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Recognizing the elusive signs and symptoms of PSGN

In children, poststreptococcal glomerulonephritis usually resolves spontaneously. In adults, however, it is a serious condition and in most cases has a poor prognosis.

Natalie Benudiz, MPT, MPAP, PA-C

Natalie Benudiz is a physician assistant and physical therapist at Bayside Medical Center in Hawthorne, California. She has indicated no relationships to disclose relating to the content of this article.

Poststreptococcal glomerulonephritis (PSGN) is an acute, immune complex-mediated inflammatory disorder of the glomerulus. It is an uncommon sequela of acute infection with streptococcal organisms that invade usually the throat or the skin. PSGN is not necessarily preventable with antibiotic treatment and remains a leading cause of acute and chronic renal failure in children. Prompt diagnosis in patients with even mild renal compromise, hypertension, and urinary abnormalities is vital, as these patients could lose kidney function without urgent treatment. This article reviews the epidemiology, etiology, and pathology of PSGN; and discusses the clinical presentation, diagnosis, differential diagnosis, treatment, prognosis, and prevention of this disease.

EPIDEMIOLOGY

PSGN manifests most often in children aged 2 to 12 years, but the disorder can develop at any age. Five percent of cases are seen in children aged 2 years or younger, and 5% to 10% of cases are seen in adults aged 49 years and older. PSGN is the most common cause of hematuria in children. The disorder affects boys more than girls at a ratio of 2:1.¹ PSGN is still a significant cause of acute renal failure in the developing world, but much less so in the United States and Europe.² Epidemics have been identified in Brazil,³ Chile,⁴ and Australia.⁵

The average risk of developing acute PSGN after infection with group A beta-hemolytic streptococci (GAS) is 15%;¹ however, this figure may be conservative because of subclinical glomerulonephritis (GN). Patients with unrecognized subclinical GN outnumber patients with apparent GN 4:1 to 10:1.¹ A recent study of 1,012 renal biopsies revealed incidental evidence of resolving or healed postinfectious GN in 10.5% of specimens,⁶ not including those from patients who had received a diagnosis of PSGN. The study did not indicate whether the cause of the initial acute infection (GAS versus another pathogen) was known to the investigators.

Siblings may be at increased risk for developing clinical or subclinical PSGN compared with their parents. One study examined 317 family contacts from 75 families of patients with diagnosed PSGN 1 to 7 days after the patient was admitted to a children’s clinic.⁷ None of the parents got the disease, but 22.3% of siblings had abnormal urinalysis results. The incidence of nephritis among 170 siblings was 9.4%. In an epidemic in Chile, investigation of 598 family contacts of patients with PSGN, mean age 18.6 years (range 2 to 58 years), revealed GAS isolates on throat swabs of 13% of contacts and in skin lesions of 47.7% of contacts.⁴ Hematuria was found in 10.6% of contacts, and low C3 complement levels were detected in 17.7%. Correlation of patients with PSGN and family contacts with possible subclinical GN was 0.61.

ETIOLOGY

PSGN develops most frequently after an acute throat or skin infection with a nephritogenic strain of GAS. GAS M types 47, 49, and 57 are the common pathogens in skin infections; GAS M types 1, 2, 4, and 12 are the common pathogens in upper respiratory infections.¹

One study examined an epidemic of acute GN in Brazil 7 days after an outbreak of pharyngitis. The patients were infected with group C Streptococcus zooepidemicus after eating cheese made with unpasteurized milk.³ This species, which rarely infects humans, is a common cause of disease in cows and horses.⁸ Four other outbreaks of infection with this species, all originating from consumption of unpasteurized milk or milk products, have been reported; PSGN manifested in two of the outbreaks and sepsis or meningitis in the other two.⁸ Unlike PSGN attributed to GAS infection, disease caused by S zooepidemicus predominantly affects adults.⁸

PSGN has become less common in the United States and Europe than in developing countries, but cases of postinfectious GN, not necessarily involving the Streptococcus species, are increasing as a result of infections such as endocarditis resulting from IV drug use.²

PATHOLOGY

The exact mechanism of glomerular injury is controversial. Several theories exist on what initiates GN:

• Antibodies to the streptococcal antigen planted in the glomerulus at the time of infection are formed.²
• An autoantibody reacts with normal glomerular tissue that is acting as an autoantigen.
• Circulating immune complexes are trapped in the glomerulus.¹

Researchers are focusing on two specific streptococcal antigens (cationic cysteine proteinase exotoxin B [SPE B] and the plasmin receptor, a glyceraldehyde phosphate dehydrogenase [Plr]) because these antigens have been found in the glomeruli of patients with acute PSGN and because serum antibodies to them have been associated with nephritogenic streptococcal infections.⁹ Batsford and colleagues compared 17 renal biopsies and 53 serum samples from patients with PSGN with appropriate controls. Using enzyme-linked immunosorbent assay (ELISA) and Western blot tests, glomerular deposits of SPE B were detected in 12 of the 17 biopsies with two borderline cases; Plr was found in one biopsy with two borderline cases.⁹ Circulating antibodies to SPE B were found in all 53 serum samples. ELISA was performed on 47 of the serum samples; circulating antibodies to Plr were found in five of those samples. In 31 control biopsies, only weak staining for each antigen was found in two cases. The study concluded that SPE B is likely the major antigen involved in the pathogenesis of most PSGN.⁹

Regardless of how PSGN is initiated, the disorder primarily affects the mesangial and endothelial cells² via alternative pathway activation of the complement cascade, leading to glomerular inflammation with chemoattractants, chemokines, and cytokines.¹ Additionally, activation of the coagulation cascade leads to fibrin deposits in the glomeruli. Cellular proliferation of parietal epithelial cells in Bowman’s space and an influx of inflammatory cells, such as macrophages and neutrophils, result in acute glomerular crescent formation.² The infiltration of leukocytes and platelets clogs glomerular capillaries, causing tissue damage and altering the filtration barrier of the basement membrane;¹ this allows subsequent deposits of preformed immune complexes to build up.² The glomerular inflammation and decreased filtration lead to fluid retention, causing edema and vascular congestion.¹

CLINICAL PRESENTATION

GN manifests about 10 days after pharyngitis or 2 weeks after a skin infection as acute nephritic syndrome (90% of cases) consisting of hematuria; mild proteinuria (less than 2 g/dl); and periorbital, dependent, or generalized edema.¹ Thirty percent to 50% of children have gross hematuria with possible dysuria lasting about 2 weeks. Microscopic hematuria, however, can last for months after the resolution of the acute illness. Oliguria may or may not be present but is transient in about 50% of the cases, and anuria is rare.

Edema can cause ascites or pleural effusions, which manifest as orthopnea, dyspnea, cough, pulmonary crackles, and gallop rhythm.¹ Adolescents are more likely to have edema that affects the face and legs, whereas younger children tend to have generalized edema.¹

Hypertension (defined as BP higher than the 95th percentile for age and sex for children, or more than 140/90 mm Hg for adults) is another important sign. It can cause headache, somnolence, altered mental status, or convulsions.¹ Nausea, vomiting, malaise, anorexia, back pain, and abdominal discomfort may also occur.¹

In one documented case, an 8-year-old boy presented to the emergency department with impending airway obstruction.¹⁰ The patient’s face had been swollen for 3 days. His condition had improved before he was brought to the clinic, and he now had only mild edema in the maxillary and periorbital regions. The boy was unable to speak but had no sore throat, fever, shortness of breath, or chest pain, and there was no change in urinary frequency or appearance. On physical examination, the oropharynx was clear. He had nontender anterior and posterior lymphadenopathy and was breathing freely without wheezing or stridor. He had a diffuse, fine maculopapular rash on his anterior torso. Radiographs showed subglottic narrowing consistent with croup. CBC, BUN, and creatinine results were all normal, and rapid strep test results were negative. Urinalysis showed 1+ proteinuria, no WBCs or RBCs. The patient was admitted to the hospital, and later developed respiratory distress and hypertension. On the third day, urinalysis showed 10 to 50 RBCs per high power field without casts, and positive antistreptolysin O (ASO) and streptozyme titers. Throat cultures remained negative. The diagnosis of PSGN was made. This case could have easily been misdiagnosed as croup, epiglottitis, or angioedema, but PSGN should always be considered in the differential when the patient presents with facial and airway edema.¹⁰

