Background

Acute glomerulonephritis is a disease characterized by the sudden appearance of edema, hematuria, proteinuria, and hypertension. It is a representative disease of acute nephritic syndrome in which inflammation of the glomerulus is manifested by proliferation of cellular elements secondary to an immunologic mechanism (see the following image).[1, 2]

A schematic representation of the proposed mechanism for acute poststreptococcal glomerulonephritis (APSGN). C = Activated complement; Pl = Plasmin; NAPlr = Nephritis-associated plasmin receptor; SK = Streptokinase; CIC = Circulating immune complex. Acute poststreptococcal glomerulonephritis (APSGN) results from an antecedent infection of the skin or throat caused by nephritogenic strains of group A beta-hemolytic streptococci.[3, 4, 5] The concept of nephritogenic streptococci was initially advanced by Seegal and Earl in 1941, who noted that rheumatic fever and acute poststreptococcal glomerulonephritis (both nonsuppurative complications of streptococcal infections) did not simultaneously occur in the same patient and differ in geographic location.[6] Acute poststreptococcal glomerulonephritis occurs predominantly in males and often completely heals, whereas patients with rheumatic fever often experience relapsing attacks.

The M and T proteins in the bacterial wall have been used for characterizing streptococci. Nephritogenicity is mainly restricted to certain M protein serotypes (ie, 1, 2, 4, 12, 18, 25, 49, 55, 57, and 60) that have shown nephritogenic potential. These may cause skin or throat infections, but specific M types, such as 49, 55, 57, and 60, are most commonly associated with skin infections. However, not all strains of a nephritis-associated M protein serotype are nephritogenic.[7] In addition, many M protein serotypes do not confer lifetime immunity. Group C streptococci have been responsible for recent epidemics of APSGN (eg, Streptococcus zooepidemicus). Thus, it is possible that nephritogenic antigens are present and possibly shared by streptococci from several groups.[2]

In addition, nontypeable group A streptococci are frequently isolated from the skin or throat of patients with glomerulonephritis, representing presumably unclassified nephritogenic strains.[7]

The overall risk of developing acute poststreptococcal glomerulonephritis after infection by these nephritogenic strains is about 15%. The risk of nephritis may also be related to the M type and the site of infection. The risk of developing nephritis infection by M type 49 is 5% if it is present in the throat. This risk increases to 25% if infection by the same organism in the skin is present.

See also Acute Glomerulonephritis, Emergent Management of Acute Glomerulonephritis, and Rheumatic Heart Disease.

PathophysiologyMost forms of acute poststreptococcal glomerulonephritis (APSGN) are mediated by an immunologic process. Cellular and humoral immunity is important in the pathogenesis of this disease, and humoral immunity in APSGN. Nonetheless, the exact mechanism by which APSGN occurs remains to be determined. The 2 most widely proposed theories include (1) glomerular trapping of circulating immune complexes and (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.”

Additional evidence has also been presented to support the anti-immunoglobulin activity or glomerular plasmin-binding activity of streptococcal antigens. The cross-reactivity of streptococci and mammalian tissue implicating molecular mimicry in acute rheumatic fever led to evidence of a similar mechanism involved in APSGN. However, the similar cross-reactivity patterns of rheumatogenic and nephritogenic strains of streptococci argue against molecular mimicry involving M proteins.

Immune complex-mediated mechanisms

An immune complex–mediated mechanism is the most widely proposed mechanism leading to the development of APSGN. 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.

