Acute Poststreptococcal Glomerulonephritis: The Most Common Acute Glomerulonephritis

After completing this article, readers should be able to:A 5-year-old boy with a history of autism spectrum disorder was seen in his pediatrician’s office approximately 3 weeks ago for a honey-crusted rash on his face, the dorsal aspect of his hands, and his legs. At that time, he was diagnosed as having impetigo and given a prescription for triple antibiotic cream to place on the skin lesions for the next 2 weeks. The lesions improved, but several weeks after the impetigo was diagnosed, the boy became less active and developed swelling of his eyelids, face, and hands. His condition culminated with notably decreased oral intake for a few days and the appearance of coffee-colored urine noted in the toilet, prompting the family to bring the boy to the local emergency department.On examination, the child is not toxic appearing and does not engage the physician but will interact with his parents. He is afebrile, with a heart rate of 92 beats per minute and a blood pressure (BP) at rest of 138/87 mm Hg. There is slight fullness to his eyelids, but he appears otherwise normocephalic. His lung, heart, and abdominal examination findings are normal, but he has leg edema (1+). His genitourinary examination findings are normal, although the physician notes that the patient pauses from playing when percussing over his costovertebral angles. His skin lesions have healed.Laboratory evaluation reveals red urine with large amounts of blood, 0.1 g/dL (1 g/L) of protein, and small amounts of leukocyte esterase, but no nitrites apparent on dipstick testing. Microscopic examination reveals 30 to 49 red blood cells, 5 to 9 white blood cells, and 3 to 4 hyaline casts per high-powered field. A complete blood cell count reveals 13,600 white blood cells, a hemoglobin level of 8.2 g/dL (82 g/L) (reference range, 11.5–13.5 g/dL [115–135 g/L]), and 278,000 platelets. Renal function test results are normal, with a serum creatinine level of 0.47 mg/dL (42 μmol/L) (reference range, 0.29–0.48 mg/dL [26–42 μmol/L]), but the serum albumin level is decreased at 2.7 g/dL (27 g/L) (reference range, 3.5–4.7 gm/dL [35–47 g/L]). The emergency department physician is considering next steps in this child’s evaluation and treatment.One of the oldest clinical observations in nephrology is the association of dark and scanty urine after scarlet fever, which was first documented in the medical literature more than 200 years ago. This postscarlatinal disorder was termed acute glomerulonephritis. Because it was later discovered in the 1920s that scarlet fever was caused by an infection with β-hemolytic streptococcus, the etiologically correct term poststreptococcal glomerulonephritis (PSGN) became synonymous with acute glomerulonephritis, and the 2 terms are often used interchangeably even today.However, acute glomerulonephritis technically describes the pathologic process characterized by inflammation and/or cellular proliferation of the glomeruli not caused by direct infection of the kidneys. It classically manifests as an acute nephritic syndrome with hematuria, proteinuria, and evidence of volume overload. However, it may also present as nephrotic syndrome (severe proteinuria, hypoalbuminemia, and edema) or as a disorder characterized by particularly rapidly progressive acute kidney injury. Of note, and much beyond streptococcal infection, there are numerous different causes of glomerulonephritis, some being primary disorders only of the kidneys and others representing multiorgan conditions with secondary renal involvement.For clarity purposes, this review focuses on PSGN. It is a primary disorder of the kidneys with extrarenal manifestations being secondary to renal dysfunction. It is also the prototypical and most widely known form of postinfectious glomerulonephritis, a term that is also used indiscriminately and interchangeably with PSGN, even though PSGN is really a subset of it.PSGN remains by far the most common glomerulonephritis in children worldwide. Its global burden has been estimated at well more than 450,000 cases annually, with most cases occurring in children. Most of these cases (97% in previous estimates) occur in developing countries, where pyodermal infections, such as impetigo, are common. Despite a lower incidence in developed countries, PSGN is still the most common glomerulonephritis in children in the United States, and its epidemiology offers interesting insights into its prevention.Group A Streptococcus (GAS) has commonly been subtyped by its surface M proteins, which help determine its virulence. Since the 1970s, however, it has been known that another protein, serum opacity factor, may be a determinant of secondary sequelae of GAS infection. Opacity factor–positive strains, which consist of a certain subset of M subtypes, have been associated with causing glomerulonephritis, explaining their classification as so-called nephritogenic strains. Interestingly, opacity factor–negative strains include those that may be rheumatogenic. Thus, the epidemiologic features of PSGN and acute rheumatic fever, the other significant complication of GAS, are not perfectly in parallel to each other because they are caused by different GAS strains but share many similarities.Nephritogenic strains of GAS may also be further subdivided into those that primarily cause pharyngitis and those that primarily cause pyoderma. The serotypes most associated with pharyngitis are M types 12, followed by 1, 4, and 25, whereas types 49, 2, 42, 56, 57, and 60 cause skin infections.Epidemics of nephritogenic GAS skin infections in the mid-20th century, including domestic outbreaks on