eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Acute Poststreptococcal Glomerulonephritis

Author: Robert G Schacht, MD, Professor, Department of Pediatrics, New York University Medical Center
Coauthor(s): Yang Sun Kim, MD, Assistant Professor, Department of Pediatrics, Division of Neonatology, New York University Medical Center; Clinical Director, Neonatology Intensive Care Unit, Bellevue Hospital; Luther Travis, MD, William W Glauser Professor of Pediatrics and Pediatric Nephrology, Department of Pediatrics, Divisions of Nephrology and Diabetes, University of Texas Medical Branch and Children's Hospital
Contributor Information and Disclosures

Updated: Jun 18, 2009

Introduction

Background

Glomerulonephritis (GN) is the term generally reserved for the various renal diseases in which inflammation of the glomerulus, manifested by proliferation of cellular elements, is secondary to an immunologic mechanism. The modification of this term by the adjective acute (eg, acute glomerulonephritis [AGN], poststreptococcal acute glomerulonephritis [PSAGN]) has imposed temporal restrictions and, as most commonly used by the clinician, defines an almost characteristic clinicopathologic correlation. The term also implies certain distinctive features concerning etiology, pathogenesis, course, and prognosis.

Prior to the development of precise serologic methodologies, coupled with clinicopathologic studies, acute glomerulonephritis was often known inappropriately as Bright disease, and almost any clinical presentation of gross hematuria was labeled erroneously as such. Most incidents of acute glomerulonephritis appear to be associated with a postinfectious state, whether bacterial or viral infections are incriminated in causation. Proven acute glomerulonephritis has been observed after staphylococcal and pneumonococcal infections, coxsackievirus B, echovirus type 9, influenza virus, and mumps. The most commonly recognized clinical picture (ie, poststreptococcal acute glomerulonephritis) follows infection with group A beta hemolytic streptococci. The physician must distinguish between poststreptococcal acute glomerulonephritis and acute glomerulonephritis secondary to other causes because the ultimate outcomes may differ.¹

Pathophysiology

Most forms of acute glomerulonephritis are mediated by an immunologic process. For poststreptococcal acute glomerulonephritis, the evidence suggests that immune complexes, preformed by the combination of specific antibodies against streptococcal antigens, localize on the glomerular capillary wall and activate the complement system. The immunologic system may also be activated by streptococcal antigens that adhere to the glomerular structures and act as "planted antigens" or by alterations in endogenous antigens. The activation of the complement cascade then generates chemotactic plasma-activated complement 5 (C5a) and platelet-derived inflammatory mediators. Various cytokines and other cellular immunity factors initiate an inflammatory response manifested by cellular proliferation and edema of the glomerular tuft.

Only a few strains of streptococci produce acute glomerulonephritis. Studies performed approximately 50 years ago led to the identification of certain strains of group A streptococci that are nephritogenic. More recently, non-group A streptococci, particularly group C, have also been demonstrated to produce glomerulonephritis.

At least 2 antigens isolated from nephritogenic streptococci, zymogen (a precursor of exotoxin B [SPEB]) and glyceraldehyde phosphate dehydrogenase (GAPDH), have been identified and are believed to be capable of initiating the immunologic response.² These fractions have a particular affinity for the glomerulus and have been demonstrated to induce an antibody response. This leads to the activation of a number of proinflammatory mediator pathways in both infiltrating and resident glomerular cells.

Although streptococcal infections are associated intimately with poststreptococcal acute glomerulonephritis, the mechanism of renal injury is still defined incompletely. Current evidence suggests that the inflammatory lesion in the glomerulus is associated with the fixation of soluble streptococcal antigen-antibody complexes. Studies have also demonstrated the ability of both SPEB and NAPlr, a streptococcal plasmin receptor, to bind and activate plasmin, thereby initiating an inflammatory cascade.

Several investigators have detected streptococcal antigen in renal biopsy material obtained early in the course of infection; however, the major evidence supporting an immune complex type of nephritis has been the finding of nodular deposits of immunoglobulin G (IgG) and the third component of complement (C3) on the capillary basement membrane. The finding of C3 in the renal glomerulus is usually associated with decreased serum concentrations of C3 and total hemolytic complement.

Decreased concentration of properdin and C3 proactivator and inconsistent decreases in the early components of complement indicate that complement activation occurs primarily by the alternate pathway. Reduced serum concentrations of C3 have been demonstrated in 80-92% of children with poststreptococcal acute glomerulonephritis. Values return to normal in most children within 6-8 weeks. The fourth component of complement (C4) value may also be depressed; however, this is an inconsistent finding.

