Postinfectious glomerulonephritis (PIGN) is an immune-mediated glomerular injury that occurs as a result of host response to an extrarenal infection. The classic example is poststreptococcal glomerulonephritis (PSGN) that often manifests a few days or a couple of weeks after a streptococcal infection. Several infectious agents including nonstreptococcal bacteria, viruses, fungi, and parasites can also cause immune-mediated glomerular changes that fall within the broad category of infection-associated glomerulonephritis (GN). These cases are described in the literature under the umbrella of “post-infectious GN,” although in several instances, the patients have concurrent infections, often brought to attention by renal disease. The epidemiology of PIGN in the developed countries has changed over the last few decades and PIGN is now predominantly because of nonstreptococcal infections. This review focuses on pathogenic mechanisms of PSGN and distinct clinicopathologic features of PIGN as seen in developed countries. Glomerular changes seen in specific infections such as hepatitis C, hepatitis B, human immunodeficiency virus, and others will not be discussed here.
PSGN occurs after a streptococcal infection in the form of either impetigo or pharyngitis. Closely linked to low socioeconomic status, the burden of PSGN is vastly different in developed versus underdeveloped nations.1 Even by conservative estimates, the median incidence of PSGN in children from less developed countries is 24.3 cases per 100,000 person-years, whereas in Western hemisphere, it is only 0.3 cases per 100,000 person-years.2 Traditionally, it is a disease afflicting children and still remains so in the third world. Infection with Streptococcus confers long-lasting immunity resulting in a dramatic decline in the incidence of PSGN in underdeveloped countries after 15 years of age.2 The epidemiological patterns in Europe and North America have changed and the disease now mainly affects elderly individuals (>60 y) with risk factors such as alcoholism, intravenous (IV) drug use, diabetes mellitus, and malignancy.3,4
The clinical features of PSGN typically manifest after a latency that ranges from 1 to 4 weeks. Longer latent intervals are seen with skin infections when compared with throat infections.5 It is a disease of children and young adults with a male predominance. Only a subset of group A streptococcal bacteria, the “nephritogenic” strains elicit a immune response causing GN.5,6 Overall, it is estimated that 15% of patients infected with nephritogenic streptococcal organisms develop GN.7
A frequent clinical presentation of PSGN is acute nephritic syndrome but it can occasionally be asymptomatic hematuria and proteinuria. On the basis of detailed studies that measured serum complement levels, antistreptolysin O (ASO) titers and urinalysis, it seems that the subclinical form of PSGN is several fold more common than overt GN.8 Rapidly progressive GN (RPGN) presentation accounts for <5% of PSGN biopsies,9 but in less developed countries with high incidence of PSGN, up to a third of patients in intensive care units have PSGN.10 Acute nephritic syndrome features include hematuria, proteinuria, edema and frequently, mild hypertension, and renal insufficiency. The proteinuria is typically mild but may be in the nephrotic range in 5% to 10% of cases.5 The hematuria can be either gross or microscopic and red blood cell casts are detectable in urine sediment. Several patients have oliguria that resolves within a week. But microscopic hematuria and mild proteinuria may persist for several months after the acute presentation.
The diagnosis of PSGN is aided by documentation of the prior streptococcal infection and the lag in renal symptoms. When the infection is subclinical, high ASO and anti-DNAase B antibody titers are helpful. Elevated ASO titers are more common in pharyngitis and anti-DNAase B levels tend to be high in skin infections.5 The reference ranges for these antibody titers vary with age of the patient and geographic location, thus requiring comparison with laboratory-specific ranges. Given the high prevalence of streptococcal infections in general population, rising or subsiding titers are of greater diagnostic value than a single high titer. In addition, ASO is only a marker of streptococcal infection (current or past) and does not imply or predict the presence of nephritogenic strain infection or PSGN.5
Hypocomplementemia is a feature of almost all active PSGN and has diagnostic utility. Alternative complement pathway activation predominates with low C3, but C4 may also be low. Typically the serum complement levels improve during recovery phase of PSGN and return to normal within 6 weeks from the onset of glomerular disease.
