READINGS DEFINITION Nephrotic syndrome (NS), also known as Nephrosis, is a condition characterized by massive proteinuria (>3.

5 g/day) and lipiduria (e.g., free fat, oval bodies, fatty casts), along with an associated hypoalbuminemia (<3 g/dL), generalized edema, and hyperlipidemia (cholesterol >300 mg/dL). (Porth & Matfin, 2009). These occur as a consequence of excessive leakage of plasma proteins into the urine because of increased permeability of the glomerular capillary membrane (Lippincott Manual of Nursing Practice, 2008). Nephrotic syndrome is not a disease itself, but the manifestation of many different glomerular diseases (Medscape, 2013). ETIOLOGIES 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. Causes of Idiopathic NS include the following: 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 (Cho et. al, 2007). In its normal state, the glomerular basement membrane is negatively charged because of the presence of various polyanions along this surface. This negative charge acts as a deterrent to filtration of negatively charged proteins, such as albumin. MPGN- Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephritis that occurs primarily in children and young adults. This entity refers to a pattern of glomerular injury based on characteristic histopathologic findings, including: (1) proliferation of mesangial and endothelial cells and expansion of the mesangial matrix, (2) thickening of the peripheral capillary walls by subendothelial immune deposits and/or intramembranous dense deposits, and (3) mesangial interposition into the capillary wall, giving rise to a double-contour or tram-track appearance on light microscopy (Medscape, 2013). MGN- Membranous glomerulonephritis (MGN) is an immunologically mediated disease in which immune complexes deposit in the subepithelial space. The antigens associated with primary membranous nephropathy are not known. They may be located in the subepithelial space. Antigen-antibody complexes can develop by the production of immune complexes in situ or by deposition (Medscape, 2013). C3GN- C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement leading to subsequent glomerular injury (Sethi et. al, 2012). IgAN- Immunoglobulin A nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. It is the most common cause of glomerulonephritis in the world. The pathogenesis of IgA nephropathy remains

incompletely understood. The characteristic pathologic findings by immunofluorescence microscopy of granular deposits of IgA and complement 3 (C3) in the glomerular mesangium suggest that this disease is the result of the deposition of circulating immune complexes leading to the activation of the complement cascade. Causes of genetic or congenital nephrotic syndrome include the following: Finnish-type congenital nephrotic syndrome (NPHS1, nephrin) 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). Denys-Drash syndrome (WT1)- Wilms tumor 1 gene provides instructions for making a protein that is necessary for the development of the kidneys and gonads (ovaries in females and testes in males) (http://ghr.nlm.nih.gov). The mutations that cause DenysDrash syndrome lead to the production of an abnormal WT1 protein that cannot bind to DNA. As a result, the activity of certain genes is unregulated, which impairs development of the kidneys and genitalia. Abnormal development of these organs leads to the signs and symptoms of Denys-Drash syndrome which include congenital nephropathy (diffuse mesangial sclerosis). Frasier syndrome (WT1)- The WT1 gene mutations that cause Frasier syndrome lead to the production of a protein with an impaired ability to control gene activity and regulate the development of the kidneys and reproductive organs, resulting in the signs and symptoms of Frasier syndrome which include focal segmental glomerulosclerosis, in which scar tissue forms in some glomeruli. Diffuse mesangial sclerosis (PLCE1)- 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. Autosomal recessive, familial FSGS (NPHS2, podocin) 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 NPHS2gene on chromosome 1. Mutations in the NPHS2 gene were originally described in patients with autosomal recessive, steroidresistant INS with FSGS on biopsy. Podocin mutations account for approximately 4555% of familial and 8-20% of sporadic cases of SRNS. Autosomal dominant, familial FSGS (ACTN4, -actinin-4; TRPC6) -Actinin-4, encoded by the gene ACTN4 on chromosome 19, cross-links actin filaments of the podocyte cytoskeleton and anchors them to the glomerular basement membrane. The TRPC6 gene on chromosome 11 encodes for a calcium channel associated with the slit diaphragm. Disruptions in either ACTN4 orTRPC6 are associated with autosomal dominant forms of FSGS. Nail-patella syndrome (LMX1B)- Nail-patella syndrome, a disorder characterized by skeletal and nail dysplasia as well as nephrotic syndrome, is caused by mutations in the LMX1Bgene, which regulates expression of type IV collagen and the podocyte proteins nephrin, podocin, and CD2AP. Pierson syndrome (LAMB2)- (laminin, beta 2 (laminin S). Pierson syndrome is a rare genetic disease that is characterized by a combination of developmental defects that mainly affect ocular and renal function. It is caused by mutations in the LAMB2 gene

