Poststreptococcal glomerulonephritis

HONORABLE MENTION

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS Laura L. Stickler, MD

Poststreptococcal glomerulonephritis is a nonsuppurative sequela of streptococcal infection that occasionally complicates pregnancy. Although group A beta-hemolytic streptococci are responsible for the majority of cases, multiple groups of streptococci can cause postinfectious glomerulonephritis. Infection of the skin or pharynx with streptococci typically precedes kidney involvement by 6 days to 2 weeks. The risk of developing acute nephritis after streptococcal infection ranges from 1–15%. This disorder usually affects children, and is more frequent in males. Poststreptococcal glomerulonephritis is considered an immune complex disease because interactions between antigen–antibody complexes and the complement system result in glomerular injury. Patients present with a wide range of complaints including hematuria, edema, malaise, lethargy, nausea, fever, weakness, anorexia, cough, and dyspnea. The most common exam findings include hypertension, edema, and hematuria. The differential diagnosis includes multisystem disease, other primary glomerular diseases, nonstreptococcal postinfectious glomerulonephritis, and urinary tract infection. The diagnosis is confirmed by the detection of antistreptococcal antibodies, and renal biopsy showing hypercellularity and proliferation. Treatment is supportive, and renal function tends to improve rapidly. Antibiotics are indicated if the patient is concurFrom the Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida.

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rently infected. Penicillin is the drug of choice, but erythromycin can be used in the penicillinallergic patient. Immunity is lifelong, but recurrences may develop after infection with a different nephritogenic strain. If signs of irreversible kidney damage are present, the disease is considered chronic. Presentation in pregnancy may be confused with preeclampsia as hypertension, edema, and proteinuria are presenting signs in both entities. Poststreptococcal glomerulonephritis may lead to preterm delivery but typically has a successful outcome. (Prim Care Update Ob/Gyns 2003; 10:24 –28. © 2003 Elsevier Science Inc. All rights reserved.)

Poststreptococcal glomerulonephritis is declining in the United States, but remains frequent worldwide. The annual number of deaths for all types of glomerulonephritis is approximately 34,000, and group A beta-hemolytic streptococci are the cause of acute glomerulonephritis in ⬎90% of cases.1 Glomerulonephritis is the third leading cause of end-stage renal disease in the United States.2 Internationally, it has replaced diabetes and hypertension as the leading cause of end-stage renal disease due to the high rate of acute glomerulonephritis after infection.2 Poststreptococcal glomerulonephritis, like rheumatic fever, is a nonsuppurative sequela of streptococcal infection of the pharynx or skin. Bright first observed that kidney disease frequently followed scarlet fever, and this correlation was confirmed by Schick in 1907.3

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Generally, poststreptococcal glomerulonephritis is thought to be an autoimmune response resulting in either the formation or deposition of immune complexes in the glomerulus or a cell-mediated response to antigen in the glomerulus. Streptococcal infection of the throat occurs most frequently in the United States and Europe, whereas skin infections occur mostly in the southern United States and South America.1 Poststreptococcal glomerulonephritis typically follows pharyngeal infection but may also result from skin infection. An unspecified upper respiratory infection, otitis media, and pharyngitis are the most common preceding conditions.4 The usual latency period is 6 to 10 days for pharyngeal infections and 2 weeks for skin infection. This reflects the time required to produce antibodies against streptococcal antigens. Poststreptococcal glomerulonephritis mostly affects children ages 6 to 10 years, but can affect adults of any age. It also occurs two times more frequently in males than in females. This disparity is less when the illness strikes adults. Poststreptococcal glomerulonephritis may occur sporadically or in epidemics. Sporadic infections typically follow pharyngeal infections, whereas epidemics can follow infections of either the throat or skin.3 Epidemics are rare but still occur in underdeveloped countries with poor hygiene and overcrowding. Multiple groups of streptococci can cause poststreptococcal glomerulonephritis, including groups A, C, and G. Group A beta-hemolytic streptococci are, by far, responsible