PSGN also may be asymptomatic or subclinical. The sibling study discussed earlier concluded that siblings were at increased risk for developing subclinical nephritis.⁷ Abnormal findings on urinalysis, transitory hypocomplementemia, and increased ASO titers may indicate subclinical disease.⁷

DIAGNOSIS

Diagnosis of PSGN is often made on clinical presentation alone, including findings of edema, hypertension, and a history of streptococcal pharyngitis or skin infection.¹¹ Serologic evidence of a recent streptococcal infection can be helpful (ASO, anti-DNase B [ADB], antihyaluronidase, antistreptokinase, or antinicotinamide adenine dinucleotidase [anti-NADase]) in indicating the presence of PSGN.¹ ASO and anti-NADase titers are elevated in 80% of patients with postpharyngitis nephritis, and antihyaluronidase and ADB titers are elevated in 80% to 90% of patients with skin infections.¹ Serial titers are more valuable than a single result. Titers become elevated 1 to 5 weeks after infection and return to preinfection levels over several months.¹ Prior antibiotic treatment can produce false-negative results.¹ Also, negative ASO titers do not exclude the diagnosis because many nephritogenic strains do not produce streptolysin.²

Urinalysis usually reveals hematuria; RBC casts (dysmorphic RBCs indicate hematuria originating in glomeruli); proteinuria, which may increase 1 to 2 weeks after onset as the glomerular filtration rate (GFR) improves; leukocytes; and hyaline and granular casts.¹ The presence of WBC casts in this case does not indicate a superimposed urinary tract infection. Only 15% of cases reportedly involve proteinuria of more than 2 g/dl.¹ A documented case described a patient with a diagnosis of PSGN and nephrotic proteinuria, and suggested that as many as 14% to 30% of adults may present with the disorder.¹² When present, nephrotic proteinuria is a strong predictor of poor renal outcomes.

Serum testing is helpful in the diagnosis of PSGN. In 25% of patients, creatinine levels are 2 mg/dL or higher.¹ Serum complement is usually reduced. Total hemolytic complement (CH50), C3, and C4 levels should all be checked.¹ In the first 2 weeks after onset, C3 and CH50 levels are depressed in more than 90% of patients with acute nephritis.¹ C4 levels are minimally depressed or normal. Complement levels return to normal within 4 to 6 weeks, and C3 levels should be checked at 6 to 8 weeks after onset to document a return to normal.¹ GFR is usually depressed during the initial stages of disease and then returns to normal as disease resolves.¹

A renal biopsy is rarely necessary. If performed, results show enlarged, bloodless, exudative glomeruli secondary to capillary occlusion; infiltration of leukocytes, monocytes, and eosinophils; and “humps” containing mainly immunoglobulin G (IgG) and C3 complement between glomerular capillary basement membrane and epithelial cells on electron microscopy (see Figure 1).⁶

DIFFERENTIAL DIAGNOSIS

Because treatment of GN is based on causative factors, determining an etiology is vital when making the diagnosis. For most causes of GN, the aim is to reverse the underlying process that is causing the glomerular inflammation.² Only when the cause is streptococcal infection is treatment generally supportive.

Conditions to consider in the differential diagnosis include hereditary nephritis, IgA nephropathy, benign hematuria, Henoch-Schönlein purpura, Wegener’s granulomatosis, antiglomerular basement membrane disease, and lupus nephritis.^1,2 The presence of extrarenal symptoms lends clues to some of the differential diagnoses.² Also, C3 levels and streptococcal antibody titers can help differentiate some of the conditions. For example, C3 levels are not depressed in Henoch-Schönlein purpura, IgA nephropathy, benign hematuria, or hereditary nephritis.¹ Furthermore, if C3 levels have been depressed for more than 6 to 8 weeks, membranoproliferative GN or lupus nephritis should be considered.⁴ Streptococcal antibody titers are not elevated in lupus.¹