which encodes for the laminin 2 protein. The laminin 2 protein is required for the formation of basement membranes and is implicated in processes such as cell proliferation and differentiation (http://pfond.cmmt.ubc.ca). Schimke immuno-osseous dysplasia (SMARCAL1)- mutations in the DNA-nucleosome restructuring mediator SMARCAL1 cause Schimke immuno-osseous dysplasia, a syndrome characterized by spondyloepiphyseal dysplasia (SED) resulting in disproportionate short stature, nephropathy, and T-cell deficiency. Galloway-Mowat syndrome - is a very rare autosomal recessive genetic disorder, consisting of a variety of features including hiatal hernia,microcephaly and nephrotic syndrome. The exact genetic defect is yet to be discovered. Oculocerebrorenal (Lowe) syndrome- This syndrome is caused by inherited mutations in the OCRL gene, mapped to chromosome Xq 26.1, which encodes the OCRL1 protein. The OCRL1 protein is an inositol polyphosphate 5-phosphatase. This protein is associated with the primary cilia of the retinal pigment epithelial cells, fibroblasts and kidney tubular cells. This suggests that this syndrome is due to dysfunction of the cilia in these cells. Secondary nephrotic syndrome refers to an etiology extrinsic to the kidney. Systemic diseases that can cause secondary nephrotic syndrome include the following: Systemic lupus erythematosus- this autoimmune disease can affect a number of organs, among them the kidney, due to the deposit ofimmunocomplexes that are typical to this disease. Malignancy - Lymphoma, leukemia Vasculitis -Wegener granulomatosis (granulomatosis with polyangiitis), Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis),polyarteritis nodosa, microscopic polyangiitis, Henoch-Schnlein purpura (HSP) Immune-complexmediated - Poststreptococcal (postinfectious) glomerulonephritis Infections that can cause secondary nephrotic syndrome include the following: Congenital syphilis, toxoplasmosis, cytomegalovirus, rubella Hepatitis B and C HIV/acquired immunodeficiency syndrome (AIDS) Malaria Drugs that can cause secondary nephrotic syndrome include the following: Penicillamine- interferes with the synthesis of collagen, which is the main structural protein of various connective tissues such as the kidneys. GoldIn the kidneys gold salts accumulate in the proximal tubules where gold inclusions can be shown within a few hours of administration (Brun et al.,1964). Although they are thought to be excreted mainly via the tubules (Brun et al., 1964), gold salts have also been shown to pass through the glomerular basement membrane. Gold salts can cause a more or less important loss of proteins in urine as a consequence of metal accumulation (Wikipedia, 2013). Nonsteroidal anti-inflammatory drugs (NSAIDs)- These NSAIDs may depress renal function by inhibiting the enzyme cyclooxygenase, thereby preventing the breakdown of arachidonic acid to prostaglandins (PGs). Some of the PGs -- specifically PGE2 and PGI2 - cause vasodilation in the kidney (Murray & Brater, 1993) and may also be involved in the release of renin (Kramer et al., 1985). Interferon

Mercury Heroin Pamidronate Lithium- lithium treatment produces a small but significant and nonprogressive elevation of the urinary excretion of albumin (Jensen et. al, 1992).

