1

THE GLOMERULAR FILTRATION BARRIER

The human kidney is a complex and vital organ
system that even in full term infants, the normal renal
function is incomplete until about 2 years of age. It consist
of about 1 million nephrons which at the tip is composed of
the glomerulus. In the glomerulus, blood from the afferent
arteriole is circulated in the glomerular capillaries which
becomes the source of the filtrate into the Bowmans space.
It is taken away from the Bowmans capsule via the efferent
arterioles. Parietal epithelial cells line the Bowmans
capsule.
The glomerular filtration barrier consist of the
podocyte, glomerular basement membrane, and the
glomerular capillary. Podocytes, or visceral epithelial cells, separate the capillaries and the urinary space.
They have cellular extensions called foot processes, which interdigitate to form slit diaphragms. The
glomerular basement membrane (GBM) is a trilaminar (lamina rara externa, lamina densa, lamina rara
interna) structure beneath the podocytes. It is mainly made up of type IV collagen, laminin, and heparin
sulfate proteoglycans. Found beneath the GBM, the endothelial layer contains pores called endothelial
fenestrations.
The structure and the composition of the glomerular basement allows it to have size, shape, and
charge selectivity. Size and shape selectivity are determined by the 50 100 nm diameter pores in the
endothelial layer, the ~40nm slit diaphragm distance, and the network of proteins in the GBM. Charge
selectivity is determined by the negatively charged sialoglycoproteins in the luminal aspect of the
podocyte membrane and the slit diaphragm. The negatively charged glycocalyx lining the endothelium
also confers a negative charge to the structure. The properties of the glomerular filtration barrier allows
it to produce an ultrafiltrate, which is cell free and contains all of the substances in plasma (electrolytes,
glucose, phosphate, urea, creatinine, peptides, low
molecular weight proteins) except proteins having a
molecular weight of 68 kd (such as albumin and globulins).
Normally only a few red blood cells (RBCs) may be passed
out in the urine [<5 RBCs per high power field (hpf)]. Certain
physiologic and pathologic events however cause a
temporary or permanent disruption in the integrity if the
GBM which allows RBCs and protein to pass into the
Bowmans space and therefore present in the urine.

HEMATURIA AND PROTEINURIA

Hematuria and proteinuria are common manifestations of glomerular diseases. Hematuria is
defined as the presence of at least 5 RBCs per microliter of urine or per high power field (hpf) in a spun
urine sample (although different sources will vary from 2 12 RBCs/hpf in a spun freshly voided urine).
The etiology of which must first be narrowed down to either from the upper or from the lower urinary
tract. Hematuria form the glomerulus is usually described as brown, cola or tea-colored, or burgundy urine
with proteinuria >100 mg/dL via dipstick and urinary microscopic findings of RBC casts, and deformed or
dysmorphic urinary RBCs (particularly acanthocytes). Gross hematuria is the term used when evidence of
blood in the urine is visible to the naked eye. Persistent microscopic hematuria is hematuria demonstrated
via 2 3 urinalysis over a 2 3 week period. Urinary tract infection is the most common cause of hematuria
but in some it may be associated with more serious diseases such as glomerulonephritis. Proteinuria
should also be quantified in all patients with hematuria.
Proteinuria could either be glomerular proteinuria, tubular proteinuria, or overflow proteinuria.
Glomerular proteinuria can be detected using the dipstick method. Urine protein electrophoresis will
show that the albumin the dominant fraction; the same as with the serum analysis. The normal rate of
protein excretion in the urine is less than 4 mg/m2/h or less than 150mg/1.73m2/day during childhood.
Abnormal proteinuria is defined as 4 to 40 mg/m2/h. Nephrotic range proteinuria is when protein
excretion exceeds 40 mg/m2/h. Excretion of protein in the urine however varies in different age groups
(Table 9.5 from Clinical Pediatric Nephrology).

Often hematuria and proteinuria are used

to differentiate between nephrotic and nephritic
glomerular syndromes; however the symptoms of
nephrotic syndromes and nephritic syndromes
may overlap and both may occur at the same
time.

NEPHROTIC & NEPHRITIC SYNDROMES

Nephrotic and nephritic syndromes differ in the way fluid is handled by the body. In nephrotic
syndrome, the excretion of protein depletes the albumin in the intravascular space leading to decrease in
oncotic pressure and subsequently fluid extravasation. In nephritic syndromes, the decrease in glomerular
filtration rate causes volume expansion in both intravascular space and extracellular space.