American Indian reservations, led to some of the advances in our understanding of the epidemiology of the disease. PSGN secondary to pyodermal infections tends to peak in the summer and fall in temperate locales, whereas PSGN secondary to pharyngitis more often occurs in the winter and spring. In more tropical climates, including much of the developing world, there is less seasonal variation of pyodermal infections and, hence, of PSGN. Generally, and similar to acute rheumatic fever, PSGN still causes a disproportionate burden of disease in poorer, rural, and indigenous communities of the world.Comparison studies of different eras in various countries indicate that the overall incidence of PSGN has decreased significantly in the developed and developing worlds. Much of this decline is related to the overall reduction of GAS pyoderma, especially in developed countries. This near eradication is likely secondary to increased overall and earlier use of antibiotics with skin infections, leading to decreased transmission of these virulent strains. The same may be said for pharyngitis-associated PSGN because streptococcal pharyngitis has been aggressively treated in the past few decades. However, other interventions, such as more readily available access to health care and more widespread fluoridation of the water, which has been found to be bactericidal to GAS, have also been speculated to have effects. (1)The reported annual incidence of PSGN in developing countries has been estimated at 9.3 cases per 100,000 persons, with rates as high as 93 per 100,000 among Aboriginal Australian children. (2) This finding contrasts with Italian biopsy data that report an annual incidence of 0.3 cases per 100,000 persons. A more recent reported local incidence in the United States from the early 2000s was 0.64 cases for every 100,000 persons, decreased from 2.18 cases from 40 years earlier. (3)This much lower incidence in developed regions is not solely due to improved medical conditions, although this likely contributed to the greater reduction in incidence seen during the past half century. It is more likely due to an underestimation of the true incidence of PSGN. Most cases in developed countries may not be referred for subspecialty care or remain subclinical if no medical attention is sought. Studies in siblings and close contacts of PSGN patients have found that the rate of subclinical disease is 3 to 4 times that of symptomatic cases. Hence, isolated microscopic hematuria in some children may actually represent the resolving sequela of such subclinical cases.Like the epidemiology of GAS infection, the pathogenesis of PSGN has been well researched throughout the years. In fact, it was correctly speculated that the glomerular injury in what came to be known as PSGN was caused by immune complexes as far back as the early 1910s, noting similarities between it and serum sickness. Subsequently, it was confirmed that immune complexes induce the pathologic changes of PSGN, but uncertainty persists as to the exact GAS antigens that cause the formation of these complexes and precisely how they come to be present in the glomeruli.There are 3 prevailing theories about the mechanism of immune complex injury to the glomeruli. The first theory is that there is formation of GAS antigen and antibody complexes in the circulation with subsequent trapping in the glomeruli. The second theory is that there is first deposition of GAS antigens into glomerular components with subsequent antibody binding in situ, resulting in immune complex formation. The third theory is that some GAS antigens in the serum resemble components of the glomerular basement membrane, commonly referred to as molecular mimicry, leading to the generation of cross-reacting antibodies and the formation of complexes in the glomeruli. Evidence supporting and contradicting each of these theories has included the patterns of complement pathway activation (contrary to the first theory) and similarities to other GAS-induced diseases (supporting the third theory), but it is currently thought that GAS antigen deposition with in situ immune complex formation is most likely.Similarly, the exact GAS antigen(s) leading to immune complex formation also remains somewhat elusive. Two of the leading candidate antigens are nephritis-associated plasmin receptor and streptococcal pyrogenic exotoxin B. Studies from different areas of the world have offered strong evidence for each antigen in evaluations of PSGN histopathology, showing the presence of antigen within the immune complexes seen in kidney biopsy samples and, serologically, elevation of antibody titers against each in PSGN patients. With strong evidence for both antigens from differing parts of the world, there may not be a single antigen that causes PSGN. Rather, several different antigens may well trigger disease in different populations, with the risk for disease development being more host related.Regardless of the exact mechanisms leading to immune complex formation and deposition, there is a common pathway of inflammatory response in the glomerulus, which results in many of the clinical signs and symptoms of the disease. The presence of immune complexes leads to complement deposition, leukocyte infiltration, and proliferation of the structural mesangial cells of the glomerulus. This, in turn, diffusely impairs capillary perfusion, resulting in a reduction of glomerular filtration, although not always to the degree that is detectable by an increase in serum creatinine level. With this decrease in filtration, water and sodium are retained, leading to an increase in extracellular volume and fluid overload. In addition, by-products of