About two in every 10,000 people experience nephrotic syndrome. Nephrotic syndrome prevalence is difficult to establish in adults because the condition is usually a result of an underlying disease. In children, it is diagnosed in more boys than girls, usually between 2 and 3 years of age (http://www.healthcommunities.com/nephrotic-syndrome-ns/overview-nephroticsyndrome.shtml). The glomerular derangements that occur with nephrosis can develop as a primary disorder or secondary to changes caused by systemic diseases such as diabetes mellitus and SLE (Alpers, 2005 and Jennette, 2008, as cited by Porth & Matfin, 2009). Among the primary glomerular lesions leading to nephrotic syndrome are minimal-change disease (lipoid nephrosis), focal segmental glomerulosclerosis, and membranous glomerulonephritis. The relative frequency of these causes varies with age. In children younger than 15 years of age, nephrotic syndrome almost always is caused by primary idiopathic glomerular disease, whereas in adults, it often is a secondary disorder (Porth & Matfin, 2009). Minimal change disease is characterized by diffuse loss (through fusion) of the foot processes of cells in the epithelial layer of the glomerular membrane. It is most commonly seen in children (peak incidence at 2 to 6 years of age), but may occasionally occur in adults. The cause of minimal-change nephrosis is unknown; however, children in whom the disease develops often have a history of recent upper respiratory infections or of receiving routine immunizations (Alpers, 2005 as cited by Porth and Matfin, 2009). It is postulated that MCD is a disorder of T cells, which release a cytokine that injures the glomerular epithelial foot processes (Medscape, 2014). This, in turn, leads to a decreased synthesis of polyanions (Medscape, 2014). The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin (Medscape, 2014). When the polyanions are damaged, leakage of albumin follows (Medscape, 2014). The identity of this circulating permeability factor is uncertain, although it is postulated that it may be hemopexin (Medscape, 2014). Hemopexin also known as beta-1Bglycoprotein binds heme with the highest affinity of any known protein. Its function is scavenging the heme released or lost by the turnover of heme proteins such as hemoglobin and thus protects the body from the oxidative damage that free heme can cause. In addition, hemopexin releases its bound ligand for internalisation upon interacting with a specific receptor situated on the surface of liver cells. This function of hemopexin is to preserve the body's iron. Minimal-change nephropathy Focal glomerulosclerosis Membranous nephropathy Hereditary nephropathies Secondary causes include the following: Diabetes mellitus Lupus erythematosus Amyloidosis and paraproteinemias Viral infections (eg, hepatitis B, hepatitis C, human immunodeficiency virus [HIV] )

 Preeclampsia
Plasma Exert colloid osmotic pressure, which helps Proteins (7.0%) maintain water balance between blood

and tissues and regulates blood volume. Albumins Smallest and most numerous blood plasma proteins; produced by liver. Function as transport proteins for several steroid hormones and for fatty acids. Globulins Produced by liver and by plasma cells, which develop from B lymphocytes. Antibodies (immunoglobulins) help attack viruses and bacteria. Alpha and beta globulins transport iron, lipids, and fat-soluble vitamins. Fibrinogen Produced by liver. Plays essential role in blood clotting.