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POSTSTREPTOCOCCAL GLOMERULONEPHRITIS

for most cases. Beta-hemolytic streptococci are classified into groups A through O by specific cell wall antigens.5 More than 60 different strains of group A beta-hemolytic streptococci exist. Those types that cause poststreptococcal glomerulonephritis are termed nephritogenic strains, and these were identified by Rammelkamp and Weaver in 1953.3 Rammelkamp was the first to recognize that not all types of group A beta-hemolytic streptococci cause nephritis. He identified the few nephritogenic strains by noticing differences in epidemiologic patterns of poststreptococcal glomerulonephritis and rheumatic fever.5 There is a constant annual incidence, attack rate, and recurrence rate of rheumatic fever, whereas poststreptococcal glomerulonephritis varies in its annual incidence, attack rate, and recurrence rate. Approximately 90% of cases of poststreptococcal glomerulonephritis are caused by only 3 of the 60 strains of group A beta-hemolytic streptococci—types 12, 4, and 1. Sporadic poststreptococcal glomerulonephritis classically results from type 12 infections of the throat, and epidemic infection is the consequence of infection with a variety of strains.3

Pathophysiology of Infection Poststreptococcal glomerulonephritis is considered an immune complex disease because glomerular injury results from interactions between antigen–antibody complexes and the complement system. Group A beta-hemolytic streptococci also cause damage by tissue destruction and toxin production.6 Possible antigens include proteinase, endostreptosin, nephritic strain–associated protein (NSAP), and nephritis plasmin– binding protein (NPBP). Three criteria must be met before an antigen is considered pathogenic. The suspected Volume 10, Number 1, 2003

antigen must be found only in nephritogenic strains. It must be identifiable within the glomerulus, and it must have antibody directed against it in convalescent sera.6 In his review of poststreptococcal glomerulonephrits, Haynes8 described several theories of glomerular injury. First, antigen is filtered and lodged in the capillary wall, where it reacts with host antibody. Second, a streptococcal product reacts with a glomerular antigen such that it is now seen as foreign, and an immune response ensues. Next, certain patients have a glomerular antigen that cross-reacts with streptococci. Finally, and generally accepted as the theory of injury, streptococcal antigen reacts with host antibody, forming a soluble complex that is filtered, but not cleared, by the glomerulus. These complexes are then deposited subendothelially along the basement membrane, where they react with complement. The complement cascade then stimulates phagocytosis and digestive activity at the basement membrane, leading to fragmentation and breakdown. This breakdown subsequently leads to the characteristic urinalysis findings. There are two phases of glomerular injury—acute and chronicprogressive.2 Acutely, glomerular injury is the consequence of the release of mediators of tissue damage by the immune reaction. The mediators include the complement cascade, coagulation factors, growth factors, and cytokines. The complement system recruits leukocytes that participate in the inflammatory response as well as phagocytosis. Complement also directly damages cells through cell lysis. Coagulation factors are responsible for fibrin deposition and crescent formation. Growth factors and cytokines activate glomerular cells to participate in their own injury and also directly damage cells. Glomerular cells respond to growth factors by proliferating, increasing their production of oxidants and pro-

teases, and increasing extracellular matrix production. This effect, in turn, leads to sclerosis and permanent cell damage. Chronic-progressive glomerular injury results from nonimmune mechanisms.2 Secondary to the injuries sustained during the acute phase, the glomerulus loses some of its filtering surface. Increased glomerular pressure occurs, with resultant sclerosis and fibrosis.

Clinical Manifestations The typical patient with poststreptococcal glomerulonephritis presents 6 to 10 days after streptococcal infection. The risk of developing acute nephritis after streptococcal infection is 1%, and increases to 10 –15% if the patient is infected with a nephritogenic strain.5 The usual manifestations are hematuria, edema, malaise, lethargy, nausea, fever, weakness, anorexia, cough, and dyspnea. Common physical findings include mild to moderate hypertension, peripheral and periorbital edema, oliguria, ascites, rales, and increased jugular venous distension. Urinalysis reveals red cell casts, hematuria, proteinuria, leukocyturia, and cylinduria. The three most common findings on initial evaluation are facial edema, hypertension, and hematuria.8 Further workup includes laboratory evaluation, chest radiograph, electrocardiogram, and renal ultrasound. Initial laboratory studies show increased antistreptococcal antibody levels (antihyaluronidase, antiproteinase, antiDNase B, antiNADase, and antistreptolysin O). Antistreptolysin O titers are elevated in 80% of cases of poststreptococcal glomerulonephritis, and if antihyaluronidase and antiDNase B titers are added, the detection rate increases to 100%.4 Positive antibody tests by themselves do not diagnose poststreptococcal glomerulonephritis, but they do indicate 25

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length, severity, and existence of a preceding streptococcal infection.5 If a patient has a low antistreptolysin O titer, then a nonstreptococcal infection, previous treatment with antibiotics, or a rare infection without a distinct immune response must be considered.5 Complement levels are decreased in approximately 78 –96% of patients.4 The erythrocyte sedimentation rate is typically elevated, but the C-reactive protein and rheumatoid factors are within normal limits. Electrolyte changes consist of increased potassium and chloride. Concentrations of rennin and aldosterone and the creatinine clearance will be decreased, whereas blood urea nitrogen (BUN) will be increased. These findings are all consistent with poor renal function. Approximately one third of patients will have cardiomegaly or a pleural effusion present on chest radiograph.4 Electrocardiogram changes consistent with hyperkalemia and hypocalcemia are found in 50% of patients.4 Renal ultrasound may show small kidneys and increased echogenicity within the renal parenchyma.2 Glomerular function tends to improve rapidly. Edema usually resolves within 1 month of the onset of illness, and proteinuria, within 2 months.5 Complement levels are decreased at the onset of disease and return to normal in 4 to 6 weeks.4 However, it may take as long as 2 to 5 years before hematuria resolves.4 In the 1940s, poststreptococcal glomerulonephritis was considered to resolve completely in most patients, with a small percentage progressing to chronic disease.7 Of those who develop chronic disease, ⬍5% progress along a continuum, whereas 5–10% initially resolve then ultimately develop chronic glomerulonephritis. 4 An even smaller group die in the first few months of the acute phase. It is now thought that if patients are observed for several years, as many as 50% will develop chronic disease.7 Re26

covery rates appear to depend on age at onset, severity of the condition at onset, and whether or not the case is sporadic or part of an epidemic. Recovery rates in children are higher than those in adults. Children and adults with epidemic glomerulonephritis tend to have favorable short- and long-term outcomes. Conversely, sporadic infections progress slowly to chronic glomerulonephritis in a small number of children, but up to one half of adults have progressive deterioration. Sporadic infections tend to be more severe than epidemic cases because sporadic cases must be clinically significant to be recognized.5 Glomerulonephritis is considered chronic if signs of irreversible damage are present.7 The potential for chronicity can be evaluated by several factors including renal biopsy, assessment of renal function, and persistence of abnormal laboratory and physical examination findings. Glomerular sclerosis on biopsy is considered evidence of irreversible damage.4 Persistently depressed complement levels, proteinuria, decreased creatinine clearance, azotemia, hypertension, and decreased glomerular filtration rates are also indicative of irreversible injury.5 Of these, proteinuria is the most reliable marker of longterm outcome.8 Whereas 75% of patients with continuing proteinuria will have hypertension, decreased glomerular filtration rate, and glomerular sclerosis, only one third of patients with resolution of proteinuria develop these same findings.7 This supports the theory that disappearance of findings does not guarantee lifelong recovery. Immunity, however, is lifelong. Antibodies to the M protein (a key component of the cell wall) develop within 2 months after infection, and they are the immunoglobulins responsible for durable immunity.5 Because these antibodies are long lasting, recurrences are unusual. When they occur, they are due to

infection with another nephritogenic strain of streptococci.

Differential Diagnosis The differential diagnosis of poststreptococcal glomerulonephritis includes several multisystem diseases, other primary glomerular diseases, nonstreptococcal postinfectious glomerulonephritis, and urinary tract infections. Urinary tract infections are perhaps the easiest to rule out because patients with glomerulonephritis will have negative cultures and negative rapid tests for bacteria and leukocyte esterase. It is important to rule out other primary glomerular diseases because of the long-term implications of these disorders. These conditions include membranoproliferative glomerulonephritis, IgA nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane nephritis, and idiopathic crescentic glomerulonephritis.2,3 Renal biopsy, assessment of serologic markers, and degree of proteinuria help to differentiate primary glomerular diseases from poststreptococcal glomerulonephritis (Table 1). Serologic markers are also useful in distinguishing between poststreptococcal glomerulonephritis and multisystem diseases. Examples of multisystem disease that are easily confused with poststreptococcal glomerulonephritis are systemic lupus erythematous (SLE), polyarteritis nodosa, microscopic polyangitis, Wegener’s granulomatosis, and essential cryoglobulinemia.2,3 Determination of serum complement levels aids in distinguishing SLE from poststreptococcal glomerulonephritis. All complement levels are low in SLE, whereas C1, C2, and C4 levels are normal in acute postinfectious glomerulonephritis. Various bacterial, viral, and parasitic infections may precede glomerulonephritis. Gram negative septicemia, infective endocarditis, Prim Care Update Ob/Gyns

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS Table 1. Comparison of Cause of Glomerulonephritis

Condition

Degree of Proteinuria (g/d)