Patients especially children with classic presentation of acute nephritic syndrome after a streptococcal infection do not undergo renal biopsy. Atypical features that prompt a biopsy procedure include RPGN, persistent gross hematuria, hypertension or nephritic syndrome, extrarenal manifestations, short latency period to renal disease, hypocomplementemia lasting >6 weeks, and patient <2 years of age. The threshold for performing a biopsy in an adult is generally lower.
The glomerular hypercellularity in PSGN is typically diffuse and global. In the early phases of PSGN, glomerular neutrophils predominate resulting in an “exudative” appearance. Subsequently, the proportion of lymphocytes and monocytes increases along with mesangial and endocapillary hypercellularity.11,12 These enlarged glomeruli demonstrate lobular configuration, but the basement membranes are normal thickness without reduplication. Glomerular fibrinoid necrosis and cellular crescents are rare, but can be prominent in the setting of clinical RPGN.3,12 The characteristic “subepithelial humps” of PSGN can sometimes be visualized on trichrome stain under oil immersion. In biopsies performed very early or late in the course of disease, the glomerular hypercellularity is only focal and segmental.13,14 Late biopsies representing resolving PSGN demonstrate only mesangial hypercellularity with patent capillary loops11,15 (Fig. 1).
The extent of acute tubular injury and tubular protein resorption droplets vary corresponding to the severity of renal dysfunction and proteinuria. Interstitial edema and inflammation is usually mild. However, interstitial and tubular neutrophil infiltrate is sometimes quite prominent, especially in “exudative” GN.16 Chronic tubulointerstitial damage is not a typical feature of PSGN and may indicate prior glomerular crescents, age-related changes, or hypertensive nephrosclerosis. Arteritis is unusual and should prompt investigation of pauci-immune GN or other causes of vasculitis.5
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Immunofluorescence microscopy (IF) highlights granular mesangial and capillary wall deposits with dominant or codominant C3. Weaker immunoglobulin (Ig) G staining is also typically seen and in some instances IgM and rarely IgA is present. Three patterns of IF with clinicopathologic implications have been described and these include “starry sky,” “garland,” and “mesangial” patterns.15 Seen in early biopsies, the starry sky pattern refers to fine granular deposits along the glomerular basement membrane (GBM), especially overlying the mesangial areas. Confluent subendothelial deposits that correspond to the garland pattern are typically observed in the setting of severe proteinuria. Resolving PSGN has isolated mesangial C3 deposits or on occasion, coexistent low intensity IgG (Fig. 1 and Table 1).
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Ultrastructural evaluation demonstrates mesangial deposits and the characteristic subepithelial “humps” mostly in the mesangial notch near the GBM reflection over mesangium. There is a positive correlation between the glomerular hypercellularity and subepithelial hump formation. When compared with membranous nephropathy, the “humps” of PSGN are much larger, but fewer, typically 4 to 5 per capillary loop. There is no substructure in the deposits and the podocytes have overlying effaced foot processes. Subendothelial deposits tend to appear early in the course of disease and generally disappear by 6 weeks.17 The recovery phase of PSGN shows isolated mesangial deposits and an occasional subepithelial hump with electron-lucent areas suggesting resolution. However in persistent disease, these “humps” may not disappear so rapidly.
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Interestingly, there is no correlation between degree of proteinuria or hematuria and severity of glomerular changes. Renal manifestations may be minimal in the setting of biopsy proven full-blown PSGN and prominent hematuria has been noted with essentially normal kidney biopsy. This clinicopathologic disconnect may be related to the variability in time interval between the onset of symptoms and biopsy.