SCHEMATIC DIAGRAM The glomerular membrane acts as a size and charge barrier through which the glomerular filtrate must pass. Increase in permeability of glomerular membrane allows proteins to escape from the plasma into the glomerular filtrate. Massive proteinuria results leading to hypoproteinemia. The largest proportion of protein lost in the urine is albumin, the smallest and most numerous blood plasma proteins, but globulins also may be lost in some diseases. Decrease of colloidal osmotic pressure of the blood results from large plasma protein loss in the urine. with subsequent accumulation of fluid in the interstitial tissues.5,6 There is also salt and water retention, which aggravates the edema. This appears to be due to several factors, including a compensatory increase in aldosterone, stimulation of the sympathetic nervous system, and a reduction in secretion of natriuretic factors. Initially, the edema presents in dependent parts of the body such as the lower extremities, but becomes more generalized as the disease progresses. Dyspnea due to pulmonary edema, pleural effusions, and diaphragmatic compromise due to ascites can develop in persons with nephrotic syndrome. The hyperlipidemia that occurs in persons with nephrosis is characterized by elevated levels of triglycerides and lowdensity lipoproteins (LDLs). Levels of high-density lipoproteins (HDLs) usually are normal. It is thought that these abnormalities are related, at least in part, to increased synthesis of lipoproteins in the liver secondary to a compensatory increase in albumin production.45 Because of the elevated LDL levels, persons with nephrotic syndrome are at increased risk for development of atherosclerosis. The largest proportion of protein lost in the urine is albumin, but globulins also may be lost in some diseases. As a result, persons with nephrosis may be vulnerable to infections, particularly those caused by staphylococci and pneumococci.5 This decreased resistance to infection probably is related to

loss of both immunoglobulins and lowmolecular-weight complement components in the urine. Many binding proteins also are lost in the urine. Consequently, the plasma levels of many ions (iron, copper, zinc) and hormones (thyroid and sex hormones) may be low because of decreased binding proteins. Many drugs require protein binding for transport. Hypoalbuminemia reduces the number of available protein-binding sites, thereby producing a potential increase in the amount of free (active) drug that is available.45 Thrombotic complications also have evolved as a risk in persons with nephrotic syndrome. These disorders reflect a disruption in the function of the coagulation system brought about by a loss of coagulation and anticoagulation factors. Renal vein thrombosis, once thought to be a cause of the disorder, is more likely a consequence of the hypercoagulable state.45 Other thrombotic complications include deep vein thrombosis and pulmonary emboli.

The pathogenesis of glomerular diseases can include a very wide gamut processes including hereditary, drug-induced, immune-mediated, infectious, and idiopathic causes. However, immune-mediated mechanisms of injury are especially important and are commonly seen in many glomerular diseases. Immune injury to the glomerulus can occur through several basic pathogenic sequences which are discussed below. Basic Glomerular Pathogenesis Overview Immune-mediated injury to the glomerulus typically arises from the deposition of Antibodies within the glomerulus, a process which can occur via a variety of distinct mechanisms as described individually below. Whatever the mechanism, the presence of antibodies within the glomerulus results in a final common pathway of immune-mediated injury. Deposition of immunoglobulins activates Complement, resulting in deposition of complement proteins. In some cases, deposited complement proteins perform the bulk of the damage, leading to impairment of the glomerular barrier. However, in other cases, activated complement proteins lead to recruitment of Macrophages which then initiate damage of glomerular structures and in doing so impair the selectivity of glomerular filtration. Preformed Immune Complex Deposition Preformed, circulating Immune Complexes composed of particles of antibody bound to antigen can easily become trapped in the Glomerulus either within the Glomerular Basement Membrane or theMesangium. In essence, this is a renal manifestation of Type III Hypersensitivity. Immune Complexesdeposited within the glomerulus generally result in a granular pattern when immunoglobulin proteins are detected by immunofluorescence. In Situ Immune Complex Formation

In this scenario, circulating antibodies react with clumps of antigen which were previously present within the Glomerular Basement Membrane (GBM). Therefore, the Immune Complex is formed 'in situ' (i.e. at its site of deposition) rather than having been preformed in the plasma. The clumps of antigen may be from circulating antigens that become trapped in the GBM; importantly, these antigens may be either from an endogenous source or in many some cases from viral proteins. Alternatively, antigenic clumps may represent proteins normally present in the GBM which possess a naturally clumpy distribution. Anti-Glomerular Basement Membrane Antibody Deposition In this scenario, a specific antibody develops that binds to a normal protein component of theGlomerular Basement Membrane (GBM), in essence a form of Type II Hypersensitivity. Here, no immune complexes are present and instead the antibody diffusely deposits along the entire length of the GBM. Anti-GBM antibody deposition appears as a ribbon-like, linear band tracking the GBM upon imunofluorescent detection of immunoglobulin proteins.

