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Pediatric Nephrotic Syndrome

  • Author: Jerome C Lane, MD; Chief Editor: Craig B Langman, MD  more...
 
Updated: May 16, 2016
 

Practice Essentials

Nephrotic syndrome, or nephrosis, is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. While nephrotic-range proteinuria in adults is characterized by protein excretion of 3.5 g or more per day, in children it is defined as protein excretion of more than 40 mg/m2/h or a first-morning urine protein/creatinine of 2-3 mg/mg creatinine or greater.

One of the most exciting developments 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 Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).

Signs and symptoms

Pitting edema is the presenting symptom in about 95% of children with nephrotic syndrome. It is typically found in the lower extremities, face and periorbital regions, scrotum or labia, and abdomen (ascites).

Other signs and symptoms of nephrotic syndrome may include the following:

  • Respiratory tract infection - A history of a respiratory tract infection immediately preceding the onset of nephrotic syndrome is frequent
  • Allergy - Approximately 30% of children with nephrotic syndrome have a history of allergy [1]
  • Macrohematuria
  • Symptoms of infection - Such as fever, lethargy, irritability, or abdominal pain due to sepsis or peritonitis
  • Hypotension and signs of shock - Can be present in children presenting with sepsis
  • Respiratory distress - Due to either massive ascites and thoracic compression or frank pulmonary edema, effusions, or both
  • Tachypnea - To compensate for mechanical restriction to breathing
  • Seizure - Due to cerebral thrombosis
  • Anorexia
  • Irritability
  • Fatigue
  • Abdominal discomfort
  • Diarrhea
  • Hypertension

See Clinical Presentation for more detail.

Diagnosis

In order to establish the presence of nephrotic syndrome, laboratory tests should confirm the existence of (1) nephrotic-range proteinuria, (2) hypoalbuminemia, and (3) hyperlipidemia. Therefore, initial laboratory testing should include the following:

  • Urinalysis
  • Urine protein quantification
  • Serum albumin
  • Lipid panel

The following tests should be performed to determine whether the nephrotic syndrome is idiopathic or secondary and, if INS has been determined, whether signs of chronic kidney disease, kidney insufficiency, or other signs exclude the possibility of minimal change nephrotic syndrome (MCNS):

  • Complete blood count (CBC)
  • Metabolic panel - levels of serum electrolytes, calcium, phosphorus, and ionized calcium, as well as of blood urea nitrogen (BUN) and creatinine
  • Testing for HIV
  • Testing for hepatitis B and C
  • Complement studies (C3, C4)
  • Antinuclear antibody (ANA), anti–double-stranded DNA antibody (in selected patients)

Other tests and procedures in selected patients can include the following:

  • Genetic studies
  • Kidney ultrasonography
  • Chest radiography
  • Mantoux test
  • Kidney biopsy

See Workup for more detail.

Management

Corticosteroids

If kidney biopsy is not initially indicated, a trial of corticosteroids is the first step in the treatment of INS.

Diuretics

Loop diuretics, such as furosemide (starting at 1-2 mg/kg/d), may improve edema. Metolazone may be beneficial in combination with furosemide for resistant edema.

Antihypertensive agents

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) can reduce hypertension and may also contribute to reducing proteinuria. However, ACE inhibitors and ARBs can cause birth defects, so adolescent women who are taking these agents must be counseled regarding use of birth control, and pregnancy testing should be considered before starting these agents.

Calcium channel blockers and beta blockers may also be used as first-line agents for hypertension.

Alkylating agents

Alkylating agents (eg, cyclophosphamide [CYP], chlorambucil, nitrogen mustard) offer the benefit of possible sustained remission after a defined course of treatment, although with the possible risk of infertility and other side effects.

Calcineurin inhibitors

Calcineurin inhibitors (eg, cyclosporin A [CSA], tacrolimus [TAC]) are steroid-sparing agents that can also be used in children who fail to respond to, or who subsequently relapse after, treatment with CYP, or in children whose families object to the use of CYP.

Home monitoring

Home monitoring of urine protein and fluid status is an important aspect of management. All patients and parents should be trained to monitor first morning urine proteins at home with urine dipstick. Urine testing at home is also useful in monitoring response (or nonresponse) to steroid treatment.

See Treatment and Medication for more detail.

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Background

Pediatric nephrotic syndrome, also known as nephrosis, 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. However, because of the great range of body sizes in children, the pediatric definition of nephrotic-range proteinuria is more cumbersome.

