PSGN and other forms of bacterial-related glomerulonephritis share several features with C3 glomerulopathy (C3G). Both diseases share alternative pathway activation and C3 deposition within the glomeruli as a hallmark, and low plasma C3 frequently occurs in both entities. On renal biopsy, immunoglobulin depositions are often detected in bacterial IRGN but may also be present in C3G. Furthermore, bacterial infections may trigger C3G. These overlaps render distinction of one entity from the other difficult in some cases. Nevertheless, the two conditions have distinct etiologies and clinical contexts. C3G is caused by acquired (autoimmune) or genetic dysregulation of the alternative pathway. In the latter, autoantibodies such as C3, C4, or C5 nephritic factor (C3NeF, C4NeF, and C5NeF) or factor H antibodies lead to overactivation of the alternative pathway. In about 25% of cases, genetic variants in complement genes such as C3, CFB, CFH, FI, or CFHR5 affect the alternative pathway. Uncontrolled and excessive alternative pathway activation results in constant C3 deposition within the glomeruli, inducing damage and inflammation. In PSGN and other bacterial IRGNs, the alternative pathway is activated by the infection and corresponding immune response. However, in children with classical, self-limiting PSGN, rare complement gene variants can be found with a similar frequency compared with children with C3G and significantly more often than in healthy individuals. Likewise, autoantibodies against factor B and C3NeF can be found in both C3G and PSGN, although with somewhat different frequencies. Therefore in cases of PSGN that do not improve on supportive treatment, a diagnosis of C3G must be actively pursued. ^{, , ,} Some argue that C3G and C3-dominant IRGN are entities in a single glomerular disease category or disease spectrum. ^{, ,} Whether complement blockade with newly developed inhibitors of the alternative pathway might be a successful strategy in subgroups of patients with bacterial IRGN will have to be determined in the future.

Glomerulonephritis following infection with group A β-hemolytic streptococci is the prototype of IRGN in children. In the early part of the 20th century, the presence of dark and scanty urine was a feared complication during epidemics of scarlet fever. However, since the mid-1900s, a notable decline in the prevalence of PSGN was observed, with most cases seen in low-resource regions.

The incidence of poststreptococcal glomerulonephritis (PSGN) shows a wide variability ranging from 6 to 24.3 cases per 100,000 person-years in high-income to lower-income countries across the world.

PSGN is predominantly seen in children; however, it can also affect adults, especially the elderly, ^, those with comorbidities such as diabetes mellitus and malignancy, those on certain drugs (chemotherapeutics or glucocorticoids), or chronic alcoholics. These comorbidities might contribute to an immunocompromised state, which makes individuals more prone to streptococcal infections. ^{, ,}

PSGN may occur as isolated cases or in clusters during epidemics. ^, Though group A β-hemolytic streptococci account for most cases, epidemics of PSGN with group C streptococcus have also been reported. The nephritogenic strains, identified on the basis of the M protein, cause pharyngitis (strains 1, 2, 4, 12, 18, and 25) and impetigo (strains 49, 55, 57, and 60), which are the most common infections leading to PSGN. ^,

PSGN is an immune complex–mediated disease. The various mechanisms of glomerular injury in PSGN are described in Fig. 34.4 . The nephritogenic antigens, nephritis-associated plasmin receptor (NAPlr) and streptococcal pyrogenic exotoxin B (SPeB), which are secreted cationic proteins, are key players in glomerular injury. ^, Both proteins have been detected in the glomeruli during the early phase of PSGN, and antibodies to NAPlr and SPeB are present in convalescent sera of PSGN patients. ^, Other important antigens implicated in the pathogenesis are streptokinase, enolase, neuraminidase, histone-like proteins, etc. ^, The immune complexes are either formed by these nephritogenic antigens and antibodies in the circulation or in situ and deposited in the glomerular basement membrane. The immune complexes activate the alternative pathway and induce glomerular inflammation. Molecular mimicry is implicated in the cross-reactivity of immune complexes formed with the streptococcal M protein against glomerular antigens like laminin and collagen. A component of autoimmunity is also implicated in the pathogenesis, as evidenced by the formation of anti-IgG and factor B antibodies (described in more detail earlier). The modification of IgG by streptococcal neuraminidase and binding of the Fc fragment of IgG to type II receptors on the streptococcal surface are postulated as mechanisms for the production of anti-IgG antibodies. A genetic susceptibility localized to HLA DR1 and DR4 has also been associated with the development of PSGN. ^,

