CHAPTER I

INTRODUCTION

BACKGROUND
Glomerulonephritis is a term used for kidney diseases with an inflammation and

proliferation of glomerular cell. The inflammation happens because of an immunologic

process that makes pathologic abnormality of glomerulus. Hitsologically there are
generalized

glomerular

inflammations

in

acute

glomerulonephritis

Acute

glomerulonephritis usually recognize based on clinical appearance such as gross hematuria,

fluid overload that manifested as edema and hypertension, and some finding of insufficiency
kidney function like increasing of BUN and creatinine.
Streptococcus beta hemolyticus group A infection in children is the first leading cause of
acute glomerulonephritis. Acute glomerulonephtitis post streptococcus infection still often
found and the main cause of non supurative kidney lesions in children on developing
country. Children with PSAGN usually has history of pharyngitis or skin infection that
caused by streptococcus. Post streptococcal acute glomerulonephritis is an classical example
of nephritic syndrome that marked by sudden gross hematuria, edema, hypertension, and
renal insufficiency.
PSAGN can happened either sproradically or epidemically. The risk of nephritis 5 %
come from streptococcus beta hemolyticus group a infection that infect throat and 25 %
affect skin which called pioderm. Eventhough the epidemic of nephritis has associated with
throat and skin infection, these disease generally sporadic. Usually this disease happened in
low socioeconomy group, associated with low hygiene and remote places .
Diagnosis established by recognizing

the history of ilness by anamnesis, physical

examination and laboratory assesment. Previous streptococcus infection can confirm

diagnosiss. Clinical diagnosis of PSAGN on children is shown by nephritic syndrome,
previous streptococcus infection and decreased C3 level.
Fortunately, most cases of AGN in children are either self-limited or amenable to therapy
although there may be devastating complications of the illness during the acute phase. Less
commonly, what begins as an apparent AGN may presage the development of a chronic
process, which ultimately may progress into irreversible end-stage renal disease (ESRD).

CHAPTER II
LITERATURE REVIEW

1. ANATOMY OF KIDNEYS
1.1 Anatomy of the Kidneys
The paired kidneys are reddish, kidney-bean-shaped organs located on the posterior
wall of abdomen, outside the peritoneal cavity. The kidneys are located between the levels of
last thoracic and third lumbar vertebrae, a position where they are partially protected by
eleventh and twelfth pair of ribs .The medial side of each kidney contains an intended region
called the hilum, through which the ureter emerges from the kidney along with blood vessels,
lymphatic vessels, and nerves. The kidney is surrounded by a tough, fibrous capsule that
protects its delicate inner structures.

If the kidney is bisected from top to bottom, the two major regions that can be
visualized are the outercortex and the inner region referred to as the medulla.The medulla is
divided into multiple cone-shaped masses of tissue called renal pyramids. The base of each
pyramid originates at the border between the cortex and medulla and terminates in the
papilla, which projects into the space of the renal pelvis, a funnel-shaped continuation of the
upper end of the ureter. The outer border of the pelvis is divided into open-ended pouches
called major calyces that extend downward and divide into minor calyces, which collect urine
from the tubules of each papilla. The walls of the calyces, pelvis, and ureter contain
contractile elements that propel the urine toward the bladder, where urine is stored until it is
emptied by micturition.

Each kidney in the human contains about 1 million nephrons, each capable of forming
urine. The kidney cannot regenerate new nephrons.Therefore, with renal injury, disease, or
normal aging, there is a gradual decrease in nephron number
1.2 Blood Supply of the Kidneys.

Blood
kidneys

flow

to

the

two

is

normally about 22

percent of the

cardiac output, or

1100

The

ml/min.

renal

artery

enters the kidney

through the hilum

and

branches

then

progressively to

form the interlobar

arteries, arcuate

arteries,

interlobular

arteries (also called

radial

arteries)

and

arterioles, which

lead

afferent
to

the

glomerular capillaries, where large amounts of fluid and solutes (except the plasma proteins)
are filtered to begin urine formation. The distal ends of the capillaries of each glomerulus
coalesce to form the efferent arteriole, which leads to a second capillary network, the
peritubular capillaries, that surrounds them renal tubules. The renal circulation is unique in
that it has two capillary beds, the glomerular and peritubular capillaries, which are arranged
in series and separated by the efferent arterioles, which help regulate the hydrostatic pressure
in both sets of capillaries. High hydrostatic pressure in the glomerular capillaries (about 60
mm Hg) causes rapid fluid filtration, whereas a much lower hydrostatic pressure in the
peritubular capillaries (about 13 mm Hg) permits rapid fluid reabsorption. By adjusting the
resistance of the afferent and efferent arterioles, the kidneys can regulate the hydrostatic
pressure in both the glomerular and the peritubular capillaries, thereby changing the rate of
glomerular filtration, tubular reabsorption, or both in response to body homeostatic demands.
The peritubular capillaries empty into the vessels of the venous system, which run parallel to
the arteriolar vessels and progressively form the interlobular vein, arcuate vein, interlobar
vein, and renal vein, which leaves the kidney beside the renal artery and ureter.

1.3 The Nephron.

Nephrons are the functional units of the kidneys. Each nephron contains (1) a tuft of
glomerular capillaries called the glomerulus, through which large amounts of fluid are filtered
from the blood, and (2) a long tubule in which the filtered fluid is converted into urine on its
way to the pelvis of the kidney. The two components of a renal corpuscle are the glomerulus
and the glomerular (Bowmans) capsule.

Blood plasma is filtered in glomerular capsule,

and then the filtered fluid passes into the renal tubule, which has three main section. In order
that fluid passes through them, renal tubule consist of a (1) proximal convoluted tubule, (2)
loop of henle (nephron loop) and (3) distal convoluted tubule. Proximal denotes the part of
the tubule attached to glomerular capsule, and distal denotes the part that is further away.
Convuluted means the tubule is tightly coiled rather than straight. The renal corpuscle and
both convoluted tubules lie within the renal cortex, the loop of henle extends into the renal
medulla, makes a hairpin turn, and then returns to the renal cortex.
The distal convuluted tubules of several nephronss empty into a single collecting duct.
Collecting ducts then unite and converge into several hundred large papillary ducts, which
drain into minor calyces. The collecting ducts and papillary ducts extend from the renal
cortex through the renal medulla to the renal pelvis.
In a nephron, the loop of Henle connects the proximal and distal convoluted tubules.
The first part of the loop of Henle dips into medulla, where it is called the descending limb of
the loop of Henle. It then makes that hairpin turn and returns to renal cortex as the ascending
limb of the loop of Henle. About 80-85 % of the nephrons are cortical nephrons. Their renal
corpuscles lie in the outer portion of the renal cortex, and they have short loops of henle that
lie mainly inthe cortex and penetrate only into outer region of renal medulla. The short loops
of Henle receive their blood supply from peritubular capillaries that arise from efferent
arterioles. The other 15-20% of nephrons are juxtamedullary nephrons. Their renal corpuscle
lies deep in the cortex, close to medulla, and they have a long loop of henle that extends into
the deepest region of the medulla. Long loops of Henle receive their blood supply from
peritubular capillaries and from the vasa recta that arise from efferent arterioles. Loop of
Henle of juxtamedullary nephrons consist of two portion , a thin ascending limb followed by
a thick ascending limb.

2. PHYSIOLOGY
Most people are familiar with one important function of the kidneys
to rid the body of waste materials that are either ingested or
produced by metabolism. A second function that is especially critical is
to control the volume and composition of the body fluids. For water and
virtually all electrolytes in the body, the balance between intake (due
to ingestion or metabolic production) and output (due to excretion or
metabolic consumption) is maintained in large part by the kidneys. This
regulatory function of the kidneys maintains the stable environment of
the cells necessary for them to perform their various activities. The
kidneys perform their most important functions by filtering the plasma
and removing substances from the filtrate at variable rates, depending
on the needs of the body. Ultimately, the kidneys clear unwanted
substances fromthe filtrate (and therefore from the blood) by excreting
them in the urine whilereturning substances that are needed back to
the blood.
The Kidney do major work of the urinary system. The other parts of
the system mainly passageaways and storage areas. Function of kidney
include :

Regulation of blood ionic composition. The kidneys help

regulate thwe blood levels of several ions, most important
sodium ions, pottasium ions, calcium ions, chloride ions,
phosphate ions.

