Acute postinfectious glomerulonephritis (PIGN) can complicate streptococcal and other infections.1 The glomerular injury is mediated by a host immune response that is triggered by an infectious agent.2 Over the last three decades there has been a decline in the number of PIGN cases affecting children in developed countries, yet it remains one of the most common glomerular diseases among the pediatric population in the United States.1,3 Children age 2 to 12 years are most commonly affected, comprising 80% to 85% of patients.4 There is a male to female ratio of 2:1 in symptomatic patients, although there is no gender predilection in subclinical cases.5 Clinical presentation can vary from asymptomatic microscopic hematuria detected incidentally on urinalysis to rapidly progressive glomerulonephritis causing acute kidney injury with a need for emergent dialysis.6 When symptomatic, PIGN classically presents with nephritic syndrome with features of hematuria, decreased urine output, edema, and hypertension, typically 1 to 2 weeks after pharyngitis or 3 to 6 weeks after a skin infection. Less commonly, it could mimic nephrotic syndrome with heavy proteinuria.7 Acute management consists mainly of supportive care and is directed at controlling blood pressure, as well as salt and water restriction to alleviate edema. The role of immunosuppressive therapy is controversial and usually reserved for patients with rapidly progressive glomerulonephritis when a renal biopsy shows cellular crescents.8 Prognosis is usually excellent in PIGN with supportive treatment only.9
Although today it is well known that many different infectious agents may cause PIGN, traditionally PIGN had been described only after streptococcal infections. Acute poststreptococcal glomerulonephritis (PSGN) was described as early as the eighteenth century.10 It was described as scant or absent urine associated with edema, which was a worrisome complication sometimes associated with scarlet fever.10 However, the first description of acute nephritis with edema and urine containing both red substance and coagulable material following a latent period after scarlatina was done by Wells in 1812.8 This was followed by Bright's description nearly 10 years later of a connection between dropsy, coagulable urine, and autopsy evidence of renal derangement.8,10 The term “Bright's disease” was used to describe acute and chronic glomerulonephritis until the middle of the last century. Experimental work by Dick and Dick11 showed beta-hemolytic streptococcus was a cause of scarlet fever. Following this discovery, Earle and Jennings used the term PSGN to describe this clinical entity for the first time in 1959, in which they presented a case of glomerulonephritis with concomitant streptococcal endocarditis.12
The true incidence of PIGN is not known because most cases are subclinical and transient. Subclinical disease is thought to be 4 to 19 times more common than symptomatic disease.13 Over the last few decades, there has been a decline in PIGN secondary to improved medical access and early antibiotic treatment of skin infections, as well as proper hygiene.7 In a retrospective comparative study conducted by Ilyas and Tolaymat14 on patients with PSGN admitted to a pediatric hospital in northeast Florida, there was a statistically significant decline in the incidence (10.9/year vs 6.4/year) and prevalence (2.18/100,000 vs 0.64/100,000) from the first cohort (1957 to 1973) to the second cohort (1999 to 2006); however, the burden of PSGN in developing countries remains between 9.5 and 28.5 new cases per 100,000 people per year.13 Fortunately, worldwide mortality due to PSGN is low, with a mean incidence of 0.028 per 100,000 in developing countries.15 It is important to note that staphylococcal-associated glomerulonephritis incidence is on the rise in developed countries, likely due to an increased rate of methicillin-resistant Staphylococcus aureus infections.16,17
Both host factors and invading organism characteristics affect glomerular response to acute infection. The same organism can have variable pathological features even within the same epidemic of a specific population.18 PSGN is the best-known example of PIGN. During the acute infection, streptococcal antigen is deposited in the glomerulus. Antibodies formed by the host immune system lead to in situ production of an antigen-antibody complex. This results in increased permeability of glomerular basement membrane and further immune complex deposition.19 However, only the nephritogenic strains (M2, M12, M49, M57, M59, and M60) of streptococci cause PIGN. Most common pathologic findings on light microscopy include diffuse endocapillary proliferative and exudative glomerulonephritis (GN).20 Electron microscopy will show subepithelial electron-dense, hump-shaped deposits.20 Patients with typical presentation of PIGN do not require a renal biopsy. However, a renal biopsy may be indicated in patients with diagnostic uncertainty, patients who present with rapidly progressive glomerulonephritis, patients who are persistently symptomatic or have low complement level beyond 6 to 8 weeks of duration, patients younger than age 2 years, or in patients who present with extrarenal manifestations.2
Clinical manifestations of PIGN include a spectrum of symptoms and signs that can be subdivided into three major categories.