Zymogen (NSAP) and NAPlr

Two major antigens have presently been identified as the potential cause(s) of APSGN: A zymogen precursor of exotoxin B (SPEB [streptococcal pyrogenic toxin B]) or nephritis strain–associated protein (NSAP), and nephritis-associated plasmin receptor (NAPlr), a glycolytic enzyme, which has glyceraldehydes-3-phosphate dehydrogenase (GAPDH) activity[8, 9, 10, 11, 12]

NSAP is a 46- to 47-kd protein that is unique to the extracellular products of nephritogenic streptococci. NSAP was demonstrated in glomerular deposits of 14 of 21 patients with APSGN, but none in control biopsy samples from 5 patients with acute kidney injury and 11 with nonstreptococcal glomerulonephritis. NSAP was also detected in serum from 96% of APSGN patients compared with 15-20% of patients with either acute kidney injury or impetigo.[13] NSAP has antigenic, biochemical, and structural similarities to streptokinase from group C streptococcal organisms, binds to plasmin, and is a plasminogen activator. However, streptokinase cannot be demonstrated in glomerular deposits for patients with APSGN, and serum levels of purified group A streptokinase were similar in patients with APSGN and those

with acute kidney injury. Thus, although NSAP and streptokinase have similarities, they appear to be 2 distinct proteins.[13]

Yoshizawa et all isolated a 43-kd protein called preabsorbing antigen (PA-Ag) that is putatively identical to endostreptosin.[14, 15] PA-Ag has the ability to “preabsorb” the antibody in convalescent sera from patients with APSGN and thus prevent its deposition in glomeruli. PA-Ag activates the alternative pathway.[15] This 43-kd protein was later identified by Yamakami et al as NAPlr.[16]

These researchers noted that NAPlr was present in 100% of the early biopsy samples from in glomeruli of patients with APSGN.[17] The glomerular distribution of NAPlr deposition and plasmin activity determined by in situ zymography are identical.

The fact that NAPlr did not co-localize with C3 in glomerular deposits suggests that (1) complement was activated by NAPlr in the circulation rather than in situ, and (2) NAPlr induced APSGN independently of complement activation by binding to the glomerular basement membrane (GBM) and mesangial matrix via its adhesive character, subsequently trapping and activating plasmin and causing in situ glomerular damage by degrading the GBM or activating latent matrix metalloproteases.[17, 18]

A proposed mechanism for acute poststreptococcal glomerulonephritis is that soluble, released NAPlr binds to glomeruli and provide a mechanism to capture plasmin activated by streptokinase. The activated plasmin bound to NAPlr associates with the GBM and mesangium. Both NAPlr and NSAP are capable of inducing chemotactic (monocyte chemoattractant protein 1) and interleukin (IL)–6 moieties in mesangial cells, promoting enhanced expression of adhesion molecules. Peripheral blood leukocytes also release other cytokines such as tumor necrosis factor-alpha, IL-8, and transforming growth factor-beta, which react with NSAP. These findings highlight the inflammatory potential of these nephritogenic antigens.[19, 20, 21, 22]

Bound plasmin can cause tissue destruction by direct action on the glomerular basement membrane or by indirect activation of procollagenases and other matrix metalloproteinases (MMPs). NAPlr can also activate the alternate complement pathway, leading to accumulation of polymorphonuclear cells and macrophages and local inflammation. In addition, the in situ–formed and circulating immune complexes can readily pass through the altered glomerular basement membrane and accumulate on the subepithelial space as humps.

Complement activation from both serum profiles and immunofluorescence patterns for glomerular deposits indicates that C3 activation in APSGN is predominantly via the alternative pathway.[23, 24, 25] The immune deposits consist of immunoglobulin G (IgG), C3, properdin, and C5.[25] These deposits rarely contain C1q or C4, both components of the classic complement pathway. A recent study also showed evidence for activation of the lectin-binding pathway from deposition of membrane-bound lipoprotein in some patients with APSGN.[26]

During the early phase of the diseases (first 2 wk), evidence of classical pathway activation is seen, as demonstrated by transient depression of serum C1q, C2, and/or C4 concentrations.[27, 28, 29]

and the presence of circulating C1-inhibitor-C1r-C1s complexes or C4d fragments. It is proposed that the circulating immune complexes in the acute stage of the disease due to classic complement pathway activation is distinct from that seen in the glomerular immune deposits. APSGN with typical findings on histopathology may occur in patients with no evidence of complement activation, as manifested by depression of serum C3 concentrations.[30, 31]

Hypocomplementemic patients differ from normocomplementemic patients by virtue of the presence of factor B in the glomerular deposits and the absence of factor H, which is a regulatory protein of the alternative pathway.[25] These findings suggest that the glomerular immune deposits of C3bBb convertase may be due to ongoing complement activation in situ rather than systemic activation. Crescentic APSGN may have an increased association with normocomplementemia. The reason for this possible association of normocomplementemia with crescent formation in APSGN is not clear.

