Nephrotic syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Ayesha A. Khan, MD[3] Olufunmilola Olubukola M.D.[4]

Nephrotic syndrome is group of signs and symptoms resulting from loss of kidney filtration capabilities leading to massive loss of protein in urine, generalized or localized body edema, hyperlipidemia and hypoproteinemia (most importantly, hypoalbuminemia). Causes of Nephrotic Syndrome can be primary (idiopathic) or secondary (from a systemic insult or immune mediated). Nephrotic syndrome (nephrosis) is defined as heavy proteinuria > 3.5 grams per 24 hours in adults. In children, nephrotic syndrome is defined as protein excretion > 40 mg/m²/h. The accurate diagnosis of nephrotic syndrome thus requires 24-hour urine collection. However, in clinical practice, urine dipstick of a qualitative measure of 3+ urinary proteins, or spot urine protein (mg)/creatinine(mg) ratio > 2 may also reflect nephrotic syndrome.

In 1484, Cornelus Roelans of Belgium described a child with “whole body swelling” and nephropathy. In 1905, Friedrich v. Müller described the term “nephrosis”. Initially, nephrosis was defined by morphological terms describing various histological alterations of the renal tubuli which were considered to be degenerative. Today nephrosis is a clinical diagnosis, and usually called nephrotic syndrome. ^[1]

Nephrotic syndrome can be classified into primary or secondary depending on the underlying etiology. Primary (idiopathic) nephrotic syndrome is defined as nephrotic syndrome due to a primary glomerular disease. Secondary nephrotic syndrome is defined as nephrotic syndrome due to a primary etiology other than glomerular disorders, such as infections, malignancies, systemic conditions, and medications.

The pathophysiology of hypoalbuminemia in nephrotic syndrome is multifactorial. Proteinuria plays an important role in the pathogenesis of hyperlipidemia in nephrotic syndrome. Neurohormonal changes in the renin-angiotensin-aldosterone system, vasopressin, atrial natriuretic peptide (ANP), and sympathetic nervous system are is implicated in edema formation in nephrotic syndrome.

Nephrotic syndrome can occur primarily or due to systemic diseases. The most common cause of nephrotic syndrome in children is minimal change disease. The most common primary causes in adults are focal segmental glomerulosclerosis (FSGS), minimal change disease, and membranous nephropathy. Approximately 30 percent of adults have secondary nephrotic syndrome due to diabetes mellitus, SLE, or amyloidosis. The most common cause of secondary nephrotic syndrome in adults is diabetes mellitus.

Nephrotic syndrome should be differentiate from other causes of glomerular disease such as Fabry’s disease, post-streptococcal glomerulonephritis, lupus nephritis, antiglomerular basement membrane disease (goodpasture’s syndrome), Cryoglobulinemia, Henoch-Schönlein purpura, amyloidosis, pulmonary-renal syndromes (vasculitis), thin basement membrane disease, Alport’s Syndrome, anti-GBM Disease, hypertensive nephrosclerosis, and subacute bacterial endocarditis. The various types of glomerular diseases may be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light, and electron microscopic features.

Idiopathic nephrotic syndrome has an incidence of 2-7 cases per 100,000 and a prevalence of 16 cases per 100,000. Nephrotic syndrome may affect children and adults alike. There is no age or ethnic predominance. The prevalence of nephrotic syndrome in children has a 2 to 1 male to female ratio.

Complications of nephrotic syndrome include infections, thrombotic events, and renal failure. Mortality and overall prognosis depends on the occurrence of complications and adherence to medications.

The hallmark of nephrotic syndrome is edema. A positive history of renal disease, systemic diseases such as diabetes mellitus, amyloidosis, or systemic lupus erythematosus, and medication use is suggestive of nephrotic syndrome. The most common symptoms of nephrotic syndrome include volume overload, foamy urine, and fatigue.

