Nephrotic syndrome.doc

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Nephrotic syndrome

DEFINITIONS

Nephrotic syndrome is a syndrome (a collection of symptoms) that occur due to variousdiseases that attack the kidneys and cause:

- Proteinuria (protein in urine)

- Decreasing levels of albumin in the blood- Accumulation of excessive salt and water

- Increased blood fat levels.

This syndrome can occur at any age.

In children, most often arise at the age of 18 months to 4 years, and more attacking boys.

CAUSENephrotic syndrome can occur due to various chronic diseases glomerulopati or broad.

A number of drugs that are toxic to the kidneys can also cause nephrotic syndrome, as

well as with intravenous heroin use.

Nephrotic syndrome can be associated with particular sensitivity.

Some types of nephrotic syndrome are derived.

Nephrotic syndrome associated with HIV (human immunodeficiency virus, causes AIDS)

occur most commonly in black people who suffer from this infection.Nephrotic syndrome developed into total renal failure within 3-4 months.

# The cause of nephrotic syndrome: The disease

- Amyloidosis- Cancer

- Diabetes- Glomerulopati- HIV Infection

- Leukemia

- Lymphoma- Gamopati monoclonal

- Multiple myeloma

- Systemic lupus erythematosus

# Drugs- Drugs that resembles aspirin pain reliever

- Gold compounds

- Heroin intravenous- Penicillamine

# Allergies

- Insect Bites- Poison ivy tree

- Poison oak

- Sunlight.


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SYMPTOMS

Initially the symptoms can include:

- Decreased appetite- Eyelid swelling

- Nyer stomach

- Pengkisutan muscle- Swelling of tissue due to accumulation of salt and water

- Foamy urine.

Stomach can swell due to fluid retention and shortness of breath may occur as a result of

fluid in the cavity surrounding the lungs (pleural effusion).

Other symptoms are swelling of the knee and pocket penis (in men).Swelling that occurs frequently move around, on the morning of fluid in the eyelids and

buried After running the liquid will be buried at the ankle.

Pengkisutan be covered by the swollen muscle.

In children can decrease blood pressure when the patient standing and low blood pressure

(which can cause shock),.Blood pressure in adult patients can be low, normal or high.

Urine production can be reduced and renal failure can occur due to low blood volume andreduced blood flow to kidneys.

Sometimes kidney failure accompanied by decreased urine formation occurs suddenly.

Nutritional deficiencies can occur due to loss of nutrients (eg glucose) into the urine.Growth can be stunted children. Will be absorbed calcium from the bones. Hair and nails

become brittle and hair loss can occur. At the fingernails will form a white horizontal line

that the cause is unknown.

Stomach lining can become inflamed (peritonitis).

Frequent opportunistic infections (infections caused by bacteria that are normally notdangerous).

The high incidence of infection is believed to occur due to the loss of antibodies into the

urine or due to reduced formation of antibodies.

Blood clotting abnormalities occur, which would increase the risk of clot formation

inside blood vessels (thrombosis), particularly in the main renal vein.

On the other hand, the blood can not freeze and cause bleeding.

High blood pressure accompanied by complications in heart and brain most likely to

occur in patients who have diabetes and connective tissue disease.

DIAGNOSIS

Diagnosis based on symptoms and results of laboratory examination.


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Laboratory examination of urine showed a high protein content.

The concentration of albumin in the blood is low because of this vital proteins excreted in

urine and its formation disrupted.Sodium concentration in urine is low and levels of potassium in the urine is high.

The concentration of fat in the blood are high, sometimes up to 10 times the normalconcentration. Lipid content in urine was also high.

Anemia can occur. Blood clotting factors can be decreased or increased.

Urine and blood analysis can show the cause.

If patients lose weight or age information, then sought the possibility of cancer.

Renal biopsy is particularly effective in classifying the typical kidney tissue damage.

TREATMENT

The goal of treatment is to address the cause.

Treating infections cause nephrotic syndrome can cure this syndrome.

If the cause is a treatable disease (eg, Hodgkin's disease or other cancers), then treat it

will reduce the symptoms of kidney.

If the cause is addicted to heroin, then stop using heroin in the early stages of nephrotic

syndrome, can eliminate the symptoms.

Patients who are sensitive to sunlight, poison oak, poison ivy or insect bites trees; should

avoid such materials.

Desensitization can cure nephrotic syndrome caused by poison oak, ivy or insect bitestree.

If the cause is drugs, then to deal with nephrotic syndrome, the use of drugs should bediscontinued.

If you can not find the exact cause, then given corticosteroids and drugs that suppress theimmune system (eg cyclophosphamide).

But these drugs can cause stunted growth in children and suppress sexual development.

Common treatment is a diet that contains protein and potassium in the normal amount ofsaturated fat and sodium low.

Too much protein increases the protein content in urine.

ACE inhibitors (eg enalapril, captopril and lisinopril) usually reduce the disposal ofprotein in urine and concentration of fat in the blood.

But in patients who have mild kidney dysfunction to severe, the drug can increase blood

potassium levels.

If the liquid buried in the stomach, to reduce symptoms are encouraged to eat smaller

portions but often.


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High blood pressure is usually treated with diuretics.

Diuretics also can reduce fluid retention and tissue swelling, but may increase the risk of

blood clots.

Anticoagulants may help control blood clot formation.

Antibiotics

Prognosis varies according to its causes, patient age and type of kidney damage that can

be known from the microscopic examination of biopsies.

The symptoms will disappear entirely if the cause is a treatable illness (eg infection or

cancer) or drugs.

Prognosis is usually good if the cause is good response to corticosteroids.

Children who are born with this syndrome rarely survive to age 1 year, some of which

can survive after undergoing kidney dialysis or transplantation.

The best prognosis was found in nephrotic syndrome due to a mild glomerulonephritis;90% patients with adult children and responds well to treatment.

Rarely develops into kidney failure, although it tends to be recurrent. But after one year

free of symptoms, recurrence is rare.

Nephrotic syndrome caused by membranous glomerulonefritis mainly occurs in adults

and in 50% of patients aged over 15 years, this disease will gradually develop into kidney

failure.50% of other patients have experienced healing or proteinuria constantly but with

adequate renal function.

In children with membranous glomerulonephritis, proteinuria will disappear completelyand spontaneously within five years after his illness was diagnosed.

Familial nephrotic syndrome and glomerulonephritis membranoproliferatif respondpoorly to treatment and prognosis is not too good.

More than half of patients with familial nephrotic syndrome die within 10 years. At 20%

pendeita worse prognosis, namely severe renal failure within two years.

In 50% patients, glomerulonephritis membranoproliferatif evolved into renal failure in 10years time. In less than 5% of patients, the disease showed improvement.

Nephrotic syndrome due to mesangial proliferative glomerulonephritis did not respond tocorticosteroids.

Treatment of nephrotic syndrome due to systemic lupus erythematosus, amyloidosis ordiabetes, are primarily intended to reduce the symptoms.

Latest treatment for lupus can reduce symptoms and improve the examination results are

abnormal, but in most patients with progressive renal failure.

In patients with diabetes, severe renal disease usually occur within 3-5 years.


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Prognosis of nephrotic syndrome caused by infection, allergy and intravenous heroin use

varies, depending on how quickly and how effectively the causes addressed.

http://medicastore.com/penyakit/719/Sindroma_Nefrotik.html

Introduction

Background

Nephrotic syndrome (NS), also known as nephrosis, is defined by the presence ofnephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. Nephrotic-

range proteinuria in adults is characterized by protein excretion of 3.5 g or more per day.

However, because of the great range of body sizes in children, the pediatric definition ofnephrotic-range proteinuria is more cumbersome. Nephrotic-range proteinuria in childrenis protein excretion of more than 40 mg/m2/h. Because 24-hour urine collections are

potentially unreliable and burdensome, especially in young children, many pediatric

nephrologists instead rely on a single, first-morning urine sample to quantify proteinexcretion by the ratio of protein to creatinine.1

The use of a first-morning urine sample eliminates the contribution of potentiallynonpathological orthostatic proteinuria, which might otherwise falsely elevate the protein

level in a urine sample collected while a patient is active during the day. A urine

protein/creatinine value of more than 2-3 mg/mg indicates nephrotic range proteinuria

and correlates with results from 24-hour urine collection.