 Regulation of blood pH. The kidneys excrete a variable amount

of hydrogen ions(H+) into the urine and conserve bicarbonate
ions (HCO3-), which are important buffer of H+ in the blood.
Regulation of blood volume. The kidney adjust blood volume
by conserving or eliminatingwater in the urine. An increase in
blood volume increasesblood pressure, a decrease in blood
volume decreases blood pressure.
Regulation of blood pressure. The kidneys also help regulate
blood pressure by secreting enzyme renin, which activates
RAA pathway. Increased renin causes increase in blood
pressure.
Maintenence of blood osmolarity. By separately regulating loss
of water and loss of solutes in the urine, the kidneys maintain
a relatively constant blood osmolarity.
Production of hormones. The kidney produce two hormones.
Calcitriol, active form of vitamin D, helps regulate calcium
homeostasis. And erythropoietin stimulates the production of
red blood cells.
Regulation of blood glucose level. Kidney can use amino acid
glutamine in gluconeogenesis, the synthesis of new glucose
molecules. They can then release glucose into the blood to
help maintain a normal blood glucose level.
Excretion of wastes and foreign substances. By forming urine,
kidneys help excrete waste.
2.1 Overview of Renal Physiology
To produce urin, nephrons, collecting ducts
perform three basic process :
1. Glomerular filtration : in the first step of urine
production, water and most solutes in blood
plasma move across the wall of glomelural
capillaries into the glomerular capsule then into
renal tubule.
2. Tubular reabsorbtion. As filteres fluid flows along
the renal tubule and through the collecting duct,
6

tubule cells reabsorb about 99 % of the filtered water and many useful solutes. The
water and solutes return to the blood as it flows through peritubular capillaries and
vasa recta. Reabsorption refers to the return of substances to the blood stream. The
term absorption, by contrast means entry of new substances into the body.
3. Tubular secretion. As fluid flows along the renal tubule and through the collecting
duct, the tubule and duct cells secrete ather materials, such as wastes, drugs,and
excess ions, into the fluid. Tubular secretion removes a substance from the blood. In
other instance of secretion-for instance, secretion of hormones- cells release
substances into interstitial fluid and blood.
The rates at which different substances are excreted in the urine represent the sum of
three renal processes, (1) glomerular filtration, (2) reabsorption of substances from the
renal tubules into the blood, and (3) secretion of substances from the blood into the renal
tubules. Expressed mathematically,
Urinary excretion rate = Filtration rate- Reabsorption rate + Secretion rate
Urine formation begins when a large amount of fluid that is virtually free of protein is
filtered from the glomerular capillaries into Bowmans capsule. Most substances in the
plasma, except for proteins, are freely filtered, so that their concentration in the
glomerular filtrate in Bowmans capsule is almost the same as in the plasma. As filtered
fluid leaves Bowmans capsule and passes through the tubules, it is modified by
reabsorption of water and specific solutes back into the blood or by secretion of other
substances from the peritubular capillaries into the tubules.

The substance shown in panel A is freely filtered by the glomerular capillaries but is
neither reabsorbed nor secreted. Therefore, its excretion rate is equal to the rate at which it
was filtered. Certain waste products in the body, such as creatinine, are handled by the
kidneys in this manner, allowing excretion of essentially all that is filtered. In panel B, the
substance is freely filtered but is also partly reabsorbed from the tubules back into the blood.
Therefore, the rate of urinary excretion is less than the rate of filtration at the glomerular
capillaries. In this case, the excretion rate is calculated as the filtration rate minus the
reabsorption rate. This is typical for many of the electrolytes of the body. In panel C, the
substance is freely filtered at the glomerular capillaries but is not excreted into the urine
because all the filtered substance is reabsorbed from the tubules back into the blood.
This pattern occurs for some of the nutritional substances in the blood, such as amino
acids and glucose, allowing them to be conserved in the body fluids. The substance in panel
D is freely filtered at the glomerular capillaries and is not reabsorbed, but additional
quantities of this substance are secreted from the peritubular capillary blood into the renal
tubules. This pattern often occurs for organic acids and bases, permitting them to be rapidly
cleared from the blood and excreted in large amounts in the urine.The excretion rate in this
case is calculated as filtration rate plus tubular secretion rate.
For each substance in the plasma, a particular combination of filtration, reabsorption, and
secretion occurs. The rate at which the substance is excreted in the urine depends on the
relative rates of these three basic renal processes.
2.2 Glomerular Fltration
Urine formation begins with filtration of large amounts of fluid through glomerular
capillaries into Bowmans capsule. Like most capillaties, the glomerular capillaries are
relatively impermeable to proteins, so that the filtered fluid is essentially protein-free and
devoid of cellular elements, including red blood cells.
The concentrations of other constituents of the glomerular filtrate, including most
salts and organic molecules, are similar to generalization include a few molecular weight
substances, such as calcium and fatty acids, that are not freely filtered because they partially
bound to the plasma protein. Almost one half of the plasma calcium and most of plasma fatty
acids are vound to proteins, and these bound portions are not filtered through the glomerular
capillaries.
The fluid that enters the capsular space is called glomerular filtrate. The fraction of
blood plasma in the afferent arterioles of the kidneys that becomes glomerular filtrate is the
8

filtration fraction. Although a filtration fraction of 0.16-0.20 is typical, the value varies
considerably in both health and disease. On average the daily volume of glomerular filtrate in
adults is 150 liters in females and 180 liters in males. More than 99% of glomerular filtrate
return to the blood stream via tubular reabsorbtion, so only 1-2 liters is axcreted in to urine.
The Filtration Membrane

The glomerular capillaries and the podocytes together encircle the capillaries, form a
leaky barrier known as the filtration membrane. The sandwichlike assembly permits filtration
of most plasma proteins, blood cells, and platelets. Substances filtered from the blood cross
three filtration barriers : (1) the glomerular endothelial cells (2) a basement membrane, and
(3) a filtration slit formes by podocytes.
(1) Glomerular endothelial cells are quite leaky because the have large fenestrations that
measure 0.07-0.1m in diameter. This size permits all solutes in blood plasma to exit
glomerular capillaries but prevents filtartion of blood cells and platelets. Located
among the glomerular capillaries and in the cleft between afferent and efferent
arterioles are mesangial cells. These contractile cells help regulate glomerular
filtration. The capillary endothelium is perforated by thousands of small holes called
fenestrate. Although the fenestration are relatively large, endothelial cells are richly
endowed with fixed negative charges that hinder the passage of plasma proteins.
(2) Surrounding the endothelium is the basement membrane, a layer of acellular material
the endothelium and the podocytes, which consist of meshwork of collagen and
proteoglycan fibrillae that have large spaces through which large amountsof water and
small solutes can filter. The basement membrane effectively prevents filtration of
plasma proteins, in part because of strong negative electrical charges associated with

the proteoglycan. Proteglycan in glycoprotein matrix has negative charge that prevent
filtration of negatively charged plasma protein.
(3) Extending from each podocyte are thousands of footlike processes termed pedicles
that encircle the outer surface of the capillaries. The spaces between pedicles are the
filtration slits. The foot processes are separated by gaps called slit pores through
which the glomerular filtrate moves. A thin membrane, the slit membrane, extends
across each filtration slit; permits the passage of molecules such as water, glucose,
vitamin, amino acids, very small proteins, ammonia, urea, and ions. Filtration slit
bridged by a thin slit diaphragm composed in large part of nephrin.
Glomeruli may be injured by diverse mechanisms in the course of number of systemic
disease, immunologically mediated disease, and some purely hereditaray conditions.
The principle of filtration is the use of pressure to force fluids and solutes through a
membrane- is the same in glomerular capillaries elsewhere in the body. However the volume
of fluid filtered by renal corpuscle is much larger than in other capillaries of the body for
three reasons :
1. Glomerular capillaries present a large surface area for filtration because they are
long and extensive. The mesangial cells regulate how much this surface area is
available for filtration. When mesangial cells are relaxed surface area is maximal,
and glomerular filtration is very high. Contractions of mesangial cells reduces the
available surface area, and glomerular filtration decreases.
2. The filtration membrane is thin and porous. Despite having a several layers, the
thickness of filtration membrane is only 0.1 mm. Glomerular capillaries also are
about 50 times leakier than capillaries in most other tissues, mainly because of
their large fenestration.
3. Glomerular capillary blood pressure is high. Because the efferent arteriole is
smaller in diameter than the afferent arteriole, resistance to the outflow of blood
from the glomerulus is high. As a result, blood pressure in glomerular capillaries
is considerably higher than in cappilaries elsewhere in the body.
2.3 Determinants of the GFR
The GFR is determined by (1) the sum of the hydrostatic and colloid osmotic forces
across the glomerular membrane, which gives the net filtration pressure, and (2) the
glomerular capillary filtration coefficient, Kf. Expressed mathematically, the GFR equals the
10

product of Kf and the net filtration pressure:

GFR = Kf \ Net filtration pressure
The net filtration pressure represents the sum of the hydrostatic and colloid osmotic
forces that either favor or oppose filtration across the glomerular capillaries. These forces
include (1) hydrostatic pressure inside the glomerular capillaries (glomerular hydrostatic
pressure, PG), which promotes filtration; (2) the hydrostatic pressure in Bowmans capsule
(PB) outside the capillaries, which opposes filtration; (3) the colloid osmotic pressure of the
glomerular capillary plasma proteins (pG), which opposes filtration; and (4) the colloid
osmotic pressure of the proteins in Bowmans capsule (pB), which promotes filtration.
(Under normal conditions, the concentration of protein in the glomerular filtrate is so low that
the colloid osmotic pressure of the Bowmans capsule fluid is considered to be zero.)
The GFR can therefore be expressed as GFR = Kf \ (PG PB pG + pB)

Net filtration pressure (NFP), the total pressure that promotes filtration, is determined as
follows : Net filtration pressure = 60 18 32 = +10 mm Hg. Thus, a pressure of only 10
mmHg causes of normal amount of blood plasma to filter from the glomerulus into capsular
space.
2.4 Regulation of Glomerular Filtration Rate
The determinants of GFR that are most variable and subject to physiologic control
include the glomerular hydrostatic pressure and the glomerular capillary colloid osmotic
pressure. These variables, in turn, are influenced by the sympathetic nervous system,
11

hormones and autacoids (vasoactive substances that are released in the kidneys and act
locally), and other feedback controls that are intrinsic to the kidneys.
a) Sympathetic Nervous System Activation Decreases GFR
Essentially all the blood vessels of the kidneys, including the afferent and the efferent
arterioles, are richly innervated by sympathetic nerve fibers. Strong activation of the renal
sympathetic nerves can constrict the renal arterioles and decrease renal blood flow and GFR.
Moderate or mild sympathetic stimulation has little influence on renal blood flow and GFR.
For example, reflex activation of the sympathetic nervous system resulting from moderate
decreases in pressure at the carotid sinus baroreceptors or cardiopulmonary receptors has
little influence on renal blood flow or GFR.
The renal sympathetic nerves seem to be most important in reducing GFR during
severe, acute disturbances lasting for a few minutes to a few hours, such as those elicited by
the defense reaction, brain ischemia, or severe hemorrhage. In the healthy resting person,
sympathetic tone appears to have little influence on renal blood flow.
b) Hormonal and Autacoid Control of Renal Circulation
There are several hormones and autacoids that can influence GFR and renal blood
flow.

Norepinephrine, Epinephrine, and Endothelin Constrict Renal Blood Vessels and

Decrease GFR.
Hormones that constrict afferent and efferent arterioles, causing reductions in GFR and renal
blood flow, include norepinephrine and epinephrine released from the adrenal medulla. In
general, blood levels of these hormones parallel the activity of the sympathetic nervous
system; thus, norepinephrine and epinephrine have little influence on renal hemodynamics
except under extreme conditions, such as severe hemorrhage. Another vasoconstrictor,
12

endothelin, is a peptide that can be released by damaged vascular endothelial cells of the
kidneys as well as by other tissues. The physiologic role of this autacoid is not completely
understood. However, endothelin may contribute to hemostasis (minimizing blood loss) when
a blood vessel is severed, which damages the endothelium and releases this powerful
vasoconstrictor. Plasma endothelin levels also are increased in certain disease states
associated with vascular injury, such as toxemia of pregnancy, acute renal failure, and chronic
uremia, and may contribute to renal vasoconstriction and decreased GFR in some of these
pathophysiologic conditions.
Angiotensin II Constricts Efferent Arterioles.
A powerful renal vasoconstrictor, angiotensin II, can be considered a circulating hormone as
well as a locally produced autacoid because it is formed in the kidneys as well as in the
systemic circulation. Because angiotensin II preferentially constricts efferent arterioles,
increased angiotensin II levels raise glomerular hydrostatic pressure while reducing renal
blood flow. It should be kept in mind that increased angiotensin II formation usually occurs in
circumstances associated with decreased arterial pressure or volume depletion, which tend to
decrease GFR. In these circumstances, the increased level of angiotensin II, by constricting
efferent arterioles, helps prevent decreases in glomerular hydrostatic pressure and GFR; at the
same time, though, the reduction in renal blood flow caused by efferent arteriolar constriction
contributes to decreased flow through the peritubular capillaries, which in turn increases
reabsorption of sodium and water. Thus, increased angiotensin II levels that occur with a lowsodium diet or volume depletion help preserve GFR and maintain normal excretion of
metabolic waste products such as urea and creatinine that depend on glomerular filtration for
their excretion; at the same time, the angiotensin IIinduced constriction of efferent arterioles
increases tubular reabsorption of sodium and water, which helps restore blood volume and
blood pressure.
Endothelial-Derived Nitric Oxide Decreases Renal Vascular Resistance and Increases
GFR.
An autacoid that decreases renal vascular resistance and is released by the vascular
endothelium throughout the body is endothelial- derived nitric oxide. A basal level of nitric
oxide production appears to be important for maintaining vasodilation of the kidneys. This
allows the kidneys to excrete normal amounts of sodium and water. Therefore, administration
of drugs that inhibit this normal formation of nitric oxide increases renal vascular resistance
and decreases GFR and urinary sodium excretion, eventually causing high blood pressure. In

13

some hypertensive patients, impaired nitric oxide production could be the cause of increased
renal vasoconstriction and increased blood pressure.
Prostaglandins and Bradykinin Tend to Increase GFR.
Hormones and autacoids that cause vasodilation and increased renal blood flow and GFR
include the prostaglandins (PGE2 and PGI2) and bradykinin. Although these vasodilators do
not appear to be of major importance in regulating renal blood flow or GFR in normal
conditions, they may dampen the renal vasoconstrictor effects of the sympathetic nerves or
angiotensin II, especially their effects to constrict the afferent arterioles. By opposing
vasoconstriction of afferent arterioles, the prostaglandins may help prevent excessive
reductions in GFR and renal blood flow.
3. ACUTE GLOMERULONEPHRITIS
3.1 DEFINITION
Glomerulonephritis
Glomerulonephritis is an inflammatory process affecting primarily the part of kidney
that filters blood called glomerulus, with infiltration and proliferation of acute inflammatory
cells. The inflammation is immunologically mediated with immune deposits in the
glomerulus. Onset of symptom is usually acute.
There can be both acute glomerulonephritis and chronic glomerulonephritis. The acute
form develops suddenly in response to an infection such as streptococcus infection. The
chronic form of glomerulonephritis can develop over several years with no or very few
symptoms. This can cause irreversible damage to kidneys and lead to complete kidney
failure.
Acute Glomerulonephritis
Acute glomerulonephritis (GN) comprises a specific set of renal diseases in which an
immunologic mechanism triggers inflammation and proliferation of glomerular tissue that
can result in damage to the basement membrane, mesangium, or capillary endothelium. Acute
poststreptococcal glomerulonephritis (PSGN) is the archetype of acute GN. Acute nephritic
syndrome is the most serious and potentially devastating form of the various renal
syndromes.
Acute nephritic syndrome is classical syndrome that occur in GNAPS, but such
patient may have rapidly progressive GN (RPGN) or nephrotic syndrome. PSGN that is
characterized pathologically by crescent forming from the cells of Bowmans capsul. If the
process progresses, the crescent will irreversibly destroy the glomerular tuft and end stage
14

renal disease (ESRD) may occur within weeks after onset of this process. Acute nephritic
syndrome

is the most serious and potentially devastating form of the various renal

syndromes.
3.2 EPIDEMIOLOGY
In

developing

countries

APSGN,

usually

occurs

in

children,

predominately males and often as epidemics. APSGN usually occurs as

sporadic cases, but epidemic outbreaks have taken place in communities
with densely populated dwellings that have poor hygienic conditions with
a high incidence of malnutrition, anemia, and intestinal parasites. In
certain regions, epidemics may occur in cyclical outbreaks every 5-7 years
for unknown reasons.
Sporadic APSGN

following

upper

respiratory

tract

infection,

pharyngitis, and tonsillitis is more common in winter and spring in

temperate areas, whereas skin infections are commonly found to precede
APSGN in the more tropical and subtropical areas, with a peak incidence
during summer and autumn.
Postinfectious GN can occur at any age but usually develops in
children. Most cases occur in patients aged 5-15 years; only 10% occur in
patients older than 40 years. Outbreaks of PSGN are common in children
aged 6-10 years. Acute nephritis may occur at any age, including infancy.
Acute GN predominantly affects males (2:1 male-to-female ratio).
Postinfectious GN has no predilection for any racial or ethnic group. A
higher incidence (related to poor hygiene) may be observed in some
socioeconomic group.