A full physical examination should be performed among patients presenting with nephrotic syndrome. Findings on physical examination suggestive of secondary etiologies may be present, such as characteristic rash in systemic lupus erythematosus (SLE), or peripheral neuropathy in diabetes mellitus.

Nephrotic syndrome is characterized by the following laboratory findings: proteinuria > 3.5g/24 hrs on 24-hour urine collection, proteinuria on urine dipstick, and urine protein/creatinine ratio > 3. When nephrotic syndrome is diagnosed (proteinuria > 3.5 g/24 hrs), additional laboratory tests are required such as serum albumin concentration, serum chemistry panel, lipid panel, and serum creatinine concentration.

Chest X-ray may show signs of pleural effusion.

Renal and abdominal doppler ultrasound may be required to investigate for renal etiologies and complications of disease, such as renal vein thrombosis. Kidney size and signs of obstruction during assessment are also important. Doppler ultrasound of the extremities is indicated if patients with nephrotic syndrome present with suspected deep vein thrombosis.

Renal vein thrombosis, a complication of nephrotic syndrome, may require any of venography, CT scan, or MRI for appropriate diagnosis.

Ultrasound-guided renal biopsy for visualization under light microscopy, immunofluorescence or immunoperoxidase, and electron microscopy is usually recommended for patients with nephrotic syndrome. Renal biopsy provides diagnostic and prognostic benefit. However, guidelines that define the timing and the circumstances to perform renal biopsy are not present. In minimal change disease, the most common primary cause of nephrotic syndrome in children, and in diabetic nephropathy, the most common secondary cause of nephrotic syndrome in adults, renal biopsy is not generally recommended and is not routinely performed. Nonetheless, patients who present with unknown or unsure etiology of nephrotic syndrome are recommended to undergo renal biopsy for definitive diagnosis.

There are currently no guidelines for the management of edema associated with nephrotic syndrome. The slow reversal of edema is important at a rate of 0.5-1 kg daily to prevent electrolyte disturbances, hypotension, ischemic acute tubular necrosis, and hemoconcentration associated with aggressive diuretic therapy. Since proteinuria is one of the most significant factors for progression of a disease and is associated with outcome, treatment of proteinuria in nephrotic syndrome must always be considered a priority. Angiotensin-converting enzyme inhibitors (ACE-I), with or without angiotensin-II receptor blockers (ARB) have been extensively studied and are well-known to decrease proteinuria and the risk of progression of renal disease in patients with nephrotic syndrome. Pneumococcal vaccines are recommended for all patients with nephrotic syndrome.

The mainstay of treatment for nephrotic syndrome is medical therapy.

Appropriate treatment of conditions that can cause nephrotic syndrome may help prevent the syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [3]

In 1484, Cornelus Roelans of Belgium described a child with “whole body swelling” and nephropathy. In 1905, Müller described the term of “nephrosis” for non-inflammatory kidney diseases.

• In 1484, Cornelus Roelans of Belgium described a child with “whole body swelling” and nephropathy.
• In 1722, Theodore Zwinger of Basel described nephrotic syndrome in children, with decreased urine output due to “obstruction and compression of the tubules of the kidney.”
• In 1827, Richard Bright described the triad of generalized edema, proteinuria, and kidney disease, as features of nephrotic syndrome.
• In 1905, Müller described the term of “nephrosis” for non-inflammatory kidney diseases.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Ali Poyan Mehr, M.D. [2]; Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3], Yazan Daaboul, Serge Korjian

Nephrotic syndrome can be classified into primary or secondary depending on the underlying etiology. Primary (idiopathic) nephrotic syndrome is defined as nephrotic syndrome due to a primary glomerular disease. The secondary nephrotic syndrome is defined as nephrotic syndrome due to a primary etiology other than glomerular disorders, such as infections, malignancies, systemic conditions, and medications.