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A few scattered subepithelial or intramembranous deposits reminiscent of PSGN “humps” can be an incidental biopsy finding and by conservative estimates of one study, it is 10.5% of all native kidney biopsies.18 The clinical indications for these biopsies were persistent renal insufficiency, subnephrotic proteinuria, microscopic hematuria, or a superimposed disease causing acute/subacute renal failure. Most cases in this study by Haas also had dominant mesangial C3 deposits on IF and over half had mesangial hypercellularity. This incidental resolved PSGN was in the background of a primary diagnosis that in most instances was diabetic nephropathy. It suggests that the burden of PSGN is largely unrecognized and diabetic nephropathy poses a particular risk.18,19 There was no universal clinical or serological documentation of prior streptococcal infection in the study by Haas and in retrospect, some of this incidental “PSGN” may represent C3 glomerulopathy, a newly characterized entity.20,21
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The differential diagnosis of PSGN depends on the histologic pattern encountered and an accurate diagnosis can be rendered only with careful clinicopathologic correlation (Table 2).5,17,21,22
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Vast majority of PSGN follow group A streptococcal infections, but epidemics of PSGN because of group C streptococci have also been reported.10 Circulating immune complexes (CIC) play a role in the pathogenesis of PSGN, as evidenced by the similarities between PSGN and acute serum sickness model.23 The glomerular immune deposits in turn activate complement pathways and coagulation cascade and induce GN. However, not all streptococcal infections cause GN despite having detectable CIC and there is no correlation between the amount of CIC and severity of GN.24 Normal patients also have CIC, indicative of prior streptococcal infections. So, other host factors and pathogen characteristics seem to determine the predisposition and severity of glomerular disease.
The nephritogenic streptococcal strains are clearly distinct from rheumatogenic strains of streptococci. Although both PSGN and rheumatic fever are immunologic complications of streptococcal infection, they virtually do not coexist in the same patient.24 The nephritogenic antigen is likely cationic with propensity to traverse the anionic GBM to subepithelial location.24,25 This free antigen deposition probably occurs early in the course of disease followed by in situ antibody binding. Abundant CICs with propensity to deposit in the subendothelium subsequently develop as the PSGN progresses.
Although certain M types of streptococci cause PSGN (types 1, 2, 4, 12, 18, 25 inducing upper respiratory tract infections and types 49, 55, 57, 60 causing impetigo), recent evidence indicates that M protein is not the nephritogenic antigen. The search for a nephritogenic antigen over the last decade have identified two proteins “nephritis-associated plasmin receptor” (NAPlr) and “streptococcal pyrogenic exotoxin B” (SPEB).24 Depending on the geographic location of the study cohort, either one can be involved in pathogenesis of PSGN.10 NAPlr, isolated from both groups A and C streptococci, seems to be the putative antigen in Japanese population with serum antibodies detected in 92% of convalescing PSGN patients and in 60% of patients with uncomplicated streptococcal infections.26 Glomerular deposition of NAPlr occurs early in the course of disease and is detectable in renal biopsies with PSGN,26 localizing to mesangial cells, endothelial cells, and neutrophils.27 NAPlr is a glyceraldehyde-3-phosphate dehydrogenase with plasmin-binding capacity, a nephritogenic property that aids in CIC deposition.28
SPEP, another nephritogenic antigen produced by group A streptococci seems to be the putative antigen in the Latin American, the United States, and the European study cohorts.29 It is a cationic protease with plasmin-binding properties, is secreted as an exotoxin and localizes to glomeruli in PSGN.30,31 Corresponding serum anti-SPEP antibodies were found in high titers in most or all patients during convalescence.32 Furthermore, these SPEB titers correlated with the presence of nephritis better than either ASO or anti-DNase B antibodies.33 The renal biopsies in these patients had SPEB antigen colocalizing with C3 in subepithelial humps. NAPlr seems to be less significant outside of Japan as NAPlr antibodies or antigens were rarely detected in serum or renal biopsies, respectively, in non-Japanese patients.32
A recent study of Streptococcal zooepidemicus strain in relation to a Brazilian epidemic of PSGN revealed lack of SPEP encoding gene, suggesting a potential new pathogenic protein.34 Although there may be more yet to be discovered nephritogenic antigens, thus far, NAplr and SPEB are two distinct antigens with pathogenicity determined by genetic background and geography.10
Both NAPlr and SPEB activate alternative complement pathway resulting in low serum complement levels and have affinity to plasmin and glomerular proteins.31,35 Although cationic free SPEB antigen deposits in the subepithelium with in situ immune-complex formation, both NAPlr and SPEB promote formation of CIC that deposit in subendothelium. These nephritogenic antigens can induce glomerular inflammation as well as local antibody production.10,36 SPEP is a superantigen capable of initiating T-cell activation and proliferation without being processed by an antigen-presenting cell. Plasmin activation by NAPlr, SPEB, and other streptococcal antigens (streptokinase, enolase) results in GBM and mesangial matrix degradation by metalloproteinases and collagenases.10,31,35 There may also be a role for innate immunity through lectin pathway activation in PSGN.37 Mannose-binding lectin recognizes streptococcal cell wall polysaccharides and activates complement pathway and this mechanism may be the first line of defense before acquired immunity (antigen-antibody interaction) becomes effective.37
Treatment and Prognosis
PSGN is generally a self-limited disease, especially in children and treatment is mainly supportive. Antibiotic therapy aimed at active streptococcal infection, which in some cases may be subclinical, is recommended. Immunosuppressive therapy is potentially beneficial in the setting of crescentic GN or nephrotic syndrome in an adult.38 Prophylactic antibiotic therapy during epidemics or in a suspected sporadic case of streptococcal pharyngitis or impetigo can prevent PSGN.