Asymptomatic or Subclinical Glomerulonephritis
Asymptomatic or subclinical glomerulonephritis presents with low-grade proteinuria (<1 g/day), microscopic hematuria, and pyuria, which is usually overlooked within the context of the illness. It is usually self-limiting, yet histopathology can demonstrate endocapillary proliferation with immunoglobulin M, C3, and rarely immunoglobulin G deposition.21,22 Studies of asymptomatic household members of symptomatic patients revealed that subclinical disease is up to 4 times more common than the classic presentation of the disease.23
Acute Nephritic Syndrome
Acute nephritic syndrome is characterized by gross or microscopic hematuria, proteinuria, and edema in addition to hypertension and different degrees of acute kidney injury. Classically, PIGN presents with sudden onset of periorbital edema, followed by cola-colored or brown urine and decreased urine output in the setting of elevated blood pressure.18 Although less common, the patient may have anuria or nephrotic range proteinuria (>3.5 g/day).18,24
Rapidly Progressive Glomerulonephritis
In approximately 1% to 3% of cases, PIGN can present as rapidly progressive glomerulonephritis (RPGN).25 It is usually characterized by rapid deterioration of kidney function with glomerular congestion, exudative cells in Bowman's capsule, and sometimes cellular crescent formation. In a study by Jellouli et al.26 on outcomes of children with postinfectious RPGN, of the 27 children included, all of them presented with acute kidney injury, and renal biopsy showed evidence of crescent formation in most of the patients. This study also found that despite supportive therapy, 11 patients required dialysis and three patients progressed to end stage renal disease (ESRD).26
Diagnosis of acute PIGN is usually suggested by patient history, and only a few laboratory tests are needed to aid in confirming the diagnosis (Table 1).27 As discussed earlier, the need for renal biopsy is limited to when there is substantial diagnostic uncertainty or when the patient presents with RPGN.
Laboratory Abnormalities Associated with Postinfectious Glomerulonephritis
Urinalysis and Urine Protein Quantification
Urine appearance could be unremarkable to a smoky or dark brown color. A dipstick test is usually positive for blood, protein, and leucocyte esterase. On microscopy, there are typically white and red blood cells (RBCs). Pyuria is present due to glomerular inflammation. Presence of RBC cast with or without dysmorphic RBCs on microscopy is pathognomonic for glomerulonephritis but not specific for PIGN. Significant proteinuria with a urine protein to creatinine ratio of more than 0.2 mg/mg is also present, and this leads to a low serum albumin.
Assessment of Kidney Function
Varying degrees of decline in estimated glomerular filtration rate (eGFR) is expected, which is temporary and usually reverts to normal upon resolution of the disease.17 A case series of 17 patients showed that the mean nadir of eGFR was 44.5 ± 22.9 mL/min/1.73 m2, which improved to 105 ± 19.4 mL/min/1.73 m2 on follow-up.28
Prior documentation of skin or pharyngeal streptococcal infection with high antistreptolysin O titer and anti-DNAase B antibody can aid in diagnosis; however, it is not required to diagnose PIGN. There is an ever-increasing body of medical literature showing other infectious etiologies causing PIGN;6,22 hence, negative serologies for streptococcus do not rule out the diagnosis of PIGN.