• Nephrotic syndrome can be classified into primary or secondary depending on the underlying etiology.^[1]

• Below table lists different types of nephrotic syndromes:^[2][3][4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian

The pathophysiology of hypoalbuminemia in nephrotic syndrome is multifactorial. Proteinuria plays an important role in the pathogenesis of hyperlipidemia in nephrotic syndrome. Neurohormonal changes in the renin-angiotensin-aldosterone system, vasopressin, atrial natriuretic peptide (ANP), and sympathetic nervous system are is implicated in edema formation in nephrotic syndrome.

The pathophysiology of hypoalbuminemia in nephrotic syndrome is multifactorial. The glomerular basement membrane (GBM) is normally formed of heparan sulfate and proteoglycans that contain anion sites.^[1] These sites occupy the lamina rara externa of the GBM. Quantitative loss of the anion sites and neutralization of the GBM charge-selective barrier are directly related to albuminuria.^[2] In nephrotic syndrome, the kidneys lose the size and charge perm-selectivity of the glomerular capillary wall and protein leakage will occur.^[3][4] As such, the glomerulus will lose the ability to prevent the passage of macromolecules, such as albumin through the barrier, and albumin excretion will ensue.^[4][5][6][7] In addition to the increased renal loss of albumin, increased renal catabolism always contributed to hypoalbuminemia.^[7][8] Although initially believed that increased albumin intake would increase serum levels of albumin, results showed that following ingestion of albumin, albuminuria was exacerbated due to protein trafficking along the renal tubules.^[8] It is thus common practice to restrict protein intake in nephrotic syndrome.^[8][9] The use of ACE-inhibitors to reduce the degree of proteinuria suggested that neurohormonal changes related to angiotensin II must have a significant role in hypoalbuminemia as well.^[1]

In addition, circulating factors, such as vascular permeability factor (VPF) and other lymphokines produced by T cells, are believed to play a role in binding to polyanions in the GBM and neutralizing the barrier.^[10][11][12] Inflammatory changes have been related to proteinuria and related ultrastructural abnormalities may also be part of the multifactorial process behind hypoalbuminemia.^[1] Hemodynamic factors, such as a reduction in glomerular plasma flow, were also shown to play a role in the urinary loss of proteins. Consequently, an increase in the clearance of proteins along the glomerular capillary is observed due to removal of water and the creation of a diffusion gradient along the Bowman’s space. When the intravascular pool of albumin is lost, interstitial stores are shifted into the intravascular compartment and are similarly lost to eventually deplete all albumin stores.^[1]

Proteinuria plays an important role in the pathogenesis of hyperlipidemia in nephrotic syndrome.^[8] When hypoalbuminemia is present, the liver increases lipoprotein synthesis due to the decreased low plasma oncotic pressure. The process by which the liver increases the production of its products is believed to be regulated by a substance that is not yet identified. Animal studies have shown that in nephrotic syndrome, enzymes like hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase – the enzyme responsible for the rate limiting step in lipid synthesis, and acyl-coenzyme-A-cholesterol acyltransferase are both increased.^[13][14][15] In parallel, activities cholesterol-7-alpha-hydroxylase and lipoprotein lipase are decreased.^[13][14][15] Both processes validate that lipid synthesis is increased in nephrotic syndrome. Hyperlipidemia due to increase apo-B containing lipoproteins occurs secondary to the decrease in oncotic pressure, not to hypoalbuminemia per se.^[1] The severity of lipid abnormalities directly correlates with the severity of proteinuria, but is not associated with the identity of glomerular lesions or primary etiology of nephrotic syndrome.^[16][17] Increased triglycerides, LDL, and VLDL are increased and also contribute to the glomerular damage in mechanisms that remain unclear.^[18] It is perhaps that abnormalities in the metabolism of triglycerides, rather than increased synthesis, are responsible for hypertriglyceridemia. It is believed that lipoprotein-mediated conversion of VLDL to LDL (via IDL) may be slowed down in nephrotic syndrome.^[19][20] In contrast, HDL2 is generally reduced whereas HDL3 is elevated due to a reduction in the lecithin-cholesterol acyltransferase activity.^[16]