The incidence of nephrotic and nephritic syndromes vary in different age groups. According to the
Department of Health, nephrotic and nephritic syndromes place 10th in the leading causes of mortality for
children 10 to 14 years of age in 2010.

NEPHROTIC SYNDROMES
Nephrotic syndrome is characterized by massive proteinuria, hypoalbuminemia, and edema,
although additional clinical features such as hyperlipidemia are usually also present. Children with this
condition often present with sudden development of periorbital swelling, with or without generalized
edema.

Epidemiology
The annual incidence of nephrotic syndrome ranges from 2 - 7 new cases per 100 000 children
and the prevalence is about 16 cases per 100 000 children, or 1 in 6000 children. Boys are about 2x as
likely as girls to develop nephrotic syndrome during the younger years but nearing adolescence and
adulthood, the disparity in incidence disappears. The presentation of nephrotic syndrome also differs
among different races. Idiopathic nephrotic syndrome is 6x more common among Asian children than in
Caucasian children in the United Kingdom, with an incidence of 16 new cases per 100 000 children per
year. In a study involving children with nephrotic syndrome, African-Americans (47%) have more chance
of having a less favorable diagnosis than Caucasians (18%) or Hispanics (11%). In a community with various
ethnicities such as in Texas, the racial distribution of nephrotic syndrome was 49% Caucasian, 20% AfricanAmerican, and 24% Hispanics.
The peak age of presentation is 2 years but 70-80% of nephrotic syndromes occur in children less
than 6 years old.

Etiology
Primary or idiopathic nephrotic syndrome (INS) is the most common form of nephrotic syndrome
in children. Glomerular lesions associated with idiopathic nephrotic syndrome include minimal change
disease (MNCS), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis,
membranous nephropathy, and diffuse mesangial proliferation.
Nephrotic syndrome may also be secondary to systemic diseases such as systemic lupus
erythematosus, Henoch-Schonlein purpura, malignancy (lymphoma and leukemia), and infections
(hepatitis, HIV, and malaria).
Hereditary nephrotic syndromes also occur in patients possessing mutations in genes encoding
critical proteins in the glomerular filtration barrier.
Nephrotic syndrome appearing in the first 3 months of age are referred to as congenital nephrotic
syndrome (CNS). These are mostly due to genetic causes especially those involved in encoding nephrin
and podocin. In one series mutations in the podocin gene (NPHS2) were shown to be responsible for up
to 40% of all cases of nephrotic syndrome occurring in the first 3 months of life. Multi-system congenital
disorders and congenital infections, such as those from syphilis and cytomegalovirus, can also present as
CNS.

From 3 months to 1 year old, 40% are due to genetic causes. Beyond 1 year, INS predominates,
wherein MNCS comprise 80% of the cases. For children more than 10 years old, the proportion of
secondary nephrotic cases

increases.

Pathogenesis
The central abnormality in all cases of nephrotic syndrome is the development of massive
proteinuria. Evidences from literature show that nephrotic syndrome may be a consequence of a primary
glomerular defect, circulating factors, or an immunological abnormality.
Primary glomerular defects have been observed in histologic samples in nephrotic syndrome and
these include: is loss of negative charge of the GBM; swelling, retraction, and effacement (spreading) of
the podocyte distal foot processes; vacuole formation, occurrence of occluding junctions, displacement
of slit diaphragms; and detachment of podocytes from the GBM.
Circulating factors or soluble mediators that may alter the capillary wall permeability have been
implicated in the development of nephrotic syndrome as evidenced by (1) development of nephrotic
syndrome in newborn babies born to mothers with nephrotic syndrome (2) Marked reduction of
proteinuria following treatment with protein A immunoadsorption (3) recurrence of FSGS in transplanted
kidneys in patients with primary FSGS and (4) induction of enhanced glomerular permeability in
experimental animals injected with serum from patients with FSGS.
Immunological abnormality leading to dysregulation of T cell function is evidenced by (1)
responsiveness of most forms of primary nephrotic syndrome to corticosteroids, alkylating agents,
calcineurin inhibitors (2) Induction of remission of nephrotic syndrome following infections with measles
and malaria (3) identification of MCNS as a paraneoplastic manifestation of Hodgkins disease and other
lymphoreticular malignancies