Most children and young adults have excellent prognosis and >90% regain normal renal function on short-term follow-up. In contrast, complete recovery in adults is in the range of 50% to 70%.5,39 Poor prognostic factors include elderly age, nephrotic syndrome, crescents, acute renal failure, low birth weight, and underlying disease or risk factor.5,12 Although acute recovery is quite common, the long-term follow studies suggest that PSGN is not entirely a benign disease.18,40 Even some children continue to have persistent non-nephrotic proteinuria or hematuria for several years. Although end-stage kidney disease is rare, based on the pooled data from PSGN studies with long-term follow-up in the range of 5 to 18 years, up to 17% of patients have mild urinary abnormalities or hypertension.10 Therefore, it is important that PSGN patients are followed up even after apparent recovery from the acute event.
POSTINFECTIOUS GLOMERULONEPHRITIS IN THE DEVELOPED WORLD
In contrast to the developing countries, acute PIGN in the western world is a disease of elderly with risk factors such as diabetes mellitus, malignancy, alcoholism, acquired immune deficiency syndrome, and IV drug use.3,39,41 It affects white males more frequently, often around fifth decade of life.3,39,41 Currently, approximately a quarter of acute PIGN is because of Streptococcus and another quarter is caused by Staphylococcus.39 Other rare organisms isolated include Pseudomonas, Pneumococcus, Enterococcus, Propionibacterium acnes, Candida, and others. In more than a third of cases with typical clinical and pathologic features of PIGN, no infectious agent is isolated. The most common sources of infection in acute PIGN are upper respiratory tract, skin, pneumonia, and endocarditis. Other infrequent but well-documented PIGN-associated infections are osteomyelitis, urinary tract infections, deep-seated abscesses, and ventriculoperitoneal shunt infections.42 The latent period between the infection and onset of renal disease ranges between 2 and 4 weeks, but in many instances, the infection is discovered only at the time of renal biopsy.43
Similar to classic PSGN, the usual presentation is acute nephritic syndrome, but nephrotic range proteinuria and nephrotic syndrome are not uncommon. Hypocomplementemia is a consistent finding in almost 80% of patients. The histologic pattern most often observed is diffuse proliferative and exudative GN followed by focal proliferative and mesangioproliferative GN5 (Fig. 2). The membranoproliferative and crescentic GN patterns are less common. Membranoproliferative GN is the favored pattern in chronic infections such as shunt nephritis and occasionally in pneumonia, deep-seated infections, and osteomyelitis.3,44,45 C3 dominance on IF is a universal feature of acute PIGN and over 90% of cases have subepithelial humps and mesangial deposits; the subendothelial deposits are typically small and few.
