Post-Streptococcal Glomerulonephritis

Introduction:
One of the oldest clinical observations in nephrology is the association of dark and scanty
urine after scarlet fever, which was first documented in the medical literature more than 200
years ago. This postscarlatinal disorder was termed acute glomerulonephritis and defined as
the “oedematous swelling with scanty, dark and at times totally suppressed urine”. Because it
was later discovered in the 1920s that scarlet fever was caused by an infection with b-
hemolytic streptococcus, the etiologically correct term was given; acute poststreptococcal
glomerulonephritis (PSGN) [1].
Glomerulonephritis (GN) is a group of diseases that injure the part of the kidney that filters
blood (called glomeruli). When the kidney is injured, it cannot get rid of wastes and extra
fluid in the body. If the illness continues, the kidneys may stop working completely,
resulting in kidney failure [1]. PSGN is the most common type of acute GN. In fact, PSGN is
interchangeably called Acute GN today.
 The incidence of acute post streptococcal glomerulonephritis (Acute PSGN) has decreased
worldwide, particularly in developed countries where it is now rare and is limited to adult
patients who have debilitating conditions, the annual burden of APSGN in developing
countries remains at a level of least 9 cases per 100,000 inhabitants. Acute PSGN is the most
studied form of acute postinfectious glomerulonephritis. These extensive studies provided us
with vital information about the pathogenesis of acute glomerulonephritis, not only APSGN,
but other forms of glomerulonephritis as well [2].
Infection is one of the most important triggers for the development of acute GN — bacterial,
viral and parasitic infections have all been implicated. However, the term ‘infection-
associated GN’ is typically reserved for GN triggered by bacterial infections, with
poststreptococcal glomerulonephritis (PSGN) being prototypical bacterial infection-
associated GN throughout most of the last century.
In this article, we will discuss the pathological features and pathogenesis of acute PSGN, and
its clinical significance.

Discussion:
Glomerulonephritides constitute a major cause of kidney injury and frequently require a
kidney biopsy for aetiological diagnosis. Among glomerulonephritides associated with
immune complexes, lupus nephritis, IgA nephropathy (IgAN), infection-associated
glomerulonephritis (GN) and membranous GN are the most commonly encountered forms.
Poststreptococcal glomerulonephritis (PSGN) is characterized by rapid deterioration of
kidney functions due to an inflammatory response (type III hypersensitivity reaction)
following streptococcal infection. This condition results from specific strains of group A
beta-hemolytic streptococci called nephrogenic streptococci. The disease affects the
glomeruli and the small blood vessels of the kidneys. PSGN most frequently presents in
children 1 to 2 weeks after a sore throat, or 6 weeks after a skin infection (impetigo) [3].

Aetiology:
Nephrogenic streptococci infection precedes PSGN, which initially affects skin or
oropharynx. More recently, PSGN is associated with skin infections (impetigo) more
frequently than throat infections (pharyngitis).[4]
Group A Streptococcus (GAS) is known to cause a wide spectrum of illnesses, including
superficial infections (such as pharyngitis and skin infections), invasive infections (such as
cellulitis, necrotizing fasciitis and pneumonia) and toxin-induced diseases. GAS has been
subtyped depending on the surface M protein and opacity factor, which are known to be
nephrogenic and can cause PSGN [5]. 
Poor hygiene, overcrowding, and low socioeconomic status are important risk factors for
streptococci outbreaks, and this explains the higher incidence of PSGN in impoverished
countries. Genetic factors are expected to predispose to the condition since almost 40% of
patients with PSGN gave a positive family history. There is no specific gene found to cause
PSGN [6].

Epidemiology:
Since 1980s, the incidence of APSGN has declined significantly worldwide. The reduction
of the incidence of APSGN is probably the result of the use of antibiotic prophylaxis and the
improvement of hygienic states.
However, PSGN is still the most common cause of kidney injury in children in the Middle
East, Africa, Australia, and worldwide. The annual incidence of new cases of PSGN in the
developing countries ranges from 8.5 to 28.5 per 100000 individuals [7]. Around 97% of
cases reported with PSGN live in underprivileged countries. The annual incidence of new
cases of PSGN worldwide is shown in figure (1).

The incidence of APSGN remains high in heavily populated tropical regions of the world
and in indigenous communities; among Aboriginal Australians, for example, the incidence is
disproportionately high (239 per 100,000 individuals per year). Higher incidence of PSGN in
developing countries is due to increased skin infections (pyoderma) [6].