Pathophysiology
In nephrotic syndrome, urinary excretion of albumin produces a hypoalbuminemic state which
causes sodium and fluid retention. The bodys compensatory response of fluid and sodium accumulation
in the extracellular space or interstitial space leads to facial or generalized edema. The movement of fluid
can be explained by the Starling equation which shows that a decrease in oncotic pressure would result
to unopposed capillary hydrostatic pressure favoring fluid extravasation and edema.
The decrease in pressure distention will be detected by mechanoreceptors in the carotid sinus,
aortic arch, left ventricle, and afferent arterioles in the glomeruli. This produces (1) increased sympathetic
nervous system (SNS) outflow from the central nervous system, (2) activation of the Renin-AngiotensinAldosterone System (RAAS), and (3) nonosmotic release of Arginine Vasopressin (AVP) from the
hypothalamus. These 3 changes result in peripheral vasoconstriction (increased SNS and angiotensin II),
sodium retention (increased SNS, angiotensin II, and aldosterone), and water retention.
The above mentioned process is called the underfill hypothesis. Even though the above
mentioned process is the more famous one, the overfill hypothesis also gains support from chronically
nephrotic patients and some animal models. The overfill hypothesis states that there is hypervolemia
intravascularly
in
contrast
with
hypovolemia
in
the
underfill
hypothesis.

Underfill hypothesis

Overfill hypothesis

Clinical Features
Nephrotic syndrome is usually diagnosed by nephrotic range proteinuria with a triad of clinical
findings associated with large urinary losses of protein. Nephrotic proteinuria refers to urinary protein
excretion greater than 40mg/m2/hr or urinary protein-creatinine ration (UPr/Cr) greater than 2. The triad
of clinical findings include (1) hypoalbuminemia (serum albumin <3.0g/dL), (2) hyperlipidemia or
hypercholesterolemia (>250mg/dL), and (3) edema.
A child with nephrotic syndrome will typically present with periorbital or generalized edema.
Edema is clinically detectable when the fluid retention exceeds 3-5% of the body weight. It is starts in the
periorbital region then to the dependent portions of the body. It is usually pitting, soft, and found on the
dependent portions of the body. Some children may have abdominal distention secondary to ascites or
anterior wall edema. Severe distention may also cause discomfort or pain; wherein bacterial peritonitis
should be ruled out. Gut edema and gut ischemia due to intravascular volume depletion can also cause
abdominal discomfort. Diarrhea due to intestinal edema may also occur. Coughing, tachypnea, and
breathing difficulties may indicate pleural effusion. Pericardial effusions and anasarca may also develop.
Hypertension may be found in 25% of the children. Painful extremities can possibly be encountered as a
manifestation of venous thrombosis, one of complications of nephrotic syndrome.
Systemic symptoms including fevers, weight loss, night sweats, polyuria, polydipsia, hair loss, oral
ulcers, rashes, abdominal pain, and joint pain or swelling should also be elicited, because they may be
manifestations of systemic diseases such as systemic lupus erythematosus, Henoch-Schnlein purpura, or
diabetes mellitus, which can all cause nephrotic syndrome. History of intake of drugs such as NSAIDS, gold,
and penicillamine may also be elicited in some patients. A careful family history may also reveal hereditary
forms of nephrotic syndrome.

Laboratory Findings
Urinalysis is essential in evaluating nephrotic syndrome. Diagnosis of nephrotic syndrome is
confirmed by the triad of generalized edema, proteinuria, albuminuria (>2+ on dipstick or urine
protein/creatinine ratio >2 mg/mg), and hypoalbuminemia (serum albumin <2.5 g/dl), although
hypercholesterolemia is also commonly present.
Microscopic examination of urine sample will
often yield RBC casts. Macroscopic hematuria is rare (3%) while microscopic hematuria is common (20%).
Fat bodies and hyaline casts can also be found in the urine.
Serum studies should include an evaluation of complete blood count, electrolytes, blood urea
nitrogen (BUN), creatinine, and albumin levels. Proteinemia is below 50 g/L in 80% of patients, and below
40 g/l in 40%. Albumin concentration usually falls below 20 g/L and may be less than 10 g/L.
Blood cholesterol or lipid is usually increased due (1) an increased hepatic synthesis of
cholesterol, triglycerides and lipoproteins, (2) a decreased catabolism of lipoproteins due to a decreased
activity of lipoprotein lipase which normally transforms VLDL to LDL, and (3) decreased LDL receptor
activity and an increased urinary loss of HDL. Total cholesterol and LDL cholesterol are elevated while HDL
cholesterol remains unchanged or low.
Serum electrolytes are usually within normal range. There may be relative hyponatremia due to
water retention. Hypocalcemia is due to hypoproteinemia. Hemoglobin levels and hematocrit are
increased in patients with plasma volume contraction. Thrombocytosis is common and may reach 5.10 8
or 109/L.