The renal survival is PIGN in the developed world is significantly worse than in epidemic form of PSGN in developing countries. Treatment is mainly aimed at control of infection.39 Depending on the study quoted, a third to two thirds of patients have persistent renal dysfunction or progress to end-stage kidney.3 These outcomes may in large part be influenced by older age and comorbidities in affected individuals.39,41
Special Subtypes of Postinfectious Glomerulonephritis
Immunoglobulin A-dominant Postinfectious Glomerulonephritis
It is a variant of PIGN with sole or dominant glomerular IgA staining along with C3.19,46,47 The histology typical of PIGN such as exudative features and subepithelial humps are usually present. The most common infectious organism isolated in these patients is Staphylococcus.48 In addition to IgA dominance, other unique features of this entity include frequent occurrence in elderly patients with diabetes and lower extremity skin wounds.19,46,47
IgA-dominant PIGN occurs exclusively in adults and the average age at diagnosis is 60 years.49 The male predominance is greater than is observed in PSGN and most patients are either White or Asian. Over half of patients diagnosed with IgA-dominant PIGN have diabetes mellitus and other less common predisposing factors are malignancy, IV drug use, alcoholism, and human immunodeficiency virus infection. The site of infection in >50% of cases is skin in the form of cellulitis, surgical wounds, skin infections, or IV line infection. Other sources of infection are endocarditis, pneumonia and deep-seated abscess. Staphylococcus, especially Staphylococcus aureus is the most common offending organism and both methicillin-resistant and methicillin-sensitive types have been isolated in these patients. Other organisms such as Staphylococcus epidermidis, Escherichia coli, Enterococcus are rarely reported. The latent period between infection and onset of renal symptoms is on average 4 weeks, but in many cases, the the infection is detected at the time of renal biopsy. The clinical presentation is nephritic syndrome, but IgA-dominant PIGN often results as acute renal failure or RPGN. The proteinuria may be severe and nephrotic syndrome occurs in up to half of the patients. Low serum complement level is helpful in the diagnosis of IgA-dominant PIGN, but has been reported in only two thirds of the patients.49
The most common pattern of glomerular injury is diffuse proliferation with exudative features, similar to PSGN.19,46,47 Isolated mesangial proliferation is uncommon but in such instances, careful clinopathologic correlation is needed to avoid a misdiagnosis of IgA nephropathy (IgAN). The lack of exudative features may represent subacute or chronic phase of GN brought to clinical attention only late in the course of disease. The glomerular crescents, when present, tend to be few but IgA-dominant PIGN can rarely present as crescentic GN (>50% crescents).
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Immunofluorescence for C3 tends to be the strongest, with a “starry sky” pattern. However, unlike usual PIGN, IgA is prominent and IgG is either weak or absent. The mesangial electron-dense deposits are observed in most cases, but it is the subepithelial “humps” on electron microscopy that point to a diagnosis of IgA-dominant PIGN.
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An underlying diabetic nephropathy with nodular mesangial sclerosis may mask the features of superimposed PIGN. In such cases, dominant C3 staining in nonsclerotic glomeruli is helpful in diagnosing PSGN. The subepithelial “humps” tend to be less prominent than mesangial or subendothelial deposits in diabetic nephropathy with PSGN.4,19,50
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Both clinically and histologically, IgA-dominant PIGN can potentially be confused with IgAN.49,51 Supporting clinical parameters for IgA-dominant PIGN are documented staphylococcal infection, hypocomplementemia, acute renal failure, and underlying diabetes mellitus. The temporal associations with infections are seen in both IgAN-dominant and IgA-dominant PIGN. Flares of IgAN can be triggered by gastrointestinal and respiratory infections, and there are reports of Henoch-Schönlein purpura (HSP) nephritis with staphylococcal infections.52 But in IgAN and HSP, the nephritis is “synpharyngitic,” with no latent phase between infection episode and renal symptoms.42 In an appropriate clinical setting, renal biopsy features of exudative GN, dominant C3 (C3>IgA), and subepithelial humps should prompt a diagnosis of IgA-dominant PIGN. In contrast, IgA> C3, λ light chain predominance, lack of significant glomerular neutrophils or “humps” would make IgAN more likely.