The central abnormality in all cases of nephrotic syndrome is the development of massive proteinuria. Although the molecular basis for this is still speculative, there is evidence in the literature that nephrotic syndrome may be a consequence of a primary glomerular defect, circulating factors, or an immunological abnormality. Primary Glomerular Defect One of the most important functions of the kidney is the filtration of blood by glomeruli, which allows excretion of fluid and waste products while retaining the majority of blood proteins and all blood cells within the vasculature. This process of filtration is made possible by the glomerular filtration barrier, which is made up of specialized fenestrated endothelial cells, the glomerular basement membrane (GBM), and glomerular epithelial cells (podocytes) whose distal foot processes are attached to the GBM. Neighboring podocyte foot processes are connected to each other by networks of specialized cell-cell junctions known as slit diaphragms. In addition, the GBM has an abundant supply of negatively charged heparin sulfate proteoglycan, resulting in negatively charged molecules being relatively more restricted from passage than positively charged molecules of the same size. In health, molecules greater than 42 in diameter are unable to cross the filtration barrier. This restriction depends largely on the structural integrity of the podocyte foot processes and slit diaphragms, as well as the GBM charge. In nephrotic syndrome there is loss of negative charge of the GBM. Other morphologic changes in podocytes that occur during development of nephrotic syndrome include swelling, retraction, and effacement (spreading) of the podocyte distal foot processes, vacuole formation, occurrence of occluding junctions, displacement of slit diaphragms, and detachment of podocytes from the GBM. The importance of podocyte and slit diaphragm structure to the pathogenesis of nephrotic syndrome is further reinforced by recent observations in humans and experimental animals that mutations in genes encoding some of the slit diaphragm proteins or their transcription factors can cause steroid-resistant nephrotic syndrome (SRNS) and/or focal segmental glomerulosclerosis (FSGS). Mutations in the gene encoding the slit diaphragm protein nephrin (NPHS1) causes CNF in infants. In addition, mutations in NPHS2 are estimated

to be responsible for up to 25% of cases of familial and sporadic SRNS in children. Mutations in the transcription factor suppressor gene WT1 result in Denys-Drash syndrome and Frasier syndrome in children, although they may also cause isolated FSGS and diffuse mesangial sclerosis (DMS). Mutations in other genes encoding podocyte and GBM proteins include (1) the actin-bundling protein -actinin 4, which causes adult-onset FSGS; (2) laminin 2, which results in Pierson syndrome; (3) CD2-associated protein (CD2AP), which results in adult-onset FSGS; (4) the LIM-homeodomain protein (encoded by LMX1B), which results in nail-patella syndrome; and (5) the chromatin regulator encoded by SMARCAL1, which results in FSGS associated with Schimke immunoosseous dysplasia. Circulating Factors There are experimental data to support the existence of soluble mediators that may alter capillary wall permeability in nephrotic syndrome. Evidence for this includes (1) development of nephrotic syndrome in newborn babies born to mothers with nephrotic syndrome who apparently transferred a soluble factor to their fetuses in utero, (2) marked reduction of proteinuria following treatment with protein A immunoadsorption in various types of primary nephrotic syndromes, (3) recurrence of FSGS in transplanted kidneys in patients with primary FSGS, with remission of recurrent disease induced by treatment with protein A immunoadsorption due to presumed removal of circulating factors, and (4) induction of enhanced glomerular permeability in experimental animals injected with serum from patients with FSGS recurrence in transplanted kidneys. Furthermore, inhibitors of glomerular permeability have also been isolated from the serum of children with FSGS and identified as components of apolipoproteins, suggesting that an imbalance between serum permeability factors and permeability inhibitors may have a pathogenic role in FSGS. Immunological Abnormality The theory that nephrotic syndrome may be due to dysregulation of the immune system has existed for more than 30 years. There are numerous reports of abnormalities of both the humoral and cellular immune responses during relapse of nephrotic syndrome. However, the idea that nephrotic syndrome may be due to dysregulation of T lymphocyte function was fi rst proposed by Shalhoub and his colleagues.51 Evidence for this includes (1) responsiveness of most forms of primary nephrotic syndrome to corticosteroids, alkylating agents, calcineurin inhibitors, and mycophenolate mofetil, all of which are known inhibitors of T lymphocyte function, (2) induction of remission of nephrotic syndrome following infections with measles and malaria, diseases known to depress cell-mediated immunity, and (3) identifi cation of MCNS as a paraneoplastic manifestation of Hodgkins disease and other lymphoreticular malignancies. Other reports have also suggested an important role of the cell-mediated immune system in nephrotic syndrome, including depressed cell-mediated immunity during relapses of MCNS alterations in T cell subsets during relapses,58,59 and increased cell surface expression of IL-2 receptors on T cells, refl ective of T cell activation.59 In addition, numerous cytokines, released in part by T lymphocytes,