Serum IgG levels are elevated in about 44% of patients with APSGN.[32] Less than 50% of patients with elevated serum IgG levels, however, have glomerular deposits of IgG. Elevated IgG levels were more likely to be found in patients with antistreptolysin O titers of greater than or equal to 833 Todd units (P < .001). However, elevated serum IgG concentrations do not correlate with severity of disease, age of the patient, or serum albumin or C3 levels. It would appear that failure to form antibody to a glomerular-bound protein produced by nephritogenic Streptococcus, is thought to be the origin of the IgG in glomerular deposits, is in some way significantly associated with elevated serum levels of IgG and antibody to streptolysin O.[32]

A mechanism for acute poststreptococcal glomerulonephritis proposed by Yoshizawa et al is shown in the image below.

A schematic representation of the proposed mechanism for acute poststreptococcal glomerulonephritis (APSGN). C = Activated complement; Pl = Plasmin; NAPlr = Nephritis-associated plasmin receptor; SK = Streptokinase; CIC = Circulating immune complex. There is considerable evidence both for and against most putative nephritogenic antigens. Genomic sequencing of nephritogenic strains of streptococci may lead to the discovery of new nephritogenic antigen candidates in conserved and differing regions of the streptococcal genome. This will lead to improved understanding of the pathogenetic mechanism(s) leading to the development of APSGN.

Nonimmune complex-mediated mechanisms

Other nonimmune complex mediated mechanisms have been proposed for the development of APSGN, such as delayed-type hypersensitivity, superantigens, and autoimmune phenomena.

A role for delayed-type hypersensitivity has been implicated in the pathogenesis of this disease. Early in the course of APSGN, resident endothelial and mesangial cells are predominantly proliferated, and this is accompanied by infiltration with polymorphonuclear leukocytes and monocytes. Macrophages are effector cells that cause resident cellular proliferation. The infiltration of macrophages in the glomeruli is mediated by complement-induced chemotaxis

and, most likely, by an antigen-specific event related to delayed-type hypersensitivity mediated by helper/inducer T cells.

Streptococcal M proteins and pyrogenic exotoxins can act as superantigens. These cause a marked expansion of T cells expressing specific T-cell receptor B-chain variable gene segments. Massive T-cell activation occurs, with release of T-cell–derived lymphokines such as IL-1 and IL-6.

Autologous IgG in APSGN becomes antigenic and elicits an anti-IgG rheumatoid factor response, leading to formation of cryoglobulins. Cryoglobulins, rheumatoid factors, and other autoimmune phenomena occur in APSGN and are thought to play a role in the pathogenesis of the disease together with streptococcal superantigens.

EpidemiologyOver the last 2-3 decades, the incidence of acute poststreptococcal glomerulonephritis (APSGN) has declined in the United States as well as in other countries, such as Japan, Central Europe, and Great Britain. The estimated worldwide burden of APSGN is approximately 472,000 cases per year, with approximately 404,000 cases being reported in children and 456,000 cases occurring in less developed countries.[33] APSGN associated with skin infections is most common in tropical areas where pyoderma is endemic, whilst pharyngitis-associated APSGN predominates in temperate climates.[33]

However, in recent years, a slight increase in the incidence of the disease has been reported, although the actual incidence is still unknown. This is particularly true in elderly persons, especially in association with debilitating conditions such as alcoholism or intravenous drug abuse.[34] The overall decline in APSGN may be due to the improvement in living conditions with less crowding. However, other factors, including decreased prevalence or infectivity of the nephritogenic streptococci, may also have contributed to the decline in incidence. The recently observed increase in incidence is more difficult to explain. In the past 30 years, large epidemics have been reported in middle-income countries, with clusters of cases in more developed countries.[35] However, in poorly developed countries, it is likely that clusters of cases of APSGN may go underreported.