For patients at an older age at presentation or with atypical presentation, additional serum
studies to exclude secondary causes of nephrotic syndrome should include C3 and C4 complement levels;
antinuclear antibody (ANA) and possibly anti-double-stranded DNA; HIV antibody; hepatitis A, B, and C
serologies; and consideration of other viral serologies such as HIV antibodies.
Renal biopsy is indicated only in the setting of atypical features such as (1) age at onset (<1 year
or >10 years), (2) steroid dependent or steroid resistance, (3) gross or persistent microscopic hematuria
or presence of red cell casts, (4) abnormal serologies, or (5) significant persistent renal failure. It is also
indicated before initiation and every 2 years of use of of second-line or third-line immunosuppressive
agents, such as cyclosporine and tacrolimus due to the known nephrotoxicity (interstitial fibrosis) of
calcineurin inhibitors.

Differential Diagnoses
Transient proteinuria which occurs after vigorous exercise, fever, significant dehydration,
seizures, and adrenergic agonist therapy. In contrast to nephrotic syndrome, the proteinuria usually is
mild (UPr/Cr < 1), and always resolves within a few days.
Postural (orthostatic) proteinuria is a benign condition defined by normal protein excretion while
recumbent, but significant proteinuria when upright. It is more common in adolescents and tall, thin
individuals and not associated with progressive renal disease. Many children with orthostatic proteinuria
continue this process into adulthood.
Tubular proteinuria is the preponderance of low-molecular-weight proteins in the urine which is
suspected in conditions associated with acute tubular necrosis (ATN), pyelonephritis, structural renal
disorders, polycystic kidney disease, and tubular toxins such as antibiotics or chemotherapeutic agents.

Forms of Nephrotic Syndrome

The various histologic glomerular lesions presenting as nephrotic syndrome are confirmed
through renal biopsy, but their different clinic-demographic profiles can be used as clues distinguish
among them.
Minimal change nephrotic syndrome (MCNS) accounts for about 85% of total cases of nephrotic
syndrome in children. The glomeruli appear normal or show a minimal increase in mesangial cells and
matrix. Findings on immunofluorescence microscopy are typically negative, and electron microscopy
simply reveals effacement of the epithelial cell foot processes. More than 95% of children with minimal
change disease respond to corticosteroid therapy.
Mesangial proliferation is characterized by a diffuse increase in mesangial cells and matrix on light
microscopy. Immunofluorescence microscopy is usually negative but may reveal trace to 1+ mesangial
IgM and/or IgA staining. Electron microscopy reveals increased numbers of mesangial cells and matrix as
well as effacement of the epithelial cell foot processes. Approximately 50% of patients with this histologic
lesion respond to corticosteroid therapy.
Focal segmental glomerulosclerosis (FSGS), glomeruli show lesions that are both focal (present
only in a proportion of glomeruli) and segmental (localized to 1 intraglomerular tufts). The lesions consist
of mesangial cell proliferation segmental scarring on light microscopy. Immunofluorescence microscopy
is positive for IgM and C3 staining in the areas of segmental sclerosis. Electron microscopy demonstrates
segmental scarring of the glomerular tuft with obliteration of the glomerular capillary lumen. Only 20% of

patients with FSGS respond to prednisone. The disease is often progressive, ultimately involving all
glomeruli, and ultimately leads to end-stage renal disease in most patients.

Summary of the differences between MCNS and FSGS

MCNS
Age
2-6, some adults
Sex
2:1 male
Manifest as nephrotic syndrome
100%
Asymptomatic proteinuria
0
Hematuria
10-20%
Hypertension
10%
Rate of progression to renal
Does not progress
failure
Light microscopy
Normal
Immunofluorescence
Negative
Response to steroids
90%

FSGS
2-10, some adults
1.3:1 male
90%
10%
60-80%
20% early
10yr
Focal sclerotic lesions
IgM, C3 in all lesions
15-20%

Treatment
Nephrotic syndrome is often classified with its response to treatment.

