Glomerulonephritis

ANCC 1.5 Contact Hours

Abstract

Expedient antimicrobial treatment of group A beta-hemolytic streptococcal tonsillopharyngitis prevents suppurative complications and rheumatic fever, however, timely therapy does not prevent acute poststreptococcal glomerulonephritis. Acute poststreptococcal glomerulonephritis is the most common form of postinfectious glomerulonephritis and a leading cause of acute and chronic renal failure in childhood. This article discusses clinical presentation, diagnostic workup, treatment, and prevention of poststreptococcal glomerulonephritis in adults and children in the primary care setting.

Timely antimicrobial treatment of group A beta-hemolytic streptococcal (GAS) tonsillopharyngitis has been the recognized preventive treatment of suppurative complications and nonsuppurative sequelae known as rheumatic fever.' Acute poststreptococcal glomerulonephritis (APG), another nonsuppurative complication, is not prevented by timely therapy.2 Unlike rheumatic fever, which is the result of pharyngeal infection, APG can be precipitated by streptococcal skin infection.3 As the most common form of postinfectious glomerulonephritis in children,4 APG is a leading cause of acute and chronic renal failure in children.5

APG is also a common cause of hematuria in children. The disease is most common between the ages of 2 and 12. Although APG can occur at any age, 5% of cases occur in children ages 2 and younger, and 5% to 10% of cases occur in adults ages 49 and older.6 The clinical presentation ranges from classic nephrotic syndrome to subclinical hematuria. In more than 90% of cases, the typical dinical presentation is acute nephritic syndrome: hematuria, mild proteinuria, edema, and hypertension with or without oliguria.7 Unrecognized subclinical cases, however, outnumber apparent nephritis by a ratio of 4:1 to 10:1.8 The average risk of developing APG after GAS infection is 15%. During epidemics, the rate ranges from 5% to 25%.6

Etiology

APG is an acute inflammatory disorder of the glomerulus initiated by a nephritogenic strain of GAS. Nephritogenic refers to the bacteria's capacity to initiate pathology in the kidney. Similarly, some streptococcal strains are considered rheumatogenic because of their propensity to cause rheumatic fever.

The varying strains of the species designated as GAS are defined by a particular surface protein: the M protein. The M protein is the major surface protein of the bacteria. It occurs in more than 80 antigenically different types, and many are nephritogenic.9 GAS skin infections with M types 47,49, and 57, and upper respiratory GAS infection with types 1, 2, 4, and 12 are most often involved in APG development.7

APG may be a consequence of streptococcal pharyngitis or pyoderma,2 and it is the most common form of immune-mediated nephritis in children. This disorder most commonly affects children between the ages of 3 and 8, with a male-to-female ratio of 2:1.4 Glomerulonephritis develops approximately 10 days after pharyngitis or 2 weeks after skin infection with a nephritic strain."

The incidence of APG following throat or skin infection with one of these strains is significant: 10% to 15%.2 This estimate may be conservative, as many cases are mild and patients do not seek care.4 Unlike rheumatic fever, a limited number of nephritogenic strains render recurrence unlikely because of type-specific, long-lasting immunity.2

APG development is probably dependent on host factors and organism characteristics. The bacteria's virulence may increase or decrease with spread. The patient's immune response, which may be influenced by genetic factors, can determine the extent of glomerular involvement and lesion type. Sequelae to infection are dependent on many elements."

Pathogenesis

APG's exact mechanism of injury remains controversial, although several theories have been postulated:12 immune complex formation between circulating antibody and glomerular 11 planted antigen," reactivity of circulating autoantibody with normal glomerular tissue acting as autoantigen-"molecular mimicry," and trapping of circulating immune complex in the glomerulus. Researchers agree that. whatever the initiating mechanism, activation of the complement cascade by the alternate pathway plays an important role in the inflammatory process. 12-14 One group of researchers found supportive evidence for the planted antigen theory by performing immunofluorescence studies on APG kidney biopsies. An antigen believed to be streptococcal proteinase was found in the glomeruli with complement prior to antibody deposition.13

The molecular mimicry hypothesis suggests that a foreign antigen, whose structure is similar to host glomerular antigen, may stimulate formation of autoantibodies. These autoantibodies may cross-react with glomerular tissue and cause injury." Additionally, immune complexes from circulation may play a role in tissue damage because of their deposition in situ.14

Regardless of the initiating mechanism, involvement of the complement cascade bythe alternate pathway ensues, resulting in glomerular inflammation from chemoattractants, chemokines, and cytokines. Tissue damage further results from infiltration of leukocytes and platelets, clogging glomerular capillaries and altering the filtration barrier of the basement membrane.12