In about 90% of patients with PIGN, serum C3 level will be low during the acute presentation. Low C3 levels usually persist for up to 6 to 8 weeks before normalizing.27,29 Because the pathogenesis of PIGN involves activation of the alternate pathway, other components of the complement pathway such as C4 will remain normal. Hence, transient low C3 with normal C4 levels is classic for PIGN and helps differentiate it from other types of glomerulonephritis.7,18,27Figure 1 shows the differential diagnosis of glomerulonephritis based on complement levels.
Differential diagnosis of patients with acute glomerulonephritis. ANCA, antineutrophil cytoplasmic antibody; Anti-GBM, anti-glomerular basement membrane; HSP, Henoch-Schönlein purpura; MPGN, membranoproliferative glomerulonephritis; PIGN, postinfectious glomerulonephritis; SBE, subacute bacterial endocarditis.
Other Laboratory Tests
Complete blood count is usually normal; however, it might show leukocytosis with a decrease in platelet count and hemoglobin level. The above changes in platelet and hemoglobin are limited and likely secondary to dilution, which might also cause mild hyponatremia. However, a drop of hemoglobin below 8 g/dL or platelets below 50,000/mL should prompt other diagnostic considerations.27
In patients with evidence of persistent group A streptococcal infection, antibiotic use is warranted. Although early treatment might decrease exposure to the bacterial antigen, it might not prevent PIGN.30 Treatment of PIGN is supportive. Sodium and water restriction are needed in patients with edema and hypertension. Patients may also need antihypertensives to control their blood pressure. Loop or thiazide diuretics are effective at reducing blood pressure and alleviating edema. When blood pressures continue to be elevated despite the use of diuretics, calcium channel blockers are typically added. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are also effective in blood pressure control; however, caution should be used in patients with impaired renal function as hyperkalemia might ensue.7 Initial hyperkalemia can usually be controlled with dietary restriction combined with diuretic therapy. If it persists, potassium binding resins can be added; however, this may increase sodium delivery to the patient, causing worsening edema and hypertension. Indications to start dialysis include hyperkalemia, fluid overload manifested usually by pulmonary edema and/or hypertensive encephalopathy, oliguria with poor response to diuretics, and symptomatic uremia or blood urea nitrogen level >100 mg/dL.18,27,31 These patients usually require a renal biopsy and may need immunosuppressive therapy with corticosteroids or corticosteroids with cyclophosphamide for crescentic disease. Evidence on the efficacy of immunosuppressive drugs in PIGN is lacking, and they might not affect the outcome.6,20,27
Prognosis and Complications
Early in the course of the illness, patients may have volume overload and hypertension, which may lead to pulmonary edema or hypertensive encephalopathy. In up to 10% of patients, a transient decrease in left ventricular ejection fraction is noted, but it is usually self-limited. In patients presenting with RPGN with need for dialysis, a small number progress to ESRD.26 Most patients with PIGN have an excellent prognosis. The disease does not recur, and most patients recover renal function. The urine output is the first thing to improve, usually doing so within the first week of hospitalization. Edema will resolve and blood pressure will normalize afterwards. Serum C3 levels typically normalize 6 to 8 weeks after initial presentation. Microscopic hematuria may persist for up to 1 year.24,32
The incidence of PIGN has declined significantly over the past three decades in developed countries, but it can still occur as a postinfectious sequela to various infectious etiologies. Presentation ranges from subclinical to RPGN. Supportive care including electrolyte imbalance correction, fluid and sodium restriction, as well as blood pressure control remain the cornerstone of management. Prognosis is usually excellent, with 90% of patients achieving full recovery. In some patients, PIGN can progress to severe acute kidney injury, temporarily requiring dialysis, and with a few patients progressing to ESRD.