Nephrotic-range proteinuria in children is protein excretion of more than 40 mg/m2/h. Because 24-hour urine collections are potentially unreliable and burdensome, especially in young children, many pediatric nephrologists instead rely on a single, first-morning urine sample to quantify protein excretion by the ratio of protein to creatinine.[2]

The use of a first-morning urine sample eliminates the contribution of potentially nonpathological orthostatic proteinuria, which might otherwise falsely elevate the protein level in a urine sample collected while a patient is active during the day. A urine protein/creatinine value of more than 2-3 mg/mg indicates nephrotic range proteinuria and correlates with results from 24-hour urine collection.

Nephrotic syndrome is a constellation of clinical findings that is the result of massive renal losses of protein. Thus, nephrotic syndrome is not a disease itself, but the manifestation of many different glomerular diseases. These diseases might be acute and transient, such as postinfectious glomerulonephritis, or chronic and progressive, such as focal segmental glomerulosclerosis (FSGS). Still other diseases might be relapsing and remitting, such as minimal change nephrotic syndrome (MCNS).

The glomerular diseases that cause nephrotic syndrome generally can be divided into primary and secondary etiologies. Primary nephrotic syndrome (PNS), also known as idiopathic nephrotic syndrome (INS), is associated with glomerular diseases intrinsic to the kidney and not related to systemic causes. The subcategories of INS are based on histological descriptions, but clinical-pathological correlations have been made.

A wide variety of glomerular lesions can be seen in INS. These include MCNS, focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulonephritis (C3GN), IgA nephropathy, diffuse mesangial proliferation, and others.

By definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney. Secondary causes of nephrotic syndrome include (1) autoimmune and vasculitic diseases, such as Henoch-Schönlein purpura (HSP), systemic lupus erythematosus, and antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis; (2) infectious diseases, such as congenital syphilis, malaria, human immunodeficiency virus (HIV), and hepatitis B and C; (3) malignancy; (4) environmental and drug exposure, such as heroin and mercury; and (5) systemic diseases such as diabetes mellitus, among many other causes (see Etiology).

Nephrotic syndrome may also be caused by genetic abnormalities. Infantile NS (presenting before age 3 mo) and congenital NS (presenting at age 4-12 mo) have been associated with defects in the nephrin gene (NPHS1), phospholipase C epsilon 1 gene (PLCE1), and the Wilms tumor suppressor gene (WT1). Mutations in the podocin gene (NPHS2) are associated with a familial, autosomal-recessive form of FSGS. Mutations in the α-actinin-4 gene (ACTN4) and the gene TRPC6 are associated with autosomal-dominant forms of familial FSGS.

Additionally, other genetic syndromes have been associated with nephrotic syndrome, such as nail-patella syndrome, Pierson syndrome, Schimke immuno-osseous dysplasia, and others. (See Pathophysiology and Etiology.)

INS is divided into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS) because response to steroids has a high correlation with histological subtype and prognosis. The landmark study of nephrotic syndrome in children, the International Study of Kidney Disease in Children (ISKDC), found that the vast majority of preadolescent children with INS had MCNS on kidney biopsy.[3, 4] Whereas 90% of children with MCNS responded to corticosteroid treatment with remission of their nephrotic syndrome, only 20% of children with FSGS responded to steroids.

This article focuses on INS, primarily SSNS (which primarily consists of MCNS). The treatment and prognosis of SRNS (primarily FSGS in children) is briefly discussed. (see Treatment). The discussion of congenital and secondary nephrotic syndrome is beyond the scope of this article.

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Pathophysiology

Proteinuria and hypoalbuminemia

Immune system

The hallmark of INS is massive proteinuria, leading to decreased circulating albumin levels. The initiating event that produces proteinuria remains unknown. However, strong evidence suggests that INS, at least in part, has an immune pathogenesis.

The effect of glucocorticoids on inducing remission in INS implicates the immune system, and particularly T-lymphocytes, in the pathogenesis of the condition. Glucocorticoids, primarily acting through the nuclear factor kappaB (NF-κB) transcription pathway, have a variety of effects, including inhibiting cytokine production and inhibiting T-cell production and proliferation.

A variety of studies provide further evidence of the role of T-cells in INS. Patients with INS in remission have alterations in the NF-κB pathway compared with healthy control subjects. NF-κB transcription is up-regulated in relapse of INS compared with remission. Additionally, nephrotic syndrome has been reported in patients with Hodgkin lymphoma, a T-cell disease. Other observations in INS include altered thymic regulation of T-cell differentiation and alterations in T-cell subsets in INS patients compared with healthy controls.

In addition to T-cells, the recent reports of remission in INS after treatment with rituximab, an anti-CD20 monoclonal antibody that results in complete depletion of B lymphocytes, implicate a role for B cells in the pathogenesis of INS.