Renal biopsy is rarely necessary for a diagnosis of APG. Diagnosis is usually based on clinical presentation and laboratory evaluation." Glomeruli are enlarged and bloodless due to capillary occlusion by proliferating mesangial and endothelial cells. Infiltration by leukocytes, monocytes, and eosinophils exists. "Humps" between the glomerular capillary basement membrane and the epithelial cells are evident on electron microscopy; these contain mainly IgG and C3 complement component (C3) (see Figure 1).4

Resolution of this inflammatory process usually occurs spontaneously and completely in children; however, adults may have residual renal impairment. Recovery is largely the result of apoptosis, or cell death, which occurs in inflammatory cells.7 After removal of the inciting stimulus (streptococcal antigen), there is dispersal of inflammatory mediators, phagocytosis of debris, and reconstruction of vascular tone and the filtration barrier. The outcome, particularly in childhood, is often a normal glomerulus.12

Clinical Presentation

Patients who develop APG may have a varied clinical picture, ranging from being asymptomatic to having severe renal failure. The most common presenting symptoms are hematuria (smoky or cola-colored), edema (periorbital, dependent, or generalized), proteinuria (mild to moderate; usually less than 2 grams/day), and hypertension (blood pressure is greater than the 95th percentile for age and sex; in adults, blood pressure is more than 140/90 mm Hg) .4,15,16 Other symptoms include nausea, vomiting, malaise, anorexia, back pain, and abdominal discomfort.8,15

Gross hematuria is present in 30% to 50% of children with APG. The urine may be smoky, tea-colored, cola-colored, or occasionally brownish green.4 Patients with gross hematuria may also complain of dysuria. Transient oliguria occurs in approximately 50% of APG patients, but anuria is rare.' Macroscopic hematuria may be present for up to a 2-week period, and microscopic hematuria may remain evident for months after illness resolution.

Edema and vascular congestion result from increased fluid retention secondary to glomerular inflammation and decreased filtration.' Edema may be mild and limited to the periorbital area or severe enough to produce pleural effusions, ascites, and hypertension." A thorough history and physical examination are essential when assessing a child with edema. Periorbital edema may be evident in children when they awaken, but it becomes more dependent as the day progresses, resulting in edema in the abdomen or lower extremities.17 The child's age is an important consideration: Edema is usually confined to the face and legs in adolescents, and generalized edema is more common in younger children. More acute symptoms of circulatory congestion include orthopnea, dyspnea, cough, pulmonary crackles, and gallop rhythm.4

Hypertension can be associated with headaches, somnolence, changed mental status, nausea, anorexia, and convulsions. 1,117 In children, significant hypertension exists when the systolic or diastolic blood pressure is equal to or greater than the 95th percentile for age and sex.18 A hypertensive emergency in children is defined as blood pressure greater than 30% above normal for age and sex or any elevation with evidence of encephalopathy, heart failure, pulmonary edema, or acute renal failure.19

In the adult, mild hypertension is 140 to 149/90 to 99 mm Hg; moderate hypertension is 160 to 179/100 to 109 mm Hg; severe hypertension is 180 to 209/110 to 119 mm Hg. Hypertensive emergencies are rare situations that require immediate blood pressure reduction (not necessarily to normal range) to prevent or limit target organ damage such as encephalopathy, intracranial hemorrhage, unstable angina, acute myocardial infarction, heart failure, and aortic aneurysm dissection. Hypertensive urgencies are situations that require blood pressure reduction within a few hours. Such situations include blood pressure that is in the upper range of severe hypertension, progressive target organ damage, or presence of optic disc edema."

Diagnostic Tests

Urinalysis typically shows abnormal findings in the presence of APG. Hematuria is present, and red cell casts are usually evident on microscopic examination." Dysmorphic red blood cells are indicative of hematuria originating in the glomeruli.8 Proteinuria is usually moderate, exceeding 2 gram/day in only 15% of patients." A transient increase in proteinuria may occur 1 to 2 weeks after onset as the glomerular filtration rate improves.8 Leukocyte, hyaline, and granular casts are also frequently seen. The presence of leukocytes and leukocyte casts should not be regarded as signs of a superimposed urinary tract infection but as a sign of glomerular inflammation.4

Serum creatinine may be elevated or may remain within normal upper limits. Approximately 25% of APG patients have serum creatinine of 2 mg/dl or more. The glomerular filtration rate is usually depressed in the initial stages of APG but approaches the normal range as the disease resolves.8