The pathophysiology of edema formation in nephrotic syndrome is still controversial. Researchers hypothesize that the “underfill” mechanism is responsible for edema formation due to loss of plasma albumin and colloid oncotic pressure, followed by increased filtration from the intravascular space to the interstitial space.^[21] Eventually, hypovolemia and renal hypoperfusion will lead to activation of the renin-angiotensin-aldosterone system (RAAS), vasopressin,^[22][23][24] atrial natriuretic peptide (ANP),^{[25][26][27][28]} and the sympathetic nervous system^[29], causing sodium retention.^[21]

The Starling equation adequately explains the net fluid movement between the intravascular and the interstitial compartments:

^{Jv is the net fluid movement between compartments; Pc is the capillary hydrostatic pressure; Pi is the interstitial hydrostatic pressure; σ is the reflection coefficient to proteins. It is a measure of vascular permeability; πc is the capillary oncotic pressure; πi is the interstitial oncotic pressure; Kf is the overall filtration permeability constant to volume flow; it is a product of the hydraulic conductance and capillary surface area. It is a measure of vascular permeability.}

Protective mechanisms against the formation of edema in hypoalbuminemia are^[21]:

1. “Washdown” of interstitial protein concentration; Increase in fluid filtration from the intravascular space into the interstitial space.
2. “Washout” of interstitial proteins; Increase in fluid delivery to interstitial space to increase lymphatic flow.

In summary, the role of the following neurohormonal changes is implicated in edema formation in nephrotic syndrome:^[21]

• Renin-angiotensin-aldosterone system
• Vasopressin
• Atrial natriuretic peptide (ANP)
• Sympathetic nervous system

Although the mechanism seemed straightforward, newer studies showed that the pathophysiology is not as simple as once thought. Even the inhibition of the RAAS pathway using ACE-inhibitors did not seem to inhibit sodium retention as expected.^{[30][31][32][33][34][35]} Volume depletion associated with nephrotic syndrome is only seen in a minority of patients.^[21] In fact, the rate at which protein loss occurs is equally important. When plasmapheresis was conducted in rats to control the rate of plasma protein reduction, rapid loss of proteins was associated with increase in RAAS and positive sodium balance with decrease in plasma and blood volumes.^[36][37][38] These changes were not seen in rats that received moderate continuous plasmapheresis. It is postulated that in some glomerular diseases, such as minimal change disease, where proteinuria occurs very rapidly, the rate of protein loss might mimic rat studies and edema formation occurs due to changes unseen in moderate protein loss.^[36][37][38]

It is believed that excessive proteinuria, as seen in patients with minimal change disease, and depletion of serum albumin creates a disequilibrium between plasma and extravascular stores of albumin in attempt to restore the plasma-to-interstitial difference in colloid oncotic pressure (COP).^[32] The disequilibrium creates a state of uncompensated hypovolemia when COP becomes < 8 mmHg.^[32] The dropping pressure temporarily stimulates aldosterone and other sodium-handling indices to retain sodium.^[32][39][40] Following sodium retention, a steady-state is reached and sodium is no longer actively retained.^[41][42][35] If a stable steady-state is not reached in cases when COP cannot be maintained above 8 mmHg, massive proteinuria persists.^[32]

Edema formation is not simply due to a sodium retention following a decrease in systemic volume and fall in plasma colloid pressure.^[43][44] Recent evidence has shown that edema formation and sodium retention may thus be less related to hypovolemia itself, but rather to a primary intrinsic dysfunction of the renal handling of sodium followed by superimposing hypovolemia.^[30][45][46] Tubular absorption is increased in patients with nephrotic syndrome, even in segments beyond the distal convoluted tubule, due to mechanisms that remain obscured.^[47][32] Nonetheless, an increase in the sodium/potassium/ATPase activity and amount associated with an increase of aldosterone-dependent expression of epithelial sodium channels (ENaC)^[48][49][50] were noted distally in the cortical collecting duct of nephrotic kidneys, emphasizing the role of the kidneys themselves in the pathogenesis of edema formation.^{[48][51][52][53]}