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.[5]

The nature of this circulating factor is not known. Various cytokines and molecules have been implicated, including the following[6] :

  • Interleukin (IL)–2, IL-4, IL-12, IL-13, IL-15, IL-18
  • IL-2 receptor
  • Interferon-γ
  • Tumor growth factor (TGF)-β
  • Vascular permeability factor
  • Nuclear factor (NF)-κB
  • Tumor necrosis factor (TNF)-α

Recently, investigators have found high circulating levels of soluble urokinase receptor (suPAR) in children and adults with FSGS. Treatment of FSGS with immunosuppressive medications led to lower levels of suPAR, and a decline in suPAR levels over 26 weeks of treatment was associated with reduction in proteinuria. Interestingly, suPAR levels were higher in patients with familial FSGS and those with podocin mutations (see below). suPAR might act as a glomerular permeability factor.[7]

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.[8]

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.[9]

Podocyte biology and genetics

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 Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).

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 toward 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 genetic mutations, such as those associated with the following[10, 11] :

  • Slit-diaphragm and podocyte cytoskeleton - NPHS1, NPHS2, TRCP6, CD2AP, ACTN4, INF2, MYH9, MYO1E
  • Phospholipases and second-messenger systems - PLCE1
  • Glomerular basement membrane - LAMB2
  • Transcription factors - WT1, LMX1B
  • Lysosomal proteins - SCARB2
  • Mitochondrial proteins - COQ2
  • DNA-nucleosome restructuring mediator - SMARCAL1

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).

FNS is characterized by massive proteinuria in the first year of life (usually within the first 3 mo) and progression to end-stage kidney disease within the first decade of life, although milder forms of the disease have been described.[10] Mutations in NPHS1 are usually associated with congenital nephrotic syndrome, but Philipe and colleagues have described NPHS1 mutations in children aged 6 months to 8 years with later-onset SRNS.[12] Santin has described NPHS1 mutations in patients with later childhood onset as well as adult-onset SRNS.[13]

Podocin is another podocyte protein that interacts with nephrin and CD2AP and is integral to the assembly of the slit diaphragm. Podocin is encoded by the NPHS2 gene on chromosome 1. Mutations in the NPHS2 gene were originally described in patients with autosomal recessive, steroid-resistant INS with FSGS on biopsy. Podocin mutations account for approximately 45-55% of familial and 8-20% of sporadic cases of SRNS.[10]

α-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.[10] Disruptions in either ACTN4 or TRPC6 are associated with autosomal dominant forms of FSGS.[9]

CD2AP, which codes for a podocyte protein that associates with podocin and nephrin, has been associated with the development of nephrotic syndrome in animal models. However, the role it plays in human nephrotic syndrome is unclear. Various case reports have demonstrated heterozygous mutations in CD2AP in patients with nephrotic syndrome and FSGS. One report describes a single patient with a homozygous mutation in CD2AP and early onset of nephrotic syndrome with FSGS and diffuse mesangial sclerosis.[10]

Because African Americans have a 3- to 4-fold higher risk of end-stage kidney disease compared with persons of European ancestry, genetic studies have sought to explain this higher propensity to kidney disease. In 2008, a strong association was found in African Americans between idiopathic and HIV-related FSGS, as well as hypertensive end-stage kidney disease, and mutations in the nonmuscle myosin heavy chain 9 (MYH9). Nonmuscle MYH9 is a podocyte protein that binds to the podocyte actin cytoskeleton to perform intracellular motor functions.[14]

However, more recent studies have demonstrated that the increased risk of kidney disease previously ascribed to MYH9 was, in fact, more strongly associated with variations in the neighboring apolipoprotein L1 (APOL1) gene. Interestingly, these APOL1 variations, which are more common in African Americans but absent in whites, are able to lyse trypanosomes and may confer resistance to African sleeping sickness (Trypanosoma brucei rhodesiense infection).[15]

Another nonmuscle myosin gene, MYO1E, was recently reported to be associated with FSGS in children. Mutation of the MYO1E gene led to disruption of the podocyte cytoskeleton.[16]

Other genetic forms of nephrotic syndrome continue to shed light on the pathogenesis of INS. Mutations in the developmental regulatory gene WT1 are associated with forms of congenital nephrotic syndrome associated with male pseudohermaphroditism, Wilms tumor (Denys-Drash syndrome), and gonadoblastoma (Frasier syndrome).