Poststreptococcal acute glomerulonephritis can occur in epidemics or, more commonly, it can be sporadic. The sporadic form is seasonal; the winter-spring peak is associated with respiratory infection, and the summer-fall peak is most often associated with pyoderma. The most common serotype of group A beta hemolytic streptococci associated with nephritis from nasopharyngeal infections is type 12, whereas type 49 is most often recovered during outbreaks of pyoderma-related poststreptococcal acute glomerulonephritis. In individuals with pharyngitis-related acute glomerulonephritis, the latent period is approximately 10 days, and more than 80% of patients exhibit a significant rise in serum titer of antistreptolysin-O (ASO).

Conversely, a latent period is difficult to define in persons with impetigo-related acute glomerulonephritis, and a rise in the titer of ASO is observed in only 50% of patients. Serum concentrations of other streptococcal indicators (eg, antihyaluronidase [AH] titer, antideoxyribonuclease B titer [anti-DNase B]) are usually elevated in individuals with poststreptococcal acute glomerulonephritis secondary to either pharyngeal or skin infections. When various antibody titers are used, almost 95% of patients with poststreptococcal acute glomerulonephritis demonstrate evidence of a prior streptococcal infection.

Although renal biopsies are now indicated rarely in children with typical poststreptococcal acute glomerulonephritis, they have contributed substantially to the understanding of this disease. Irrespective of the degree of severity of the initial inflammatory response, the histologic picture is consistent and specific. As observed by light microscopy, glomerular changes are generalized and diffuse. The glomerular tufts usually appear enlarged and swollen, and a moderate-to-marked increase in proliferation of mesangial and epithelial cells is present.

Polymorphonuclear leukocytes are also often observed as part of the inflammatory process. In persons with the most severe disease, the glomeruli appear bloodless because of the associated edema of the capillary walls, which impedes glomerular perfusion. A direct correlation exists between the severity of the histologic process and the clinical manifestations of the disease during the acute phase and possibly the prognosis.

Granular deposits of IgG and C3 are typically found when the specimen is studied by immunofluorescent microscopy; other immunoglobulins (Igs) and fibrinogen often are observed. Electron microscopy of renal tissue from patients with poststreptococcal acute glomerulonephritis usually reveals subepithelial electron-dense deposits (humps).

In most patients with moderate-to-severe acute glomerulonephritis, 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.

Frequency

United States

Acute postinfectious glomerulonephritis was the most common nonsuppurative disease of the kidneys; its incidence declined only to increase again in recent years, albeit slightly. Because a high percentage of persons affected with acute postinfectious glomerulonephritis have mild disease and are asymptomatic (estimates of the ratio of asymptomatic to symptomatic patients vary from 2:1-3:1), the actual incidence of the disease is not known. Less crowded living conditions may have contributed to the apparent decline in incidence of poststreptococcal acute glomerulonephritis over the past few decades; however, other factors, including decreased prevalence or infectivity of the nephritogenic streptococci, may also have contributed to the decline. The recently observed increase in incidence is more difficult to explain.

Mortality/Morbidity

The ultimate prognosis in persons with acute glomerulonephritis depends largely on the severity of the initial insult. In an extremely small proportion of hospitalized patients, the initial injury is so severe that either persistent renal failure or progression to renal failure generally occurs. However, in most patients, histologic regression of the disease is the rule, and the ultimate prognosis is good. Clinical manifestations of the disease rarely recur after the first 3 months, and second episodes of acute glomerulonephritis are uncommon.

Epidemic poststreptococcal acute glomerulonephritis appears to end in virtually complete resolution and healing in all patients. The prognosis is also favorable for approximately 95% of children with sporadic poststreptococcal acute glomerulonephritis. The prognosis for persons with acute glomerulonephritis secondary to other causes is less certain. The disease appears to have a poorer prognosis in adults, particularly in elderly individuals. The cause of this difference is unknown.

The clinical course is largely predictable. Edema usually resolves within 5-10 days, and blood pressure (BP) usually returns to normal within 2-3 weeks, although persistence of elevated pressures for as many as 6 weeks is compatible with complete resolution. Gross hematuria usually disappears within 1-3 weeks; however, it subsequently may recur following physical activity. The C3 concentration returns to normal by 6-8 weeks after onset in more than 95% of patients.

Urinary abnormalities resolve at a slower pace. Proteinuria may disappear within the first 2-3 months or may decrease slowly over 6 months. Intermittent or postural proteinuria has been noted in a few patients for as long as 1-2 years after onset. Microscopic hematuria usually disappears after 6 months; however, its presence for as long as 1 year is not uncommon. 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 that the disease has entered a chronic phase if both hematuria and proteinuria persist for more than 12 months.

While 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.

Race

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

Sex

The disease is more prevalent in males in all regions of the world; the male-to-female ratio range is 1.7-2:1. The reasons for this male predominance are not known.