A laboratory evaluation for positive serologic evidence of an antecedent streptococcal infection is an essential component in the diagnosis of APG, particularly when a history of recent infection does not exist (for example, a culture of streptococci from throat or skin infection or the presence of characteristic lesions)." Many of the cell wall and extracellular products of GAS are antigenic. Antibodies of five of these extracellular products are used to identify a recent streptococcal infection: antistreptolysin 0 (ASO), anti-DNase B (ADB), antihyaluronidase, antistreptokinase, and anti-nicotinamide adenine dinucleotidase (anti-NADase).10

The infection site has a pronounced effect on the body's immune response to streptococci. These differences are reflected in serologic titers that detect antibodies to enzymes produced by the organisms." The ASO and anti-NADase titers are elevated in 80% of patients with postpharyngitis nephritis. The antihyaluronidase and ADB titer are elevated in 80% to 90% of patients with skin infections.20

Serologic tests used to measure antibody response include ASO titer, which detects streptolysin; ADB, which detects DNase B; and the streptoenzyme test, which detects antibodies to ASO, antihyaluronidase, antiNADase, and ADB.5,8,20,21 In 80% of children with APG, a fourfold rise in the ASO titer can be seen. This titer, however, may not be elevated after streptococcal skin infection. Therefore, ADB or streptoenzyme is more accurate for documenting prior streptococcal infection.22

Serial rising titer results, occurring over several weeks, are more valuable than a single result. The titers are elevated 1 to 5 weeks after infection and fall to their preinfection level over several months.20,,21 The antibody response to extracellular antigens may be blunted by antibiotic treatment. Consequently, negative results in a patient who received prior antimicrobial treatment do not exclude an APG diagnosis.8,20

The immune complex pathogenesis present in APG is further supported by a reduction in serum complement. The complement system consists of more than 25 plasma proteins that interact in a cascade fashion to produce mediators of inflammation and immunity. The cascade can be activated by nonspecific antigens (alternate pathway) or by antigen-antibody complexes (classical pathway)?.21 Although existing immunoassays can identify each individual protein, test results are variable. To assess the complement system, a complement screen should include the total hemolytic complement (CH50); C3, which comprises 70% of the total protein in the complement system; and CA complement component.21,24

In the first 2 weeks of acute nephritis, the C3 and CH50 levels are depressed in more than 90% of APG patients.4,12,21 Reduced complement levels occur when the consumption of complement exceeds its production.21 Serum CA levels are minimally depressed or normal in APG.4,12,21 Complement levels usually return to normal within 4 to 6 weeks.6,12 A follow-up serum C3 should be obtained 6 to 8 weeks after the onset of acute illness to document the return of normal levels.4

Renal biopsy is rarely indicated in APG but may be considered when unusual clinical features cast doubt on the diagnosis, such as massive proteinuria in the acute stage, normal serum complement, or a progressively increasing serum creatinine.7 A serum C3 that remains depressed for more than 3 months, severely impaired renal function, or ongoing macroscopic hematuria and proteinuria are also indications that a biopsy should be considered.5

Differential Diagnosis

The presentation of acute glomerulonephritis with various etiologies may appear similar. Disorders that may be confused with APG include hereditary nephritis, IgA nephropathy, benign hematuria, other forms of postinfectious glomerulonephritis, HenochSchonlein purpura, and lupus nephritis. Evaluation of C3 and streptococcal antibody titers help differentiate these disorders from APG. For example, C3 levels will not be depressed in Henoch-Schonlein purpura, IgA nephropathy, benign hematuria, or hereditary nephritis. Streptococcal antibody titers will probably not be elevated in other forms of postinfectious nephritis or lupus nephritis.4

Figure 2 provides key serologic markers valuable in differentiating causes of acute nephritic syndrome. The clinician should consider key factors in the history and physical examination that are indicative of streptococcal pharyngeal infection, skin infection, and absence of systemic disease evidence. This information and the laboratory testing results guide the clinician in making an accurate APG diagnosis.

The timing of hematuria, edema, and hypertension after streptococcal infection may further clarify the diagnosis. A short latent period between the infection and the onset of indicators for glomerulonephritis may represent an exacerbation of a previously unrecognized glomerulopathy rather than APG. Additionally, other features of chronic renal failure may be evident, such as indicators of long-standing hypoalbuminemia and proteinuria in excess of 3.5 grams in 24 hours.2

Persistent hypocomplementemia of 6 to 8 weeks duration indicates the likelihood of membranoproliferative glomerulonephritis. A renal biopsy should be performed to more definitively reach a diagnosis.4

The diagnostic workup can be cost-effective if pertinent historical and clinical data are used to streamline preliminary differential diagnoses. A urinalysis and appropriate serology can then indicate the need for further diagnostic studies.