Mutations in phospholipase C epsilon 1 (PLCE1), a cytoplasmic enzyme required for podocyte maturation, have been associated with as many as 28% of cases of congenital nephrotic syndrome due to isolated (nonsyndromic) diffuse mesangial sclerosis. Nail-patella syndrome, a disorder characterized by skeletal and nail dysplasia as well as nephrotic syndrome, is caused by mutations in the LMX1B gene, which regulates expression of type IV collagen and the podocyte proteins nephrin, podocin, and CD2AP.[17]

Pierson syndrome, characterized by microcoria, abnormal lens shape, cataracts, blindness, severe neurological deficits, congenital nephrotic syndrome and progressive kidney failure, is caused by a mutation in the LAMB2 gene that codes for laminin b2, which is found in glomerular basement membrane, retina, lens and neuromuscular synapses.[10]

Other rare forms of nephrotic syndrome have been associated with mutations in SCARB2, which codes for a lysosomal protein; disruption of this gene causes a syndrome of myoclonus epilepsy and glomerulosclerosis. Alterations in the mitochondrial protein coded by the gene COQ2 are associated with a syndrome of encephalopathy and nephropathy. Finally, 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.[11]

The role of alterations in the slit diaphragm in MCNS has not been elucidated. Podocin appears to be expressed normally in MCNS but decreased in FSGS. Mutations in nephrin and podocin do not at this time appear to play a role in steroid-sensitive nephrotic syndrome. However, acquired alterations in slit diaphragm architecture might play a role in INS apart from actual mutations in the genes encoding podocyte proteins. Various authors have reported changes in expression and distribution of nephrin in MCNS.

Coward et al demonstrated that nephrotic plasma induces translocation of the slit diaphragm proteins nephrin, podocin, and CD2AP away from the plasma membrane into the cytoplasm of the podocyte.[18] 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.

Thus, in addition to the traditional immunological theories of INS pathogenesis, it has become clear in recent years that INS is a podocytopathy. Podocytes also possess glucocorticoid receptors, which can lead to stabilization of the podocyte cytoskeleton and inhibit apoptosis. Cyclosporine, another important treatment for INS, can act directly on the podocyte by inhibiting phosphorylation of the podocyte protein synaptopodin, which plays an important role in the maintenance of the glomerular basement membrane.[5]

Apart from the podocyte and slit diaphragm, alterations in the glomerular basement membrane also likely play a role in the proteinuria of nephrotic syndrome. In INS, the glomerular capillary permeability to albumin is selectively increased, and this increase in filtered load overcomes the modest ability of the tubules to reabsorb protein.

In its normal state, the glomerular basement membrane is negatively charged because of the presence of various polyanions along this surface, such as heparan sulfate, chondroitin sulfate, and sialic acid. This negative charge acts as a deterrent to filtration of negatively charged proteins, such as albumin. Experimental models in which the negative charges are removed from the basement membrane show an increase in albuminuria. Children with MCNS have been reported to have decreased anionic charges in the glomerular basement membrane.[17]

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 (PV) 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.

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 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 (eg, as albumin infusion or angiotensin-converting enzyme [ACE] inhibitor administration).

Coupled with these discrepancies is the fact that, in the steroid-responsive nephrotic, diuresis usually begins before plasma albumin has significantly increased and before plasma oncotic pressure has changed. Some investigators have demonstrated a blunted responsiveness to atrial natriuretic peptide (ANP) despite higher-than-normal circulating plasma levels of ANP.[19]

Another model of edema formation, the "overfill hypothesis," postulates a primary defect in renal sodium handling. 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 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.[19]

A more recent theory of edema formation posits 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.[19]

Thus, the precise cause of the edema and its persistence is uncertain. A complex interplay of various physiologic factors, such as the following, probably contribute:

  • Decreased oncotic pressure
  • Increased activity of aldosterone and vasopressin
  • Diminished atrial natriuretic hormone
  • Activities of various cytokines and physical factors within the vasa recti

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), low-density lipoproteins (LDL), and lipoprotein(a), with resultant increases in total cholesterol and LDL-cholesterol. The level of high-density lipoprotein (HDL) cholesterol is normal or low. Elevations in triglyceride levels occur with severe hypoalbuminemia.

The traditional explanation for hyperlipidemia in 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.[19, 20]

Thrombosis

Patients with nephrotic syndrome are at increased risk for thrombosis. The incidence rate of thromboembolic complications (TEC) is about 25% in adults with nephrotic syndrome. The risk of TEC varies with the underlying disease. Infants with congenital nephrotic syndrome have an incidence of TEC of about 10%. The risk of thrombosis increases throughout childhood, and adolescents are at higher risk than younger children after the first year of life. The risk of TEC also is greater in secondary compared with primary nephrotic syndrome. Children with membranous nephropathy and nephrotic syndrome are at high risk of TEC, with an incidence of approximately 25%.[21] One study found the subclinical rate of pulmonary embolism in children with nephrotic syndrome to be 28% using scintigraphic pulmonary ventilation and perfusion studies.[22]

The risk of TEC is greatest earlier in the course of nephrotic syndrome. The median time from diagnosis of nephrotic syndrome to TEC was found to be 70 days in a recent study. Other studies have shown that the majority of TEC occur within the first 3 months of diagnosis.[21]

Renal vein thrombosis, deep vein thrombosis, and pulmonary embolism (PE) are the most frequently encountered TEC in children. Other venous sites of thrombosis include the superior sagittal sinus, other cerebral venous sites, and the inferior vena cava.

