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THE PATHOPHYSIOLOGY OF NEPHROTIC SYNDROME IN

CHILDREN

Written by:Written by:

Sarita AmeliaSarita Amelia

030.07.235030.07.235

The Faculty of Medicine Trisakti UniversityThe Faculty of Medicine Trisakti University

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CHAPTER I

INTRODUCTION

Nephrotic syndrome (NS) is defined by the presence of nephrotic-range proteinuria,

edema, hyperlipidemia, and hypoalbuminemia. Nephrotic-range proteinuria in adults is

characterized by protein excretion of 3.5 g or more per day. 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 pediatric

nephrologists instead rely on a single, first-morning urine sample to quantify protein

excretion by the ratio of protein to creatinine.

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

congenital, primary and secondary etiologies. Causes of nephrotic syndrome include the

following:

INS (Idiopathic Nephrotic Syndrome)

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. This includes 80-90 % cases of nephrotic syndrome in children.

The subcategories of INS are based on histological descriptions, but clinical-

pathological correlations have been made. A wide variety of glomerular lesions can be

seen in INS. Primary causes of nephrotic syndrome include:

o MCNS (Minimal Change Nephrotic Syndrome): 85 % of childhood cases

o FSGS (Focal Segmental Glomerulosclerosis): 9 % of childhood cases

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o MPGN (Mesangial Proliferative Glomerulonephritis) : about 2 % of childhood

cases

o Membranoproliverative glomerulonephritis (MPGN)

o IgA nephropathy

Secondary nephrotic syndrome

By definition, secondary nephritic syndrome refers to an etiology extrinsic to the

kidney. Secondary causes of nephrotic syndrome include:

o Infections, include: congenital syphilis, TORCH, Malaria, HIV, etc.

o Drugs, include: penicillamine, gold, nonsteroidal anti-inflammatory drugs

(NSAIDs) , interferon, mercury, heroin, pamidronate and lithium

o Systemic disease, include: Systemic lupus erythematosus, Malignancy -

Lymphoma, leukemia, Vasculitis-Wegener granulomatosis, Henoch-Schnlein

purpura (HSP), etc.

Genetic nephrotic syndrome/congenital nephrotic syndrome

In some rare cases, 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 the following genetic defects:

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

syndrome (WT1), Frasier syndrome (WT1), Autosomal recessive, familial FSGS

(NPHS2, podocin), Autosomal dominant, familial FSGS (ACTN4, -actinin-

4; TRPC6), etc.

The features of the nephrotic syndrome include:

Glomerular dysfunction leading to excessive urinary protein excretion

(formerly defined as >3.5 g/day but there appears to be individual variation)

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Hypoalbuminaemia as a result of urinary protein loss (albumin levels usually

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CHAPTER II

PATHOPHYSIOLOGY OF NEPHROTIC SYNDROME IN CHILDREN

2.1. Physiology

In normal people, all your blood flows through your kidneys, which are the

key organs in the complex system that removes excess fluid and waste material from

the blood. Blood that flows into your kidneys is diffused through filtering structures

called nephrons. Each nephron contains a tuft of capillary blood vessels (glomerulus)

and tiny tubules that lead to larger collecting tubes. The glomeruli filter fluid from

your blood, extracting both waste products and substances your body needs

sodium, phosphorus and potassium. The substances your body needs are reabsorbed

into your bloodstream. The rest is excreted in your urine through tubules that lead into

the ureters the tubes that lead to the bladder.

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Nephrotic syndrome is a kidney disorder that causes your body to excrete too

much protein in your urine. Nephrotic syndrome is usually caused by damage to the

clusters of small blood vessels, called glomeruli, in your kidneys that filter waste and

excess water from your blood. When healthy, these vessels keep blood protein from

seeping into your urine and out of your body. When damaged, they don't perform this

function effectively, where millions of tiny kidney filters leaking protein into the

urine which can be detected by urine dip stick. So less protein left in blood then fluid

can leak out of your blood and lead to swelling all over your body (edema).