metabolism normally filtered in the urine, such as potassium, urea, and organic acids, may also accumulate.As noted historically, PSGN typically presents with symptoms of nephritis after a latency period after the instigating GAS infection. It typically affects children between 4 and 12 years of age and is rarely seen in individuals younger than 2 years or older than 18 years. The latency period after infection may vary from 1 to 2 weeks after pharyngitis to 3 to 6 weeks after skin infections.The most common presenting symptoms are the classic triad of glomerulonephritis: gross hematuria, edema, and hypertension. However, a number of patients may have only subclinical involvement with microscopic hematuria, normal to just mildly elevated BP, and no obvious edema, and these patients may accordingly never come to medical attention.Hematuria is seen in virtually all patients with PSGN, but only one-third of them may note gross hematuria. In these patients, their dark urine may be better described as tea or coke because hemoglobin in the urine and after a in that The gross hematuria may to the gross hematuria with in the subsequent weeks after acute these are and should about other causes of gross hematuria, especially other and a subspecialty Microscopic hematuria will often for and even to a few years after subclinical PSGN may actually be the cause of a of isolated that is later by is described as being present in to of all patients. Because the cause of edema is fluid and sodium and not in the urine, is not typically edema is also but may be seen in more cases. Evidence of heart has also been described in to of cases when being sought. gross hematuria, edema also tends to be only to often edema because they share the same fluid and It occurs in to of patients with PSGN and in approximately half of all cases. tends also to be acute in typically resolving after approximately However, it be during this such as or have been described in to one-third of all PSGN patients, and has been reported in to of patients in developing urine, or may be seen in less than half of all patients, although a disproportionate number of patients to have this common symptoms presenting with PSGN, likely secondary to some degree of or include and of PSGN is by clinical especially when there is a history of recent GAS infection, and only a few are for of GAS pharyngitis at the of acute infection is by or streptococcal antigen because results are only to of the when at the later of nephritic In addition, GAS pharyngitis is seen in only to of patients presenting with a to to and of patients actually have other likely of the of impetigo is often and a the for a GAS is not an to there are other to a recent GAS infection in the of a recent serum titers against GAS have been used to indicate infection, with titers being the most commonly titers typically will peak approximately 2 to 4 weeks after an of pharyngitis and remain elevated for several a in titers over may be there are of titers in common clinical titers are often not to an increase but only at the of with nephritic This may be early in the PSGN the increase and peak in and to a It has also been reported that may be in patients have been treated with them less titers also not typically in GAS skin infections because may be by in the elevated titers may in a for to 6 in some individuals and be in much further from their GAS against other GAS antigens may also be used to the especially when in with may also be seen with GAS they elevated with pyodermal infections as more than GAS antigen has greater than a single antigen There are several available that antigen titers and and but they also have high the test of in the of PSGN, as well as in most other postinfectious is serum especially because is a of the pathogenesis of the disease. are decreased in more than of all cases of PSGN. This decrease tends to occur even the development of nephritis symptoms and persists for to weeks. a level is often with nephritic which leads to medical is not of PSGN because several other may also be associated with However, as seen in PSGN, is virtually of the disease. Of it is not known at the of if the is to be of serum in patients with acute nephritis symptoms is that this test is in other causes of glomerulonephritis. In PSGN, the complement pathway is but other pathway such as are typically not both and may help some of the other may complement as a for with complement to decreased Interestingly, and the of these the of the of titers with disease of as should be in renal with complete blood cell and renal function testing. dipstick test results will often large amounts of blood and protein, whereas leukocyte test results may also be Microscopic examination of the urine often some being present and at times even white blood cell In a red blood cells in the urine may and red blood cell casts may also be The presence of red blood cell casts is not for PSGN but is of glomerular disease in blood cell count may and somewhat decreased and hemoglobin white blood cell may be seen secondary to the recent GAS infection or the inflammation with PSGN. may be mildly decreased from serum but may about other pathologic mechanisms causing or may be mildly or with one-third of patients having a hemoglobin level less than g/dL less than g/dL g/L) should also about other are often normal, but may be seen from with fluid overload. and be seen if renal function is significantly increase in blood level be seen in to of patients, although elevation in serum creatinine occurs in only of patients. However, if there is a significant elevation in creatinine of of creatinine every 12 is because there are rapidly progressive of nephritis