- Wenderfer SE, Gaut JP. Glomerular diseases in children. Adv Chronic Kidney Dis. 2017;24(6):364–371. doi:10.1053/j.ackd.2017.09.005 [CrossRef] PMID:29229167
- Kambham N. Postinfectious glomerulonephritis. Adv Anat Pathol. 2012;19(5):338–347. doi:10.1097/PAP.0b013e31826663d9 [CrossRef] PMID:22885383
- Honsová E. Postinfectious glomerulonephritis in adults: a hidden face of an old disease. Article in Czechk. Cesk Patol. 2016;52(1):61–64. PMID:27108558
- Hicks J, Mierau G, Wartchow E, Eldin K. Renal diseases associated with hematuria in children and adolescents: a brief tutorial. Ultrastruct Pathol. 2012;36(1):1–18. doi:10.3109/01913123.2011.620731 [CrossRef] PMID:22292732
- Simckes AM, Spitzer A. Poststreptococcal acute glomerulonephritis. Pediatr Rev. 1995;16(7):278–279. doi:10.1542/pir.16-7-278 [CrossRef] PMID:7624281
- Hunt EAK, Somers MJG. Infection-related glomerulonephritis. Pediatr Clin North Am. 2019;66(1):59–72. doi:10.1016/j.pcl.2018.08.005 [CrossRef] PMID:30454751
- Rawla P, Padala SA, Ludhwani D. Poststreptococcal Glomerulonephritis. StatPearls Publishing; 2019.
- Eison TM, Ault BH, Jones DP, Chesney RW, Wyatt RJ. Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis. Pediatr Nephrol. 2011;26(2):165–180. doi:10.1007/s00467-010-1554-6 [CrossRef] PMID:20652330
- Zaffanello M, Cataldi L, Franchini M, Fanos V. Evidence-based treatment limitations prevent any therapeutic recommendation for acute poststreptococcal glomerulonephritis in children. Med Sci Monit. 2010;16(4):RA79–RA84. PMID:20357732
- Rodríguez-Iturbe B, Batsford S. Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet. Kidney Int. 2007;71(11):1094–1104. doi:10.1038/sj.ki.5002169 [CrossRef] PMID:17342179
- Dick GF, Dick GH. Experimental scarlet fever. J Am Med Assoc. 1923;81(14):1166–1167. doi:10.1001/jama.1923.02650140010004 [CrossRef]
- Glassock RJ, Alvarado A, Prosek J, et al. Staphylococcus-related glomerulonephritis and poststreptococcal glomerulonephritis: why defining “post” is important in understanding and treating infection-related glomerulonephritis. Am J Kidney Dis. 2015;65(6):826–832. doi:10.1053/j.ajkd.2015.01.023 [CrossRef] PMID:25890425
- Rodriguez-Iturbe B, Musser JM. The current state of poststreptococcal glomerulonephritis. J Am Soc Nephrol. 2008;19(10):1855–1864. doi:10.1681/ASN.2008010092 [CrossRef] PMID:18667731
- Ilyas M, Tolaymat A. Changing epidemiology of acute post-streptococcal glomerulonephritis in Northeast Florida: a comparative study. Pediatr Nephrol. 2008;23(7):1101–1106. doi:10.1007/s00467-008-0778-1 [CrossRef] PMID:18373105
- Jackson SJ, Steer AC, Campbell H. Systematic review: estimation of global burden of non-suppurative sequelae of upper respiratory tract infection: rheumatic fever and post-streptococcal glomerulonephritis. Trop Med Int Health. 2011;16(1):2–11. doi:10.1111/j.1365-3156.2010.02670.x [CrossRef] PMID:21371205
- Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685–694. doi:10.1016/S1473-3099(05)70267-X [CrossRef] PMID:16253886
- Berríos X, Lagomarsino E, Solar E, Sandoval G, Guzmán B, Riedel I. Post-streptococcal acute glomerulonephritis in Chile—20 years of experience. Pediatr Nephrol. 2004;19(3):306–312. doi:10.1007/s00467-003-1340-9 [CrossRef] PMID:14689289