The initial treatment for new-onset nephrotic syndrome generally includes Prednisone
60mg/m2/day (maximum 80 mg/d) for 4 to 8 weeks followed by 40 mg/m2 every other day for 4 to 8
weeks, and then a gradual taper until it is discontinued. Approximately 75% of the children enter remission
within 2 weeks of treatment and 90-95% enter remission in the initial 4 weeks of treatment.
Edema can be managed by salt restriction, moderate fluid restriction, and judicious use of
diuretics. Albumin can be initiated with 25% albumin at 1-2 g/kg/d either as a continuous infusion or

10

divided q 6-8 hours. Albumin treatment should continue for 4 to 6 hours before initial administration of
diuretics to minimize the risk of worsening any intravascular volume depletion that may be present. In
general, slowly increasing the serum albumin level to ~2.8 g/dl adequately restores the intravascular
oncotic pressure and volume, but there appears to be little additional clinical benefit to increasing the
albumin level to normal values. Diuretic, usually furosemide, is incorporated to lessen the extracellular
fluid. Furosemide incorporation with albumin transfusion or post transfusion also prevents dissipation of
furosemide into the interstitial space. Protein intake is also suggested to be approximately 130% to 140%
of the RDA for age.
Hyperlipidemia is usually transient and require no therapeutic interventions to dietary restrictions
of lipids. In a few chronic cases, hydroxymethylglutaryl CoA (HMG CoA) reductase inhibitors (statins) can
be used.
Angiotensin converting enzyme inhibitors (ACEIs)
are increasingly being used in the management of
persistent proteinuria and control of hypertension in
children with Steroid-Resistant Nephrotic syndrome
(SRNS) or Steroid-Dependent Nephrotic syndrome (SDNS).
Its antiproteinuric effects include reduction of glomerular
capillary plasma flow rate, decrease in transcapillary
hydraulic pressure, and alteration of the permeability of
the glomerular filtration barrier.
For SRNS, Calcineurin inhibitors such as
Cyclosporine,
alkylating
agents,
and
other
immunosuppressives.

Complications
Patients with nephrotic syndrome are prone to infections due to the excretion of IgG, abnormal
T lymphocyte function, and decreased levels of factors (factor B and D) for the alternate complement
pathway. Serious infections developed in as many as 75% of children with nephrotic syndrome, and the
mortality rate was almost 60%. In the past 3 decades, an estimated 70% of deaths in children with
nephrotic syndrome occur due to infection, 50% of which are due to peritonitis. Other than peritonitis,
cellulitis, and sepsis are also common. Streptococcus pneumonia is the most common offending agent,
although infections by Gram-negative organisms such as Escherichia coli and Haemophilus influenzae, are
also commonly seen. The use of steroids and other immunosuppressive agents is also a risk factor for
infections.
Infections, hypovolemia, hypercoagulable state, and immobilizations are predisposing factors for
thrombosis. A study found out that furosemide was found to be the major risk factor for thrombosis,
having been used in 78% of cases of thrombosis (7 of 9 children). Decreased coagulation inhibitors such
asantithrombin III are also usually seen, due to urinary losses, and appear to correlate with the degree of
hypoalbuminemia. The incidence of thromboembolism in children has been reported to range from 1.8 5%. The majority of episodes of thrombosis in children are venous in origin, although arterial thrombosis
has been reported in 1945% of cases. The most common sites for thrombosis are the deep leg veins,

11

inferior vena cava, and ileofemoral veins although other blood vessels may also be affected. Pain and
swelling of an extremity is suggestive of a deep venous thrombosis.
Children with nephrotic syndrome may have restricted growth. Urinary loss of protein hormones
could lead to stunting and hypothyroidism. Corticosteroid therapy can also cause decreased bone
formation and increased bone resorption.
Acute Renal Failure (ARF) in nephrotic syndrome is usually transient but rare cases may require
temporary dialysis. ARF in the setting of nephrotic syndrome may be due to: renal vein thrombosis,
reduced renal perfusion, acute tubular necrosis, interstitial edema within the renal parenchymal bed, and
alterations in glomerular permeability.

Prognosis
The single most important prognostic factor for maintenance of long-term normal renal function
in nephrotic syndrome is the patients initial response to corticosteroids. Steroid responsiveness varies by
renal histologic type. Steroid responsiveness was 93% for MCNS, 30% for FSGS, 56% for mesangial
proliferative glomerulonephritis, 7% for MPGN, and 0% for membranous nephropathy.
Relapses of nephrotic syndrome occur commonly in SSNS. Only 30% patients with SSNS will never
experience a relapse, although the overall tendency to relapse decreases with time. The risk factors for
frequent relapses or a steroid-dependent course include, age of less than 5 years at onset and prolonged
time to initial remission.