Streptococci produce streptokinase, which binds to plasminogen to convert it to plasmin. Plasmin, in turn, increases the invasiveness of the organism. NAPlr released into circulation by streptococci traps plasmin in the glomeruli and causes degradation of the glomerular basement membrane and activation of the complement cascade, and it incites inflammatory cell infiltration within the glomerulus. Plasmin binds to the endothelium, mesangium, and infiltrating neutrophils. During the early phase of the disease, plasmin deposits have been demonstrated in the glomerulus by direct immunofluorescence. The localization of NAPlr and plasmin to various components of the glomerulus is shown in Fig. 34.5 . Plasmin triggers the alternative pathway, releasing anaphylatoxins C3a and C5a, which facilitate the migration of neutrophils and activation of macrophages. In addition, NAPlr can directly activate the alternative pathway via conversion of C3. NAPlr also stimulates helper T cells, which in turn activate macrophages. The activated macrophages release growth factors, which cause endothelial and mesangial cell proliferation. ^{, ,} NAPlr and associated plasmin deposits have been found in other glomerular diseases like ANCA vasculitis, Ig A vasculitis, and MPGN type 1. This entity was previously termed streptococcal infection–related nephritis (SIRN).

Histology of glomeruli from a patient with poststreptococcal glomerulonephritis.

The photomicrographs show histologic staining for complement 3 (C3), nephritis-associated plasmin receptor (NAPlr) , and plasmin deposits in the glomeruli of poststreptococcal glomerulonephritis. Though the glomeruli show staining for NAPlr (fluorescein isothiocyanate, green ) (A) and C3 (Alexa Fluor 594, red) (B), they are not colocalized (C). Plasmin activity assessed by in situ zymography was found to be positive and had a similar distribution to the NAPlr staining in the glomeruli (D).

Images provided by Dr. Takashi Oda, Professor, Department of Nephrology and Blood Purification, Tokyo Medical University, Tokyo, Japan.

Although the alternative pathway is the most important complement pathway in the pathogenesis of PSGN, there is also evidence for activation of the lectin pathway by the streptococcal neuraminidase, and polymorphisms in lectin pathway genes aggravating the immune reactions have been described. ^, The classical pathway plays a minor role and may be activated in the early phase of the disease by the binding of the streptococcal H protein to the Fc receptor of IgG. However, streptococcal chemokine-binding evasins may bind to C4b and prevent activation of the classical pathway. ^, This might be one explanation for the low or absent activity of the classical pathway in PSGN despite immune complex deposition.

Streptococcal pyrogenic exotoxin B (SPeB) was found to colocalize with NAPlr. It has been demonstrated in subepithelial humps and can prompt the release of cytokines MCP1, IL-1b, TNF, IL-6, IL-8, and TGF-β from leukocytes instigating glomerular inflammation. ^{, ,} The cationic structure of the toxin increases its affinity to the glomerular basement membrane. Immune complexes formed against SPeB activate plasmin and contribute to the degradation of the glomerular basement membrane. SPeB also plays a role in complement activation. ^, However, SpeB can also block innate host defense via degradation of lytic complement factors. ^{, , , ,}

Several other streptococcal enzymes and molecules are involved in the pathogenesis of glomerular injury. Streptokinase binds and activates plasmin, the complement cascade, and inflammatory pathways. Streptococcal neuraminidase alters IgG by desialylation and results in the production of immune complexes against IgG. Neuraminidase also contributes to the degradation of the glomerular basement membrane and the influx of neutrophils. Streptococcal enolase likewise binds plasmin and contributes to glomerular injury. In addition, histone-like proteins produced by streptococci can activate inflammatory pathways.