have been reported to be variably altered during nephrotic syndrome.60,61 It should be noted, however, that despite numerous reports, none of these cytokines has proven to be both present in the majority of cases of MCNS and able to induce signifi cant proteinuria in experimenta CAUSES 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. Secondary nephrotic syndrome refers to an etiology extrinsic to the kidney. Nephrotic syndrome in childhood is largely primary or idiopathic, although a small proportion of cases are secondary to infectious agents and other glomerular and systemic diseases. The etiology of nephrotic syndrome is also age dependent. Most cases appearing in the first 3 months of life are referred to as congenital nephrotic syndrome (CNS) and are due to genetic diseases. Although there has been no systematic study of the etiology of nephrotic syndrome presenting in the rest of the first year of life (3 to 12 months), there are data suggesting that up to 40% of cases during this time may also be due to genetic causes. Beyond the first year of life and in the first decade, most cases are due to primary or idiopathic nephrotic syndrome, whereas the proportion of secondary nephrotic syndrome cases increases beyond the first 10 years of life. Congenital Nephrotic Syndrome Nephrotic syndrome appearing in the first 3 months of life is referred to as congenital nephrotic syndrome (CNS). Most cases in this age group are due to genetic causes, the majority being mutations in the gene encoding nephrin, a podocyte slit diaphragm protein. These mutations were first described in the Finnish, hence the name congenital nephrotic syndrome of the Finnish type (CNSF). The incidence of CNF is highest in Finland but occurs in other populations as well. Congenital nephrotic syndrome is not synonymous with CNF, because mutations in other genes encoding podocyte slit diaphragm proteins, such as podocin, can also cause earlyonset nephrotic syndrome. In one series mutations in the podocin gene (NPHS2) were shown to be responsible for up to 40% of all cases of nephrotic syndrome occurring in the first 3 months of life. Nephrotic syndrome in the first 3 months of life may also be part of multisystemic syndromes such as Pierson syndrome, nail-patella syndrome, Denys-Drash syndrome, and others. Drugs to which particular attention must be given include many antibiotics, histamine H2-receptor antagonists, digoxin, anticonvulsants and non-steroidal anti-inflammatory drugs (NSAIDs). Types of nephrotic syndrome: Minimal change disease Most common pathology found in childhood nephrotic syndrome (77-85% of cases)

Usually idiopathic, though an association with Hodgkin lymphoma has been studied in adult cases As name implies, light microscopy of renal biopsy samples shows no change on electron microscopy, effacement of the foot processes can be seen Immunofluorescent staining for immune complexes is negative

Foot process effacement seen in minimal change disease Focal segmental glomerulosclerosis Accounts for 10-15% of cases More common in adults Light microscopy of renal biopsy sample shows scarring, or sclerosis, of portions of selected glomeruli which can progress into global glomerular sclerosis and tubular atrophy Like minimal change disease, will see effacement of foot processes on EM and in most cases, negative