Nephrotic syndrome is a constellation of clinical findings that is the result of massive

renal losses of protein. Thus, nephrotic syndrome is not a disease itself, but themanifestation of many different glomerular diseases. These diseases might be acute and

transient, such aspostinfectious glomerulonephritis, or chronic and progressive, such as

focal segmental glomerulosclerosis (FSGS). Still other diseases might be relapsing andremitting, such as minimal change nephrotic syndrome (MCNS).

The glomerular diseases that cause nephrotic syndrome generally can be divided intoprimary and secondary etiologies. Primary nephrotic syndrome (PNS), also known as

idiopathic nephrotic syndrome (INS), is associated with glomerular diseases intrinsic tothe kidney and not related to systemic causes. The subcategories of INS are based on

histological descriptions, but clinical-pathological correlations have been made. A widevariety of glomerular lesions can be seen in INS. These include MCNS, focal segmental

glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative

glomerulonephritis (MPGN), diffuse mesangial proliferation and others.
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By definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney.

Secondary causes of nephrotic syndrome include Henoch-Schnlein purpura (HSP),

systemic lupus erythematosus, diabetes mellitus, syphilis,human immunodeficiencyvirus (HIV), hepatitis B and C, malignancy, vasculitis, and drug exposure (heroin,

mercury, and others), among many other etiologies (seeCauses).

Nephrotic syndrome may also be caused by genetic abnormalities. Infantile NS

(presenting before age 3 mo) and congenital NS (presenting at age 4-12 mo) have been

associated with defects in the nephrin gene (NPHS1), phospholipase C epsilon 1 gene(PLCE1), and the Wilms tumor suppressor gene (WT1). Mutations in the podocin gene

(NPHS2) are associated with a familial, autosomal-recessive form of FSGS. Mutations in

the -actinin-4 gene (ACTN4) and the gene TRPC6are associated with autosomal-

dominant forms of familial FSGS. Additionally, other genetic syndromes have beenassociated with nephrotic syndrome, such asNail-Patella syndrome, Pierson syndrome,

Schimke immuno-osseous dysplasia, and others. (See Pathophysiology and Causes)

INS is divided into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome(SRNS) because response to steroids has a high correlation with histological subtype and

prognosis. The landmark study of nephrotic syndrome in children, the International Studyof Kidney Disease in Children (ISKDC), found that the vast majority of preadolescent

children with INS had MCNS on kidney biopsy.2,3Whereas 90% of children with MCNS

responded to corticosteroid treatment with remission of their nephrotic syndrome, only20% of children with FSGS responded to steroids.

This article focuses on INS, primarily SSNS (which primarily consists of MCNS). The

treatment and prognosis of SRNS (primarily FSGS in children) is briefly discussed. Thediscussion of congenital and secondary nephrotic syndrome is beyond the scope of this

article.

Pathophysiology

Proteinuria and Hypoalbuminemia

The immune system and proteinuria

The hallmark of INS is massive proteinuria, leading to decreased circulating albuminlevels. The initiating event that produces proteinuria remains unknown. INS is believed to

have an immune pathogenesis. Studies have shown abnormal regulation of T-cell subsets

and expression of a circulating glomerular permeability factor. Evidence of the immune-mediated nature of INS is demonstrated by the fact that immunosuppressive agents, suchas corticosteroids and alkylating agents, can result in remission of nephrotic syndrome.

Furthermore, nephrotic syndrome has been known to remit during infection with the

measles virus, which suppresses cell-mediated immunity. However, the precise nature ofthe immune pathogenic process has yet to be defined.

A circulating factor may play a role in the development of proteinuria in INS. This can be
http://emedicine.medscape.com/article/984105-overviewhttp://emedicine.medscape.com/article/1008066-overviewhttp://emedicine.medscape.com/article/1008066-overviewhttp://emedicine.medscape.com/article/969023-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/982920-overview#ClinicalCauseshttp://emedicine.medscape.com/article/982920-overview#ClinicalCauseshttp://emedicine.medscape.com/article/947391-overviewhttp://emedicine.medscape.com/article/982920-overview#IntroductionPathophysiologyhttp://emedicine.medscape.com/article/982920-overview#ClinicalCauseshttp://emedicine.medscape.com/article/984105-overviewhttp://emedicine.medscape.com/article/1008066-overviewhttp://emedicine.medscape.com/article/969023-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/982920-overview#ClinicalCauseshttp://emedicine.medscape.com/article/947391-overviewhttp://emedicine.medscape.com/article/982920-overview#IntroductionPathophysiologyhttp://emedicine.medscape.com/article/982920-overview#ClinicalCauses


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demonstrated by the rapid development of proteinuria in recurrence of nephrotic

syndrome after kidney transplantation, the improvement in nephrotic syndrome in such

patients after treatment with plasmapheresis, and the experimental induction ofproteinuria in animals by plasma from patients with INS. However, the nature of this

circulating factor is not known. Various cytokines and molecules have been implicated,

including interleukin (IL)-2, IL-2 receptor, IL-4, IL-12, IL-13, IL-15, IL-18, interferon-,tumor growth factor (TGF)-, vascular permeability factor, nuclear factor (NF)-B, and

tumor necrosis factor (TNF)-.4

The association of allergic responses with nephrotic syndrome also illustrates the role of

the immune system in INS. Nephrotic syndrome has been reported to occur after allergicreactions to bee stings, fungi, poison ivy, ragweed, house dust, jellyfish stings and cat fur.

Food allergy might play a role in relapses of INS; a reduced-antigenic diet was associated

with improved proteinuria and complete remission in one study.5Additionally, INS is 3-4times more likely in children with human leukocyte antigen (HLA)-DR7. Steroid

sensitive INS has also been associated with HLA-B8 and theDQB1 gene of HAL-

DQW2. A greater incidence of INS is also observed in children with atopy and HLA-B12.6

Genetics, the podocyte, and proteinuria

Perhaps the most exciting development in recent years in understanding thepathophysiology of nephrotic syndrome has occurred in the area of podocyte biology (see

the image below).

Schematic drawing of the glomerular barrier. Podo = podocytes; GBM =

glomerular basement membrane; Endo = fenestrated endothelial cells; ESL

= endothelial cell surface layer (often referred to as the glycocalyx).

Primary urine is formed through the filtration of plasma fluid across the

glomerular barrier (arrows); in humans, the glomerular filtration rate

(GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min,with the filtration fraction being 20%. The concentration of albumin in

serum is 40 g/L, while the estimated concentration of albumin in primary

urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from

Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the

American Physiological Society (www.the-aps.org).

[ CLOSE WINDOW ]


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The glomerular filtration barrier consists of the fenestrated capillary endothelium, the

extracellular basement membrane, and the intercalated podocyte foot processes,connected by 35-45 nm slit diaphragms. Nephrotic syndrome is associated with the

biopsy finding of fusion (effacement) of podocyte foot processes. This effacement of the

podocytes long was thought to be a secondary phenomenon of nephrotic syndrome.