Streptococcal infections and PSGN are most commonly seen in the age group of 5 to 15 years with a male preponderance. Glomerulonephritis occurs after a latency period of 1 to 2 weeks after streptococcal pharyngitis and 3 to 6 weeks after skin infections. The incidence of PSGN is much higher after skin infections (25%) when compared with pharyngitis (5%–10%). ^, The subclinical presentation of PSGN is four to five times more common than overt clinical syndromes. Acute nephritic syndrome is the most common presentation (90%). Less common manifestations are nephrotic syndrome (5%–10%) and rapidly progressive glomerulonephritis (3%–5%). ^{, ,} In children with PSGN, older age, nadir complement C3, and nephrotic-range proteinuria are potential risk factors for kidney injury. The timeline of the onset, progression, and recovery of PSGN is described in Fig. 34.6 .

Timeline of the onset of clinical and laboratory features, course of glomerulonephritis, and recovery in relation to the streptococcal infection in poststreptococcal glomerulonephritis. A SO, Antistreptolysin O; C3, complement 3; HTN, hypertension.

Laboratory evaluation of PSGN includes urinalysis, which demonstrates subnephrotic-range proteinuria, dysmorphic red blood cells, and red blood cell casts. Complement C3 levels are low in more than 95% of children with PSGN. Complement C3 levels decline early in the course of the disease during the latent phase and return to normal in 6 to 8 weeks. ^, Clinical evidence of a recent streptococcal infection may not be found in all patients. An antistreptolysin O titer >200 international units or >330 Todd units or a rising titer of antistreptolysin O or anti-DNAse B provides serologic evidence of previous streptococcal infection but is not diagnostic of streptococcal infection. The antistreptolysin O titers peak at 3 to 5 weeks and anti-DNAse B at 6 to 8 weeks after infection. The sensitivity and specificity for the combination of antistreptolysin O and anti-DNAase B are 96% and 89%, respectively. The sensitivity and specificity of anti-DNAse B may be higher when compared with antistreptolysin O for PSGN after skin infections.

Although a kidney biopsy is not required to establish the diagnosis of PSGN in children, it may be indicated when there is no evidence of infection, in cases with rapid and progressive deterioration in kidney function, prolonged and atypical clinical course, or associated comorbid conditions that confound the diagnosis. Diagnosis of PSGN in adults may be more difficult because the comorbid immunocompromised state and comorbidities can mask symptoms of the infection. Also, clinical signs associated with glomerulonephritis (edema, hypertension, and renal dysfunction) might be attributed to comorbidities, such as diabetes, heart failure, or preexisting arterial hypertension. Since PSGN is a much less frequent cause of acute glomerulonephritis in adults, we suggest renal biopsy even in patients with a typical history to confirm diagnosis. PSGN in the elderly tends to have a more severe and prolonged course, often with incomplete recovery.

An alternate diagnosis should be considered when there are systemic symptoms, persistently elevated or increasing creatinine, and persistent hypocomplementemia.

The histopathologic hallmark of PSGN is diffuse, exudative proliferative glomerulonephritis with immunofluorescence showing capillary and mesangial staining for IgG and C3 ( Fig. 34.7 ). Crescents are rarely seen in PSGN. In the late phase of illness, the biopsy may only show mesangial hypercellularity with lymphocytic infiltration. The findings on immunofluorescence also change from deposits of C3 and IgG in the capillary walls and mesangium (starry sky appearance) in the early phase to resorption of capillary wall deposits (mesangial pattern) in later phases. Coarse granular deposits along the capillary wall create a “garland” pattern in some cases. Electron microscopy demonstrates the characteristic subepithelial humps ( Fig. 34.8 ). Some deposits may be seen in the mesangial and subendothelial areas as well.

Histology of glomeruli from a patient with poststreptococcal glomerulonephritis.

The light microscopic picture (hematoxylin-eosin stain) (A) shows endocapillary and mesangial proliferation with neutrophilic infiltration (yellow arrow). The immunofluorescence shows granular deposits of C3 (B) and IgG (C) deposits along the glomerular capillary loops and mesangium. C3, Complement 3; IgG, immunoglobulin G.

Images kindly provided by Dr. Anila Abraham, Nephropathologist, Renopath, Chennai, India.