3.3 ETIOLOGY
The causal factors that underlie acute GN can be broadly divided into infectious and
noninfectious groups.
1. Infectious
The most common infectious cause of acute GN is infection by Streptococcus species (ie,
group A, beta-hemolytic). Two types have been described, involving different serotypes:
Serotype 12 - Poststreptococcal nephritis due to an upper respiratory infection,
occurring primarily in the winter months
15

Serotype 49 - Poststreptococcal nephritis due to a skin infection, usually observed in

the summer and fall and more prevalent in southern regions of the United States

PSGN usually develops 1-3 weeks after acute infection with specific nephritogenic strains
of group A beta-hemolytic streptococcus. The incidence of GN is approximately 5-10% in
persons with pharyngitis and 25% in those with skin infections.
Nonstreptococcal postinfectious GN may also result from infection by other bacteria,
viruses, parasites, or fungi. Bacteria besides group A streptococci that can cause acute GN
include diplococci, other streptococci, staphylococci, and mycobacteria. Salmonella
typhosa, Brucella suis, Treponema pallidum, Corynebacterium bovis, and actinobacilli
have also been identified.
Cytomegalovirus (CMV), coxsackievirus, Epstein-Barr virus (EBV), hepatitis B virus
(HBV),rubella, rickettsiae (as in scrub typhus), and mumps virus are accepted as viral
causes only if it can be documented that a recent group A beta-hemolytic streptococcal
infection did not occur. Acute GN has been documented as a rare complication of
hepatitis A.
2. Noninfectious
Noninfectious causes of acute GN may be divided into primary renal
diseases, systemic diseases, and miscellaneous conditions or agents.
Primary renal diseases that can cause acute GN include the following:

Membranoproliferative glomerulonephritis ( MPGN) - This is due to the expansion

and proliferation of mesangial cells as a consequence of the deposition of
complements. Type I refers to the granular deposition of C3; type II refers to an
irregular process.

Berger disease (IgG-immunoglobulin A [IgA] nephropathy) - This causes GN as a

result of diffuse mesangial deposition of IgA and IgG.

Pure mesangial proliferative GN

Idiopathic rapidly progressive glomerulonephritis - This form of GN is characterized

by the presence of glomerular crescents. Three types have been distinguished: Type I

16

is an antiglomerular basement membrane disease, type II is mediated by immune

complexes, and type III is identified by antineutrophil cytoplasmic antibody (ANCA).
Multisystem systemic diseases that can cause acute GN include the
following:

Vasculitis (eg, granulomatosis with polyangiitis) - This causes glomerulonephritis that

combines upper and lower granulomatous nephritides).

Collagen-vascular diseases (eg, systemic lupus erythematosus [SLE]) This causes

glomerulonephritis through renal deposition of immune complexes).

Hypersensitivity vasculitis This encompasses a heterogeneous group of disorders

featuring small vessel and skin disease.

Cryoglobulinemia This causes abnormal quantities of cryoglobulin in plasma that
result in repeated episodes of widespread purpura and cutaneous ulcerations upon

crystallization.
Polyarteritis nodosa - This causes nephritis from a vasculitis involving the renal

arteries.
Henoch-Schnlein purpura This causes a generalized vasculitis resulting in

glomerulonephritis.
Goodpasture syndrome This causes circulating antibodies to type IV collagen and

often results in a rapidly progressive oliguric renal failure (weeks to months).

Miscellaneous noninfectious causes of acute GN include the following:

Guillain-Barr syndrome

Irradiation of Wilms tumor

Diphtheria-pertussis-tetanus (DPT) vaccine

Serum sickness

Epidermal growth factor receptor activation, and possibly its inhibition by cetuximab.

3.4 PATHOLOGY
Glomerular lesions in acute GN are the result of glomerular deposition or in situ
formation of immune complexes. On gross appearance the kidneys appear symmetrically
enlarged. Histopathologic changes include swelling of the glomerular tufts and infiltration
17

with polymorphonucleocytes. Glomeruli appear enlarged and relatively bloodless and show
diffuse mesangial cell proliferation, with an increase in mesangial matrix. Polimorphonuclear
leukocyte infiltration is common in glomeruli during the early stage of the disease. Crescent
and interstitial inflammation may be seen in severe cases, but these changes are not specific
for post streptococcal GN. Immunofluorescence microscopy reveals a pattern of lumpybumpy deposits of immonuglobulin and complement on the glomerular basement membrane
and in the mesangium. On electron microscopy, electron-dense deposits, or humps, are
observed on the epithelial side of the GBM.
The glomerulus may be injured by several mechanisms, but it has only a limited
number of histopathologic responses; different disease states can produce similar microscopic
changes.Proliferation of glomerular cells occurs in most forms of glomerulonephritis and may
be generalized, involving all glomeruli, or focal, involving only some glomeruli and sparing
others. Within a single glomerulus, proliferation may be diffuse, involving all parts of the
glomerulus, or segmental, involving only 1 or more tufts, but not others. Proliferation
commonly involves the endothelial and mesangial cells and is often associated with an
increase in the mesangial matrix. Mesangial proliferation can result from deposition of
immune complex within the mesangium. The resultant increase in cell size and number, and
production of mesangial matrix, can increase glomerular size and narrow the lumens of
glomerular capillaries, leading to renal insufficiency.
Crescent formation in Bowmans space (capsule) is a result of proliferation of parietal
epithelial cells. Crescents develop in several forms of glomerulonephritis (termed rapidly
progressive or crescenteric) and are a characteristic response to deposition of fibrin in
Bowmans space. Newly formed crescents contain fibrin, the proliferating epithelial cells of
Bowmans space, basement membranelike material produced by these cells, and
macrophages that might have a role in the genesis of glomerular injury. Over the subsequent
days to weeks, the crescent is invaded by connective tissue and becomes a fibroepithelial
crescent. This process generally results in glomerular obsolescence. Crescent formation is
often associated with glomerular cell death. The necrotic glomerulus has a characteristic
eosinophilic appearance and usually contains nuclear remnants. Crescent formation is usually
associated with generalized proliferation of the mesangial cells and with either immune
complex or anti-GBM antibody deposition in the glomerular capillary wall.

18

Certain forms of acute glomerulonephritis show glomerular exudation of blood cells,

including neutrophils, eosinophils, basophils, and mononuclear cells. The thickened
appearance of GBM can result from a true increase in the width of the membrane (as seen in
membranous glomerulopathy), from massive, deposition of immune complexes that have
staining characteristics similar to the membrane (as seen in systemic lupus erythematosus), or
from the interposition of mesangial cells and matrix into the subendothelial space between
the endothelial cells and the GBM. The last can give the basement membrane a split
appearance, as seen in type I membranoproliferative glomerulonephritis and other diseases.
Sclerosis refers to the presence of scar tissue within the glomerulus. Occasionally,
pathologists use this term to refer to an increase in mesangial matrix. Tubulointerstitial
fibrosis is present in all patients who have glomerular disease and who develop progressive
renal injury. This fibrosis is initiated by injury to the renal tubules, resulting in mononuclear
cell infiltrates that release soluble factors that have fibrosis-promoting effects. Matrix
proteins of the renal interstitium begin to accumulate, leading to eventual destruction of renal
tubules and peritubular capillaries. The actual transformation of tubular epithelium to
mesenchymal tissue can contribute to progressive tubulointerstitial fibrosis.

3.5 PATHOGENESIS
Glomerular injury may be a result of genetic, immunologic, perfusion, or coagulation
disorders. Genetic disorders of the glomerulus result from mutations in the exons of DNA
encoding proteins located within the glomerulus, interstitium, or tubular epithelium;
mutations in the regulatory genes controlling DNA transcription; abnormal posttranscriptional modification of RNA transcripts; or abnormal post-translational modification
of proteins. Immunologic injury to the glomerulus results in glomerulonephritis, which is a
19

generic term for several diseases and a histopathologic term signifying inflammation of the
glomerular capillaries.
Evidence that glomerulonephritis is caused by immunologic injury includes
morphologic and immunopathologic similarities to experimental immune-mediated
glomerulonephritis; the demonstration of immune reactants (immunoglobulin, complement)
in glomeruli; abnormalities in serum complement; and the finding of autoantibodies (antiGBM) in some of these diseases .
There appear to be 2 major mechanisms of immunologic injury: glomerular
deposition of circulating antigen-antibody immune complexes and interaction of antibody
with local antigen in situ. In the latter circumstance, the antigen may be a normal component
of the glomerulus (thenoncollagenous domain [NC-1] of type IV collagen, a putative antigen
in human anti-GBM nephritis) or an antigen that has been deposited in the glomerulus.

In PSGN, the exact

triggers

for

the

formation of the immune

complexes are unclear.