Treatment

APG treatment is supportive and focuses on the clinical manifestations of acute nephritis. Therapy goals include controlling blood pressure and treating volume overload.12 The acute syndrome is treated with restricted sodium and limited fluid intake.1,12 A 2-gram sodium and potassium diet controls sodium intake and prevents or limits hyperkalemia in patients with decreased or absent urinary output.4.20 In the presence of significant edema or hypertension, furosemide usually provides prompt diuresis and reduced blood pressure.12,20 Finally, the clinician should treat infection in carrier patients and close contacts.

Antihypertensives

Hypertension may be mild to moderate or severe, which requires emergent treatment. The initial management of the adult patient with severe hypertension includes IN. diazoxide (1 to 3 mg/kg) every 15 minutes up to a maximum of 150 mg, nitroprusside (0.3 to 10 mcg/kg/minute), labetalol (20 mg IN. bolus slowly over 2 minutes) with an additional 40 to 80 mg every 10 minutes to a maximum of 300 mg, or hydralazine (10 to 20 mg I.V.) as needed.10

In the pediatric population, which is the more frequently affected group, initial management of severe hypertension includes IN. diazoxide (1 to 3 mg/kg) every 15 minutes up to a maximum of 150 mg, nitroprusside (0.3 to 10 mcg/kg/minute), labetalol (0.2 mg/kg IN. bolus for more than 2 minutes), and hydralazine (0.2 to 0.6 mg/kg IN. bolus). The safety and efficacy of labetalol in children has not been established.10

If multiple doses are required, maintenance antihypertensive therapy should be initiated.' Labetalol or nifedipine may be taken orally with loop diuretics until renal function improves and blood pressure returns to normal limits." Angiotensin-converting enzyme inhibitors should be avoided because they can cause hyperkalemia.7 Strict bed rest is not necessary once the patient's condition improves and energy levels rise.7,11

Penicillin Therapy

All APG patients with evidence of throat or skin infection should receive antibiotic therapy with penicillin or, in cases of penicillin allergy, erythromycin.4,7,12 Infected family members and close contacts of the patient should also receive penicillin therapy. For patients with skin infections, attention to personal hygiene is also an essential part of treatment and recovery. 12

Prognosis

The short-term prognosis of APG in children is favorable.2,7,11,12 Fewer than 2% of children progress to end-stage renal disease. Hypertension and gross hematuria usually resolve over several weeks, although microscopic hematuria may persist for several years. Proteinuria resolves over several months.4 The limited number of adults who develop APG, however, may develop chronic glomerulonephritis and renal impairment.2,7,11,12

Controversy exists regarding the validity of complete resolution in children. Some researchers suggest that unexplained cases of chronic nephritis in adults may have started in childhood as subclinical APG.5 Additionally, investigators have proposed that a discrete relative hyperperfusion of remaining intact nephrons could result in clinically significant renal damage, developing insidiously many years after apparent APG resolution.

Herthelius and Berg have undertaken a long-term follow-up study to examine this hypothesis." They are evaluating clearance of inulin and p-aminohippuric acid, indicators of glomerular filtration rate and effective renal plasma flow, in patients at 5, 10, 15, and 20 years after disease onset. This research will help determine if healing actually occurs in the glomerulus or if clinically significant damage develops gradually.

Prevention

Unlike rheumatic fever, researchers do not commonly believe that antibiotic therapy prevents APG development. Researchers have found that acute glomerulonephritis occurs despite appropriate antimicrobial treatment during epidemic streptococcal events.2

Prevention may play a role in limiting the spread of nephritogenic streptococcal strains and is valuable during epidemics for at-risk populations, such as patients who are immunodeficient or already affected by renal compromise.' Penicillin might halt transmission of these strains and prevent infection.26 Timely treatment of streptococcal infection may limit the time of antigen availability and immune-complex formation and potentially decrease acute glomerulonephritis severity.7,15

APG in Practice

APG is a leading cause of acute nephritic syndrome.10 Awareness of this nonsuppurative sequelae of GAS infection can help streamline diagnosis, resulting in a more timely and costeffective treatment. Based on the history and physical examination, appropriate laboratory analyses can be obtained while concurrently referring the patient to a nephrologist. An accurate diagnosis helps the nephrologist delineate appropriate therapy and anticipate potential developments, thus encouraging the maintenance of optimal renal function.17

Follow-up is needed to monitor the course of APG. Serial complement (C3) levels, serum creatinine, and appropriate urine screening for hematuria and proteinuria is necessary to ensure resolution of glomerular inflammation and return to premorbid renal status. The clinician should provide educational, emotional, and continued medical management to the patient and family as the syndrome progresses toward resolution.