NEPHRITIC SYNDROMES
Nephritic syndrome is due to glomerular injury with glomerular inflammation. Clinical
presentations of nephritic syndrome include acute nephritic syndrome, syndrome of rapidly progressive

12

glomerulonephritis, syndrome of recurrent macroscopic hematuria, and syndrome of chronic

glomerulonephritis.
Glomerulonephritis is characterized by glomerular hematuria and other cardinal features of
glomerular injury such as proteinuria, hypertension, edema, oliguria, and renal insufficiency. There are
many types of glomerulonephritis; the classification of which are usually based on histologic examination.
Acute nephritis is defined as acute glomerular injury with: Acute kidney injury (AKI) (oliguria,
uremia, and elevated creatinine), hypertension (salt and water retention), hematuria (microscopic or
macroscopic with red cell casts on microscopy),
peripheral and/or pulmonary edema, and
proteinuria (which can reach nephrotic range in
nephritic-nephrotic syndrome).
Acute nephritis can be caused by post
infectious nephritis, HenochSchnlein purpura
(HSP), IgA nephropathy (IgAN), Systemic lupus
erythematous (SLE), Membranoproliferative
glomerulonephritis (MPGN, anti-GBM disease, or
pauci-immune glomerulonephritis. The main
cause of acute nephritic syndrome is acute post
infectious glomerulonephritis, which usually
follows a streptococcal infection.

ACUTE POST INFECTIOUS GLOMERULONEPHRITIS

Acute post infectious glomerulonephritis (APIG) is characterized by the sudden onset of gross
hematuria, edema, hypertension, renal insufficiency and/or evidence of antecedent streptococcal
infection and interstitium concentrations. Approximately 80% is caused by Streptococcal infections,
wherein it is more appropriately termed Acute Post Streptococcal Glomerulonephritis (APSGN)11. The
following discussions will use APSGN since it is a prototype for other APIG.

Epidemiology
APIG is the most common renal pathology in underdeveloped countries. In hot climates with high
humidity, it can be a complication of pyoderma. In countries with moderate and cold climates, it is a
complication of upper respiratory tract infections (pharyngitis) during the winter months. Populations at
risk were children and soldiers due to intimate contact, overcrowded living conditions, and poor hygiene
and sanitation systems. sThe male: female ratio is up to 2:1 and it is most common in children aged 3 to12
years.

Etiology
APIG can be due to various pathogenic organisms ranging from bacteria to parasites.

Some sources simply use post-streptococcal glomerulonephritis or PSGN instead of APSGN. Denis F. Geary, Franz
Schaefer. 2008. Comprehensive pediatric nephrology. Mosbly Elsevier. Philadelphia.

13

Group A -hemolytic Streptococcus is the most common etiologic agent. The capsular M-protein
defines whether the bacterial strain is nephritogenic. Nephritogenic strains are divided into pharyngitisassociated serotypes (1, 3, 4, 12 and 49) and skin infection-associated serotypes (2,49, 55, 57, and 60).

Pathogenesis
APSGN is an immune complex disease although the nature of the nephritogenic antigen is still
unknown. The proposed mechanisms involve: (1) deposition of circulating immune complexes containing
nephritogenic antigen in glomeruli, (2) implantation of the nephritogenic antigen into glomerular
structures and in situ formation of immune complexes, (3) molecular mimicry between streptococcal
antigens and normal glomerular antigens that react with antibodies against streptococcal antigens, and
(4) direct activation of the complement system by implanted streptococcal antigens.

Pathology
The most typical feature observed via light microscopy is
diffuse enlargement of all glomeruli due to hypercellularity. Swelling
of the endothelial cells leads to the obliteration of the capillary loops.
There is increased number of mesangial cells. There is recruitment of
numerous inflammatory cells in the glomeruli, mainly
polymorphonuclear leukocytes and monocytes; thus this
pathological picture is termed exudative proliferative
glomerulonephritis.
Immunofluorescent study shows irregular granular deposits
of complement and immunoglobulins. The most common finding is
the presence of C3 and IgG, but C4, C1q, IgM, fibrinogen, and factor
B may be also found.

14

Starry sky is the fine granular deposition of C3 and IgG along the capillary walls in the 1st week of
the disease. Mesangial pattern is found between the 4th and 6th week after disease onset (C3, which is
found in mesangial location). Garland type is characterized by
dense, confluent deposits along the capillary loops, while
mesangial and endocapillary locations are preserved.