Histology of glomeruli from a patient with poststreptococcal glomerulonephritis.

(A and B) Periodic acid–Schiff and hematoxylin-eosin–stained sections, respectively, showing a proliferative, exudative pattern of injury. (C and D) From direct IF study showing peripheral and mesangial coarse granular deposits of IgG and C3c with C3c deposits being dominant. (E and F) From electron microscopy showing subepithelial humps.

Histopathology images have been provided by Dr. Swarnalatha Gowrishanker, Nephropathologist, Apollo Hospital, Hyderabad, India.

PSGN is most often a self-limiting condition and requires supportive treatment only. Resolution of clinical symptoms occurs within 2 to 3 weeks. The levels of complement C3 return to normal after 6 to 8 weeks. Microscopic hematuria, however, may persist for 1 to 2 years after an episode of PSGN. ^, Recurrence of PSGN is extremely rare. ^,

Furosemide is the drug of choice in children with features of hypervolemia and hypertension. A calcium channel blocker may be added to control hypertension. ^{, ,} Angiotensin-converting enzyme inhibitors are generally avoided in the acute phase of the illness because they may reduce the glomerular filtration rate and worsen hyperkalemia. Notably, a large retrospective observational study from India suggests a better outcome with renin-angiotensin system (RAS) blockade in adult patients with bacterial IRGN; however, patients fulfilling the criteria for PSGN were in the minority in the population investigated. Restriction of salt, fluid, and potassium intake is recommended in the early phase of the disease. Intravenous antihypertensive medications may be required in children presenting with acute severe hypertension. Dialysis is rarely needed, except in some children presenting with rapidly progressive glomerulonephritis.

The role of immunosuppressants even in the case of crescentic glomerulonephritis is limited. Immunosuppression with corticosteroids and alkylating agents has been used in cases with crescentic glomerulonephritis, but there is little evidence of benefit on long-term outcomes. Even among adults, the role of steroids in the treatment of PIGN is restricted to severe cases, although the benefits seem to be limited.

Antibiotic therapy is not warranted in all cases of PSGN because the infection has subsided by the time the nephritis develops. Antibiotic therapy does not reduce the risk of developing PSGN. ^, Antibiotic prophylaxis with penicillin may be advised for close contact with children with streptococcal infection, during epidemics, and in those with a streptococcal carrier state. Two vaccines are under development for PSGN. The MJ8VAX consisting of a 29 amino acid peptide of the carboxy terminal of M protein as antigen is in phase 1 trials. The StrepAnova, a 30-valent vaccine with antigen derived from M protein, is in phase 2 trials.

The most common differential diagnoses are C3 glomerulopathy (see earlier), systemic lupus erythematosus, and IgA nephropathy. ^,

The prognosis of PSGN is good, and complete recovery is seen in most children. Long-term follow-up studies in children found that about 20% of children with PSGN had persistently abnormal urinalysis; however, less than 1% developed kidney failure. The prevalence of proteinuria (7.2%), microscopic hematuria (5.4%), arterial hypertension (3%), and azotemia (0.9%) on follow-up was comparable with that in the normal population. Children from low-resource countries with more severe disease at onset or AKI requiring dialysis had a higher incidence of sequelae including proteinuria, hypertension, and azotemia. The risk of proteinuria and chronic kidney disease (CKD) in young adults has been associated with a combined history of low birth weight and PSGN, especially in those with subsequent obesity. Outcomes in adults with PSGN are worse than those in children, with residual hypertension, glomerulosclerosis, or CKD being seen in 30% to 50% of elderly patients, although a remission rate of 83% has been reported in more current and younger cohorts.

Patients typically present with AKI, hematuria, and glomerular proteinuria, often in the nephrotic range. Serum C3 may be normal or low. ^, Sometimes, the underlying staphylococcal infection is obvious, such as in superficial skin infections or dental abscesses. Other infection sites, in contrast, may not be obvious, as in the case of chronic osteomyelitis, endocarditis, prosthesis, or pacemaker wire infections. About 20% of patients with SAGN may develop concomitant leukocytoclastic vasculitis. Moreover, some patients with SAGN, particularly in the setting of endocarditis, are ANCA positive. ^, Thus SAGN may mimic IgA vasculitis or ANCA-associated vasculitis, and a high index of suspicion is required.