Clinically manifestations of PSGN are more common in males than in females with a ratio of
2:1. However; the incidence of subclinical PSGN is almost equal in both sexes. The disease
most frequently affects children between the age of 3 and 12 (with the peak incidence
between 5 to 6 years), and seniors greater than 60 years old. Racial factors were not found to
play a role [8].
Fig. 1 | Global APSGN incidence. World map showing the incidence of acute post-streptococcal glomerulonephritis
(APSGN) per 100,000 person years. Data are based on biopsy studies and large population-based calculations
performed during the specified study periods. Satoskar, A. A., Parikh, S. V., & Nadasdy, T. (2020). Epidemiology,
pathogenesis, treatment and outcomes of infection-associated glomerulonephritis. Nature reviews. Nephrology,
16(1), 32–50.

Pathology:
Acute PSGN is immunological; representing a type III hypersensitivity reaction. The exact
mechanism by which PSGN occurs is not fully determined. Body response to nephrogenic
streptococcal infection is by forming immune complexes containing the streptococcal
antigen with a human antibody [9]. Some theories suggest that these immune complexes
become deposited in kidney glomeruli reaching through the circulation. Others think that the
condition results from an “in situ” formation of the antigen-antibody complex within the
kidney glomeruli. This “In situ immune complex formation” is either due to a reaction
against streptococci antigens deposited in the glomerular basement membrane or due to an
antibody reaction against glomerular components that cross-react with streptococcal antigen
due to molecular mimicry [6]. Possible pathogenic mechanisms are summed in figure (2).
The presence of immune complexes leads to the activation of the alternate complement
pathway causing infiltration of the leukocytes, and proliferation of the mesangial cells in the
glomerulus thus impairing the capillary perfusion and glomerular filtration rate (GFR).
Reduction in GFR can lead to renal failure (oliguria or anuria), acid-base imbalance,
electrolyte abnormalities, volume overload, edema, and hypertension [8]. 
Fig 2| Possible pathogenic mechanism of poststreptococcal glomerulonephritis. A) The putative nephritogenic
antigens SpeB or zymogen and GADPH are normally repelled in both their free and antibody-bound forms by the
negatively charged GBM. B) However, these antigens can interact with plasmin or plasminogen to activate
procollagenase and latent MMPs. C) The active enzymes (and the nephritogenic antigen itself, in the case of SpeB or
zymogen) degrade the GBM, and abolish its negative charge. D) The nephritogenic antigen and immune complexes
can then pass through the damaged GBM and form the characteristic 'hump'-like deposits under the podocyte
processes. E) Damage to the GBM also causes effacement of podocyte foot processes, which leads to loss of protein
in the urine. Abbreviations: GADPH, streptococcal glyceraldehyde phosphate dehydrogenase; GBM, glomerular
basement membrane; MMP, matrix metalloproteinase; SpeB, streptococcal cationic proteinase exotoxin B.
Kanjanabuch, T., Kittikowit, W. & Eiam-Ong, S. An update on acute postinfectious glomerulonephritis worldwide. Nat
Rev Nephrol 5, 259–269 (2009).

Light microscope picture:

The majority of cases (72%) show diffuse proliferative and exudative glomerulonephritis
(GN). The glomeruli in these cases are often enlarged and show global endocapillary
hypercellularity with variable and often large numbers of neutrophils (Figure 3).
After the first 1-2 weeks of the disease, there is a progressive decline in cellularity, initially
from the loss of the neutrophils, which results in a combined mesangial and endocapillary
proliferative GN. Over the ensuing weeks, endocapillary hypercellularity is lost, resulting in
a predominantly mesangial proliferative GN that is visible by light microscopy [8].
Fig 3: Acute PSGN with severely proliferative and exudative GN. The glomerulus is enlarged and markedly
hypercellular with a large number of neutrophils. (Hx&E x200). Rodriguez-Iturbe B, Haas M. Post-Streptococcal
Glomerulonephritis. Streptococcus pyogenes : Basic Biology to Clinical Manifestations.