In PSGN, involvement of

derivatives

of

streptococcal proteins has

been

reported.

streptococcal neuraminidase may alter host immunoglobulin G (IgG). IgG combines with
host antibodies. IgG/anti-IgG immune complexes are formed and then collect in the
glomeruli. In addition, elevations of antibody titers to other antigens, such as antistreptolysin
O or antihyaluronidase, DNAase-B, and streptokinase, provide evidence of a recent
streptococcal infection.
20

Most forms of acute poststreptococcal glomerulonephritis (APSGN) are mediated by

an immunologic process. Cellular and humoral immunity is important in the pathogenesis of
this disease, and humoral immunity particularly in APSGN. Nonetheless, the exact
mechanism by which APSGN occurs remains to be determined. The 2 most widely proposed
theories include (1) glomerular trapping of circulating immune complexes and (2) in situ
immune antigen-antibody complex formation resulting from antibodies reacting with either
streptococcal components deposited in the glomerulus or with components of the glomerulus
itself, which has been termed molecular mimicry.
Morphologic studies and a depression in the serum complement (C3) level provide
strong evidence that ASPGN is mediated by immune complexes. Precise mechanism by
which nephritogenic streptococci induce immunologic injury continue to be elucidated.
Several mechanism of immune injury have been supported by experimental models and
human studies and include circulating immune complex formation with streptococcal
antigens and susequent glomerular deposition, moleculary mimicry whereby circulating
antibodies elicated by streptococcal antigens react with normal glomerular antigens, in situ
immune complex formation of sntistreptococcal antibodies with glomerular deposited
antigen, and complement activation by directly deposited streptococcal antigens.
Group A streptococci possess M proteins, and nephritogenic strain are related to the M
protein serotype. The search for precise nephritogenic antigen suggest that pyogenic exotoxin
(SPE B) and nephritis-associated streptococcalplasmin receptor (NAPlr) are promising
candidates. Both have been identified in glomeruli of affected patients, and in one study,
circulating antibodies to SPE B were found in all patients. Crossreactivity of SPE B and other
M proteins with various components of the glomerular basement membrane also give
evidence for molecular mimicry.
Immune complex-mediated mechanisms

21

In immune complexmediated diseases, antibody is produced against and combines

with a circulating antigen that is usually unrelated to the kidney. The immune complexes
accumulate in GBMs and activate the complement system, leading to immune injury. As
antibody enters the circulation, it forms immune complexes with antigen. Although the
amount of antigen in the circulation exceeds that of antibody (antigen excess), the complexes
formed are small, remain soluble in the circulation, and are deposited in glomeruli. The
processes involved in glomerular localization are not well understood but include
characteristics of the complex (concentration, charge, size), and/or the glomerulus (mesangial
trapping, negatively charged capillary wall); hydrodynamic forces, and the influence of
various chemical mediators (angiotensin II, prostaglandins). With deposition of immune
complexes in glomeruli, rabbits develop an acute proliferative glomerulonephritis.
Immunofluorescence microscopy demonstrates granular (lumpy-bumpy) deposits containing
immunoglobulin and complement in the glomerular capillary wall. Electron microscopic
studies show these deposits to be on the epithelial side of the GBM and in the mesangium.For
the next few days, as additional antibody enters the circulation, the antigen is ultimately
removed from the circulation and the glomerulonephritis subsides. An example of in situ
antigen-antibody interaction is anti- GBM antibody disease, in which antibody reacts with
antigen(s)of the GBM. Immunopathologic studies reveal linear deposition of immunoglobulin
and complement along the GBM as in Goodpasture syndrome and certain types of rapidly
progressive glomerulonephritis. The inflammatory reaction that follows immunologic injury
results from activation of 1 or more mediator pathways. The most important of these is the
complement system, which has 2 initiating sequences: the classic pathway, which is activated
by antigen-antibody immune complexes, and the alternative or properdin pathway, which is
activated by polysaccharides and endotoxin. These pathways converge at C3; from that point
on, the same sequence leads to lysis of cell membranes. The major noxious products of
complement activation are produced after activation of C3 and include anaphylatoxin (which
stimulates contractile proteins within vascular walls and increases vascular permeability) and
chemotactic factors (C5a) that recruit neutrophils and perhaps macrophages to the site of
complementactivation, leading to consequent damage to vascular cells and basement
membranes. The coagulation system may be activated directly, after endothelial cell injury
22

that exposes the thrombogenic subendothelial layer (thereby initiating the coagulation
cascade), or it may be activated indirectly, after complement activation. Consequently, fibrin
is deposited within glomerular capillaries or within Bowmans space as crescents. Activation
of the coagulation cascadecan also activate the kinin system, which produces additional
chemotactic and anaphylatoxin-like factors.
An immune complexmediated mechanism is the most widely proposed mechanism
leading to the development of APSGN. Nephritogenic streptococci produce proteins with
unique antigenic determinants. These antigenic determinants have a particular affinity for
sites within the normal glomerulus. Following release into the circulation, the antigens bind
to these sites within the glomerulus. Once bound to the glomerulus, they activate complement
directly by interaction with properdin.
Glomerular-bound streptococcal antibodies also serve as fixed antigens and bind to
circulating antistreptococcal antibodies, forming immune complexes. Complement fixation
via the classic pathway leads to the generation of additional inflammatory mediators and
recruitment of inflammatory cells.
-

Zymogen (NSAP) and NAPlr

Two major antigens have presently been identified as the potential cause(s) of APSGN: A
zymogen precursor of exotoxin B (SPEB [streptococcal pyrogenic toxin B]) or nephritis
strainassociated protein (NSAP), and nephritis-associated plasmin receptor (NAPlr), a
glycolytic enzyme, which has glyceraldehydes-3-phosphate dehydrogenase (GAPDH)
activity with plasmin-binding capacity, a nephritogenic property that aids in circulating
immune complex deposition. NSAP is a 46- to 47-kd protein that is unique to the
extracellular products of nephritogenic streptococci. NSAP was demonstrated in glomerular
deposits of 14 of 21 patients with APSGN, but none in control biopsy samples from 5 patients
with acute kidney injury and 11 with nonstreptococcal glomerulonephritis. NSAP was also
detected in serum from 96% of APSGN patients compared with 15-20% of patients with
either acute kidney injury or impetigo. NSAP has antigenic, biochemical, and structural
similarities to streptokinase from group C streptococcal organisms, binds to plasmin, and is a
plasminogen activator. However, streptokinase cannot be demonstrated in glomerular
deposits for patients with APSGN, and serum levels of purified group A streptokinase were
similar in patients with APSGN and those with acute kidney injury. Thus, although NSAP and
streptokinase have similarities, they appear to be 2 distinct proteins.

23

Yoshizawa et all isolated a 43-kd protein called preabsorbing antigen (PA-Ag) that is
putatively identical to endostreptosin. PA-Ag has the ability to preabsorb the antibody in
convalescent sera from patients with APSGN and thus prevent its deposition in glomeruli.
PA-Ag activates the alternative pathway. This 43-kd protein was later identified by Yamakami
et al as NAPlr.These researchers noted that NAPlr was present in 100% of the early biopsy
samples from in glomeruli of patients with APSGN.The glomerular distribution of NAPlr
deposition and plasmin activity determined by in situ zymography are identical.
The fact that NAPlr did not co-localize with C3 in glomerular deposits suggests that: (1)
complement was activated by NAPlr in the circulation rather than in situ, and (2) NAPlr
induced APSGN independently of complement activation by binding to the glomerular
basement membrane (GBM) and mesangial matrix via its adhesive character, subsequently
trapping and activating plasmin and causing in situ glomerular damage by degrading the
GBM or activating latent matrix metalloproteases.
SPEP is another group A streptococcal nephrogenic antigen most often isolated in Latin
America, the United States, and Europe. It is a cationic protease with plasmin-binding
properties. It localizes to glomeruli in patients with APSGN and is secreted as an exotoxin.
Corresponding serum anti-SPEP antibodies occur in most patients during convalescence.
SPEP titers correlate better with nephritis than either ASOT or anti-DNase B antibodies.
A proposed mechanism for acute poststreptococcal glomerulonephritis is that soluble,
released NAPlr binds to glomeruli and provide a mechanism to capture plasmin activated by
streptokinase. The activated plasmin bound to NAPlr associates with the GBM and
mesangium. Both NAPlr and NSAP are capable of inducing chemotactic (monocyte
chemoattractant protein 1) and interleukin (IL)6 moieties in mesangial cells, promoting
enhanced expression of adhesion molecules. Peripheral blood leukocytes also release other
cytokines such as tumor necrosis factor-alpha, IL-8, and transforming growth factor-beta,
which react with NSAP. These findings highlight the inflammatory potential of these
nephritogenic antigens.
Bound plasmin can cause tissue destruction by direct action on the glomerular basement
membrane or by indirect activation of procollagenases and other matrix metalloproteinases
(MMPs). NAPlr can also activate the alternate complement pathway, leading to accumulation
of polymorphonuclear cells and macrophages and local inflammation. In addition, the in situ
24