However, theories have shifted towards the podocyte as playing a primary role in the

development of proteinuria. The understanding of the pathophysiology of proteinuria inrenal diseases has greatly expanded with insights into the molecular biology of the

podocyte. Various forms of INS have been described with mutations in podocyte genes,

such as those associated with the slit-diaphragm and podocyte cytoskeleton

(NPHS1NPHS2, TRCP6, CD2AP, ACTN4); the glomerular basement membrane(LAMB2); mitochondria (COQ2); and transcription factors (WT1, LMX1B).7

Nephrin is a transmembrane protein that is a major structural element of the slit

diaphragm and is encoded by theNPHS1 gene on chromosome 19. Mutations in theNPHS1 gene are responsible for autosomal recessive, congenital nephrotic syndrome of

the Finnish type (FNS). FNS is characterized by massive proteinuria in the first year oflife (usually within the first 3 mo) and progression to end-stage kidney disease within the

first decade of life, although patients with milder forms of the disease have been

described.7Although mutations inNPHS1 are usually associated with congenitalnephrotic syndrome, Philipe and colleagues have describedNPHS1 mutations in children

aged 6 months to 8 years with later onset SRNS.8Additionally, Santin has described

NPHS1 mutations in patients with later childhood onset as well as adult-onset SRNS.9

Podocin is another podocyte protein that interacts with nephrin and CD2AP and is

integral to the assembly of the slit diaphragm. Podocin is encoded by the NPHS2 gene on

chromosome 1. Mutations in theNPHS2 gene were originally described in patients withautosomal recessive, steroid-resistant INS with FSGS on biopsy findings. Podocin

mutations account for approximately 45-55% of familial and 8-20% of sporadic cases of

SRNS.7

-Actinin-4, encoded by the geneACTN4 on chromosome 19, crosslinks actin filaments

of the podocyte cytoskeleton and anchors them to the glomerular basement membrane.

The TRPC6gene on chromosome 11 encodes for a calcium channel associated with theslit diaphragm.7Disruptions in eitherACTN4 orTRPC6are associated with autosomal

dominant forms of FSGS.6

CD2AP, which codes for a podocyte protein that associates with podocin and nephrin,

has been associated with the development of nephrotic syndrome in animal models.

However, the role it plays in human nephrotic syndrome is unclear. Various case reportshave demonstrated heterozygous mutations in CD2APin patients with nephrotic

syndrome and FSGS. One report describes a single patient with a homozygous mutation

in CD2APand early onset of nephrotic syndrome with FSGS and diffuse mesangial

sclerosis.7


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Nonmuscle myosin heavy chain 9 (MYH9) is a podocyte protein that binds to the

podocyte actin cytoskeleton to perform intracellular motor functions.10MYH9polymorphisms are estimated to account for more than 40% of end-stage kidney disease

cases among blacks and has been associated with FSGS, HIV-associated nephropathy,

and focal global glomerulosclerosis (which had been previously attributed tohypertensive nephrosclerosis in many patients). The E1 haplotype of MYH9 is present in

60% of blacks compared with 4% of individuals with European ancestry.11

Other genetic forms of nephrotic syndrome continue to shed light on the pathogenesis of

INS. Mutations in the developmental regulatory gene WT1 are associated withDenys-

Drash syndrome and Frasier syndrome, forms of congenital nephrotic syndrome

associated with male pseudohermaphroditism, Wilms tumor(Denys-Drash syndrome),and gonadoblastoma (Frasier syndrome). Mutations in phospholipase C epsilon 1

(PLCE1), a cytoplasmic enzyme required for podocyte maturation, have been associated

with as many as 28% of cases of congenital nephrotic syndrome due to isolated

(nonsyndromic) diffuse mesangial sclerosis. Nail-patella syndrome, a disordercharacterized by skeletal and nail dysplasia as well as nephrotic syndrome, is caused by

mutations in theLMX1B gene, which regulates expression of type IV collagen and thepodocyte proteins nephrin, podocin, and CD2AP.12

Pierson syndrome, characterized by microcoria, abnormal lens shape, cataracts,blindness, severe neurological deficits, congenital nephrotic syndrome and progressive

kidney failure, is caused by a mutation in theLAMB2 gene that codes for laminin b2,

which is found in glomerular basement membrane, retina, lens and neuromuscular

synapses.7

The role of alterations in the slit diaphragm in MCNS has not been elucidated. Podocin

appears to be expressed normally in MCNS but decreased in FSGS. Mutations in nephrinand podocin do not at this time appear to play a role in steroid-sensitive nephrotic

syndrome. However, acquired alterations in slit diaphragm architecture might play a role

in INS apart from actual mutations in the genes encoding podocyte proteins. Variousauthors have reported changes in expression and distribution of nephrin in MCNS.

Coward et al demonstrated that nephrotic plasma induces translocation of the slit

diaphragm proteins nephrin, podocin, and CD2AP away from the plasma membrane intothe cytoplasm of the podocyte.13These authors also demonstrated the normal plasma

might contain factors that maintain the integrity of slit diaphragm architecture and that

the lack of certain factors (rather than the presence of an abnormal circulating factor)might be responsible for alterations in the podocyte architecture and development of INS.

Apart from the podocyte and slit diaphragm, alterations in the glomerular basement

membrane also likely play a role in the proteinuria of nephrotic syndrome. In INS, the

glomerular capillary permeability to albumin is selectively increased, and this increase infiltered load overcomes the modest ability of the tubules to reabsorb protein. In its normal

state, the glomerular basement membrane is negatively charged because of the presence
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of various polyanions along this surface, such as heparan sulfate, chondroitin sulfate, and

sialic acid. This negative charge acts as a deterrent to filtration of negatively charged

proteins, such as albumin. Experimental models in which the negative charges areremoved from the basement membrane show an increase in albuminuria. Children with

MCNS have been reported to have decreased anionic charges in the glomerular basement

membrane.12

Edema

The classical explanation for edema formation is a decrease in plasma oncotic pressure,as a consequence of low serum albumin levels, causing an extravasation of plasma water

into the interstitial space. The resulting contraction in plasma volume leads to stimulation

of the renin-angiotensin-aldosterone axis and antidiuretic hormone. The resultantretention of sodium and water by the renal tubules contributes to the extension and

maintenance of edema.

While the classical model of edema (also known as the "underfill hypothesis") seemslogical, certain clinical and experimental observations do not completely support thistraditional concept. First, the plasma volume (PV) has not always been found to be

decreased and, in fact, in most adults, measurements of PV have shown it to be increased.

Only in young children with MCNS have most (but not all) studies demonstrated areduced PV. Additionally, most studies have failed to document elevated levels of renin,

angiotensin, or aldosterone, even during times of avid sodium retention. Active sodium

reabsorption also continues despite actions that should suppress renin effects (such as

albumin infusion or ACE inhibitor administration).

Coupled with these discrepancies is the fact that, in the steroid-responsive nephrotic,

diuresis usually begins before plasma albumin has significantly increased and beforeplasma oncotic pressure has changed. Some investigators have demonstrated a blunted

responsiveness to atrial natriuretic peptide (ANP) despite higher than normal circulating

plasma levels of ANP.14

Another model of edema formation is known as the "overfill hypothesis." In this model, aprimary defect in renal sodium handling is postulated. A primary increase in renal sodium

reabsorption leads to net salt and water retention and subsequent hypertension. ANP

might play a role is this mechanism; studies have shown an impaired response to ANP innephrotic syndrome. This ANP resistance, in part, might be caused by overactive efferent

sympathetic nervous activity, as well as enhanced tubular breakdown of cyclic guanosine

monophosphate. Other mechanisms that contribute to a primary increase in renal sodiumretention include overactivity of the Na+ -K+ -ATPase and renal epithelial sodium channel

(RENaC) in the cortical collecting duct and shift of the Na+/H+ exchangerNHE3 from the

inactive to active pools in the proximal tubule.14

A more recent theory of edema formation states that massive proteinuria leads to

tubulointerstitial inflammation and release of local vasoconstrictors and inhibition of


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vasodilation. This leads to a reduction in single-nephron glomerular filtration rate and

sodium and water retention.14

Thus, the precise cause of the edema and its persistence is uncertain. A complex interplayof various physiologic factors (such as decreased oncotic pressure, increased activity of

aldosterone and vasopressin, diminished atrial natriuretic hormone, activities of variouscytokines and physical factors within the vasa recti) probably contribute to the

accumulation and maintenance of edema.

Hyperlipidemia

INS is accompanied by disordered lipid metabolism. Apolipoprotein (apo)-B containinglipoproteins are elevated, including very-low-density lipoprotein (VLDL), intermediate-

density lipoprotein (IDL), and low-density lipoproteins (LDL) and lipoprotein(a), with

resultant increases in total cholesterol and LDL-cholesterol. High-density lipoprotein(HDL)-cholesterol is normal or low. Elevations in triglycerides occur with severe

hypoalbuminemia. The traditional explanation for hyperlipidemia in INS was theincreased synthesis of lipoproteins that accompany increased hepatic albumin synthesisdue to hypoalbuminemia. However, serum cholesterol levels have been shown to be

independent of albumin synthesis rates.

Decreased plasma oncotic pressure may play a role in increased hepatic lipoprotein

synthesis, as demonstrated by the reduction of hyperlipidemia in patients with INS

receiving either albumin or dextran infusions. Also contributing to the dyslipidemia of

INS are abnormalities in regulatory enzymes, such as lecithin-cholesterol acyltransferase,lipoprotein lipase and cholesterol ester transfer protein.14,15

Thrombosis

Patients with nephrotic syndrome are at increased risk for thrombosis (seeComplications). Various factors play a role in the increased incidence of thrombosis.

Abnormalities described in INS include increased platelet activation and aggregation;

elevation in factors V, VII, VIII, and XIII and fibrinogen; decreased antithrombin III,proteins C and S, and factors XI and XII; and increased activities of tissue plasminogen

activator and plasminogen activator inhibitor-1. These abnormalities in hemostatic

factors, combined with potential hypovolemia, immobility, and increased incidence ofinfection, lead to a hypercoagulable state in INS.16,17

Infection

Patients with INS are at increased risk of infection, especially with Streptococcus

pneumoniae, but other infections are common as well (seeComplications). INS is

associated with low immunoglobulin (Ig)G levels, which do not appear to be the result ofurinary losses. Instead, low IgG levels seem to be the result of impaired synthesis, again

pointing to a primary disorder in lymphocyte regulation in INS. Additionally, increased

urinary losses of factor B are noted, a cofactor of C3b in the alternative pathway of
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complement, which plays an important role in the opsonization of encapsulated

organisms such as S pneumoniae. Impaired T-cell function may also be present in INS,

which contributes to the susceptibility to infection. Finally, the medications used to treatINS, such as corticosteroids and alkylating agents, further suppress the immune system

and increase the risk of infection.17

Frequency

United States

The reported annual incidence rate is 2-7 cases per 100,000 children younger than 16

years. The cumulative prevalence rate is approximately 16 cases per 100,000individuals.18The ISKDC found that 76.6% of children with INS had MCNS on kidney

biopsy findings, with 7% of cases associated with FSGS on biopsy findings.2,19Some

studies have suggested a change in the histology of INS over the past few decades,although the overall incidence of INS has remained stable. The frequency of FSGS

associated with INS appears to be increasing. A review of the literature suggested a 2-fold increase in the incidence of FSGS in recent decades.20However, another study foundno evidence of an increasing incidence of FSGS.21

Mortality/Morbidity

Since the introduction of corticosteroids, the overall mortality of INS has decreaseddramatically from over 50% to approximately 2-5%. Despite the improvement in

survival, INS is usually a chronic, relapsing disease and most patients experience some

degree of morbidity, including the following:

Hospitalization, in some instances Frequent monitoring both by parents and by physician

Administration of medications associated with significant adverse events

A high rate of recurrence (relapses in >60% of patients)

The potential for progression to chronic kidney failure and end-stage kidney

failure (ESKD)

Additionally, INS is associated with an increased risk of multiple complications,

including edema, infection, thrombosis, hyperlipidemia, acute kidney failure, and

possible increased risk of cardiovascular disease.

See Complications and Prognosis for a more detailed discussion of the above.

Race

Black and Hispanic children appear to have an increased risk of steroid-resistant

nephrotic syndrome and FSGS.21,22An increased incidence of INS is reported in Asian

children, (6 times the rate seen in European children). An increased incidence of INS isalso seen in Indian, Japanese, and Southwest Asian children. Primary, SSNS is rare in
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Africa, where nephrotic syndrome is more likely to be secondary or steroid-resistant.

These variations in ethnic and geographic distribution of INS underscore the genetic and

environmental influences in the development of PNS.17

Sex

In children younger than 8 years at onset, the ratio of males to females varies from 2:1 to3:2 in various studies. In older children, adolescents, and adults, the male-to-female

prevalence is approximately equal. ISKDC data indicate that 66% of patients with either

MCNS or FSGS are male, whereas 65% of individuals with MPGN are female.

Age

Of patients with MCNS, 70% are younger than 5 years. Only 20-30% of adolescents with

INS have MCNS on biopsy findings. In the first year of life, genetic forms of INS andsecondary nephrotic syndrome due to congenital infection predominate.18

Clinical

History

Edema is the presenting symptom in about 95% of children with nephrotic syndrome

(NS). The edema in the early phase is intermittent and insidious, and its presence may notbe appreciated. A common story is for a child present to a primary care practitioner

repeatedly for periorbital edema, which is ascribed to "allergies" until the edema

progresses. It usually appears first in areas of low tissue resistance (such as the

periorbital, scrotal, and labial regions) and can rapidly progress or slowly progress.Ultimately, it becomes generalized and can be massive (anasarca). The edema is pitting

and typically depends on nature, is more noticeable in the face in the morning, and is

predominately in lower extremities later in the day.

A history of a respiratory tract infection immediately preceding the onset of nephrotic

syndrome is frequent, but the relevance to causation is uncertain. Upper respiratory

infections, otitis media, and other infections are often associated with relapses of

idiopathic nephrotic syndrome (INS) as well. A history of allergy is present inapproximately 30% of children. A hypersensitivity event, such as a reaction to bee sting

or poison ivy, has been reported to precede the onset of INS.17

Children with nephrotic syndrome occasionally present with gross hematuria. The

frequency of macrohematuria depends on the histological subtype of nephrotic syndrome.

It is more common in those patients with membranoproliferative glomerulonephritis(MPGN) than in other causes, but its frequency in minimal change nephrotic syndrome

(MCNS) has been reported to be as high as 3-4% of cases. Statistically, a higher

percentage of patients with focal segmental glomerulosclerosis (FSGS) have

microhematuria than those with MCNS, but this is not helpful in differentiating between
http://emedicine.medscape.com/article/994656-overviewhttp://emedicine.medscape.com/article/994656-overview


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types of nephrotic syndrome in the individual patient. Given the risk of thrombosis in

INS, renal vein thrombosis must be considered in patients with significant hematuria.

Rarely, a child can present with other symptoms secondary to thrombosis, such as seizurecaused by cerebral thrombosis.

A child might be brought to medical attention for symptoms of infection, such as fever,lethargy, irritability, or abdominal pain due to sepsis or peritonitis. Peritonitis can be

mistaken for appendicitis or other cause of acute abdomen unless the child's proteinuriaand edema are appreciated.

Anorexia, irritability, fatigue, abdominal discomfort, and diarrhea are common. GIdistress can be caused by ascites, bowel wall edema, or both. Respiratory distress can

occur, due to either massive ascites and thoracic compression or frank pulmonary edema,

effusions, or both.

Except in rare cases of familial INS, no significant family history of kidney disease or

INS is usually noted. Children are typically healthy prior to onset of INS and, except forhistory of allergy and atopy noted above, do not usually have a significant past medical

history related to INS.

Physical

The most common clinical finding is edema. The edema is pitting and is typically found

in the lower extremities, face and periorbital regions, scrotum and labia, and abdomen

(ascites). In those children with marked ascites, mechanical restriction to breathing maybe present, and the child may manifest compensatory tachypnea. Pulmonary edema and

effusions can also cause respiratory distress.

Hypertension can be present and is more common in children with FSGS and MPGN

rather than MCNS. Physical findings can also be present due to complications of INS.Abdominal tenderness might indicate peritonitis. Hypotension and signs of shock can be

present in children presenting with sepsis. Thrombosis can cause various findings,

including tachypnea and respiratory distress (pulmonary thrombosis/embolism),hematuria (renal vein thrombosis), and seizure (cerebral thrombosis).

Causes

Causes of nephrotic syndrome include the following:

INS

o MCNS

o FSGS

o MPGN

o Membranous glomerulonephritis (MGN)

o IgA nephropathy

o Idiopathic crescentic glomerulonephritis


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Genetic nephrotic syndrome/congenital nephrotic syndrome

o Finnish-type congenital nephrotic syndrome (NPHS1, nephrin)

o Denys-Drash syndrome (WT1)

o Frasier syndrome (WT1)

o Diffuse mesangial sclerosis (WT1, PLCE1)

o Autosomal recessive, familial FSGS (NPHS2, podocin)o Autosomal dominant, familial FSGS (ACTN4, -actinin-4; TRPC6)

o Nail-patella syndrome (LMX1B)

o Pierson syndrome (LAMB2)

o Schimke immuno-osseous dysplasia (SMARCAL1)

o Galloway-Mowat syndrome

o Oculocerebrorenal (Lowe) syndrome

Secondary nephrotic syndrome

o Infections

Congenital syphilis, toxoplasmosis, cytomegalovirus, rubella

Hepatitis B and C

HIV/acquired immunodeficiency syndrome (AIDS) Malaria

o Drugs

Penicillamine

Gold Nonsteroidal anti-inflammatory drugs (NSAIDs)

Interferon

Mercury Heroin

Pamidronate

Lithium

o Systemic disease Systemic lupus erythematosus

Malignancy - Lymphoma, leukemia

Vasculitis -Wegener granulomatosis, Churg-Strauss syndrome,

polyarteritis nodosa, microscopic polyangiitis, Henoch-Schnlein

purpura (HSP)

Immune-complexmediated - Poststreptococcal glomerulonephritis

Author: Jerome C Lane, MD, Assistant Professor of Pediatrics, Northwestern

University Medical School; Attending Physician, Department of Pediatrics, Division of

Kidney Diseases, Children's Memorial Hospital, Chicago

Medscape

eMedicine
http://emedicine.medscape.com/article/969023-overviewhttp://emedicine.medscape.com/article/1000028-overviewhttp://emedicine.medscape.com/article/963090-overviewhttp://emedicine.medscape.com/article/968523-overviewhttp://emedicine.medscape.com/article/998942-overviewhttp://emedicine.medscape.com/article/1004557-overviewhttp://emedicine.medscape.com/article/1007428-overviewhttp://www.medscape.com/http://emedicine.medscape.com/http://emedicine.medscape.com/article/969023-overviewhttp://emedicine.medscape.com/article/1000028-overviewhttp://emedicine.medscape.com/article/963090-overviewhttp://emedicine.medscape.com/article/968523-overviewhttp://emedicine.medscape.com/article/998942-overviewhttp://emedicine.medscape.com/article/1004557-overviewhttp://emedicine.medscape.com/article/1007428-overviewhttp://www.medscape.com/http://emedicine.medscape.com/


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eMedicine Specialties > Pediatrics: General Medicine >

Nephrology

Nephrotic Syndrome

Author: Jerome C Lane, MD, Assistant Professor of Pediatrics, Northwestern

University Medical School; Attending Physician, Department of Pediatrics, Division ofKidney Diseases, Children's Memorial Hospital, Chicago

Contributor Information and Disclosures

Updated: May 12, 2010

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Introduction

Background

Nephrotic syndrome (NS), also known as nephrosis, is defined by the presence ofnephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. Nephrotic-

range proteinuria in adults is characterized by protein excretion of 3.5 g or more per day.However, because of the great range of body sizes in children, the pediatric definition ofnephrotic-range proteinuria is more cumbersome. Nephrotic-range proteinuria in children

is protein excretion of more than 40 mg/m2/h. Because 24-hour urine collections are

potentially unreliable and burdensome, especially in young children, many pediatricnephrologists instead rely on a single, first-morning urine sample to quantify protein

excretion by the ratio of protein to creatinine.1
http://emedicine.medscape.com/specialtieshttp://emedicine.medscape.com/pediatrics_generalhttp://emedicine.medscape.com/pediatrics_general#nephrologyhttp://emedicine.medscape.com/article/982920-printmailto:enter%20email%20address%20here?Subject=eMedicine%20Article%20-%20Nephrotic%20Syndrome&Body=I%20thought%20you%20might%20be%20interested%20in%20this%20article%20from%20eMedicine.%20You%20may%20either%20click%20on%20the%20following%20link%20or%20copy%20and%20paste%20it%20into%20your%20browser.%0Dhttp://emedicine.medscape.com/article/982920-overview%0D%0A%0D%0AeMedicine%20is%20the%20leading%20provider%20of%20clinical%20medical%20information%20for%20medical%20professionals%20and%20consumers.%20To%20explore%20eMedicine%20today,%20visit%20http://emedicine.medscape.comhttp://emedicine.medscape.com/article/982920-diagnosishttp://emedicine.medscape.com/article/982920-treatmenthttp://emedicine.medscape.com/article/982920-followuphttp://emedicine.medscape.com/article/982920-mediahttp://as.webmd.com/event.ng/Type=click&FlightID=173227&AdID=280387&TargetID=32830&Values=205&Redirect=http:/www.medscape.com/infosite/prolia?src=0_0_ad_newshttp://as.webmd.com/event.ng/Type=click&FlightID=173227&AdID=280387&TargetID=32830&Values=205&Redirect=http:/www.medscape.com/infosite/prolia?src=0_0_ad_newsmailto:enter%20email%20address%20here?Subject=eMedicine%20Article%20-%20Nephrotic%20Syndrome&Body=I%20thought%20you%20might%20be%20interested%20in%20this%20article%20from%20eMedicine.%20You%20may%20either%20click%20on%20the%20following%20link%20or%20copy%20and%20paste%20it%20into%20your%20browser.%0Dhttp://emedicine.medscape.com/article/982920-overview%0D%0A%0D%0AeMedicine%20is%20the%20leading%20provider%20of%20clinical%20medical%20information%20for%20medical%20professionals%20and%20consumers.%20To%20explore%20eMedicine%20today,%20visit%20http://emedicine.medscape.comhttp://emedicine.medscape.com/article/982920-printhttp://emedicine.medscape.com/specialtieshttp://emedicine.medscape.com/pediatrics_generalhttp://emedicine.medscape.com/pediatrics_general#nephrologyhttp://emedicine.medscape.com/article/982920-printmailto:enter%20email%20address%20here?Subject=eMedicine%20Article%20-%20Nephrotic%20Syndrome&Body=I%20thought%20you%20might%20be%20interested%20in%20this%20article%20from%20eMedicine.%20You%20may%20either%20click%20on%20the%20following%20link%20or%20copy%20and%20paste%20it%20into%20your%20browser.%0Dhttp://emedicine.medscape.com/article/982920-overview%0D%0A%0D%0AeMedicine%20is%20the%20leading%20provider%20of%20clinical%20medical%20information%20for%20medical%20professionals%20and%20consumers.%20To%20explore%20eMedicine%20today,%20visit%20http://emedicine.medscape.comhttp://emedicine.medscape.com/article/982920-diagnosishttp://emedicine.medscape.com/article/982920-treatmenthttp://emedicine.medscape.com/article/982920-followuphttp://emedicine.medscape.com/article/982920-mediahttp://as.webmd.com/event.ng/Type=click&FlightID=173227&AdID=280387&TargetID=32830&Values=205&Redirect=http:/www.medscape.com/infosite/prolia?src=0_0_ad_newshttp://as.webmd.com/event.ng/Type=click&FlightID=173227&AdID=280387&TargetID=32830&Values=205&Redirect=http:/www.medscape.com/infosite/prolia?src=0_0_ad_news


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The use of a first-morning urine sample eliminates the contribution of potentially

nonpathological orthostatic proteinuria, which might otherwise falsely elevate the protein

level in a urine sample collected while a patient is active during the day. A urineprotein/creatinine value of more than 2-3 mg/mg indicates nephrotic range proteinuria

and correlates with results from 24-hour urine collection.

Nephrotic syndrome is a constellation of clinical findings that is the result of massive

renal losses of protein. Thus, nephrotic syndrome is not a disease itself, but the

manifestation of many different glomerular diseases. These diseases might be acute andtransient, such aspostinfectious glomerulonephritis, or chronic and progressive, such as

focal segmental glomerulosclerosis (FSGS). Still other diseases might be relapsing and

remitting, such as minimal change nephrotic syndrome (MCNS).

The glomerular diseases that cause nephrotic syndrome generally can be divided into

primary and secondary etiologies. Primary nephrotic syndrome (PNS), also known as

idiopathic nephrotic syndrome (INS), is associated with glomerular diseases intrinsic to

the kidney and not related to systemic causes. The subcategories of INS are based onhistological descriptions, but clinical-pathological correlations have been made. A wide

variety of glomerular lesions can be seen in INS. These include MCNS, focal segmentalglomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative

glomerulonephritis (MPGN), diffuse mesangial proliferation and others.

By definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney.

Secondary causes of nephrotic syndrome include Henoch-Schnlein purpura (HSP),systemic lupus erythematosus, diabetes mellitus, syphilis,human immunodeficiency

virus (HIV), hepatitis B and C, malignancy, vasculitis, and drug exposure (heroin,

mercury, and others), among many other etiologies (seeCauses).

Nephrotic syndrome may also be caused by genetic abnormalities. Infantile NS

(presenting before age 3 mo) and congenital NS (presenting at age 4-12 mo) have been

associated with defects in the nephrin gene (NPHS1), phospholipase C epsilon 1 gene(PLCE1), and the Wilms tumor suppressor gene (WT1). Mutations in the podocin gene

(NPHS2) are associated with a familial, autosomal-recessive form of FSGS. Mutations in

the -actinin-4 gene (ACTN4) and the gene TRPC6are associated with autosomal-dominant forms of familial FSGS. Additionally, other genetic syndromes have been

associated with nephrotic syndrome, such asNail-Patella syndrome, Pierson syndrome,

Schimke immuno-osseous dysplasia, and others. (See Pathophysiology and Causes)

INS is divided into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome

(SRNS) because response to steroids has a high correlation with histological subtype andprognosis. The landmark study of nephrotic syndrome in children, the International Study

of Kidney Disease in Children (ISKDC), found that the vast majority of preadolescent

children with INS had MCNS on kidney biopsy.2,3Whereas 90% of children with MCNS

responded to corticosteroid treatment with remission of their nephrotic syndrome, only20% of children with FSGS responded to steroids.
http://emedicine.medscape.com/article/980685-overviewhttp://emedicine.medscape.com/article/984105-overviewhttp://emedicine.medscape.com/article/1008066-overviewhttp://emedicine.medscape.com/article/1008066-overviewhttp://emedicine.medscape.com/article/969023-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/982920-overview#ClinicalCauseshttp://emedicine.medscape.com/article/982920-overview#ClinicalCauseshttp://emedicine.medscape.com/article/947391-overviewhttp://emedicine.medscape.com/article/982920-overview#IntroductionPathophysiologyhttp://emedicine.medscape.com/article/982920-overview#ClinicalCauseshttp://emedicine.medscape.com/article/980685-overviewhttp://emedicine.medscape.com/article/984105-overviewhttp://emedicine.medscape.com/article/1008066-overviewhttp://emedicine.medscape.com/article/969023-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/982920-overview#ClinicalCauseshttp://emedicine.medscape.com/article/947391-overviewhttp://emedicine.medscape.com/article/982920-overview#IntroductionPathophysiologyhttp://emedicine.medscape.com/article/982920-overview#ClinicalCauses


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This article focuses on INS, primarily SSNS (which primarily consists of MCNS). The

treatment and prognosis of SRNS (primarily FSGS in children) is briefly discussed. The

discussion of congenital and secondary nephrotic syndrome is beyond the scope of thisarticle.

Pathophysiology

Proteinuria and Hypoalbuminemia

The immune system and proteinuria

The hallmark of INS is massive proteinuria, leading to decreased circulating albumin

levels. The initiating event that produces proteinuria remains unknown. INS is believed tohave an immune pathogenesis. Studies have shown abnormal regulation of T-cell subsets

and expression of a circulating glomerular permeability factor. Evidence of the immune-

mediated nature of INS is demonstrated by the fact that immunosuppressive agents, such

as corticosteroids and alkylating agents, can result in remission of nephrotic syndrome.Furthermore, nephrotic syndrome has been known to remit during infection with the

measles virus, which suppresses cell-mediated immunity. However, the precise nature of

the immune pathogenic process has yet to be defined.

A circulating factor may play a role in the development of proteinuria in INS. This can be

demonstrated by the rapid development of proteinuria in recurrence of nephroticsyndrome after kidney transplantation, the improvement in nephrotic syndrome in such

patients after treatment with plasmapheresis, and the experimental induction of

proteinuria in animals by plasma from patients with INS. However, the nature of thiscirculating factor is not known. Various cytokines and molecules have been implicated,

including interleukin (IL)-2, IL-2 receptor, IL-4, IL-12, IL-13, IL-15, IL-18, interferon-,tumor growth factor (TGF)-, vascular permeability factor, nuclear factor (NF)-B, and

tumor necrosis factor (TNF)-.4

The association of allergic responses with nephrotic syndrome also illustrates the role of

the immune system in INS. Nephrotic syndrome has been reported to occur after allergic

reactions to bee stings, fungi, poison ivy, ragweed, house dust, jellyfish stings and cat fur.

Food allergy might play a role in relapses of INS; a reduced-antigenic diet was associatedwith improved proteinuria and complete remission in one study.5Additionally, INS is 3-4

times more likely in children with human leukocyte antigen (HLA)-DR7. Steroid

sensitive INS has also been associated with HLA-B8 and theDQB1 gene of HAL-

DQW2. A greater incidence of INS is also observed in children with atopy and HLA-B12.6

Genetics, the podocyte, and proteinuria

Perhaps the most exciting development in recent years in understanding the

pathophysiology of nephrotic syndrome has occurred in the area of podocyte biology (see

the image below).


22/41






(GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min,

with the filtration fraction being 20%. The concentration of albumin in





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The glomerular filtration barrier consists of the fenestrated capillary endothelium, the

extracellular basement membrane, and the intercalated podocyte foot processes,connected by 35-45 nm slit diaphragms. Nephrotic syndrome is associated with the

biopsy finding of fusion (effacement) of podocyte foot processes. This effacement of the

podocytes long was thought to be a secondary phenomenon of nephrotic syndrome.

However, theories have shifted towards the podocyte as playing a primary role in the

development of proteinuria. The understanding of the pathophysiology of proteinuria inrenal diseases has greatly expanded with insights into the molecular biology of the

podocyte. Various forms of INS have been described with mutations in podocyte genes,

such as those associated with the slit-diaphragm and podocyte cytoskeleton

(NPHS1NPHS2, TRCP6, CD2AP, ACTN4); the glomerular basement membrane(LAMB2); mitochondria (COQ2); and transcription factors (WT1, LMX1B).7

Nephrin is a transmembrane protein that is a major structural element of the slit

diaphragm and is encoded by theNPHS1 gene on chromosome 19. Mutations in theNPHS1 gene are responsible for autosomal recessive, congenital nephrotic syndrome of

the Finnish type (FNS). FNS is characterized by massive proteinuria in the first year oflife (usually within the first 3 mo) and progression to end-stage kidney disease within the

first decade of life, although patients with milder forms of the disease have been

described.7Although mutations inNPHS1 are usually associated with congenitalnephrotic syndrome, Philipe and colleagues have describedNPHS1 mutations in children

aged 6 months to 8 years with later onset SRNS.8Additionally, Santin has described

NPHS1 mutations in patients with later childhood onset as well as adult-onset SRNS.9

Podocin is another podocyte protein that interacts with nephrin and CD2AP and is

integral to the assembly of the slit diaphragm. Podocin is encoded by the NPHS2 gene on

chromosome 1. Mutations in theNPHS2 gene were originally described in patients withautosomal recessive, steroid-resistant INS with FSGS on biopsy findings. Podocin

mutations account for approximately 45-55% of familial and 8-20% of sporadic cases of

SRNS.7

-Actinin-4, encoded by the geneACTN4 on chromosome 19, crosslinks actin filaments

of the podocyte cytoskeleton and anchors them to the glomerular basement membrane.