Age

Acute glomerulonephritis has been reported in infants as young as 1 year and in adults as old as 90 years; however, the disease occurs with the greatest frequency in children aged 4-12 years, with a peak prevalence in individuals aged approximately 5-6 years.³

Clinical

History

• Most patients with acute glomerulonephritis (AGN) exhibit milder symptoms and/or signs somewhere between the extremes described below.
  • At one extreme is the asymptomatic child whose disease is discovered only by examination of the urine. Based on surveillance studies of the siblings and/or household contacts of children affected with poststreptococcal acute glomerulonephritis (PSAGN), at least 50% of persons with laboratory evidence of nephritis (ie, abnormal urinalysis) appear to have no symptoms or signs of clinical illness.
  • At the other extreme is the child who presents with severe disease manifested by oliguria, edema, hypertension, and azotemia and with proteinuria, hematuria, and urinary casts (cylindruria).
• In those patients whose acute glomerulonephritis is the result of a postinfectious cause (ie, poststreptococcal acute glomerulonephritis being the most common), a latent period of 7-21 days between onset of the streptococcal infection and development of clinical glomerulonephritis is characteristic.⁴
• This latent period, more clearly defined after pharyngeal infections than after pyoderma, averages approximately 10 days.
• The development of clinical nephritis (ie, hematuria and/or edema) either during or within 2-5 days after the onset of a respiratory tract infection is atypical and suggests the possibility of some other form of glomerulonephritis.
• Gross hematuria and/or edema represent the most common clinical presentation.
• One or both findings usually appear abruptly and may be associated with various degrees of malaise, lethargy, anorexia, fever, abdominal pain, and headache. Observant parents may also note oliguria.
• An insidious onset of edema is more indicative of other forms of renal disease.
• An occasional child may have a scarlatiniform rash or evidence of a viral exanthema, but petechial or purpuric rashes suggest other conditions.
• Almost characteristic by their absence are arthralgia, arthritis, carditis, hepatic involvement, and GI bleeding.
• Edema is the most frequent manifesting symptom.
  • According to some investigators, edema is found in approximately 85% of patients.
  • Edema usually appears abruptly and first involves the periorbital area, but it may be generalized.
  • The degree of edema widely varies and depends on a number of factors, including the severity of glomerular involvement, the fluid intake, and the degree of hypoalbuminemia.
• Gross hematuria occurs at onset in 30-50% of children with poststreptococcal acute glomerulonephritis who require hospitalization.
  • The urine is usually described as being smoky, cola colored, tea colored, or rusty. The color is usually dependent on the amount of blood present and the pH of the urine.
  • Observant parents may note oliguria.
  • Clots are exceedingly rare in persons with acute glomerulonephritis.
• Hypertension is the third cardinal feature of poststreptococcal acute glomerulonephritis and is reported in 50-90% of children who are hospitalized with acute glomerulonephritis.
• The pathogenesis of the hypertension is unknown; however, pathogenesis is probably multifactorial and related only in part to extracellular fluid (ECF) volume expansion.
• The magnitude of the increase in blood pressure (BP) widely varies; however, systolic pressures greater than 200 mm Hg and diastolic pressures greater than 120 mm Hg are not unusual.
• Hypertensive encephalopathy has been reported in approximately 5% of hospitalized children and is the most serious early complication of this disease.
  • In these patients, hypertension is usually severe and is accompanied by signs of CNS dysfunction such as headache, vomiting, depressed sensorium, confusion, visual disturbances, aphasia, memory loss, coma, and convulsions.
  • Hypertensive encephalopathy has been reported in the occasional individual with minimal or no edema and with minimal urinary abnormalities.
• Circulatory congestion is apparent in most children admitted to the hospital but is responsible only rarely for significant early symptoms.
• Dyspnea, orthopnea, and cough may be present.
• Pulmonary rales are often audible.
• At times, the only evidence of congestion is detected on chest radiograph. A prominent cardiac shadow may be present until onset of diuresis.
• In the patient with an otherwise normal cardiovascular system, cardiac failure is unusual.
• Pallor is common at onset and is not explained entirely by the anemia.