Since the major cause of nephrotic Syndrome in children is the primary

etiology that leads to the primary Nephrotic Syndrome, which is about 80-90% cases

of all, this paper focuses on the pathophysiology of the primary Nephrotic Syndrome

or also known as the Idiopathic Nephrotic Syndrome (INS). Here are the explanations

of each element in the pathophysiology of Nephrotic Syndrome in children or the

Idiopatic Nephrotic Syndrome based on the recent studies and research.

2.2. Proteinuria and Hypoalbuminemia

2.2.1. The Immune System and Proteinuria

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The hallmark of Idiopathic Nephrotic Syndrome (INS) is massive proteinuria,

leading to decreased circulating albumin levels. 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, such as

corticosteroids and alkylating agents, can result in remission of nephrotic syndrome.

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

nephrotic syndrome 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 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)-.

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 associated with improved proteinuria and complete remission in

one study.5 Additionally, INS is 3-4 times more likely in children with human

leukocyte antigen (HLA)-DR7. Steroid sensitive INS has also been associated with

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HLA-B8 and the DQB1 gene of HAL-DQW2. A greater incidence of INS is also

observed in children with atopy and HLA-B12.

We can apply this pathophysiology of this immune system-related proteinuria

in nephrotic syndrome to MCNS (minimal change nephrotic syndrome). MCNS is the

most common cause of the nephrotic syndrome in children, accounting for 90% of

cases under the age of 10 years and more than 50% in older children. It has been

proposed that MCNS reflects a disorder of T-lymphocytes. These T cells are thought

to release a cytokine so-called permeability factor that injures the glomerular

epithelial cells. The identity of this permeability factor is still uncertain. Epithelial cell

damage may lead to albuminuria in MCNS by altering the metabolism of polyanions,

such as heparan sulphates, that constitute most of the normal charge barrier to the

glomerular filtration of macromolecules such as albumin. This can lead to the

increased glomerular permeability that allows the increased passage of large amounts

of low-molecular weight anionic proteins during ultrafiltration.

Therefore, eventhough the exact nature of the immune pathogenic process in

nephrotic syndrome has yet to be defined, we can explain how the immune reaction in

the body can cause the glomerular injury that leads to increased glomerular

permeability then patients will show proteinuria in their laboratory test results.

2.2.2. Genetics, the Podocyte, and Proteinuria

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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).

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.

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 in renal diseases has greatly expanded with insights into the molecular

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The classical explanation for edema formation is a decrease in plasma oncotic

pressure, as a consequence of low serum albumin levels, causing the increased

transudation or extravasation of plasma water into the interstitial space. This

transudation can lead to the accumulation of fluid in the extracellular space (eg,

tissue), or edema. A decrease in intravascular volume is thought to cause renal

hypoperfusion further enhancing salt and water retention by leading to stimulation of

the renin-angiotensin-aldosterone system and anti diuretic hormone due to the

resulting contraction in plasma volume.

While the classical model of edema (also known as the "underfill hypothesis")

seems logical, certain clinical and experimental observations do not completely

support this traditional 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 a reduced 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).

Another model of edema formation is known as the "overfill hypothesis." In

this model, a primary 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 in nephrotic 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

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that contribute to a primary increase in renal sodium retention 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.

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

to tubulointerstitial inflammation and release of local vasoconstrictors and inhibition

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

and sodium and water retention.

Thus, the precise cause of the edema and its persistence is uncertain. A

complex interplay of various physiologic factors (such as decreased oncotic pressure,

increased activity of aldosterone and vasopressin, diminished atrial natriuretic

hormone, activities of various cytokines and physical factors within the vasa recti)

probably contribute to the accumulation and maintenance of edema. And since the

exact pathophysiology of this condition remains unknown, many people still stick to

the classical theory to explain the process of forming edema in nephrotic syndrome.

2.4. Hyperlipidemia

INS is accompanied by disordered lipid metabolism. Apolipoprotein (apo)-B

containing lipoproteins 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

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INS was the increased synthesis of lipoproteins that accompany increased hepatic

albumin synthesis due 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.

Therefore, to be concluded, we can say that hyperlipidemia in patients with

nephrotic syndrome is thought to be caused by these following aspects: the

stimulation of the liver to increase synthesis of all plasma proteins (including the

lipoproteins), due to their low level in the blood; and reduction of lipoprotein

catabolism due to reduced levels of lipoprotein lipase in blood.

2.5. Thrombosis

Patients with nephrotic syndrome are at increased risk for thrombosis. 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 of

infection, lead to a hypercoagulable state in INS.

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Thus, we can say that in nephrotic syndrome, there are increased risks of

arterial andvenous thrombosis due to loss of anti-thrombin III and plasminogen in the

urine, combined with an increase in hepatic synthesis of clotting factors.

2.6. Infection

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

Streptococcus pneumoniae, but other infections are common as well. INS is

associated with low immunoglobulin (Ig)G levels, which appear to be the result of

urinary losses at first. But according to the recent studies, they do not appear to be that

way. 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 protein of C3b in the

alternative pathway of 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 treat INS, such as

corticosteroids and alkylating agents, further suppress the immune system and

increase the risk of infection.

2.7. Overview

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According to the explanation of each aspect of pathophysiology of nephrotic

syndrome, the pathophysiology of nephrotic syndrome in children can be summarized

to the following overview.

The commonest cause of nephrotic syndrome in children, which includes 80-

90 % cases of all, is the primary etiology leading to the idiopathic nephrotic syndrome

(INS). INS is believed to have immune pathogenesis in which occurs some idiopathic

immune reaction where some abnormality of T-lymphocytes occurs in patients with

nephrotic syndrome. These impaired T-lymphocytes are thought to release various

cytokines so called the permeability factor that causing the glomerular injury. This

immune reaction is considered idiopathic because according to the recent studies, the

initiating event of the immune reaction and the identity of this permeability factor is

still uncertain.

This glomerular injury may lead to proteinuria in nephrotic syndrome by

altering the metabolism of polyanions, such as heparan sulphates, that constitute most

of the normal charge barrier to the glomerular filtration of macromolecules such as

albumin. This can cause the increased glomerular permeability that allows the

increased passage of large amounts of low-molecular weight anionic proteins during

the filtration process in glomeruli leading to excessive protein urinary excretion.

Thus, proteinuria will be found in the results of laboratory test of patients with

nephrotic syndrome. This proteinuria will lead to the other characteristics that we can

find in patients with nephrotic syndrome.

Massive proteinuria can cause low levels in serum albumin. So thats why you

can find hypoalbuminemia in patients with nephrotic syndrome. Then as result,

plasma oncotic pressure is decreased that leads to the increased transudation, or

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extravasation of plasma water into interstitial spaces. This can cause an accumulation

of fluid in extracellular space or tissue that is called edema.

If the process of forming edema keeps continuing in the body where the

plasma water is leaking out the blood vessel, intravascular volume will be decreasing

then the renal hypoperfusion will occur in advance and activate the Renin-

Angiotensin-Aldosteron system.

Renin-angiotensin-aldosteron system is stimulated by the decreased plasma

volume that triggers the production of renin by kidneys as a first step. Renin is an

enzyme which activates angiotensinogen produced by liver to angiotensin I. Then

angiotensin I is converted to angiotensin II by ACE (Angiotensin Converting

Enzyme) produced by lungs. Angiotensin II can trigger the production of aldosteron

and anti diuretic hormone which enhanced the salt and water retention. The resultant

retention of sodium and water by the renal tubules contributes to the extension and

maintenance of edema.

As mentioned above, proteinuria in nephrotic syndrome can lead to

hypoalbuminemia or low levels of serum albumin. This hypoalbuminemia also

induces the stimulation of the liver to increase synthesis of all plasma proteins. This

stimulation includes the synthesis of lipoproteins. Besides that, in idiopathic nephrotic

syndrome, we can also find abnormalities in regulating enzymes of lipid metabolism

such as lipoprotein lipase and cholesterol ester transfer protein. Thus, the increased

synthesis of lipoproteins in liver, combined with the reduction of lipoprotein

catabolism due to reduced levels of lipoprotein lipase in blood, both contribute to the

increased serum lipoprotein levels which leads to hyperlipidemia in patients with

nephrotic syndrome.