Shunt nephritis was first reported in 1965 and arises from infected ventricular shunts implanted for hydrocephalus. ^, It usually develops within 5 years after implantation but may occur much later. Patients often show systemic signs and symptoms of ongoing inflammation, such as recurring fever, hepatosplenomegaly, and leukocytoclastic vasculitis of the skin. Most patients have hematuria and subnephrotic or nephrotic-range proteinuria. Kidney function may be normal but can range all the way to rapidly progressive glomerulonephritis. ^, The most common causative organism is S. epidermidis, but Propionibacterium acnes may also occur. Both might be mistaken as a contaminant. Other pathogens associated with shunt nephritis include S. aureus, Escherichia coli, Corynebacterium sp., Pseudomonas sp., and fungi such as Fusarium. ^, Cerebrospinal fluid and blood cultures are often negative (in 27% and 57%, respectively). Serologic workup often reveals low C3, and ANA, ANCA, or rheumatoid factor may be positive. ^, Typically, renal biopsy displays a membranoproliferative pattern, with immunofluorescence depicting granular subendothelial and mesangial deposits, often containing polyclonal immunoglobulins (IgM and IgG) and C3. Crescents may be observed. On electron microscopy, deposits are subendothelial and mesangial. Therapy should include immediate surgical removal of the shunt along with antibiotic treatment. Renal outcome is good if diagnosis is made early and therapy is instituted timely. However, delayed diagnosis and late shunt removal are associated with a poor renal and neurologic prognosis even with pathogen-directed antibiotic treatment. ^, There is no established role for immunosuppression in shunt nephritis, and its use should be avoided.

Since ventriculoperitoneal (VP) shunts have largely replaced ventriculoatrial (VA) shunts, the incidence of shunt nephritis has dramatically decreased. ^{, ,} However, in individuals with VA or VP shunts who present with nephritic or nephrotic syndrome and proliferative glomerulonephritis on renal biopsy, the index of suspicion must still be high.

Apart from the entities described earlier that are defined on the basis of a specific pathogen, a site of infection, or a histologic characteristic, many cases of glomerulonephritis associated with bacterial infections do not fit into any of these categories. In a retrospective study from India of adult patients with bacterial IRGN, which represents the largest reported cohort of bacterial IRGN to date, a considerable number of patients had gram-negative infections and the urinary tract was the most frequent site of infection. This study also analyzed the association of latency from time of infection to onset of the glomerular disease with pathogens, as well as its role regarding outcomes. Latency was defined as “parainfectious” if glomerular disease was diagnosed with ongoing infection, “periinfectious” if features of glomerular disease ensued within 1 to 7 days of the resolution of infection, or “postinfectious” when at least 7 days had passed between resolution of infection and onset of glomerular disease manifestations. In this cohort, the most common causative agents in postinfectious glomerulonephritis were Streptococci, and the most common site of infection was the skin. Parainfectious glomerulonephritis was commonly associated with gram-negative bacteria and urinary tract infections and thus mostly did not fit into any of the previously described entities (i.e., SAGN or infective endocarditis–related glomerulonephritis). Renal outcomes were worst in cases of parainfectious glomerulonephritis. RAS blockade was associated with better kidney survival, whereas glucocorticoid treatment had no effect, similar to previous studies. ^{, ,}

The most common forms of viral IRGNs are due to infection with hepatitis B and C. Hepatitis E virus may also cause glomerulonephritis, especially in chronic infections in immunocompromised hosts.