Clinical Features
Approximately 90% of APSGN cases occur in young
children after streptococcal pharyngeal or skin infections. The
latency period from infection to presentation is 714 days for
pharyngeal and 1421 days for post-impetigo disease. One-third
of APSGN patients develop discrete microscopic hematuria
and/or proteinuria in the latent period.
Usually the disease has sudden onset with development
of nephritic syndrome (edema, oliguria, azotemia, hematuria,
and hypertension). At the onset of the disease, initial nonspecific
symptoms may be present, such as pallor, malaise, low-grade
fever, lethargy, anorexia, and headache. Dull abdominal or flank
pain may be present.
Gross hematuria with brownish (coke-or-tea-colored)
discoloration of urine is present in 30% to 70% of patients while
microscopic hematuria is present in all patients.
There is edema from retention of salt and water. Most children have mild morning periorbital
edema. Also edema may be located in the pretibial area and may be generalized (anasarca) with presence
of pleural effusion and ascites. Mild edema may not often be recognized by parents, but it becomes
obvious when a child had significant weight loss in the diuretic phase.
Hypertension is the 3rd cardinal sign in APSGN. It is found in up to 70% of hospitalized children. It
Retention of water and salt leads to expansion of the extracellular fluid volume with consequent
suppression of the renin-angiotensin-aldosterone axis. Normalization of the blood pressure correlates
with increased diuresis and recovery of renal function. If elevated blood pressure persists 4 weeks after
disease onset, rapidly progressive disease or chronic glomerulonephritis should be suspected.

Laboratory Findings
Urinalysis with microscopic studies would show red cell casts are present in association with
dysmorphic of red cells, frequently presenting doughnut shape with one or more blebs. Macroscopic
hematuria usually disappears after a few days but microscopic hematuria may persist for a year and
occasionally exacerbates during febrile episodes and more rarely after strenuous exercise.
Massive proteinuria with or without other features of the nephrotic syndrome are found in
about 24% of the cases and its persistence is a risk factor for progression to chronic renal disease.
A mild dilutional anemia may be seen at the onset of the disease, and is due to expansion of the
extracellular fluid volume. Serologic testing would, in 90% of the cases, show a reduction in serum
complement levels. Typically, complement levels normalize in 6 - 8 weeks. If hypocomplementemia

15

persists more than 3 months, an alternative diagnosis, such as membranoproliferative

glomerulonephritis, should be strongly considered. IgG and IgM serum levels are elevated 8090% of the
patients with APSGN.
Rising antistreptococcal antibody titers are the usual clinical indication of a preceding
streptococcal infection since positive cultures are obtained in only 2025% of the cases. Antistreptolysin
O titers and anti-DNAse B titers are the most frequently elevated antibody titers after streptococcal throat
infections and after streptococcal impetigo, respectively.
Renal Biopsy is the confirmatory test in difficult cases.

Differential Diagnoses
Urinary tract infection (UTI) is the most common identifiable cause of hematuria in children;
hence other symptoms, of edema and hypertension, as well as the progression of the disease should not
be missed out in the examination of the patient. Hematuria may also occurs in sickle cell trait or disease,
after strenuous exercise, and after renal trauma.
Benign familial hematuria is a relatively common, nonprogressive, usually autosomal dominant
disorder, characterized by thinning of the glomerular basement membrane (GBM).

Treatment
Antibiotic therapy is indicated if there are still signs of streptococcal infection (pharyngitis,
pyoderma) or patients have a positive throat or skin culture. Antibiotic treatment does not alter the
course of the disease, but it is very important in preventing the spread of nephritogenic strains of GABHS.
A 10-day course of systemic antibiotic therapy recommended to limit the spread of nephritogenic
strain. Penicillin is the drug of choice. Oral penicillin V (or erythromycin for allergic patients) is preferred
over parenteral penicillin. Amoxicillin or Co-amoxiclav can also be given as alternatives.
In those with over 30% crescents seen in histologic examination, they may be treated with pulse
methylprednisolone 0.5-1.0 g/1.73 m2 for 3 - 5 days. Salt intake should be limited to less than 1.0 g/day.
Protein intake should be limited to 1.0 g/kg/day. Loop diuretics (furosemide 1-2 mg/kg/day) are indicated
if there is moderate circulatory congestion. Higher doses up to 5 mg/kg per intravenous (IV) dose are
indicated if there is pulmonary edema.