formed and circulating immune complexes can readily pass through the altered glomerular
basement membrane and accumulate on the subepithelial space as humps.
Complement activation from both serum profiles and immunofluorescence patterns for
glomerular deposits indicates that C3 activation in APSGN is predominantly via the
alternative pathway. The immune deposits consist of immunoglobulin G (IgG), C3, properdin,
and C5. These deposits rarely contain C1q or C4, both components of the classic complement
pathway. A recent study also showed evidence for activation of the lectin-binding pathway
from deposition of membrane-bound lipoprotein in some patients with APSGN.
During the early phase of the diseases (first 2 wk), evidence of classical pathway activation is
seen, as demonstrated by transient depression of serum C1q, C2, and/or C4 concentrations.
and the presence of circulating C1-inhibitor-C1r-C1s complexes or C4d fragments. It is
proposed that the circulating immune complexes in the acute stage of the disease due to
classic complement pathway activation is distinct from that seen in the glomerular immune
deposits. APSGN with typical findings on histopathology may occur in patients with no
evidence of complement activation, as manifested by depression of serum C3 concentrations.
Hypocomplementemic patients differ from normocomplementemic patients by virtue of the
presence of factor B in the glomerular deposits and the absence of factor H, which is a
regulatory protein of the alternative pathway. These findings suggest that the glomerular
immune deposits of C3bBb convertase may be due to ongoing complement activation in situ
rather than systemic activation. Crescentic APSGN may have an increased association with
normocomplementemia. The reason for this possible association of normocomplementemia
with crescent formation in APSGN is not clear.
Serum IgG levels are elevated in about 44% of patients with APSGN. Less than 50% of
patients with elevated serum IgG levels, however, have glomerular deposits of IgG. Elevated
IgG levels were more likely to be found in patients with antistreptolysin O titers of greater
than or equal to 833 Todd units (P < .001). However, elevated serum IgG concentrations do
not correlate with severity of disease, age of the patient, or serum albumin or C3 levels. It
would appear that failure to form antibody to a glomerular-bound protein produced by
nephritogenic Streptococcus, is thought to be the origin of the IgG in glomerular deposits, is
in some way significantly associated with elevated serum levels of IgG and antibody to
streptolysin O.
25

There is considerable evidence both for and against most putative nephritogenic antigens.
Genomic sequencing of nephritogenic strains of streptococci may lead to the discovery of
new nephritogenic antigen candidates in conserved and differing regions of the streptococcal
genome. This will lead to improved understanding of the pathogenetic mechanisms leading to
the development of APSGN.
3.6 CLINICAL MANIFESTATION
Poststreptococcal glomerulonephritis is most common in children aged 5-12 years old
and uncommon before age 3 years. The rarity of PSAGN in very young children was
attributed to the low rate of streptococcal pharyngitis in this age group and immature immune
or antibody response. Twice as many males are diagnosed with PSAGN as females.
Typical patient develops an acute nephritic syndrome 1-2 week after a precededing
streptococcal pharingtis or 3- 6 week after a streptococcal pyoderma. The history of spesific
infection may be absent, because symptoms may have been mild or have resolved withous
patient receiving spesific treatment.
The severity of kidney involvement varies from asymptomatic microscopic hematuria
with normal renal function to gross hematuria with acute renal failure. Depending on the
severity of renal involvement, patients can develop various degrees of edema,hypertension,
and oliguria. Patients are at risk for developing encephalopathy and/or heart failure secondary
to hypertension or hypovolemia. Hypertensive encelopathy should be considered in patint
with blurred vision, severe headaches, altered mental status, or new seizures. Encephalopathy
canalso result from the direct toxic effects of streptococcal antigens on the central nervous
system.
Children with PSAGN most often seek medical attention for edema or gross
hematuria, occasionally symptoms or signs of hypertension will be the initial presenting
featureleading to the diagnosis. The triad of edema, hematuria and hypertension is classic for
PSAGN. Three phases of the disease can be identified: the latent phase, the acute phase, and
the recovery phase.

26

The latency period between the streptococcal infection and the onset of the clinical
syndrome ranges from 333 days but on average is 714 days. Hematuria is present in
essentially all patients. The classic description of tea- or cola-colored urine occurs in
approximately 2560% of patients. Proteinuria is also typically present, but nephrotic
syndrome is rare in most case series.
Edema is the most frequent and sometimes the only clinical finding. According to
some investigators, edema is found in approximately 85% of patients. Edema usually appears
abruptly and first involves the periorbital area, but it may be generalized. The degree of
edema widely varies and depends on a number of factors, including the severity of
glomerular involvement, the fluid intake, and the degree of hypoalbuminemia.
Hypertension occurs in approximately 8090% of cases . Cerebral complications of
hypertension including headaches, seizures, mental status changes, and visual changes occur
in 3035% of children. The mechanism for hypertension is most likely retention of sodium
and water with resulting expansion of the extracellular space. As with other causes of
glomerulonephritis, fractional excretion of sodium is generally less than 1%, similar to prerenal azotemia. Renin levels (plasma renin activity) are typically low at presentation. Fluid
retention correlates with suppression of the plasma renin activity. Patients may sometimes
present with clinical and radiologic signs of pulmonary edema. While dyspnea is a presenting
complaint in only 5% of patients, evidence for congestive heart failure was found in half of
the children in one early series.
Nonspecific symptoms suchas malaise, lethargy, abdominal pain, or flank pain are
common. The acute phase generally resolves within 6-8 week. Although urinary protein
27

excretion and hypertension usually normalize by 4-6 week after onset, persistent microscopic
hematuria can persist for 1-2 year after the initial presentation.
Atypical presentations of PSAGN include those individuals with sub-clinical disease
and those presenting with acute illness, usually related to hypertension or edema in the
absence of overtly abnormal urine. There are numerous case reports of children who present
with extreme manifestations, usually from hypertensive crises, who do not display the typical
urinary findings at presentation . Serial examination of the urine after presentation may
eventually confirm the suspicion of acute glomerulonephritis. Another atypical feature at
presentation is the presence of a typical Henoch-Schnlein purpura rash . The diagnosis of
PSAGN was confirmed by renal biopsy in those cases.
3.7 DIAGNOSIS
Urinalysis shows

red blood cells (RBCs), often in association with RBC casts,

proteinuria, and polymorphonuclear leukocytes. ; red blood cell and white blood cell casts
are usually identified. In the early part of the acute phase, urinary leukocytes may
predominate over red blood cells.
The glomerular filtration rate (GFR) is often decreased during the acute phase of the
disease. Increased blood urea nitrogen (BUN) was noted in 6065% of patients with
decreased estimated creatinine clearance less than 90 ml/min/1.73 m2 present in 20%.
Hypoalbuminemia is quite common. In one large study of PSAGN serum albumin was lower
than 3.0 g/dl in 46% and less than 2.5 g/dl in 15% .
Confirmation of the diagnosis requires clear evidence of a prior streptococcal
infection. A positive throat culture report might support the diagnosis or might simply
represent the carrier state. On the other hand, a rising antibody titer to streptococcal antigen
confirms a recent streptococcal infection. The antistreptolysin O titer is commonly elevated
after a pharyngeal infection but rarely increases after streptococcal skin infections. The
serological markers most commonly used by the clinician are anti-streptolysin O (ASO) titer
and depression of serum C3 level. Increased antibody levels to antistreptococcal antigens
[ASO, anti-hyaluronidase (A-H) and anti-DNAase] are documented less often than low
levels of C3. In an early study, the sensitivity of an elevated ASO titer was extremely high
(97%), but the specificity was only 80%. Early descriptions of the time course for increasing
ASO and A-H titers show that in group of patients with typical (previously known as typeA)
acute glomerulonephritis, ASO was increased above normal in 72% .Cases following
28