The TRPC6gene on chromosome 11 encodes for a calcium channel associated with theslit diaphragm.7Disruptions in eitherACTN4 orTRPC6are associated with autosomal

dominant forms of FSGS.6

CD2AP, which codes for a podocyte protein that associates with podocin and nephrin,

has been associated with the development of nephrotic syndrome in animal models.

However, the role it plays in human nephrotic syndrome is unclear. Various case reportshave demonstrated heterozygous mutations in CD2APin patients with nephrotic

syndrome and FSGS. One report describes a single patient with a homozygous mutation

in CD2APand early onset of nephrotic syndrome with FSGS and diffuse mesangial

sclerosis.7


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Nonmuscle myosin heavy chain 9 (MYH9) is a podocyte protein that binds to the

podocyte actin cytoskeleton to perform intracellular motor functions.10MYH9polymorphisms are estimated to account for more than 40% of end-stage kidney disease

cases among blacks and has been associated with FSGS, HIV-associated nephropathy,

and focal global glomerulosclerosis (which had been previously attributed tohypertensive nephrosclerosis in many patients). The E1 haplotype of MYH9 is present in

60% of blacks compared with 4% of individuals with European ancestry.11

Other genetic forms of nephrotic syndrome continue to shed light on the pathogenesis of

INS. Mutations in the developmental regulatory gene WT1 are associated withDenys-

Drash syndrome and Frasier syndrome, forms of congenital nephrotic syndrome

associated with male pseudohermaphroditism, Wilms tumor(Denys-Drash syndrome),and gonadoblastoma (Frasier syndrome). Mutations in phospholipase C epsilon 1

(PLCE1), a cytoplasmic enzyme required for podocyte maturation, have been associated

with as many as 28% of cases of congenital nephrotic syndrome due to isolated

(nonsyndromic) diffuse mesangial sclerosis. Nail-patella syndrome, a disordercharacterized by skeletal and nail dysplasia as well as nephrotic syndrome, is caused by

mutations in theLMX1B gene, which regulates expression of type IV collagen and thepodocyte proteins nephrin, podocin, and CD2AP.12

Pierson syndrome, characterized by microcoria, abnormal lens shape, cataracts,blindness, severe neurological deficits, congenital nephrotic syndrome and progressive

kidney failure, is caused by a mutation in theLAMB2 gene that codes for laminin b2,

which is found in glomerular basement membrane, retina, lens and neuromuscular

synapses.7

The role of alterations in the slit diaphragm in MCNS has not been elucidated. Podocin

appears to be expressed normally in MCNS but decreased in FSGS. Mutations in nephrinand podocin do not at this time appear to play a role in steroid-sensitive nephrotic

syndrome. However, acquired alterations in slit diaphragm architecture might play a role

in INS apart from actual mutations in the genes encoding podocyte proteins. Variousauthors have reported changes in expression and distribution of nephrin in MCNS.

Coward et al demonstrated that nephrotic plasma induces translocation of the slit

diaphragm proteins nephrin, podocin, and CD2AP away from the plasma membrane intothe cytoplasm of the podocyte.13These authors also demonstrated the normal plasma

might contain factors that maintain the integrity of slit diaphragm architecture and that

the lack of certain factors (rather than the presence of an abnormal circulating factor)might be responsible for alterations in the podocyte architecture and development of INS.

Apart from the podocyte and slit diaphragm, alterations in the glomerular basement

membrane also likely play a role in the proteinuria of nephrotic syndrome. In INS, the

glomerular capillary permeability to albumin is selectively increased, and this increase infiltered load overcomes the modest ability of the tubules to reabsorb protein. In its normal

state, the glomerular basement membrane is negatively charged because of the presence
http://emedicine.medscape.com/article/943103-overviewhttp://emedicine.medscape.com/article/943103-overviewhttp://emedicine.medscape.com/article/943103-overviewhttp://emedicine.medscape.com/article/989398-overviewhttp://emedicine.medscape.com/article/986581-overviewhttp://emedicine.medscape.com/article/943103-overviewhttp://emedicine.medscape.com/article/943103-overviewhttp://emedicine.medscape.com/article/989398-overviewhttp://emedicine.medscape.com/article/986581-overview


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of various polyanions along this surface, such as heparan sulfate, chondroitin sulfate, and

sialic acid. This negative charge acts as a deterrent to filtration of negatively charged

proteins, such as albumin. Experimental models in which the negative charges areremoved from the basement membrane show an increase in albuminuria. Children with

MCNS have been reported to have decreased anionic charges in the glomerular basement

membrane.12

Edema

The classical explanation for edema formation is a decrease in plasma oncotic pressure,as a consequence of low serum albumin levels, causing an extravasation of plasma water

into the interstitial space. The resulting contraction in plasma volume leads to stimulation

of the renin-angiotensin-aldosterone axis and antidiuretic hormone. The resultantretention of sodium and water by the renal tubules contributes to the extension and

maintenance of edema.

While the classical model of edema (also known as the "underfill hypothesis") seemslogical, certain clinical and experimental observations do not completely support thistraditional concept. First, the plasma volume (PV) has not always been found to be

decreased and, in fact, in most adults, measurements of PV have shown it to be increased.

Only in young children with MCNS have most (but not all) studies demonstrated areduced PV. Additionally, most studies have failed to document elevated levels of renin,

angiotensin, or aldosterone, even during times of avid sodium retention. Active sodium

reabsorption also continues despite actions that should suppress renin effects (such as

albumin infusion or ACE inhibitor administration).

Coupled with these discrepancies is the fact that, in the steroid-responsive nephrotic,

diuresis usually begins before plasma albumin has significantly increased and beforeplasma oncotic pressure has changed. Some investigators have demonstrated a blunted

responsiveness to atrial natriuretic peptide (ANP) despite higher than normal circulating

plasma levels of ANP.14

Another model of edema formation is known as the "overfill hypothesis." In this model, aprimary defect in renal sodium handling is postulated. A primary increase in renal sodium

reabsorption leads to net salt and water retention and subsequent hypertension. ANP

might play a role is this mechanism; studies have shown an impaired response to ANP innephrotic syndrome. This ANP resistance, in part, might be caused by overactive efferent

sympathetic nervous activity, as well as enhanced tubular breakdown of cyclic guanosine

monophosphate. Other mechanisms that contribute to a primary increase in renal sodiumretention include overactivity of the Na+ -K+ -ATPase and renal epithelial sodium channel

(RENaC) in the cortical collecting duct and shift of the Na+/H+ exchangerNHE3 from the

inactive to active pools in the proximal tubule.14

A more recent theory of edema formation states that massive proteinuria leads to

tubulointerstitial inflammation and release of local vasoconstrictors and inhibition of


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vasodilation. This leads to a reduction in single-nephron glomerular filtration rate and

sodium and water retention.14

Thus, the precise cause of the edema and its persistence is uncertain. A complex interplayof various physiologic factors (such as decreased oncotic pressure, increased activity of

aldosterone and vasopressin, diminished atrial natriuretic hormone, activities of variouscytokines and physical factors within the vasa recti) probably contribute to the

accumulation and maintenance of edema.