Finally, it is important to recognize that the pathology of edema formation is not homogeneous and that sodium retention alone cannot explain edema formation in nephrotic syndrome.^[21] On the contrary, the extent of edema may be very different even with the same degree of proteinuria.^[32] Several hypotheses suggest that patient and disease characteristics may account for the varying degree of edema in patients with similar amounts of proteinuria.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2], Yazan Daaboul, Serge Korjian

Nephrotic syndrome can occur primarily or due to systemic diseases. The most common cause of nephrotic syndrome in children is minimal change disease. The most common primary causes in adults are focal segmental glomerulosclerosis (FSGS), minimal change disease, and membranous nephropathy. Approximately 30 percent of adults have secondary nephrotic syndrome due to diabetes mellitus, SLE, or amyloidosis. The most common cause of secondary nephrotic syndrome in adults is diabetes mellitus.

Nephrotic syndrome can occur primarily or due to systemic diseases. The most common cause of nephrotic syndrome in children is minimal change disease. The most common primary causes in adults are focal segmental glomerulosclerosis (FSGS), minimal change disease, and membranous nephropathy. Approximately 30 percent of adults have secondary nephrotic syndrome due to diabetes mellitus, SLE, or amyloidosis.^{[1][2][3][4][5][6][7]}

Primary renal disorders, such as primary glomerulonephritides, may cause primary nephrotic syndrome. Differentiation between different types of glomerular diseases is often made by clinical suspicion and by renal biopsy, which includes light microscopy, immunofluorescence, and ideally electron microscopy.

Secondary causes of renal disorders cause secondary nephrotic syndrome. The most common cause of secondary nephrotic syndrome in adults is diabetes mellitus. Shown below is a table of the causes of nephrotic syndrome by age group.^[8]

^{Adapted from Rose BD. Pathophysiology of renal diseases, ed. 2. New York, McGraw-Hill, 1987,p. 167}

• Agalsidase beta
• Certolizumab pegol
• Coagulation factor IX
• Olsalazine
• Sodium aurothiomalate
• Trimethadione
• Ziv-aflibercept

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Nephrotic syndrome should be differentiate from other causes of glomerular disease such as Fabry’s disease, post-streptococcal glomerulonephritis, lupus nephritis, antiglomerular basement membrane disease (goodpasture’s syndrome), Cryoglobulinemia, Henoch-Schönlein purpura, amyloidosis, pulmonary-renal syndromes (vasculitis), thin basement membrane disease, Alport’s Syndrome, anti-GBM Disease, hypertensive nephrosclerosis, and subacute bacterial endocarditis. The various types of glomerular diseases may be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light, and electron microscopic features.

Nephrotic syndrome should be differentiate from other causes of glomerular disease. The various types of glomerular diseases may be differentiated from each other based on associations, presence of pitting edema, hemeturia, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The following table differentiates between various types of glumerular diseases:

Some infectious diseases such as HIV, HBV, HCV, syphilis, leprosy, malaria, and schistosomiasis may cause glomerular diseases.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian

Idiopathic nephrotic syndrome has an incidence of 2-7 cases per 100,000 and a prevalence of 16 cases per 100,000.^[1] Nephrotic syndrome may affect children and adults alike. There is no age or ethnic predominance. The prevalence of nephrotic syndrome in children has a 2 to 1 male to female ratio.^[2]

Idiopathic nephrotic syndrome has an incidence of 2-7 cases per 100,000 and a prevalence of 16 cases per 100,000.^[1]

Approximately 70-90% of children less than 10 years of age with nephrotic syndrome are diagnosed with minimal change disease (MCD), a common form of primary glomerulonephritis characterized by normal glomeruli on light microscopy and by podocyte effacement on electron microscopy.^[3][4][5] In older children, MCD still accounts for 50% of nephrotic syndrome.^[4][5] In adults, the prevalence of MCD is much lower. Adult-onset MCD only comprises 10-15% of all cases of MCD. On the other hand, the incidence of other primary glomerulonephritides and other causes of secondary nephrotic syndrome, such as infections, malignancies, and vasculitides are much more common.