pyoderma re more likely to demonstrate elevated anti-DNAase B titer than an elevated ASO
titer.
The serum C3 level is significantly reduced in >90% of patients in the acute phase.
The acute reduction of serum C3 concentration in PSAGN with the typical return to normal
levels within six weeks of onset is of foremost diagnostic importance when renal biopsy is
not performed. Depression of serum C3 level in PSAGN has been shown to precede the
onset of hematuria. Hypertension usually resolves within 12 weeks, and rarely requires
long-term treatment . Renal biopsy is indicated in cases in which the clinical diagnosis is not
clear in order to confirm the diagnosis or in the presence of significant renal insufficiency to
rule out crescentic glomerulonephritis.
The recovery phase occurs after resolution of fluid overload with diuresiseither
spontaneous and/or pharmacologically inducedalong with normalization of blood pressure
and resolution of proteinuria and gross hematuria. During this phase, the C3 level returns to
normal in the majority of affected children. PSAGN has occurred in patients previously
diagnosed (by biopsy) with IgA nephropathy. Because IgA nephropathy is the most
commonly occurring type of chronic glomerulonephritis and often goes undiagnosed, the
association with PSAGN is most likely the chance occurrence of the two conditions in the
same individual.
The best single antibody titer to document cutaneous streptococcal infection is the
anti-deoxyribonuclease (DNase) B level. If available, a positive streptozyme screen (which
measures multiple antibodies to different streptococcal antigens) is a valuable diagnostic tool.
Serologic evidence for streptococcal infections is more sensitive than the history of recent
infections and far more sensitive than positive bacterial cultures obtained at the time of onset
of acute nephritis.Magnetic resonance imaging of the brain is indicated in patients with
severe neurologic symptoms and can demonstrate reversible posterior leukoencephalopathy
in the parieto-occipital areas on T2-weighted images. Chest x-ray is indicated in those with
signs of heart failure or respiratory distress, or physical exam findings of a heart gallop,
decreased breath sounds, rales, or hypoxemia. The clinical diagnosis of poststreptococcal GN
is quite likely in a child presenting with acute nephritic syndrome, evidence of recent
streptococcal infection, and a low C3 level. However, it is important to consider other
diagnoses such as systemic lupuserythematosus and an acute exacerbation of chronic GN.
Renal biopsy should be considered only in the presence of acute renal failure, nephrotic
syndrome, absence of evidence of streptococcal infection, or normal complement levels. In
addition, renal biopsyis considered when hematuria and proteinuria, diminished renal
29

function, and/or a low C3 level persist more than 2 mo after onset. Persistent
hypocomplementemia can indicate a chronic form of postinfectious GN or another disease
such as membranoproliferative GN.
Renal Biopsy
A renal biopsy is generally not indicated for diagnosis of PSAGN, but is usually
performed when atypical clinical features occur. Such features that could lead to a biopsy are
normocomplementemia , failure to document a recent streptococcal infection by a rise in
ASO or streptozyme titer, and renal insufficiency, particularly when the GFR remains less
than 30 ml/min/1.73 m2 for more than one week. In the past, some pediatric nephrologists
recommended a renal biopsy for patients with presumed PSAGN whose C3 concentration
remained depressed for more than eight weeks after clinical onset, mainly to exclude the
diagnosis of membranoproliferative glomerulonephritis (MPGN). One study documented
failure of C3 to become normal by eight weeks in five of 20 patients despite typical
improvement in clinical features, including resolution of proteinuria and normal kidney
function. Renal biopsies that were performed in three of these patients showed typical
findings of PSAGN. Thus, persistent hypocomplementemia with resolving features of acute
glomerulonephritis does not exclude the diagnosis of PSAGN, and the authors and others felt
that the renal biopsy could be deferred.
3.8 DIFFERENTIAL DIAGNOSIS
Postinfectious GN must be differentiated from the following conditions:

Immunoglobulin A (IgA) nephritis - The latent period between infection and onset of
nephritis is 1-2 days; alternatively, nephritis may be concomitant with upper
respiratory tract infection (ie, synpharyngitic nephritis, in contrast to the
postpharyngitic nephritis seen in poststreptococcal GN [PSGN], which occurs 1-3

weeks later).
Membranoproliferative GN (MPGN), types I and II - This is a chronic disease, but it
can manifest with an acute nephritic picture with hypocomplementemia; failure of

acute nephritis to resolve should prompt consideration of this possibility.

Lupus nephritis - Gross hematuria is unusual in lupus nephritis.
GN of chronic infection - This can manifest as acute nephritis. Unlike PSGN, in
which the infection may have resolved by the time nephritis occurs, patients with

30

nephritis of chronic infection have an active infection at the time nephritis becomes
evident. Circulating immune complexes play an important role in the pathogenesis of

acute GN in these diseases.

Vasculitis - Nephritis of methicillin-resistant Staphylococcus aureus (MRSA) may be

associated with vasculitic lesions of the lower extremities.

Predominantly nonglomerular diseases - Thrombotic thrombocytopenic purpura
(TTP), hemolytic-uremic syndrome (HUS), atheroembolic renal disease, and acute
hypersensitivity interstitial nephritis may present with features of acute nephritic
syndrome and should be differentiated.

GN is a recognized complication of various chronic infections. Classic examples

include bacterial endocarditis caused by viridans Streptococcus and other organisms, and
ventriculoatrial shunts infected with Staphylococcus epidermidis. Other infections, observed
less commonly in children than adults, include hepatitis B virus, hepatitis C virus, syphilis,
and candidiasis. Parasitic infections associated with glomerular disease include malaria,
schistosomiasis,

leishmaniasis,

filariasis,

hydatid

disease,

trypanosomiasis,

and

toxoplasmosis. In each condition, the infecting organism has low virulence and the host is
chronically infected with foreign antigen. In the presence of high levels of circulating
antigen, the hosts antibody response leads to formation of immune complexes that deposit in

31

the kidneys and initiate glomerular inflammation. Foreign antigens can also stimulate an
autoimmune response through the production of antibodies that cross react with such antigens
incorrectly recognized as glomerular structural components.

The finding of certain hematologic abnormalities can narrow the differential

diagnosis. Anemia in this setting may be caused by intravascular dilution secondary to
hypervolemia associated with acute renal failure; decreased RBC production in chronic renal
failure; hemolysis from hemolytic-uremic syndrome or SLE; or blood loss from pulmonary
hemorrhage, as seen in Goodpasture syndrome, or melena in patients with Henoch-Schnlein
purpura or hemolytic-uremic syndrome. Inspection of the peripheral blood smear might
reveal a microangiopathic process consistent with the hemolytic-uremic syndrome. The
presence of autoantibodies in SLE can result in a positive Coombs test, the presence of
antinuclear antibody, leukopenia, and multisystem disease. Thrombocytopenia can result
from decreased platelet production (malignancies) or increased platelet consumption (SLE,
idiopathic thrombocytopenic purpura, hemolytic-uremic syndrome, renal vein thrombosis).
Although urinary RBC morphology may be normal with lower tract bleeding and dysmorphic

32

from glomerular bleeding, cell morphology is not reliable to unequivocally delineate the site
of hematuria. A bleeding diathesis is an unusual cause of hematuria. Coagulation studies are
not routinely obtained unless personal or family history suggests a bleeding tendency.

3.9 COMPLICATIONS
Acute complications result from hypertension and acute renal dysfunction.
Hypertension is seen in 60% of patients and is associated with hypertensive encephalopathy
in 10% of cases. Although the neurologic sequelae are often reversible with appropriate
management, severe prolonged hypertension can lead to intracranial bleeding. Other potential
complications include heart failure, hyperkalemia, hyperphosphatemia, hypocalcemia,
acidosis,seizures, and uremia. Acute renal failure can require treatment with dialysis.
3.10 PREVENTION
Early systemic antibiotic therapy for streptococcal throat and skin infections does not
eliminate the risk of GN. Family members of patients with acute GN, especially young
children, should be considered at risk and be cultured for group A -hemolytic streptococci and
treated if appropriate. Family pets, particularly dogs,have also been reported as carriers.
A vaccine targeted against group A streptococci will prevent both invasive disease and
nonsuppurative complications. The current thrust of group A streptococcal vaccine research
has been to target the M protein. A 26-valent vaccine has been developed that targets the
variable region of the M proteins of the most common rheumatogenic cocci. Unfortunately,
no M protein from nephritogenic streptococci were included in the vaccine. In addition, the
most common M protein types in the developing world differ from those of more developed
countries, thus rendering the vaccine less efficacious. The most effective public health
measure in the developing world is to improve hygiene and provide better housing conditions
to avoid overcrowding. This offers the best hope for elimination of epidemic pyoderma and
thus preventing APSGN.
3.11 MANAGEMENT AND TREATMENT
The treatment of glomerulonephritis falls into two categories. Supportive treatment
such as blood pressure control and dialysis is immediate and frequently life saving, but does
33