Biopsy

Serology

Poststreptococcal glomerulonephritis

Proliferation, inflammatory infiltration, crescent formation

⬍3.5

Membranoproliferative glomerulonephritis

Mesangial and subendothelial deposits, glomerular proliferation Focal proliferation, globular immune complex deposits Extensive crescent formation, inflammatory infiltration Linear immune complex deposition along GBM

Antistreptococcal antibodies, decreased complement levels Hypocomplementemia None

⬍3.5

Anti-GBM antibodies, ANCA antibodies Anti-GBM antibodies

⬍3.5

IgA nephropathy Rapidly progressive glomerulonephritis Anti-GBM nephritis

⬎3.5

⬍3.5

GBM ⫽ glomerular basement membrane.

staphylococcal septicemia, syphilis, typhoid fever, chicken pox, measles, mumps, and mononucleosis are just a few examples.3 Again, serologic studies may aid in confirming the diagnosis.

Diagnosis The diagnosis of poststreptococcal glomerulonephritis depends on physical findings, laboratory abnormalities, and pathologic changes. There are three main laboratory findings that support the diagnosis of poststreptococcal glomerulonephritis: confirmation of group A beta-hemolytic streptococci in the throat or skin, identification of antistreptococcal antibodies, and documentation of decreased complement levels.8 Two physical findings consistently found in patients with poststreptococcal glomerulonephritis are edema and hypertension.8 The type of abnormal antistreptococcal antibodies that are present depends on whether the preceding infection was located in the pharynx or skin. Antistreptolysin O titers become abnormal after throat infections in two thirds of patients infected with type 12 group A beta-hemolytic streptococci (not all type 12 strains produce streptolysin S and O).3 If impetigo was the preceding infection, the anti-DNase and antihyaluronidase titers may be Volume 10, Number 1, 2003

elevated.3 C50 and C3 are the most useful complement levels to check.3 They are decreased early in the course of the patient’s illness and return to normal by 6 to 8 weeks. Renal biopsy helps determine disease activity, chronicity, and potential reversibility.2 There is a stepwise progression of events within the glomerulus that can be documented with biopsy. First, IgG antibody attaches to streptococcal antigens lodged within the glomerulus. These immune complexes are granular in nature and initiate proliferation of endothelial and mesangial cells.7 Pathology specimens at this stage appear hypercellular. Early on, these immune complexes are located subendothelially as well as in the mesangial matrix.1 Once the immune complex activates the complement cascade, the permeability of the basement membrane increases because of fragmentation and phagocytosis. 1 Antibodies against exposed glomerular basement membrane proteins develop. Linear deposits of antibody–antigen complexes now form, initiating sclerosis.7 Sclerosis typically appears as proliferation subsides.7

Treatment Treatment of poststreptococcal glomerulonephritis is mostly supportive, but must be tailored to the

individual patient. Years ago, it was thought that all patients should be hospitalized and placed on bedrest. Now, patients are only placed on bedrest during the acute phase of the illness. Adjuvant therapies include nutritional restrictions, antihypertensives, diuretics, and antibiotics.4 Over the past 40 years, mortality rates have decreased from 8% to 1% because of improvements in the treatment of hypertension and volume overload.5 Hospitalization is indicated if there is severely reduced renal function, signs of uremia, intractable vomiting, lethargy, hypertensive encephalopathy, oliguria, pulmonary congestion, or severe edema.4 Nutritional restrictions are determined based on the degree of hypertension, renal function, and edema.4 Protein should be restricted to 0.5 g/kg per day if the BUN is ⬎75–100 mg percent or if azotemia is present. Sodium restriction is necessary in the presence of severe edema or hypertension. Fluid restriction to insensible water losses plus urine output is indicated when edema and oliguria are present. Hypertension usually resolves with bedrest. If diastolic pressures remain ⬎100 mgHg, do not decrease over 2 to 4 hours, or increase, or if symptoms of encephalopathy develop, then additional treatment is necessary.4 Medications frequently 27

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used include hydralazine, reserpine, alpha-methyldopa, diazoxide, lasix, and magnesium sulfate. Magnesium sulfate must be used with caution if renal failure exists because of the increased risk of magnesium toxicity.4 Diuretics are used as adjuvants for blood pressure treatment, to reduce edema, and to test renal function.4 Finally, antibiotics are indicated to eradicate a current infection.5 Penicillin is the drug of choice. The appropriate dose is 500 mg orally qid for 10 days. In penicillin-allergic patients, erythromycin (500 mg orally qid for 10d) may be substituted. All family members should be cultured and treated if positive, as 20% of siblings have subclinical infection.5 Timely treatment of streptococcal pharyngitis or impetigo should help prevent subsequent poststreptococcal glomerulonephritis.

