or viral infections. Although the exact frequency is
difficult to determine, at least one series of patients with GAS pharyngitis
revealed 24% to have subclinical glomerulonephritis by urinalysis, and almost
all had corresponding abnormalities (i.e., mild mesangial proliferation or
hypercellularity) on kidney biopsy. An older, larger series in children found
that subclinical disease was 20 times more likely than overt
glomerulonephritis. These observations support the notion that a large proportion of mild and transient PIGN goes unrecognized.
TREATMENT
There is no specific treatment for
PIGN other than removing the trigger for autoimmune attack. Here the term
“postinfectious” can be dangerously misleading because, as previously stated,
the renal disease often begins during the course of a chronic infection. To
limit the inflammatory process, the infection must be identified and eradicated.
A biopsy that shows PIGN with no previously suspected source should prompt a
thorough investigation for occult sources of infection, including blood
cultures to evaluate for subacute bacterial endocarditis, a careful dental
examination, and evaluation of any indwelling foreign bodies such as
ventriculoatrial shunts, vascular grafts, or pacemaker wires. Meanwhile, any
person diagnosed with PSGN should be treated with a full course of antibiotics
to eliminate any residual infection.
Unfortunately, PIGN may progress
despite eradication of infection, especially in the setting of infection with S. aureus or Brucella. In such cases,
immunosuppressive treatment is sometimes attempted. Similarly, in crescentic
PIGN there has been anecdotal use of corticosteroids and or cytotoxic agents
with some success. No highquality clinical trials, however, have been
performed.
A separate issue is the question of
routine antibiotic treatment of pharyngitis to prevent the development of PSGN.
Because the majority of pharyngitis cases are not caused by GAS, and because
even GAS pharyngitis usually has a benign course, empiric antibiotics are
discouraged. Several useful clinical decision algorithms to predict the
likelihood of bacterial pharyngitis and guide antibiotic therapy have been
proposed, such as the Centor criteria. Indeterminate scores should not be
treated with antibiotics unless there is a positive rapid streptococcal antigen
test or a positive throat culture. The exception is for epidemics of GAS, where
close contacts to infected cases should receive prophylactic treatment with
penicillin.
PROGNOSIS
The prognosis for PIGN varies
according to age and comorbidities. The prognosis for children with PSGN is
excellent; nephritic symptoms usually begin to improve within a week of
presentation, and full recovery is the norm. Approximately 20% of children may
have persistent urinary abnormalities over the long term (5 to 18 years), but
impaired glomerular filtration is uncommon.
In adults, the prognosis is much
worse, likely in large part due to the underlying comorbidities and chronic
infections that predispose to PIGN. Only about half of patients
will achieve complete remission of their renal disease. Poor prognostic
indicators include age over 60 years, nephrotic-range proteinuria, “garland”
immunofluorescence pattern, and crescentic glomerulonephritis. Especially poor
outcomes occur in patients with underlying diabetic glomerulosclerosis, with
one study reporting all affected patients having permanently impaired renal function
and more than 80% reaching ESRD during a mean follow-up of 19 months.