not attempt to reverse the underlying pathology. Specific treatments aim to prevent and
reverse glomerular inflammation and ultimately to preserve renal function, such treatments
are often highly toxic and rely on non specific suppression of the entire emmune system.
They carry immediate risk overwhelming infection and the later risk of reproductive toxicity
and malignancy. In choosing such therapies we need to select patients in whom kidney
recovery is unlikely to occur spontaneously but where toxicity can be justified by the
potential reversibility of the condition.
Treatment remains largely supportive and usually addresses the most urgen problem
hypertension. Salt restriction and loop diuretics are the first line treatment for fluid overload
and hypertension, thereafter hypertensive therapy is often transitioned to vasodilators. ACE
inhibitors are generally not used during acute phase due to potential for decrease in GFR and
hyperkalemia. In those indivisuals with hypertensive emergencies, continues infusion of antihypertensive medication is the preferred initial approach.
The importance of supportive therapies in acute glomerulonephritis can not be over
emphasised. Tight blood pressure control, appropriate use of diuretics, and control
hyperkalemia, uraemia, and fluid overload, if necessary by dialysis, are quite literally life
saving. Blood pressure control is vital not just in the short term but also later for any patient
left even with mild renal impairment or proteinuria, with ACEI having a particular place for
their additional antiproteinuric and antifibrotic effects.
Management is directed at treating the acute effects of renal insufficiency and
hypertension. Although a 10-day course of systemic antibiotic therapy with penicillin is
recommended to limit the spread of the nephritogenic organisms, antibiotic therapy does not
affect the natural history of GN. Sodium restriction, diuresis usually with intravenous
furosemide, and pharmacotherapy with calcium channel antagonists, vasodilators,or
angiotensin-converting enzyme inhibitors are standard therapies used to treat hypertension.
Immunosupression has not been proven to be effective, although it is often used in the
clinical setting of rapidly glomerulonephrits or when crescent are seen in biopsy.
In most cases of post-streptococcal glomerulonephritis where inflammation does
resolve spontaneously, supportive therapies alone will be sufficient with improved renal
function being seen between four and 14 days after the initial acute failure in 95% of patients.
Serum creatinine generally returns to baseline levels by four weeks but haematuria may
persist for six months and mild proteinuria may be present in a few patients even at 10 years.
Rarely haematuria and proteinuria persist long term and are accompanied by hypertension
and declining renal function. For most other causes of glomerulonephritis however, if renal
34

function is to be preserved, we must aim to reverse underlying event causing glomerular

inflammation.
1. Diet and Activity
A low-sodium, low-protein diet should be prescribed during the
acute phase, when edema and hypertension are in evidence;
however,

prolonged

dietary

restrictions

are

not

warranted.

Limitation of fluid and salt intake is recommended in the child who

has either oliguria or edema. Curtailment of fluid to amounts
consistent with insensible losses helps to minimize vascular
overload and hypertension. In patients with oliguric acute kidney
injury,

potassium

intake

should

be

restricted

to

prevent

hyperkalemia.
Limited activity is probably indicated during the early phase of the
disease, particularly if hypertension is present. Bedrest may lessen
the degree and duration of gross hematuria if present; however,
longer periods of bedrest do not appear to influence the course or
long-term

prognosis;

therefore,

they

are

generally

not

recommended.
2. Inpatient Management
General management begins with a decision to admit the child with acute
glomerulonephritis to the hospital or merely have him or her undergo frequent
outpatient examinations. Hospitalization is indicated if the child has significant
hypertension or a combination of oliguria, generalized edema, and elevation of serum
creatinine or potassium.
-

Severe hypertension
Severe hypertension, or that associated with signs of cerebral
dysfunction, demands immediate attention. Three drugs are
commonly cited as having a high benefit-to-risk ratio:
1. Labetalol (0.5-2 mg/kg/h intravenously [IV]),
2. Diazoxide, and

35

3. Adnitroprusside (0.5-2 mcg/kg/min IV; in patients with severe

hypertension that is refractory to the previous agents).
Recently, sodium nitroprusside has been replaced by the use of
nicardipine in the United States and much of Western Europe
(start at 5 mg/h intravenously [IV], increase by 2.5 mg/h every 515 min as needed, maximum dose 15 mg/h). Discontinue if
hypotension or tachycardia is present (may restart at 3-5 mg/h
IV). In combination with any of these agents, the simultaneous IV
administration of furosemide at doses of 2 mg/kg may be
merited. Diazoxide use for blood pressure (BP) control is limited
because, once administered, no further control of pressure is
possible, unlike labetalol or nitroprusside.
Severe hypertension without encephalopathy can be treated in
the

manner

described

above

or,

more

commonly,

by

administration of vasodilator drugs, such as hydralazine or

nifedipine. The doses of these drugs can be administered either
by injection or by mouth and can be repeated every 10-20
minutes until a suitable response is obtained. For most children,
-

the need for more than 2-3 doses is unusual.

Mild-to-moderate hypertension
Mild-to-moderate hypertension does not warrant emergency
management and is treated most effectively with bedrest, fluid
restriction, and less-frequent doses of the medications mentioned
above. The use of loop diuretics, such as furosemide (1-3
mg/kg/d oral [PO], administered 1-2 times daily), may hasten
resolution of the hypertension.
For patients

resistant to treatment, either hydralazine or

nifedipine is indicated. Angiotensin-converting enzyme (ACE)

inhibitors are effective, although these agents have the potential
to produce hyperkalemia and usually are not first-line drugs in
acute glomerulonephritis.
-

Edema
Edema and circulatory congestion are usually not sufficiently
marked to produce more than minimal discomfort. Restriction of
36

fluids to those amounts needed to replace insensible losses is the

best treatment for edema and circulatory congestion.

Loop

diuretics (furosemide) administered PO have been reported to

reduce

the length of hospitalization

in children who are

edematous. If congestion is marked, administer furosemide

parenterally (2 mg/kg).
-

Anuria or oliguria
Anuria or severe and persistent oliguria may occur in 3-6% of
children with acute glomerulonephritis and may necessitate
hospitalization. Fortunately, both of these conditions are usually
transient. Because they may be ototoxic, avoid large doses of
furosemide in children with symptoms of anuria or severe and
persistent oliguria. In addition, osmotic diuretics, such as
mannitol, are contraindicated, as they might increase vascular
volume.

Other medical management strategies

A course of penicillin can be administered to avoid contamination
of contacts with a nephritogenic strain of streptococci; however,
in most instances, these contacts do not develop overt acute
glomerulonephritis. Such therapy may not influence the course of
the disease in the index patient, but it may alter the response
that confers type-specific immunity. Throat cultures of immediate
family members might detect patients who are asymptomatic but
infected.
Steroid therapy is indicated only in patients with severe
crescentic glomerulonephritis or in those with rapidly progressive
glomerulonephritis. Selected patients with Henoch-Schnlein
purpura

(HSP)

nephritis

and

membranoproliferative

glomerulonephritis (MPGN) also may benefit from such agents.

An experienced nephrologist should make decisions regarding
the indication for such treatment.
37

3. Long-Term Monitoring
Long-term follow-up

for

patient

following

acute

poststreptococcal

glomerulonephritis (APSGN) primarily consists of blood pressure measurements and urine

examinations for protein and blood. In general, examinations are performed at 4- to 6-week
intervals for the first 6 months and at 3- to 6-month intervals thereafter, until both hematuria
and proteinuria have been absent and the blood pressure has been normal for 1 year.
Documenting that the low C3 has returned to normal after 8-10 weeks may be useful.
Follow up at 0-6 weeks as frequently as necessary to determine the following:

Hypertension has been controlled.

Edema has started to resolve.
Gross hematuria has resolved.
Azotemia has resolved.

Follow up at 8-10 weeks after onset to assess the following:

Azotemia has subsided.
Anemia has been corrected.
Hypertension has resolved.
C3 and C4 concentrations have returned to normal.
Follow up at 3, 6, and 9 months after onset to check the following:
Hematuria and proteinuria are subsiding gradually.
Blood pressure is normal.
Follow up at 12 months after onset to evaluate that proteinuria and microscopic hematuria
have disappeared. Follow up at 2, 5, and 10 years after onset to check the patient's urine,
blood pressure, and serum creatinine level are normal.
3.12 PROGNOSIS
Complete recovery occurs in >95% of children with APSGN. Recurrences are
extremely rare. Mortality in the acute stage can be avoided by appropriate management of
38

acute renal failure, cardiac failure, and hypertension. Infrequently, the acute phase is severe
and leads to glomerulosclerosis and chronic renal disease in <2% of affected children. The
true incidence of chronic renal disease that emerges later in adulthood as a result of childhood
APSGN and reduction of functioning nephron number remains unknown.

CHAPTER IV
SUMMARY

4.1 SUMMARY
Acute glomerulonephritis (GN) is a disease characterized by the sudden appearance of
edema, hematuria, proteinuria, and hypertension. It is a representative disease of acute
nephritic syndrome in which inflammation of the glomerulus is manifested by proliferation of
cellular elements secondary to an immunologic mechanism, that determines complement
activation.
Glomerulonephritis requires prompt diagnosis. When even mild degrees of renal
insufficiency are documented, immediate referral to a nephrologist is necessary to ensure that
serious conditions, such as RPGN, are correctly diagnosed and aggressively managed. In an
adolescent with macroscopic hematuria, the demonstration of dysmorphic RBCs, RBC casts,
and proteinuriaindicates that the bleeding is of glomerular origin. Physicians caring for
adolescents with chronic GN should have a basic understanding of the specific disorders.
They may be involved in blood pressure monitoring and should be aware of the potential side
effects of the antihypertensive and immunosuppressive medications used in patients with GN.

39

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41

of

Acute
at: