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THE PATHOPHYSIOLOGY OF NEPHROTIC SYNDROME IN CHILDREN

Written by: Sarita Amelia 030.07.235

The Faculty of Medicine Trisakti University

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 clinicalpathological correlations have been made. A wide variety of glomerular lesions can be seen in INS. Primary causes of nephrotic syndrome include:
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MCNS (Minimal Change Nephrotic Syndrome): 85 % of childhood cases FSGS (Focal Segmental Glomerulosclerosis): 9 % of childhood cases

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

cases
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Membranoproliverative glomerulonephritis (MPGN) IgA nephropathy Secondary nephrotic syndrome

By definition, secondary nephritic syndrome refers to an etiology extrinsic to the kidney. Secondary causes of nephrotic syndrome include:
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Infections, include: congenital syphilis, TORCH, Malaria, HIV, etc. Drugs, include: penicillamine, gold, nonsteroidal anti-inflammatory drugs

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


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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:
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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, -actinin4; 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) 3

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

in range <2530 g/l)


Peripheral oedema due to hypoalbuminaemia Hypercholesterolaemia/dyslipidaemia Normal detoxifying renal function (at least initially), oliguri

The reported annual incidence rate for nephrotic syndrome is 2-7 cases per 100,000 children younger than 16 years. In children younger than 8 years at onset, the ratio of males to females varies from 2:1 to 3:2 in various studies. The landmark study of nephrotic syndrome in children, the International Study of Kidney Disease in Children (ISKDC) (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. Since the introduction of corticosteroids, the overall mortality of INS has decreased dramatically from over 50% to approximately 2-5%.

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.

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 6

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 reducedantigenic 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

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

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

biology of the podocyte. Various forms of INS have been described with mutations in podocyte genes (NPHS1NPHS2, TRCP6, CD2AP, ACTN4); the glomerular basement membrane (LAMB2); mitochondria (COQ2); and transcription factors (WT1, LMX1B). Nephrin is a transmembrane protein that is a major structural element of the slit diaphragm and is encoded by the NPHS1 gene on chromosome 19. Mutations in the NPHS1 gene are responsible for autosomal recessive, congenital nephrotic syndrome of the Finnish type (FNS). Podocin is another podocyte protein that interacts with nephrin and CD2AP. Podocin is encoded by the NPHS2 gene on chromosome 1. Mutations in the NPHS2 gene were originally described in patients with autosomal recessive, steroid-resistant INS with FSGS on biopsy findings. -Actinin-4, encoded by the gene ACTN4 on chromosome 19, crosslinks actin filaments of the podocyte cytoskeleton and anchors them to the glomerular basement membrane. 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. Coward et al demonstrated that nephrotic plasma induces translocation of the slit diaphragm proteins nephrin, podocin, and CD2AP away from the plasma membrane into the cytoplasm of the podocyte.13 These 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.

2.3.

Edema

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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+ exchanger NHE3 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. Highdensity lipoprotein (HDL)-cholesterol is normal or low. Elevations in triglycerides occur with severe hypoalbuminemia. The traditional explanation for hyperlipidemia in 12

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 lecithincholesterol 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. 13

Thus, we can say that 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.

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 8090 % 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 15

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 ReninAngiotensin-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. 16

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. 18

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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