Globally, as many as 50% of cases may be subclinical, although it is known that APSGN continues to have a wide distribution. A high percentage of affected persons have mild disease and are asymptomatic (estimates of the ratio of asymptomatic to symptomatic patients vary from 2:1 to 3:1); thus, the actual incidence of the disease is not known.

APSGN usually occurs as sporadic cases, but epidemic outbreaks have taken place in communities with densely populated dwellings that have poor hygienic conditions with a high incidence of malnutrition, anemia, and intestinal parasites. In certain regions, epidemics may occur in cyclical outbreaks every 5-7 years for unknown reasons.

A strong seasonal variation is also noted; sporadic APSGN following upper respiratory infection, pharyngitis, and tonsillitis is more common in winter and spring in temperate areas, whereas skin infections are commonly found to precede APSGN in the more tropical and subtropical areas, with a peak incidence during summer and autumn.

The disease is more frequent in children aged 2-12 years, with a peak prevalence in individuals aged approximately 5-6 years,[36] although it has been reported in infants as young as 1 year and in adults as old as 90 years. However, in most large series, 5-10% of patients are older than 40 years, and 5% are younger than 2 years. Although a male predominance is noted in symptomatic cases (male-to-female ratio, 1.7-2:1) for unknown reasons, when subclinical and clinical disease is taken into account, the rates are the same in males and females.

No racial predilection is noted for acute poststreptococcal glomerulonephritis; the condition is reported in all ethnic and cultural groups. In urban populations, a predilection toward minority populations is observed; however, this may be related more to the socioeconomic factor of overcrowding than to any racial predilection.

Prognosis The course and prognosis for acute poststreptococcal glomerulonephritis (APSGN) is well known and almost always favorable in children, but this is not so with nonstreptococcal forms of the condition. In addition, for unknown reasons, the prognosis for individuals with APSGN is not as good for adults (particularly elderly persons) as it appears to be for children. In elderly patients with debilitating conditions (eg, malnutrition, alcoholism, diabetes, chronic illness), the incidences of azotemia (60%), congestive heart failure (40%), and nephrotic-range proteinuria (20%) are high. Death may occur in 20-25% of these patients.[37, 38] Prolonged follow-up observation appears to be indicated. The ultimate prognosis in individuals with APSGN largely depends on the severity of the initial insult.

Epidemic poststreptococcal acute glomerulonephritis appears to end in virtually complete resolution and healing in all patients, and the prognosis is favorable for 95% of children with acute sporadic poststreptococcal glomerulonephritis. The prognosis for persons with acute glomerulonephritis secondary to other causes is less certain.

Edema usually resolves within 5-10 days, and the blood pressure usually returns to normal after 2-3 weeks, even though persistence of elevated pressures for as many as 6 weeks is compatible with complete resolution.

Urinary abnormalities resolve at various times after onset. Proteinuria may disappear within the first 2-3 months or may slowly decrease over 6 months. Intermittent or postural proteinuria has been noted for 1-2 years after onset.

Gross hematuria usually disappears within 1-3 weeks but may be exacerbated by physical activity. C3 concentration returns to normal in more than 95% of patients by the end of 8-10 weeks. Microscopic hematuria usually disappears after 6 months, but its presence for as long as 1 year should not cause undue concern, and even more prolonged hematuria (1-3 y) has been observed in some patients who ultimately have demonstrated complete resolution of their renal disease. Strongly consider the possibility of chronic renal disease when both hematuria and proteinuria persist longer than 12 months.

In a few hospitalized patients, the initial injury is so severe that either persistent renal failure or progressive renal failure ensues. However, histologic regression of the disease in most patients is predictable, and the ultimate prognosis is good.

Although clinical resolution occurs in most patients, several authors report time-related reduction in precise measurements of renal function, as well as diminished renal functional reserve. These studies further support the thesis that any significant loss of nephrons leads to hyperfiltration of the remaining units. Studies that have followed up children with APSGN for 10-20 years have shown that approximately 20% of the patients have abnormal urine analyses, with less than 1% having azotemia.[39]

Clinical manifestations of the disease rarely recur after the first 3 months, and second episodes of acute glomerulonephritis are rare.

