Pediatric Nephrotic Nephritic Syndromes

7/23/2019 Pediatric Nephrotic Nephritic Syndromes

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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 efferentarterioles. 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 50100 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 [


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HEMATURIA AND PROTEINURIA

Hematuria and proteinuria are common manifestations of glomerular diseases. Hematuria isdefined 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 23 urinalysis over a 23 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).


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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 10thin 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.


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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 inCaucasian 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% African-

American, 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 syndromein 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 nephroticsyndrome (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.


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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 inexperimental 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


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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 fluidcan 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-Angiotensin-

Aldosterone 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


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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 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 urineprotein/creatinine ratio >2 mg/mg), and hypoalbuminemia (serum albumin


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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 (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 distinguishamong 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 intraglomerulartufts). 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


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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 FSGSAge 2-6, some adults 2-10, some adults

Sex 2:1 male 1.3:1 male

Manifest as nephrotic syndrome 100% 90%

Asymptomatic proteinuria 0 10%

Hematuria 10-20% 60-80%

Hypertension 10% 20% early

Rate of progression to renal

failure

Does not progress 10yr

Light microscopy Normal Focal sclerotic lesions

Immunofluorescence Negative IgM, C3 in all lesions

Response to steroids 90% 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/m2every 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


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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 offurosemide 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 pneumoniais 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,


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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 SYNDROMESNephritic syndrome is due to glomerular injury with glomerular inflammation. Clinical

presentations of nephritic syndrome include acute nephritic syndrome, syndrome of rapidly progressive


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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), Membranoproliferativeglomerulonephritis (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 POSTINFECTIOUS GLOMERULONEPHRITISAcute postinfectious 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.

1Some sources simply use post-streptococcal glomerulonephritis or PSGN instead of APSGN. Denis F. Geary, Franz

Schaefer. 2008. Comprehensive pediatric nephrology. Mosbly Elsevier. Philadelphia.


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Group A -hemolytic Streptococcusis the most common etiologic agent. The capsular M-protein

defines whether the bacterial strain is nephritogenic. Nephritogenic strains are divided into pharyngitis-

associated 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.


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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 nonspecificsymptoms 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 andoccasionally 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


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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 dominantdisorder, 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 m2for 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.


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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 GlomerulonephritisRapidly 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 non-specific 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/m2to a maximum of 750 mg/m2,IV pulses of methylprednisolone (15-20 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 GLOMERULONEPHRITISAlso 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 NEPHROPATHYIgA 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.

Documents

Pediatric Nephrotic Nephritic Syndromes