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The etiology and pathogenesis of IgA deposition in PIGN likely involves IgA-dominant host immune responses against specific pathogens. It is known that Staphylococcus, especially the methicillin-resistant types, can cause polyclonal increases in serum IgA, massive T-cell activation and release of lymphokines, potentially facilitated by a bacterial “superantigen.” These superantigen proteins that bind directly to MHC class II molecule on antigen-presenting cells have been detected in several microbes including staphylococci and streptococci.53 Staphylococcal enterotoxin has been initially implicated as a superantigen,54 but staphylococci lacking enterotoxin can also cause IgA-dominant PIGN, indicating an alternate pathogenic antigen. Recently, a S. aureus cell envelope antigen designated as “probable adhesion” was identified in IgAN, HSP, and postmethicillin-resistant S. aureus GN, colocalizing with glomerular IgA deposits.55 It appears that S. aureus, a common colonizing bacterium in nasal and oral flora contributes to the pathogenesis of IgAN and in disease causing infections, can result in PIGN.55 Although “probable adhesion” may be the antigen trigger for IgA-dominant PIGN, but it is unknown if the IgA secreted by the host is abnormal as in IgAN. It is also of interest that diabetic patients develop IgA-rich immune responses in circulation when compared with normal population, especially in the presence of diabetic complications and end organ damage.56 High serum IgA levels in diabetic patients likely represent an immune response to advanced glycosylation end products.56 The IgA-rich environment in diabetics coupled with IgA-specific responses to staphylococcal superantigen precipitates a unique variant of PIGN with glomerular IgA deposits.
Treatment and Prognosis
The reported cases of IgA-dominant PIGN were treated with antibiotics and a subset received steroids as well, but with no clear benefit. Despite adequate therapy, majority of patients, especially diabetics have either progressed to end-stage kidney or had persistent renal dysfunction on follow-up. Thus, when compared with classic PIGN, the outcome of IgA-dominant PIGN is significantly inferior, possibly driven by the advanced age of the patients as well as underlying diabetes mellitus.
Before the antibiotic era, infective endocarditis mainly affected previously damaged heart valves as in rheumatic fever. The endocarditis-associated GN was often seen in subacute infections by less virulent organisms such as Streptococcal viridians. This indolent course favored a prolonged antibody response and CIC formation, thus predisposing to the development of GN. Now with adequate antibiotic therapy and prophylaxis, the most common clinical setting for endocarditis-associated GN is acute infections of normal heart valves by S. aureus in IV drug abusers.57 Although more than half of endocarditis-associated GN is now because of S. aureus, several other causative agents such as S. epidermidis, Enterococcus, Hemophilus influenza, Actinobacillus, Chlamydia, Bartonella henselae, Coxiella burnetti, etc. have been isolated. Other nonimmune renal complications of endocarditis are renal infarcts and abscesses caused by septic emboli and drug-induced interstitial nephritis.43,58
Clinically, patients with acute bacterial endocarditis present with fever, anemia, heart murmur, hepatosplenomegaly, and in some cases skin purpura and retinal hemorrhages (Roth spots). The symptoms in subacute bacterial endocarditis are subtle and it may only be detected during the work up of GN. The reported frequency of GN in infective endocarditis ranges from 2% to 60% and this high variability can be attributed to the selection bias toward patients with severe GN and skewed data from referral centers and postmortem studies.57 The duration of endocarditis does not seem to greatly influence the risk of the developing GN and renal manifestations have been reported to occur within 7 to 10 days of clinical illness. Nephritic syndrome is the usual presentation, but based on severity of glomerular changes and time course of the disease, the symptoms can range from RPGN to asymptomatic hematuria and proteinuria. Hypocomplementemia is frequently seen and the degree of complement depression correlates with severity of renal disease and infection. Quite often, rheumatoid factor is positive and temporally related to appearance of CIC in patients with endocarditis-associated GN.59 On occasion, patients with infectious endocarditis and GN have circulating antineutrophil cytoplasmic antibody (ANCA), specifically the PR3 type.