that may emergency Interestingly, the of sodium is often in PSGN patients, that their kidneys are more as if volume has by sodium somewhat biopsy is typically not to the of PSGN. A biopsy only be if there are features that are not of PSGN, such as normal complement or nephrotic a biopsy is if there is of by a increase in serum creatinine or PSGN biopsy findings include those from the pathogenesis of the glomeruli with increased and of including will be for and/or of immune complex However, the finding of PSGN is seen on microscopic in which immune are seen in the as large or of PSGN most other types of which also to present including primary glomerular such as glomerulonephritis, nephritis and, other of postinfectious glomerulonephritis. on the of are secondary such as and glomerulonephritis as of as well as all conditions in which the kidneys are only that may be most a history and examination may help among some of these of the first should be about recent in the past the of nephritis to the patient a recent GAS infection, which but may not have Of note, a history of but infection be present for other postinfectious but also for a number of the other because they are disorders that be by acute symptoms of include and oral and abdominal and and and A family history should about with or or kidney examination findings include the presence of a on the or lower or and swelling of the first evaluations to determine the cause of glomerulonephritis is serum of and There are a number of that are associated with and Of note, patients with postinfectious glomerulonephritis may also present with a history of symptoms and similar findings of but of the features of PSGN is the latency period in which there is of symptoms the development of In many of the other postinfectious to with symptoms of infection, such as with some active infections and antigen there is activation of the classic complement pathway and of and which may these infections from PSGN. In these a blood or other evaluations for active infection, such as inflammatory or may be the of GAS infection, glomerulonephritis is often from PSGN. However, will often beyond weeks in glomerulonephritis. which may with include a complete blood cell antibody and antibody testing. these results not help in the and even if they a renal biopsy may be antibiotic of the GAS infection may help nephritis development and the of infection to In developing where PSGN is more antibiotic use in individuals has the of nephritogenic GAS strains during the and early antibiotic the of GAS antigen and the degree of it has not been to PSGN. A review of of found a antibiotic against the development of but there few cases of PSGN for this to be different given during a with the of found no in the rates of developing PSGN. although GAS infections should still be treated in a what has been for other GAS it is not apparent that antibiotic is for the of primary of PSGN, it is in the sequelae of the disease edema, and renal these sequelae present early in the disease and to be but vary in patients may or every other to their to a is in patients creatinine level is increased over normal or to is greater than for age and or have symptoms with their hypertension. these same patients will likely for more acute for these symptoms or more of their renal the edema and of PSGN share a common their should include some degree of fluid and sodium intake with may be whereas should be in those with more significant edema or some degree of renal to of because are not as when renal function is less than 30 The 2 may be as but should be because of the risk of in PSGN. have been to be more than other single greater is the of a or may be have been associated with fluid and edema and should not be the but they are likely to be when used in with a to and should be used with and receptor are often in the of PSGN. they may not be as with fluid because these patients have serum and However, are likely to be elevated in patients with PSGN have decreased glomerular capillary In fact, studies have found better and in PSGN patients treated with an than with other including However, the with the use of these remains the for further glomerular and is and/or remain for in PSGN. to be an a should be typically be with intake in the with the use of such as sodium be but they are a of sodium to the fluid that or rapidly blood mg/dL are all for in these patients. is it is often only the glomerular inflammation to and some kidney function has been patients symptoms are to a renal may be by the especially if there is evidence of which indicate a greater degree of acute However, there is no evidence that is in PSGN, even in more this may be more to the than to the for PSGN, its overall is typically within and serum creatinine to within 3 to 4 weeks. associated often tends to after whereas microscopic hematuria for several to a few years. of PSGN is although there have been of this with from different nephritogenic strains. rates to PSGN from to per 100,000 from from developing whereas in developed are The causes of in these patients to be related to volume such as heart or to care interventions, such as and in more of PSGN reported as with a small of patients having sequelae for 5 to years. However, within the more studies have beyond with somewhat different hematuria or proteinuria, have been reported in as few as but to of PSGN patients after years. is less but seen in of patients, whereas from kidney disease is noted in less than in several complement the findings of nephrotic and biopsy findings of formation are all of patients with a disease and may be for the first and or persists after that first to a is for this article, and on the