Physical

• Edema is the most frequent and sometimes the only clinical finding. Edema may be either local (eg, periorbital) or generalized.
• Both systolic and diastolic hypertension may be present to a varying degree.
• Pallor is common.
• In some patients, pulmonary rales are audible.
• Either bradycardia or tachycardia may be observed.
• The sensorium may be depressed, and the degree of depression depends on the severity of encephalopathy.
• Other postinfectious causes of acute glomerulonephritis must be considered in the differential diagnosis (see Differentials) of poststreptococcal acute glomerulonephritis since the syndrome of acute glomerulonephritis has been reported following many other bacterial illnesses (eg, Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Rickettsia rickettsiae, Mycoplasma species, Meningococcus species, Leptospira species).
  • In addition, certain viral illnesses have preceded the onset of fairly typical acute glomerulonephritis; among the most common are varicella-zoster virus, cytomegalovirus, and the Epstein-Barr virus.
  • In the evaluation of a patient with acute glomerulonephritis, if evidence of a prior streptococcal infection is missing or inconclusive, then a search for another infectious cause appears appropriate.
• Immunoglobulin A (IgA)-associated glomerulonephritis may be confused with poststreptococcal acute glomerulonephritis.⁵
  • In the form of IgA nephropathy associated with a typical anaphylactoid purpura (ie, Henoch-Schönlein purpura [HSP] nephritis), the characteristic rash and the associated symptoms of either abdominal pain or arthritis and/or arthralgia help in the differentiation; however, in atypical cases, marked similarity may be present.
  • All of the clinical manifestations of poststreptococcal acute glomerulonephritis have been reported in persons with HSP nephritis, although significant hypertension and edema are found less commonly in individuals with HSP than in those with poststreptococcal acute glomerulonephritis.
  • Urticarial or purpuric rashes, abdominal complaints, and arthritis and/or arthralgia are found almost exclusively in persons with HSP.
  • Evidence of a prior streptococcal illness is usually lacking in individuals with HSP nephritis, and complement values (C3 and/or C4) are usually normal.
• Berger disease or IgA nephropathy usually presents as an episode of gross hematuria occurring during the early stages of a respiratory illness; no latent period exists, and hypertension or edema is uncommon.
  • Recurrent episodes of gross hematuria, associated with respiratory illnesses, followed by persistent microscopic hematuria, are highly suggestive of IgA nephropathy.
  • In contrast, poststreptococcal acute glomerulonephritis usually does not recur, and second episodes are rare.
• Mesangiocapillary or membranoproliferative glomerulonephritis (MPGN) may have a presentation that is virtually identical to that of poststreptococcal acute glomerulonephritis. Distinguishing features include the following:
  • The initial manifestations are often more serious in persons with MPGN than in those with IgA nephropathy; the renal function is reduced markedly (ie, large elevation of serum creatinine).
  • Evidence of preexisting streptococcal infection is absent, although cases of MPGN have been reported in which clear evidence of such an infection is present.
  • In most cases, C3 levels are depressed persistently, past 6 weeks.
  • Urinary abnormalities persist past the time of expected resolution for poststreptococcal acute glomerulonephritis.
• Crescentic glomerulonephritis is the term used to describe a histologic picture of severe proliferative glomerulonephritis.
  • In persons with crescentic glomerulonephritis, in addition to inflammatory changes within the glomerular tuft, extensive proliferation exists within the Bowman space, leading to the formation of synechiae between the glomerular tuft and Bowman capsule.
  • The clinical picture is generally referred to as rapidly progressive glomerulonephritis and may be secondary to numerous causes, including an immune-complex mediated poststreptococcal nephritis. The initial clinical picture is generally severe, and resolution appears delayed.
• Other forms of glomerulonephritis (eg, systemic lupus erythematosus [SLE] nephritis, familial nephritis, chronic glomerulonephritis) may occasionally be confused with poststreptococcal acute glomerulonephritis when an acute exacerbation of the previously present nephropathy is present. In addition to the lack of expected complete resolution, other features suggest a condition other than poststreptococcal acute glomerulonephritis.

Causes

• Clinical manifestations are either the direct or indirect result of the glomerular inflammatory response, and the degree of involvement determines the severity of symptoms and signs.
  • Glomerular inflammation (ie, cellular proliferation, edema) reduces glomerular filtration without a coexistent decrease in total renal blood flow.
  • The reduced volume of glomerular filtration and the normal tubular function lead to an increase in the reabsorption of salt and water, with resulting oliguria and edema.
    • The edema first collects in those sites where tissue resistance is low, such as the periorbital area.
    • Later, it becomes more generalized, and, in those few patients in whom loss of albumin and/or vascular congestion is exaggerated with resultant hypoalbuminemia, the edema even may simulate that of the nephrotic syndrome.
• The precise etiology of the hypertension is less well explained and probably multifactorial.
  • ECF volume is increased, but the elevated systemic pressure does not always return to normal levels with diuresis.
  • Plasma renin levels are expected to be low due to the expanded ECF volume; however, plasma renin levels have been reported variously as low, normal, or slightly increased.
  • The lack of response to drug-induced blockade of the renin-angiotensin system does not support this system as a primary cause for hypertension.
  • Various cytokines known to have pressor effects are increased and may have an important role in the etiology of hypertension.

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