Electron Microscopy
The characteristic ultrastructural finding of acute poststreptococcal GN is the presence of
large subepithelial electron-dense deposits with a “hump-like” appearance. The number of
these deposits varies considerably between different cases; they can be quite segmental or
rather numerous, although not so much so as to suggest a membranous nephropathy. The
size of the subepithelial “humps” may also vary considerably within any given glomerulus
[10]. In early post-infectious lesions, these deposits are distributed at various points along
glomerular capillaries, although even at this stage, there is some tendency for the greatest
number of deposits to be concentrated at or near the glomerular basement membrane
reflection over mesangial areas (Figure 4).
 1. Fig 7. Large, subepithelial, hump-like scattered deposits in acute postinfectious glomerulonephritis. The
deposits are irregularly spaced and frequently mottled (TEM x6800). Atlas of Renal Pathology. American
Journal of Kidney Diseases, Volume 31, Issue 5.

Prognosis:
The prognosis of acute PSGN is excellent for children. In contrast, elderly patients who
develop acute PSGN usually present with debilitating conditions (malnutrition, alcoholism,
diabetes, or chronic illness) and have a high incidence of azotemia (60%), congestive heart
failure (40%), and proteinuria in the nephrotic range (20%). Death may occur in as many as
20 to 25% of these patients [11].

Clinical features & treatment:

Approximately 50% of children with PSGN are asymptomatic and are discovered
accidentally during routine urine analysis. The classic triad of glomerulonephritis includes
hematuria, edema, and hypertension. Typically, patients give a history of a recent
streptococcal infection such as pharyngitis, tonsillitis, or impetigo. However; some patients
develop PSGN without experiencing symptoms of respiratory tract infection or pyoderma,
which can be a diagnostic challenge [12].
The most common presenting symptom is gross hematuria as it occurs in 30 to 50% of cases
with acute PSGN; patients often describe their urine as smoky, tea-colored, cola-colored, or
rusty. Edema is seen in about 65-90% of the cases. Puffiness of the eyelids (periorbital
edema) is typical for the nephritic syndrome.
PSGN is a self-limiting condition in most cases, and thus only symptomatic treatment is
needed. Supportive treatment aims at controlling the complications of volume overload such
as hypertension and edema, which are prominent during the acute phase of the disease [6].

Reference:
1. Rodriguez-Iturbe B, Musser JM. The current state of poststreptococcal glomerulonephritis. J Am Soc
Nephrol. 2008;19(10):1855‐1864.
2. Earle DP. Poststreptococcal acute glomerulonephritis. Hosp Pract. 1985;20(7):84E–J, O–P (U
passim. Epub 15 July 1985).
3. Blyth CC, Robertson PW, Rosenberg AR. Post-streptococcal glomerulonephritis in Sydney: a 16-
year retrospective review. J Paediatr Child Health. 2007 Jun;43(6):446-50.
4. Hunt EAK, Somers MJG. Infection-Related Glomerulonephritis. Pediatr. Clin. North Am. 2019
Feb;66(1):59-72.
5. Carapetis, J. R., Steer, A. C., Mulholland, E. K. & Weber, M. The global burden of group A
streptococcal diseases. Lancet Infect. Dis. 5, 685–694 (2005).
6. VanDeVoorde RG. Acute poststreptococcal glomerulonephritis: the most common acute
glomerulonephritis. Pediatr Rev. 2015 Jan;36(1):3-12; quiz 13.
7. Rodriguez-Iturbe B, Musser JM. The current state of poststreptococcal glomerulonephritis. J. Am.
Soc. Nephrol. 2008 Oct;19(10):1855-64.
8. Rawla P, Padala SA, Ludhwani D. Poststreptococcal Glomerulonephritis. [Updated 2020 May 30].
In: StatPearls.
9. Balasubramanian R, Marks SD. Post-infectious glomerulonephritis. Paediatr Int Child Health. 2017
Nov;37(4):240-247.
10. Nasr S. H., Markowitz G. S., Stokes M. B., Said S. M., Valeri A. M., D'Agati V. D. Acute
postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the
literature. Medicine (Baltimore). 2008;87(1):21–32.
11. Washio M, Oh Y, Okuda S, Yanase T, Miishima C, Fujimi S, Ohchi N, Nanishi F, Onoyama K,
Fujishima M: Clinicopathological study of poststreptococcal glomerulonephritis in the elderly. Clin
Nephrol 41: 265–270, 1994.
12. Pais PJ, Kump T, Greenbaum LA. Delay in diagnosis in poststreptococcal glomerulonephritis. J.
Pediatr. 2008 Oct;153(4):560-4.