Nephrotic syndrome may affect children and adults alike. There is no age or ethnic predominance. In total, the incidence of nephrotic syndrome is the same for adults and for children. Idiopathic nephrotic syndrome has an incidence of 2-7 cases per 100,000 and a prevalence of 16 cases per 100,000.^[1]

According to observational studies, the prevalence of nephrotic syndrome in children has a 2 to 1 male to female ratio.^[2] In adults, however, the prevalence is the same in both genders.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Multiple risk factors may be involved in the nephrotic syndrome, such as family history, gender, and obesity. Also, diseases such as Hodgkin lymphoma, leukemia, viral diseases, and medications such as lithium, D-penicillamine can be risk factors for developing different types of nephrotic syndromes.

Risk factors of nephrotic syndrome depend on the type of syndromes, as below:

Risk factors of development of minimal change disease include:^[1]

• Children within the Age >1 year but <8 years
• Hodgkin lymphoma
• Leukemia
• Recent viral illness
• Toxins such as mercury, gold, bee stings, fire coral exposure.
• Medication such as^[2]
  • Salazopyrin
  • Tiopronin
  • Lithium
  • D-penicillamine
  • Tyrosine-kinase inhibitor

The following are considered risk factors for the development of focal segmental glomerulosclerosis (FSGS):^[3]

• Male gender
• Black race
• Family history
• Heroin abuse
• Drugs known to be associated with FSGS
• Chronic viral infection
• Single kidney status
• Obesity

Below conditions and toxins can be a risk factor for nephrotic syndrome^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

There is insufficient evidence to recommend screening for nephrotic syndrome.

There is insufficient evidence to recommend screening for nephrotic syndrome.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian

Complications of nephrotic syndrome include infections, thrombotic events, and renal failure. Mortality and overall prognosis depends on the occurrence of complications and adherence to medications.

In children, the mean age for presentation of nephrotic syndrome is approximately 1-8 years. According to Madani and colleagues^[1], who studied nephrotic syndrome in 502 pediatric patients, 67% of patients were in the range of 1-5 years of age. Other studies showed similar age distribution in children.^[2][3][4][5] The mean age among adults is much more difficult to calculate because unlike children whose primary disease is almost always minimal change disease, secondary etiologies of nephrotic syndrome, such as HIV and diabetes, are much more common and corresponding age distribution is very wide.^[6]

Patients with nephrotic syndrome are at increased risk of infections due to several mechanisms:

• Urinary loss of immunoglobulins^[6]

• Delay in complement-dependent opsonisation of encapsulated organisms, such as S. pneumoniae^[7]

• Reduction in factors B and I^[7]
• Decrease of blood flow to mesenteric regions^[6]

Patients with nephrotic syndrome who complain of abdominal pain must always be assessed for peritonitis that requires paracentesis. The rate of spontaneous bacterial peritonitis is 2-6%^[8] which contributes to 1-2% of mortality in these patients. In addition to encapsulated bacteria, gram-negative bacterial organisms, such as E. coli, are also especially important infectious agents in patients with nephrotic syndrome.^[9] Pneumonias, urinary tract infections, and skin infections, such as cellulitis, erysipelas, and lymphangitis are also common.^[6] Since patients are often treated with immunosuppressants, the susceptibility to bacterial and viral infections is further heightened in these patients.^[10][7]