Unique Implications in Pregnancy Poststreptococcal glomerulonephritis is rarely reported in pregnancy. Of those pregnancies complicated by streptococcal infection, only 1 in 40,000 will develop poststreptococcal glomerulonephritis.9 The differential diagnosis in pregnancy includes urinary tract infection and primary glomerular disease as in the nonpregnant state, but preeclampsia also must be considered. Urinary tract infection and preeclampsia can be ruled out with urinalysis, urine culture, and physical examination. Most other nephritides can be excluded by serologic tests. Renal biopsy is almost never indicated in pregnancy. In a case report by Shepherd and Shepherd9 a 34-year-old woman, G2P1, presented at 24 weeks of gestation with marked edema and active urinary sediment. She had documented streptococcal pharyngitis at 21 weeks and was treated with penicillin. Laboratory evaluation 28

showed increased antistreptolysin titers and decreased complement levels. At 31 weeks, hospitalization was required secondary to mild hypertension and decreased renal function. She required bedrest and observation only. After documentation of fetal lung maturity, she delivered a preterm infant without fetal complications. Her renal function returned to normal after delivery. In 1980, Singson et al.10 described a mother who completely recovered from poststreptococcal glomerulonephritis and had normal renal function 18 years later. Their patient presented 1 month after a tooth extraction, for which she received prophylactic tetracycline, with the complaint of nausea and weight gain. She had passed “smoky urine” 10 days after the procedure. She was noted to have periorbital and pedal edema, active urine sediment, oliguria, abnormal renal function, and an elevated antistreptolysin O titer. Renal biopsy confirmed the diagnosis. After several days of hospitalization, her oliguria and renal function improved, and she remained stable until she delivered a healthy infant at term. Early reports suggested that poststreptococcal glomerulonephritis during pregnancy resulted in poor outcomes, including worsening maternal renal function and possible fetal death.10 We now recognize that those patients with poor outcomes probably had exacerbations of chronic disease.10 The two cases noted above demonstrate that mothers suffering from acute postinfectious glomerulonephritis can have successful pregnancy outcomes.

Conclusion Poststreptococcal glomerulonephritis, along with rheumatic fever, is a nonsuppurative sequela of impetigo or streptococcal pharyngitis. It consistently presents with hematuria, hypertension, and edema. Diagnosis is confirmed with docu-

mentation of abnormal antistreptococcal antibodies, decreased complement levels, and characteristic findings on renal biopsy. Treatment is supportive, with bedrest only necessary in the acute phase. Once thought to resolve completely, it now appears that many patients develop chronic renal disease. In contrast, poor outcomes were previously expected during pregnancy, but most cases now tend to end successfully. References 1. Lange K, Treser G. Acute poststreptococcal glomerulonephritis. Mechanism and sequelae—attempts at a unifying concept. Clin Nephrol 1972;1:55–60. 2. Couser WG. Glomerulonephritis. Lancet 1999;353:1509 –15. 3. Tejani A, Ingulli E. Poststreptococcal glomerulonephritis. Current clinical and pathologic concepts. Nephron 1990;55:1–5. 4. Lewy JE. Acute poststreptococcal glomerulonephritis. Pediatr Clin North Am 1976;23:751–9. 5. Haynes BF. A brief review. Poststreptococcal glomerulonephritis. Tex Med 1973;69:60 –8. 6. Oliveria DB. Poststreptococcal glomerulonephritis: getting to know an old enemy. Clin Exp Immunol 1997; 107:8 –10. 7. Baldwin DS, Gluck MC, Schacht RG, Moussalli A, Gallo GR. Longterm follow-up of poststreptococcal glomerulonephritis. Ann Intern Med 1974;80:342–58. 8. Popovic-Rolovic M, Kostic M, Antic-Peco A, Jovanovic O, Popovic D. Medium- and long-term prognosis of patients with acute poststreptococcal glomerulonephritis. Nephron 1991;58:393–9. 9. Shepherd J, Shepherd C. Poststreptococcal glomerulonephritis: a rare complication in pregnancy. J Fam Pract 1992;34:630 630 –2. 10. Singson E, Fisher KF, Lindheimer MD. Acute poststreptococcal glomerulonephritis in pregnancy: case report with an 18-year follow-up. Am J Obstet Gynecol 1980;137: 857–8. Address correspondence and reprint requests to Laura L. Stickler, MD, P.O. Box 100294, Gainesville, FL 32610. Prim Care Update Ob/Gyns