REFERENCES

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3. Dajani A, Taubert K, Ferrieri P, et al.: Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: A statement for health professionals.

Pediatrics 1995;96(4):758-64.

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6. Rodriguez-Iturbe,B: Acute endocapillary glomerulonephritis. In: Davison AM, Cameron JS, Grunfeld JP, et at., eds. Oxford textbook of clinical nephrology, 2nd edition. New York, N.Y: Oxford University Press, 1998;613-22.

7. Rodriguez-Iturbe B: Postinfectious glomerulonephritis. Am J Kidney Dis 2000;35(I):xivi-xiviii,

8. Madaio MP: Postinfectious glomerulonephritis. In: Jacobson HR, Striker GR, Klahr S, eds. The principles and practice of nephrology. New York, N.Y: Mosby, 1995;122-25.

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11. Davison AM: Infection-related glomerulonephritis. In: Davison AM, Cameron JS, Grunfeld JP, et al., eds. Oxford textbook of clinical nephrology, 2nd edition. New York, N.Y.: Oxford University Press, 1998;667-69.

12. Brady HR, Brenner BM: Pathogenetic mechanisms of glomerular injury. In: Fauci AS, ed. Harrison's principles of internal medicine, 14th edition. New York, N.Y.: McGraw-Hill, 1998;1529-36.

13. Cu GA, Mezzano S, Barman JD, et al.: Immunohistochemical and serological evidence for the role of streptococcal proteinase in acute post-streptococcal glomerulonephritis. Kidney Int 1998;54:819-26.

14. Oliveira DBG: Poststreptococcal glomerulonephritis: Getting to know an old enemy. Clin Exp Immunol 1998;107:8-10.

15. Shulman ST, Tanz RR: Nonsuppurative poststreptococcal diseases: Rheumatic fever and acute glomerulonephritis. In: Long SS, Pickering LK, Prober CG, eds. Principles and practice of pediatric infectious diseases. New York, NX: Churchill Livingstone, 1997;807-12.

16. National Institutes of Health The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure (NIH publication no. 98-4080). Bethesda, Md.: National Heart, Lung, and Blood Institute, 1997.

17. Goldberg EA: Physical assessment of children ages I to 10 years with renal disease. J Am Nephrology Nurses Association 1997;24:222-28.

18. Fox JA: Primary health care of children. New York, N.Y.: Mosby, 1997;452-54.

19. Nordby JA: Neurological presentation of poststreptococcal glomerulonephritis. Clin Pediatr 1997;36(2):105-08.

20. Foster MR: Serologic evaluation of the renal patient. In: Jacobson HR, Striker GR, Klahr S, eds. The principles and practice of nephrology. New York, NX: Mosby, 1995;71-84.

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22. Nelson WE: Textbook of pediatrics, 14th edition. Philadelphia, Pa.: W.B. Saunders Co., 1992;1323-96.

23. Peterson FY, Symes J, Springer P: Inflammation and immunity. In: Copstead LEC, ed. Perspectives on pathophysiology. Philadelphia, Pa.: W.B. Saunders Co., 1994;172-99.

24. Marble DA: Rheumatic diseases. In: Traub SL, ed. Interpreting laboratory data. Bethesda, Md., 1996;382-83.

25. Herthelius M, Berg U: Renal function during and after childhood acute poststreptococcal glomerulonephritis. Pediatr Nephrol 1999;13:907-11.

26. Johnson F, Carapetis J, Patel MS, et al.: Evaluating the use of penicillin to control outbreaks of acute poststreptococcal glomerulonephritis. Pediatr Infect Dis J 1999;18:327-32.

27. Fickenscher L: Evaluating adult hematuria. Nurse Pract 1999;58-65.

Mary Margaret Lang, RN, MSN Carol Towers, RN, MSN

ABOUT THE AUTHORS

Mary Margaret Lang, RN, MSN, is a certified registered NP, University of Scranton, Scranton, Pa.

Carol Towers, RN, MSN, is a certified registered NP, University of Scranton, Scranton, Pa.

Copyright Springhouse Corporation Aug 2001
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