The rate of thromboembolism may be as high as 40% in adults; whereas it is much lower in children at a rate of 2-5%.^[11] Several factors contribute to thromboembolism in nephrotic syndrome^[11]:

• Increase in platelet aggregation
• Increase in concentration of fibrinogen
• Urinary loss of antithrombin III
• Increase in blood viscosity
• Decrease in blood flow

Thromboembolism is considered the second most important cause of mortality in nephrotic syndrome. The risk of thromboembolism increases as other risk factors of thrombosis are also present, such as immobility, indwelling catheters, use of diuretics or steroids.^[6] Thromboembolism may occur at any site; common locations include deep veins of the extremities, cerebral veins, renal veins, and pulmonary veins. Although arterial occlusion is much less common, its prognostic significance is much graver than venous thromboembolism and is associated with mortality.^[11] Considerably, the use of heparin may not be as efficient in nephrotic syndrome due to the insufficiency of antithrombin III required by the drug for anticoagulation.^[12]

The clinical presentation of nephrotic syndrome per represents a high-risk profile for cardiovascular disease. Patients may present with hypertension, hyperlipidemia, anemia, renal disease, and exposure to steroids, all of which are considered risk factors for the development of cardiovascular disease and cardiovascular events.^[13][14]

Acute renal failure, in as early as within 4 weeks of nephrotic syndrome, is a more common complication in adult males > 60 years.^[15] Additional cardiovascular risk factors, like hypertension, and iatrogenic causes, like fluid withdrawal and surgeries, are also important in the development of acute renal failure.^[15] Renal failure in nephrotic syndrome is due to multiple factors. Acute tubular necrosis (ATN) corresponds to approximately 60% of acute renal failure in nephrotic syndrome. Interstitial edema, especially due to medications given for patients, like diuretics and steroids, are responsible for the remainder of cases.^[15]

Osteoporosis is generally a complication of corticosteroid use in nephrotic syndrome. However, medication-induced osteoporosis is not the only factor that predisposes patients to loss of bone density. Urinary loss of components required for osteogenesis, such as vitamin D-binding protein is also involved.^[16][17][18]

Anemia is commonly seen in patients with nephrotic syndrome but has been poorly evaluated. Recent studies have shown that perhaps the association between anemia and nephrotic syndrome are exaggerated and may not be as important as once believed.^[19] Anemia be present even without the presence of worsening kidney function. Several reasons predispose patients with nephrotic syndrome to the development of anemia, but the true pathogenesis has not been revealed yet. Some hypothesize that urinary loss of erythropoietin (EPO) and abnormal physiological response to EPO are the culprit of anemia.^[20][13] Nonetheless, these claims have not been validated in the literature and are still prone to debate.^{[21][22][23][24]} Additionally, iron stores are thought to be depleted in nephrotic syndrome with urinary loss of transferrin, contributing to the pathogenesis as an iron-resistant microcytic hypochromic anemia. Similarly, some researchers noted that ferritin is in fact increased in patients with nephrotic syndrome, not decreased as once postulated.^[25][19] The reason behind such elevation in ferritin remains unclear. Generally, administration of EPO resolves the anemia in these patients.^[13]

Urinary loss of insulin-like growth factor (IGF) binding proteins may cause a decrease in serum concentration of IGF-I and IGF-II. Corticosteroids, often used in the treatment of nephrotic syndrome, may also suppress growth.^[11]

• Prognosis of nephrotic syndrome is highly dependent on the underlying etiology.
• In children, most cases of nephrotic syndrome are due to minimal change disease (MCD), which generally carries an excellent prognosis when appropriate treatment with steroid is initiated.^[6]
• Children with congenital nephrotic syndrome and those whose MCD progress into focal segmental glomerulosclerosis (FSGS) are not responsive to steroids and thus have a poorer prognosis and end up requiring renal replacement therapy.^[6][26]