Approximately 240 to 300 million people worldwide are living with chronic hepatitis B, ^, and 3% to 5% of them may develop kidney disease. The incidence of HBV-associated glomerulonephritis in Europe and the United States is lower than in Asia and Africa due to a lower prevalence of chronic HBV infections. HBV immunization can successfully prevent infection and consequently development of HBV-associated glomerulonephritis in patients who have not been infected. The most common form of HBV-associated glomerulonephritis is membranous nephropathy. However, HBV may also cause membranoproliferative glomerulonephritis in the setting of virus-associated mixed cryoglobulinema. ^, Interestingly, patients with HBV-associated membranous nephropathy more often have lower complement levels compared with patients with non–infection-associated forms of membranous nephropathy. PLAR2 antibodies can be positive in HBV-associated membranous nephropathy, even if less frequent compared with primary membranous nephropathy. ^, HBV-associated membranous nephropathy may resolve spontaneously in children, especially if seroconversion from HBeAg to anti-HBe occurs. Spontaneous resolution is less frequent in adults. ^, Therapy consists of treating the underlying infection with interferon-α or antiviral medication. Lamivudine is not recommended due to the high resistance rates. Entecavir or tenofovir alafenamide fumarate (TAF) are preferred for first-line therapy. ^,

Glomerulonephritis occurs in up to half of patients with HCV infection. The most common form is MPGN in the setting of type 2 cryoglobulinemia. Less frequently, HCV-positive patients may develop membranous nephropathy; however, the causal role of the virus is debated. Other, less common forms of glomerulonephritis that have been described in HCV-positive patients in the literature are FSGS, IgA nephropathy, fibrillary, and immunotactoid, but causality has not been proven. Novel treatments for HCV have largely eliminated HCV-related glomerulonephritis. Patients with HCV-associated glomerulonephritis should be treated with direct-acting antiviral therapy. The choice of regimen should be based on GFR, drug-drug interactions, previous treatment, stage of liver fibrosis, and comorbidities. If pangenotypic regimens are not used, HCV genotype should guide therapy in combination with the features mentioned earlier.

In patients with moderate to severe cryoglobulinemia and glomerulonephritis (see Chapter 35), immunosuppressive drugs such as systemic glucocorticoids and rituximab are recommended, in addition to antiviral therapy. In the most severe and life-threatening cases, plasmapheresis (PLEX) can be added. PLEX should also be considered before rituximab infusion in patients with a high cryocrit (>10%) to avoid severe systemic reactions due to direct interaction of rituximab with cryoglobulins, which can lead to serum sickness or vasculitis. ^, Nephrologists dealing with HCV-associated glomerulonephritis need to collaborate closely with infectious disease specialists and/or hepatologists to optimize treatment regimens and manage complications.

HIV can cause different forms of glomerulonephritis, the most common being HIVAN and HIV-associated immune complex kidney disease (abbreviated HIVICK or HIVICD).

HIVAN

Histologically, HIVAN manifests as a collapsing FSGS with concomitant tubular microcysts, tubulointerstitial inflammation, and tubuloreticular inclusion bodies in glomerular endothelial cells on electron microscopy (see Africa, Chapter 75 ). It classically presents with proteinuria in the nephrotic range and decreased kidney function. Patients are usually not hypertensive and display normal-sized or enlarged kidneys. As stated earlier, glomerulonephritis ensues from direct damage of visceral and parietal epithelial cells by the virus, which also affects tubular epithelial cells. ^, Classical HIVAN occurs almost exclusively in individuals of African descent and is more frequent in patients from sub-Saharan Africa, where approximately three quarters of the globally affected 40 million patients with HIV infection live. This is largely due to the higher prevalence of apolipoprotein L1 (APOL1) risk alleles, which also confer a higher risk for CKD due to non-HIV diseases, such as FSGS or hypertensive nephrosclerosis. ^, The association of high-risk APOL1 genotypes and collapsing glomerulonephritis has also been described in glomerulonephritis associated with other viruses, such as cytomegalovirus, parvovirus B19, and EBV.

Similar to HCV, highly active antiretroviral therapy has greatly reduced the incidence of HIVAN in patients undergoing therapy and is the treatment of choice for affected individuals. RAS blockade might be helpful to reduce proteinuria. ^{, ,} In patients with severe interstitial inflammation, glucocorticoids might be beneficial but should be used cautiously. Recently, it has been shown that a small molecule inhibitor (inaxaplin) of APOL1 function can reduce proteinuria in patients with primary FSGS homozygous for the APOL1 risk alleles G1 or G2. Whether this approach will also benefit patients with HIVAN needs to be determined.

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