Complications

The most common acute complication is hypertension with or without central nervous system (CNS) manifestations.

Anemia is common early in the disease and is primarily due to dilution, although in 2 instances, autoimmune hemolytic anaemia was documented in the early stages of APSGN.[40, 41] Anemia tends to resolve with diuresis. A few patients may have diminished erythropoiesis in the recovery phase and have some persisting anemia.

An occasional patient develops pulmonary edema because of the marked increase in vascular volume that is present in the early phase of the disease.

Congestive heart failure is rare but has been reported. Definite myocarditis has also been documented.

In most patients with moderate to severe APSGN, a measurable reduction in volume of glomerular filtrate (GF) is present, and the capacity to excrete salt and water is usually diminished, leading to expansion of the extracellular fluid (ECF) volume. The expanded ECF volume is responsible for edema and, in part, for hypertension, anemia, circulatory congestion, and encephalopathy. Persistence or worsening of azotemia is always troubling and may suggest acute kidney injury. The presence of acute kidney injury may suggest an alternate diagnosis (eg, membranoproliferative glomerulonephritis [MPGN], Henoch-Schönlein purpura [HSP], systemic lupus erythematosus [SLE]) or a severe or worsening APSGN, such as observed in those with crescentic glomerulonephritis or rapidly progressive glomerulonephritis.[42]

Patient Education Clearly and specifically explain the nature of the disease, its course, and the eventual prognosis of the condition to the child (if old enough to understand) and the parents and/or caregivers. They need to understand that, although complete resolution is expected, a small possibility exists for persistent disease, and that an even smaller possibility exists for progression. This information is necessary for some patients to ensure that compliance with the follow-up program occurs.

Clearly outline a follow-up plan and discuss the plan with the family. Blood pressure measurements and urine examinations for protein and blood constitute the basis of the follow-up plan. Perform examinations at 4- to 6-week intervals for the first 6 months and at 3- to 6-month intervals thereafter, until both hematuria and proteinuria have been absent and the blood pressure

has been normal for 1 year. Documenting that the low C3 has returned to normal after 8-10 weeks may be useful.

For patient education information, see High Blood Pressure Center, as well as Blood in the Urine and Chronic Kidney Disease.