Another clue to differentiate PSGN from other renal diseases is the amount of time from the acute streptococcal infection to the onset of GN. PSGN usually develops 10 days to 2 weeks after acute infection; if the latency period is too short, PSGN may not be the cause of the renal impairment.¹

In children, hypoalbuminemia and proteinuria of more than 3.5 g/dL in 24 hours indicate other causes of chronic renal failure.¹ Adults may present with nephrotic proteinuria,¹² but adult nephrotic syndrome most commonly results from minimal change kidney disease (more than 70% of cases) and an infectious process is usually not present. With acute PSGN, infection manifests itself as an elevated total WBC count and changes on the differential blood smear.¹¹

TREATMENT

Assuming the acute infection is resolved, treatment of PSGN is supportive; control BP and treat volume overload by restricting sodium and fluid intake.¹ Furosemide may be given in cases of severe edema or hypertension.¹ Severe fluid overload may require dialysis.² Long-term strict BP control may be necessary if the patient is left with some degree of renal impairment.² ACE inhibitor use is controversial because these drugs can cause hyperkalemia.¹ However, in addition to controlling hypertension, ACE inhibitors have antiproteinuric and antifibrotic effects on the kidney.² Hygiene is emphasized for those patients with skin infections.¹ Follow-up is required, with repeat measurements of C3 and creatinine levels, and urinalysis for hematuria and proteinuria until all results are normalized.

Some study results support treating streptococcal infections in the family contacts of PSGN patients, especially siblings, with penicillin or erythromycin (if the contact is penicillin-allergic).^1,7 In the Chilean epidemic mentioned earlier, a correlation analysis of patients with PSGN and family contacts with possible subclinical GN also suggests that prophylactic antibiotic treatment be given to family contacts.⁴ A subset of older adults who present with renal insufficiency and nephrotic proteinuria, as well as a family history of end-stage renal disease (ESRD), and who demonstrate cellular crescents on renal biopsy may need aggressive treatment with intravenous and/or oral prednisone to stall the development of chronic renal failure.¹²

PROGNOSIS

PSGN resolves spontaneously with complete clinical recovery 4 to 14 days after the initial acute insult in 95% of children with the disease.² Hypertension and gross hematuria resolve without any intervention within 6 months; microscopic hematuria, however, may persist for years, and subnephrotic proteinuria may take up to 10 years to completely resolve. C3 levels return to normal within 6 to 8 weeks in 95% of children with PSGN.⁴ PSGN progresses to ESRD in less than 2% of children with the disease.¹ Recurrence is unlikely because of the limited number of nephritogenic strains and type-specific long-lasting immunity.¹ Patients who were followed in the PSGN epidemic in Chile were discharged after 2 years of follow-up with normal clinical and laboratory parameters.⁴

Adults may experience residual renal impairment; 30% to 50% of adults with PSGN can be expected to have residual hypertension, renal insufficiency, or abnormal urinalysis results on long-term follow-up.¹² PSGN progresses to ESRD in 3% to 5% of adult patients. The long-term prognosis for patients with crescentic GN and nephrotic proteinuria is not known but is likely to be worse.¹²

Some unexplained cases of chronic nephritis may have started as subclinical acute PSGN in which resolution was not complete. Morphologic abnormalities of glomeruli, such as mesangial hypercellularity and matrix expansion, deposits of C3 and immunoglobulins, and resorbed subepithelial and mesangial deposits with irregularities of the glomerular basement membrane, often persist even in patients who continue to have minimal urinary abnormalities months to years after the acute episode of PSGN.⁶

A retrospective cohort study done on aboriginal children in Australian communities where GAS is endemic found that PSGN in childhood is a risk factor for albuminuria and hematuria in later life.⁵ Chronic renal disease and ESRD also occur in adults at higher rates in these communities. It was suggested that about 25% of overt albuminuria cases may be attributable to PSGN in childhood. The study followed 472 children aged 2 to 15 years for a mean of 14.6 years (range 6 to 18 years) and subjects were divided into three groups. Group 1 consisted of 63 children who received a diagnosis of PSGN with documented edema or hypertension at the 90th percentile or higher for age range plus greater than trace amounts of hematuria or proteinuria on dipstick urinalysis. Group 2 consisted of 86 children with greater than trace amounts of hematuria or proteinuria but no edema or hypertension. Group 3 was a control group of 323 children with no symptoms and normal urinalysis results or no symptoms and no urinalysis performed or recorded. The odds of overt albuminuria were found to be more than six times higher for the PSGN group compared with the control group, after adjustment for age and sex. The odds of hematuria were more than three times higher in those who had PSGN compared with controls, and the odds of either hematuria or overt albuminuria were five times higher in the PSGN group, after adjustment for age and sex.⁵

An evaluation of 69 patients 2 years after an outbreak in Brazil of PSGN associated with group C S zooepidemicus found a higher rate of hypertension and frequent renal abnormalities, including progression to ESRD, among these patients.³ In this study, 95% of the patients were older than 15 years (mean age 34 years), and the majority were women. Renal biopsies from nine patients indicated glomerular disease consistent with PSGN. Patients with microalbuminuria (n = 22) were found to have significantly higher diastolic BP (98 mm Hg versus 88 mm Hg, P = .02) than patients without microalbuminuria (n = 43). At follow-up, 42% (27 of 65) of patients had hypertension; microalbuminuria was detected in 34% (22 of 65) of patients. Microalbuminuria was found in several patients who did not have reduced creatinine clearance; however, a lower GFR without microalbuminuria was observed in some patients. Thirty percent of patients had reduced GFR measured via creatinine clearance.³

Using the same methodology, 56 of these patients were re-examined 3 years later. In the follow-up study, no other patients had developed ESRD, and one patient continued to receive dialysis.¹³ Compared with the 2-year evaluation, the proportion of patients with microalbuminuria (22%) and hypertension (30%) decreased, but the percentage of cases with reduced renal function increased (49%). Of the eight patients with creatinine clearance of less than 60 mL/min, most were elderly and had hypertension, and three had a diagnosis of diabetes. All of these factors could be affecting their prognosis.

PREVENTION

The best way to prevent PSGN is to limit the spread of nephritogenic streptococcal strains, especially during epidemics. Penicillin may be used for prophylaxis. Adam and colleagues conducted a randomized controlled study on the incidence of poststreptococcal sequelae after GAS tonsillopharyngitis by comparing 10 days of penicillin V oral suspension, 32.7 mg/kg/d in three divided doses, with 5 days of amoxicillin/clavulanate, 37.5 mg/kg/d in two divided doses; cefibuten, 9 mg/kg/d; cefuroxime, 20 mg/kg/d in two divided doses; loracarbef, 15 mg/kg/d in two divided doses; clarithromycin, 15 mg/kg/d in two divided doses; or erythromycin, 40 mg/kg/d in two divided doses.¹⁴ The investigators followed 4,782 subjects aged 1 to 18 years with a diagnosis of culture-positive GAS tonsillopharyngitis for 1 year. Although recurrence was more common among those receiving the 10-day penicillin V treatment (24.4% versus 21.9%, P = .03), the incidence of poststreptococcal sequelae was not found to be different between the groups.¹⁴

Timely treatment of streptococcal infection also may decrease the severity of GN,¹ but complete prevention of GN in patients with streptococcal infections is still elusive. A recent evidence-based systematic review confirmed that antibiotics reduce the occurrence of rheumatic fever, otitis media, and peritonsillar abscess, but not of GN or sinusitis.¹⁵ The review also stated that treating only patients whose cultures were positive for Streptococcus increases the ratio of effectiveness, suggesting that testing for the presence of Streptococcus among patients with pharyngitis may be advantagous.¹⁵

CONCLUSION

PSGN is still a threat to those afflicted with streptococcal skin or throat infections, especially children. The disease may be more prevalent than previously thought because of a high number of unrecognized subclinical cases. The long-term effects of PSGN also may be more significant than earlier believed, as evidenced by renal biopsy and outcomes studies. Treatment is supportive and complete prevention is not yet possible. Practitioners should keep a high index of suspicion for PSGN, so that the potential for renal damage is minimized.

Acknowledgement: Thank you to John Mabee, PA-C, PhD, for his assistance.

REFERENCES

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