The histologic changes in endocarditis-associated GN are quite diverse, with most common being focal segmental proliferation followed by diffuse endocapillary proliferation.5,17 Exudative features indistinguishable from typical PSGN can be seen as well. The extent of glomerular necrosis and crescents varies and on occasion, can involve >50% of glomeruli. Membranoproliferative GN resembling MPGN type I is not uncommon, especially with chronic infections and the biopsy typically shows diffuse mesangial and endocapillary proliferation, lobular accentuation, and GBM reduplication. Depending on the time course of the disease, glomerular synechiae representative of healed necrosis may be present. The resolving phase of endocarditis-associated GN usually shows only mesangial proliferation. The tubular atrophy and fibrosis correlates with extent of glomerular necrosis and crescents. Immunofluorescence reveals mesangial and/or capillary wall granular deposits with C3 and typically less intense IgM or IgG. IgA staining is not usually prominent unless it is a IgA-dominant PIGN. Ultrastructurally, the deposits are in mesangial, subepithelial, intramembranous, and subendothelial locations. In the early and acute phase of disease, the deposits are preferentially in the subepithelium, whereas the subacute phase is characterized by subendothelial and mesangial deposits.57 As in classic PSGN, only residual mesangial deposits are seen in the healing phase after antibiotic therapy. Complete lack of deposits in an endocarditis-associated necrotizing or crescentic GN should prompt evaluation of ANCA disease triggered by infection.43,60
The patients with endocarditis-associated GN have CIC, compatible with an immune-mediated process.57 These CIC are deposited in glomeruli and there is also evidence for in situ immune complex formation. The nephritogenic bacterial antigens were identified within the affected glomeruli in S. aureus and streptococcal infections.59
Treatment consists of antibiotic therapy and surgical removal of valvular vegetations to eradicate the infection. Corticosteroid therapy may be helpful in some cases. Patients with crescentic GN reportedly benefit from plasmapharesis.61,62 Although complete resolution is possible with early detection and therapy, the renal survival in patients with chronic infections is worse than in classic PSGN.
Infections of ventriculoatrial shunts inserted as palliative therapy for hydrocephalus can occasionally lead to GN, commonly referred to as shunt nephritis. It is an immunologic complication of chronic infection with activation of classic complement pathway. The incidence of shunt infection is rather high (27% in some series) but only a very small proportion actually develop GN (2% or less).63,64 The bacterial colonization of the shunt may persist for several years without overt clinical symptoms. Subsequently, the time interval between the shunt operation and a diagnosis of shunt nephritis can range from 4 weeks to as long as 21 years.44,45,63,64 The vast majority of patients are children, but there are several reports of adult cases. The ventriculoperitoneal shunts are now preferred over ventriculoatrial shunts because of lower rates of complications including shunt infections.44
The nonspecific symptoms of shunt nephritis such as fever, malaise, nausea, hypertension, and renal dysfunction, may result in an erroneous diagnosis of urinary tract infections.44 Recurrent fevers, anemia, hepatosplenomegaly, and cerebral symptoms should raise suspicion for chronic shunt infection. In addition to hematuria and proteinuria, some patients develop nephrotic syndrome. Serum complement C3 is low in almost 90% and C4 is low in 50% of patients with shunt nephritis. Other supportive laboratory results include elevated erythrocyte sedimentation rate or cryoglobulins and positive blood cultures. Prior antibiotic therapy may result in negative blood and cerebrospinal fluid cultures in patients with shunt nephritis. The most common organism isolated from the shunt is S. epidermidis, a skin contaminant likely introduced during surgical procedure. It accounts for approximately 75% of all shunt infections and several other microorganisms such as S. aureus, Corynebacterium, Listeria, Pseudomonas, Bacillus species have been identified.44,45
The glomerular changes are variable, such as diffuse proliferative, mesangial proliferative, or membranoproliferative, although the latter predominates. A few neutrophils may be present in glomeruli and occasional cases have crescents. The membranoproliferative pattern is characterized by GBM duplication and mesangial cell interposition. The extent of tubular atrophy and interstitial fibrosis depends on the chronicity of glomerular lesions and extent of crescents. The immune deposits in mesangium and subendothelium stain predominantly with C3, IgM, and to a lesser extent IgG.
Treatment of shunt nephritis includes antibiotic therapy and removal of the infected shunt. If treated appropriately, most patients recover their renal function within a few weeks; hypocomplementemia also resolves.44,45,65 If the biopsy demonstrates significant chronic damage, such patients eventually progress to end-stage kidney.
A renal biopsy diagnosis of PIGN can be challenging, especially when associated with sporadic infections as seen in the developed countries. Lack of prior history of infection, diverse histologic patterns, and prominent IgA staining are a few factors that can lead to an erroneous diagnosis. Increased awareness of atypical features and careful clinical and serological correlation are helpful in rendering a prompt diagnosis.
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