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Patients with nephrotic syndrome are also have an increased risk for

thrombosis due to various abnormalities such as decreased antithrombin III, proteins

C and S; and increased activities of tissue plasminogen activator and plasminogen

activator inhibitor-1. This abnormality is thought to be related with massive

proteinuria in idiopathic nephrotic syndrome when there is loss of anti thrombin,

protein C and S in the urine along with the other plasma proteins. This condition,

combined with an increase in hepatic synthesis of clotting factors, both contribute to

the increased risk for thrombosis in nephrotic syndrome.

Aside from thrombus, patients with nephrotic syndrome have also an

increased risk for infection which is thought to be related with the massive proteinuria

as well. According to the old theory, this increased risk for infection is due to the loss

of immunoglobulin in urine along with other plasma proteins. But according to the

new theory, it states that what occurs during proteinuria contributing to the risk of

infection in nephrotic syndrome is actually the increased urinary losses of factor B, a

cofactor protein of C3b in the alternative pathway of complement, which plays an

important role in the opsonization of encapsulated organisms such as S pneumoniae.

The recent studies also suggest that low levels of IgG that does occur in nephrotic

syndrome is probably due to the primary disorder of lymphocyte regulation in

idiopathic nephrotic syndrome. Thus, the urinary losses of factor B, combined with

the idiopathic low levels of IgG, both contribute to the increased risk for infection in

nephrotic syndrome.

CHAPTER III

CONCLUSION

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Nephrotic syndrome (NS) is defined by the presence of nephrotic-range proteinuria,

edema, hyperlipidemia, and hypoalbuminemia. Nephrotic-range proteinuria in adults is

characterized by protein excretion of 3.5 g or more per day. The reported annual incidence

rate for nephrotic syndrome is 2-7 cases per 100,000 children younger than 16 years. The

glomerular diseases that cause nephrotic syndrome generally can be divided into congenital,

primary and secondary etiologies. 80-90 % cases of nephrotic syndrome in children is the

primary or idiopathic one leading to idiopathic nephrotic syndrome.

The pathophysiology of nephrotic syndrome in children comprises following element:

Proteinuria and hypoalbuminemia

o Proteinuria and immune system

The hallmark of Idiopathic Nephrotic Syndrome (INS) is massive proteinuria,

leading to decreased circulating albumin levels. 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.

o Genetics, the podocyte and proteinuria

The glomerular filtration barrier consists of the fenestrated capillary endothelium,

the extracellular basement membrane, and the intercalated podocyte foot

processes, connected by slit diaphragms. The effacement of the podocytes long

was thought to be a secondary phenomenon of nephrotic syndrome. Various

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

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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 resultant retention of sodium and water by the renal tubules contributes

to the extension and maintenance of edema.

Hyperlipidemia

Hyperlipidemia in patients with nephrotic syndrome is thought to be caused by these

following aspects: the stimulation of the liver to increase synthesis of all plasma

proteins (including the lipoproteins), due to their low level in the blood; and reduction

of lipoprotein catabolism due to reduced levels of lipoprotein lipase in blood.

Thrombus

In nephrotic syndrome, there are increased risks of arterial and venous thrombosis due

to loss of anti-thrombin III and plasminogen in the urine, combined with an increase

in hepatic synthesis of clotting factors.

Infection

Idiopathic nephrotic syndrome is associated with low IgG levels, which appear to be

the result of urinary losses at first. But according to the recent studies, low IgG levels

seem to be the result of impaired synthesis due to a primary disorder in lymphocyte

regulation in INS. Additionally, increased urinary losses of factor B are noted, a

cofactor protein of C3b in the alternative pathway of complement, which plays an

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important role in the opsonization of encapsulated organisms such as S pneumoniae.

Thus, the urinary losses of factor B, combined with the idiopathic low levels of IgG,

both contribute to the increased risk for infection in nephrotic syndrome.

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