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Latar belakang

Glomerulonefritis adalah penyakit yang ditandai dengan kemunculan busung, hematuria, proteinuria, dan hipertensi. Itu adalah penyakit perwakilan Sindrom nefritis akut di mana peradangan glomerulus diwujudkan oleh proliferasi unsur selular yang sekunder untuk mekanisme kekebalan (lihat gambar berikut).[1, 2]Terdapat penggambaran skematik dari mekanisme yang diusulkan untuk glomerulonefritis poststreptococcal (APSGN). C = aktif komplemen; Pl = Plasmin; NAPlr = radang buah pinggang yang terkait plasmin reseptor; SK = Streptokinase; CIC = beredar kompleks imun.Glomerulonefritis poststreptococcal (APSGN) hasil dari infeksi yg di atas kulit atau tenggorokan yang disebabkan oleh nephritogenic strain Grup A streptokokus beta hemolytic.[3, 4, 5] Konsep nephritogenic streptokokus awalnya maju oleh Seegal dan Earl pada tahun 1941, yang mencatat bahwa rematik dan glomerulonefritis poststreptococcal (kedua nonsuppurative komplikasi infeksi Streptococcus) Apakah tidak terjadi pada pasien yang sama dan sekaligus berbeda dalam lokasi geografis.[6] Glomerulonefritis poststreptococcal muncul di laki-laki dan sering benar-benar menyembuhkan, sedangkan pasien dengan rematik sering mengalami serangan relapsing.Protein m dan t di dinding bakteri telah digunakan untuk mencirikan streptokokus. Nephritogenicity dibatasi terutama untuk tertentu m protein serotipe (yaitu 1, 2, 4, 12, 18, 25, 49, 55, 57, dan 60) yang telah menunjukkan potensi nephritogenic. Ini dapat menyebabkan infeksi kulit atau tenggorokan, tetapi jenis m tertentu, seperti 49, 55, 57, dan 60, paling sering dikaitkan dengan infeksi kulit. Namun, tidak semua strain e. Coli tipe terkait radang buah pinggang protein m yang nephritogenic.[7] Selain itu, banyak m protein serotipe tidak menganugerahkan kekebalan seumur hidup. Kelompok c streptokokus telah bertanggung jawab untuk baru-baru ini epidemi APSGN (misalnya, Streptococcus zooepidemicus). Dengan demikian, sangat mungkin bahwa nephritogenic antigen hadir dan mungkin bersama oleh streptokokus dari beberapa kelompok.[2]Selain itu, nontypeable Grup A streptokokus sering terisolasi dari kulit atau tenggorokan pasien dengan glomerulonefritis, mewakili agaknya unclassified nephritogenic strain.[7] Keseluruhan risiko mengembangkan glomerulonefritis poststreptococcal setelah infeksi oleh strain nephritogenic ini adalah sekitar 15%. Risiko radang buah pinggang mungkin juga berkaitan dengan tipe m dan tempat infeksi. Risiko mengembangkan infeksi radang buah pinggang dengan jenis M 49 adalah 5% jika hadir di tenggorokan. Risiko ini meningkat menjadi 25% jika infeksi oleh organisme yang sama di kulit hadir.Lihat juga glomerulonefritis, manajemen muncul glomerulonefritis akut dan penyakit jantung Rheumatic.BerikutnyaPatofisiologiSebagian besar bentuk glomerulonefritis poststreptococcal (APSGN) ditengahi oleh proses kekebalan. Seluler dan imunitas humoral adalah penting dalam patogenesis penyakit ini, dan imunitas humoral di APSGN. Namun, mekanisme tepat oleh APSGN yang terjadi tetap harus ditentukan. 2 Yang paling luas diusulkan meliputi teori (1) glomerular perangkap yang beredar kompleks imun dan pembentukan kompleks imun antigen (2) di situ-antibodi dihasilkan dari antibodi bereaksi dengan komponen baik Streptococcus disimpan di glomerulus atau dengan komponen glomerulus itu sendiri, yang disebut "mimikri molekuler."Bukti tambahan juga disajikan untuk mendukung aktivitas anti-immunoglobulin atau glomerular kegiatan plasmin mengikat antigen streptococcus. Cross-reactivity streptokokus dan mamalia jaringan implicating mimikri molekuler di akut rematik menyebabkan bukti dari mekanisme serupa yang terlibat dalam APSGN. Namun, pola-pola serupa cross-reactivity rheumatogenic dan nephritogenic strain streptokokus menentang mimikri molekuler yang melibatkan protein M.Mekanisme imun ditengahi kompleksMekanisme imun complex–mediated adalah mekanisme paling luas diusulkan pengembangan APSGN. Nephritogenic streptokokus menghasilkan protein dengan determinan antigenic unik. Faktor-faktor penentu antigenic ini memiliki afinitas tertentu untuk situs dalam normal glomerulus. Setelah rilis ke sirkulasi, antigen yang mengikat ke situs tersebut dalam glomerulus. Sekali terikat glomerulus, mereka mengaktifkan komplemen langsung oleh interaksi dengan properdin.Glomerular-terikat Streptococcus antibodi juga berfungsi sebagai antigen tetap dan mengikat beredar antibodi antistreptococcal, membentuk kompleks imun. Melengkapi fiksasi melalui jalur klasik mengarah ke generasi tambahan mediator inflamasi dan perekrutan sel peradangan.Zymogen (NSAP) dan NAPlrDua besar antigen saat ini telah diidentifikasi sebagai potensi cause(s) dari APSGN: prekursor zymogen exotoxin B (SPEB [Streptococcus pyrogenic racun B]) atau radang buah pinggang strain–associated protein (NSAP),