Hyperlipidemia

INS is accompanied by disordered lipid metabolism. Apolipoprotein (apo)-B containinglipoproteins are elevated, including very-low-density lipoprotein (VLDL), intermediate-

density lipoprotein (IDL), and low-density lipoproteins (LDL) and lipoprotein(a), with

resultant increases in total cholesterol and LDL-cholesterol. High-density lipoprotein(HDL)-cholesterol is normal or low. Elevations in triglycerides occur with severe

hypoalbuminemia. The traditional explanation for hyperlipidemia in INS was theincreased synthesis of lipoproteins that accompany increased hepatic albumin synthesisdue to hypoalbuminemia. However, serum cholesterol levels have been shown to be

independent of albumin synthesis rates.

Decreased plasma oncotic pressure may play a role in increased hepatic lipoprotein

synthesis, as demonstrated by the reduction of hyperlipidemia in patients with INS

receiving either albumin or dextran infusions. Also contributing to the dyslipidemia of

INS are abnormalities in regulatory enzymes, such as lecithin-cholesterol acyltransferase,lipoprotein lipase and cholesterol ester transfer protein.14,15

Thrombosis

Patients with nephrotic syndrome are at increased risk for thrombosis (seeComplications). Various factors play a role in the increased incidence of thrombosis.

Abnormalities described in INS include increased platelet activation and aggregation;

elevation in factors V, VII, VIII, and XIII and fibrinogen; decreased antithrombin III,proteins C and S, and factors XI and XII; and increased activities of tissue plasminogen

activator and plasminogen activator inhibitor-1. These abnormalities in hemostatic

factors, combined with potential hypovolemia, immobility, and increased incidence ofinfection, lead to a hypercoagulable state in INS.16,17

Infection

Patients with INS are at increased risk of infection, especially with Streptococcus

pneumoniae, but other infections are common as well (seeComplications). INS is

associated with low immunoglobulin (Ig)G levels, which do not appear to be the result ofurinary losses. Instead, low IgG levels seem to be the result of impaired synthesis, again

pointing to a primary disorder in lymphocyte regulation in INS. Additionally, increased

urinary losses of factor B are noted, a cofactor of C3b in the alternative pathway of
http://emedicine.medscape.com/article/982920-followup#FollowupComplicationshttp://emedicine.medscape.com/article/982920-followup#FollowupComplicationshttp://emedicine.medscape.com/article/982920-followup#FollowupComplicationshttp://emedicine.medscape.com/article/982920-followup#FollowupComplicationshttp://emedicine.medscape.com/article/982920-followup#FollowupComplications


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complement, which plays an important role in the opsonization of encapsulated

organisms such as S pneumoniae. Impaired T-cell function may also be present in INS,

which contributes to the susceptibility to infection. Finally, the medications used to treatINS, such as corticosteroids and alkylating agents, further suppress the immune system

and increase the risk of infection.17

Frequency

United States

The reported annual incidence rate is 2-7 cases per 100,000 children younger than 16

years. The cumulative prevalence rate is approximately 16 cases per 100,000individuals.18The ISKDC found that 76.6% of children with INS had MCNS on kidney

biopsy findings, with 7% of cases associated with FSGS on biopsy findings.2,19Some

studies have suggested a change in the histology of INS over the past few decades,although the overall incidence of INS has remained stable. The frequency of FSGS

associated with INS appears to be increasing. A review of the literature suggested a 2-fold increase in the incidence of FSGS in recent decades.20However, another study foundno evidence of an increasing incidence of FSGS.21

Mortality/Morbidity

Since the introduction of corticosteroids, the overall mortality of INS has decreaseddramatically from over 50% to approximately 2-5%. Despite the improvement in

survival, INS is usually a chronic, relapsing disease and most patients experience some

degree of morbidity, including the following:

Hospitalization, in some instances Frequent monitoring both by parents and by physician

Administration of medications associated with significant adverse events

A high rate of recurrence (relapses in >60% of patients)

The potential for progression to chronic kidney failure and end-stage kidney

failure (ESKD)

Additionally, INS is associated with an increased risk of multiple complications,

including edema, infection, thrombosis, hyperlipidemia, acute kidney failure, and

possible increased risk of cardiovascular disease.

See Complications and Prognosis for a more detailed discussion of the above.

Race

Black and Hispanic children appear to have an increased risk of steroid-resistant

nephrotic syndrome and FSGS.21,22An increased incidence of INS is reported in Asian

children, (6 times the rate seen in European children). An increased incidence of INS isalso seen in Indian, Japanese, and Southwest Asian children. Primary, SSNS is rare in
http://emedicine.medscape.com/article/982920-followup#FollowupComplicationshttp://emedicine.medscape.com/article/982920-followup#FollowupPrognosishttp://emedicine.medscape.com/article/982920-followup#FollowupComplicationshttp://emedicine.medscape.com/article/982920-followup#FollowupPrognosis


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Africa, where nephrotic syndrome is more likely to be secondary or steroid-resistant.

These variations in ethnic and geographic distribution of INS underscore the genetic and

environmental influences in the development of PNS.17

Sex

In children younger than 8 years at onset, the ratio of males to females varies from 2:1 to3:2 in various studies. In older children, adolescents, and adults, the male-to-female

prevalence is approximately equal. ISKDC data indicate that 66% of patients with either

MCNS or FSGS are male, whereas 65% of individuals with MPGN are female.

Age

Of patients with MCNS, 70% are younger than 5 years. Only 20-30% of adolescents with

INS have MCNS on biopsy findings. In the first year of life, genetic forms of INS andsecondary nephrotic syndrome due to congenital infection predominate.18

Clinical

History

Edema is the presenting symptom in about 95% of children with nephrotic syndrome

(NS). The edema in the early phase is intermittent and insidious, and its presence may notbe appreciated. A common story is for a child present to a primary care practitioner

repeatedly for periorbital edema, which is ascribed to "allergies" until the edema

progresses. It usually appears first in areas of low tissue resistance (such as the

periorbital, scrotal, and labial regions) and can rapidly progress or slowly progress.Ultimately, it becomes generalized and can be massive (anasarca). The edema is pitting

and typically depends on nature, is more noticeable in the face in the morning, and is

predominately in lower extremities later in the day.

A history of a respiratory tract infection immediately preceding the onset of nephrotic

syndrome is frequent, but the relevance to causation is uncertain. Upper respiratory

infections, otitis media, and other infections are often associated with relapses of

idiopathic nephrotic syndrome (INS) as well. A history of allergy is present inapproximately 30% of children. A hypersensitivity event, such as a reaction to bee sting

or poison ivy, has been reported to precede the onset of INS.17

Children with nephrotic syndrome occasionally present with gross hematuria. The

frequency of macrohematuria depends on the histological subtype of nephrotic syndrome.

It is more common in those patients with membranoproliferative glomerulonephritis(MPGN) than in other causes, but its frequency in minimal change nephrotic syndrome

(MCNS) has been reported to be as high as 3-4% of cases. Statistically, a higher

percentage of patients with focal segmental glomerulosclerosis (FSGS) have

microhematuria than those with MCNS, but this is not helpful in differentiating between


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types of nephrotic syndrome in the individual patient. Given the risk of thrombosis in

INS, renal vein thrombosis must be considered in patients with significant hematuria.

Rarely, a child can present with other symptoms secondary to thrombosis, such as seizurecaused by cerebral thrombosis.

A child might be brought to medical attention for symptoms of infection, such as fever,lethargy, irritability, or abdominal pain due to sepsis or peritonitis. Peritonitis can be

mistaken for appendicitis or other cause of acute abdomen unless the child's proteinuriaand edema are appreciated.

Anorexia, irritability, fatigue, abdominal discomfort, and diarrhea are common. GIdistress can be caused by ascites, bowel wall edema, or both. Respiratory distress can

occur, due to either massive ascites and thoracic compression or frank pulmonary edema,

effusions, or both.

Except in rare cases of familial INS, no significant family history of kidney disease or

INS is usually noted. Children are typically healthy prior to onset of INS and, except forhistory of allergy and atopy noted above, do not usually have a significant past medical

history related to INS.

P

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