16

Prognosis
Complete recovery occurs in 95% of children with post-strep GN. Mortality avoided by
appropriate management of acute renal failure, cardiac failure and hypertension. Infrequently acute
phase maybe severe and lead to glomerular hyalinization and chronic kidney disease. Recurrences is
extremely rare.

Rapidly Progressive Glomerulonephritis

Rapidly Progressive Glomerulonephritis or RPGN is a clinical syndrome characterized by an acute
nephritic illness accompanied by a rapid loss of renal function (>50% decrease in GFR) over days to weeks.
The terms RPGN and crescentic GN are used interchangeably. There is a large presence of epithelial
crescents in the Bowmans space involving 50% or more glomeruli.

Etiology
RPGN is believed to be the result of severe nonspecific glomerular injury, with numerous underlying
causes.

Pathogenesis
There is a physical gap in the glomerular capillary
wall and glomerular basement membrane (GBM). Breaks
in the integrity of the capillary wall lead to passage of
plasma proteins and inflammatory mediators into the
Bowmans space with fibrin formation, influx of
macrophages and T cells, and release of proinflammatory
cytokines.
The presence of coagulation factors and various
proliferating cells, chiefly macrophages, parietal
glomerular epithelial cells, and interstitial fibroblasts
initiates the development of crescents.

Clinical Manifestations
The spectrum of presenting features is variable,
and includes macroscopic hematuria (in 6090% patients), oliguria (60100%), hypertension (6080%)
and edema (6090%) (10, 13, 18). The illness may be complicated by the occurrence of hypertensive
emergencies, pulmonary edema and cardiac failure. Occasionally, RPGN has an insidious onset with the
initial symptoms being fatigue or edema. Nephrotic syndrome is rare and seen in patients with less severe
renal insufficiency.

Diagnosis
There is hematuria in all patients with dysmorphic red cells and red cell casts seen microscopically.
Most also have gross hematuria. A variable degree of nonselective proteinuria (2+ to 4+) is present in
more than 65% of patients. Urinalysis also shows leukocyte, granular, and tubular epithelial cell casts.

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Renal insufficiency is present at diagnosis in almost all cases, with the plasma creatinine
concentration often exceeding 3 mg/dl (264 mol/L).

Treatment
The specific treatment of RPGN broadly comprises two phases: (1) induction of remission and its
(2) maintenance. Combination therapy with high-dose corticosteroids and cyclophosphamide is the
current standard for induction treatment, with additional therapy for those with life- or organ threatening
disease. The treatment includes Cyclophosphamide oral dose of 2 mg/kg/day, or IV starting at 500 mg/m2
and increased monthly by 125 mg/m2 to a maximum of 750 mg/m2,IV pulses of methylprednisolone (1520 mg/kg, maximum 1 g/day) for 3 to 6 days,
followed by high-dose oral prednisone (1.5-2
mg/kg daily) for 4 weeks, tapering to 0.5
mg/kg daily by 3months and alternate-day
prednisone for 6 to 12 months.
The requirement for maintenance
therapy in RPGN depends on the underlying
disease.

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
Also referred to as mesangiocapillary glomerulonephritis, Membranoproliferative
glomerulonephritis is a collection of morphologically related but pathogenetically distinct disorders. They
are characterized by glomerular hypercellularity, increased mesangial matrix, and thickening of the
peripheral capillary walls.

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The morphologic pattern upon light microscopy shows a pattern of injury characterized by
mesangial proliferation and thickening of the peripheral GBM. The thickening is due to mesangial cell
interposition with double contours of the GBM and cloverleaf-like accentuation of the glomerular tuft

IGA NEPHROPATHY
IgA nephropathy is a glomerular disease characterized by the presence of IgA deposits prevalent
over other classes of immunoglobulins. It can be observed in association with features of systemic
vasculitis in Henoch- Schnlein purpura or can be renal limited, as described by Berger (primary IgAN).
It presents as recurrent episodes of gross hematuria concomitant with upper respiratory tract
infections or other mucosal inflammatory processes. The 1st episode of macroscopic hematuria generally
occurs between 15 and 30 years of age. Affected children do not present symptoms or urinary signs before
the age of 3 thereafter the frequency increases with age. Gross hematuria affects 30% to 40% of children
with IgAN.
The treatment is based on the clinical features. Medical interventions range from no specific
treatment to ACEI or Angtiotensin Receptor Blockers (ARBs) to Prednisone or Prednisolone.