- Kanjanabuch T, Kittikowit W, Eiam-Ong S. An update on acute postinfectious glomerulonephritis worldwide. Nat Rev Nephrol. 2009;5(5):259–269. doi:10.1038/nrneph.2009.44 [CrossRef] PMID:19384327
- Vinen CS, Oliveira DBG. Acute glomerulonephritis. Postgrad Med J. 2003;79(930):206–213. doi:10.1136/pmj.79.930.206 [CrossRef] PMID:12743337
- Nasr SH, Markowitz GS, Stokes MB, Said SM, Valeri AM, D'Agati VD. Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature. Medicine (Baltimore). 2008;87(1):21–32. doi:10.1097/md.0b013e318161b0fc [CrossRef] PMID:18204367
- Yoshizawa N, Suzuki Y, Oshima S, et al. Asymptomatic acute poststreptococcal glomerulonephritis following upper respiratory tract infections caused by Group A streptococci. Clin Nephrol. 1996;46(5):296–301. PMID:8953117
- Sitprija V, Pipantanagul V, Boonpucknavig V, Boonpucknavig S. Glomerulitis in typhoid fever. Ann Intern Med. 1974;81(2):210–213. doi:10.7326/0003-4819-81-2-210 [CrossRef] PMID:4210565
- Rodríguez-Iturbe B, Rubio L, García R. Attack rate of poststreptococcal nephritis in families. A prospective study. Lancet. 1981;1(8217):401–403. doi:10.1016/S0140-6736(81)91788-8 [CrossRef] PMID:6110037
- Sarkissian A, Papazian M, Azatian G, Arikiants N, Babloyan A, Leumann E. An epidemic of acute postinfectious glomerulonephritis in Armenia. Arch Dis Child. 1997;77(4):342–344. doi:10.1136/adc.77.4.342 [CrossRef] PMID:9389241
- Serrano Viñuales I, Ruiz Del Olmo Izuzquiza I, Romero Salas Y, Montaner Ramón A, Justa Roldán ML. Postinfectious rapidly progressive glomerulonephritis in a pediatric patient. Article in Spanish. Arch Argent Pediatr. 2019;117(4):e363–e367. PMID:31339276
- Jellouli M, Maghraoui S, Abidi K, et al. Outcome of rapidly progressive glomerulonephritis post-streptococcal disease in children. Article in French. Nephrol Ther. 2015;11(6):487–491. doi:10.1016/j.nephro.2015.04.005 [CrossRef] PMID:26206771
- van de Voorde RG III, . Acute poststreptococcal glomerulonephritis: the most common acute glomerulonephritis. Pediatr Rev. 2015;36(1):3–12. doi:10.1542/pir.36-1-3 [CrossRef] PMID:25554106
- Ayoob RM, Schwaderer AL. Acute kidney injury and atypical features during pediatric poststreptococcal glomerulonephritis. Int J Nephrol. 2016;2016:5163065. doi:10.1155/2016/5163065 [CrossRef] PMID:27642522
- Cameron JS, Vick RM, Ogg CS, Seymour WM, Chantler C, Turner DR. Plasma C3 and C4 concentrations in management of glomerulonephritis. BMJ. 1973;3(5882):668–672. doi:10.1136/bmj.3.5882.668 [CrossRef] PMID:4200478
- Grøndahl C, Rittig S, Povlsen JV, Kamperis K. Protracted clinical course of postinfectious glomerulonephritis in a previously healthy child. Case Rep Nephrol Dial. 2016;6(1):70–75. doi:10.1159/000445678 [CrossRef] PMID:27226969
- Langlois DM, Andreae M. Group A streptococcal infections. Pediatr Rev. 2011;32(10):423–430. doi:10.1542/pir.32-10-423 [CrossRef]
- Lewy JE. Acute poststreptococcal glomerulonephritis. Pediatr Clin North Am. 1976;23(4):751–759. doi:10.1016/S0031-3955(16)33358-2 [CrossRef] PMID:136630
Laboratory Abnormalities Associated with Postinfectious Glomerulonephritis
||Smoky, dark brown, or yellow
||Positive blood, protein, leucocyte esterase
||White and red blood cells, red blood cell casts, dysmorphic red blood cells
||Normal or high
||Low C3, normal C4