Arterial thrombosis, although less common than venous TEC, can occur and has been reported at the axillary, subclavian, femoral, coronary, and mesenteric arteries.[23]

Nephrotic syndrome is a hypercoagulable state. The increased risk of thrombosis can be attributed to 2 basic mechanisms: (1) urine losses of antithrombotic proteins and (2) increased synthesis of prothrombotic factors.[24] Abnormalities described in INS include decreased antithrombotic factors and increased synthesis of pro-thrombotic factors.

Decreased antithrombotic factors include the following:

  • Antithrombin III
  • Proteins C and S (conflicting data)

Increased synthesis of prothrombotic factors include the following:

  • Increased platelet number, platelet activation and aggregation
  • Elevation in levels of factors V, VIII, von Willebrand factor, α2-plasmin inhibitor, plasminogen activator inhibitor 1, and fibrinogen
  • 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.[1, 25]

Infection

Patients with INS are at increased risk of infection. Peritonitis and sepsis are the most common and serious infections. Peritonitis occurs at a rate of approximately 2-6% and may be accompanied by sepsis or bacteremia. The predominant bacterial causes are Streptococcus pneumoniae and Gram-negative enteric organisms such as Escherichia coli.[26]

Various infections can also occur, including meningitis, cellulitis, viral infections, and others. Varicella is a particular concern in immunosuppressed patients and can be lethal. Prompt recognition and treatment with acyclovir (or postexposure prophylaxis with varicella-zoster immune globulin [VZIG]) is essential. Routine childhood varicella immunization has alleviated some of the concern regarding this complication.

Infection, viral or bacterial, can trigger relapse of INS and further complicate the course of the condition.

Risk of infection may be increased in INS because of low immunoglobulin (Ig)G levels, which do not appear to be the result of urinary losses. Instead, low IgG levels seem to be the result of impaired synthesis, again pointing to a primary disorder in lymphocyte regulation in INS.

Additionally, increased urinary losses of factor B are noted. This is a cofactor 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.[1]

Acute kidney failure

Acute kidney failure (AKF) is a rare complication of INS, occurring in about 0.8% of cases.[27] Causes include the following[27] :

  • Rapid progression of underlying disease (nephrotic syndrome other than MCNS, secondary nephrotic syndrome)
  • Bilateral renal vein thrombosis
  • Acute interstitial nephritis (AIN) due to drug therapy (eg, antibiotics, nonsteroidal anti-inflammatory agents [NSAIDs], diuretics)
  • Acute tubular necrosis (ATN) due to hypovolemia or sepsis

Use of ACE inhibitors or angiotensin II receptor blockers (ARBs) in conjunction with volume depletion can also precipitate AKF.

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Etiology

Causes of INS include the following:

  • MCNS
  • FSGS
  • MPGN
  • Membranous glomerulonephritis (MGN)
  • C3 glomerulonephritis
  • Idiopathic crescentic glomerulonephritis

Causes of genetic or congenital nephrotic syndrome include the following:

  • Finnish-type congenital nephrotic syndrome ( NPHS1, nephrin)
  • Denys-Drash syndrome ( WT1)
  • Frasier syndrome ( WT1)
  • Diffuse mesangial sclerosis ( WT1, PLCE1)
  • Autosomal recessive, familial FSGS ( NPHS2, podocin)
  • Autosomal dominant, familial FSGS ( ACTN4, α-actinin-4; TRPC6)
  • Nail-patella syndrome ( LMX1B)
  • Pierson syndrome ( LAMB2)
  • Schimke immuno-osseous dysplasia ( SMARCAL1)
  • Galloway-Mowat syndrome
  • Oculocerebrorenal (Lowe) syndrome

Infections that can cause secondary nephrotic syndrome include the following:

Drugs that can cause secondary nephrotic syndrome include the following:

  • Penicillamine
  • Gold
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Interferon
  • Mercury
  • Heroin
  • Pamidronate
  • Lithium

Systemic diseases that can cause secondary nephrotic syndrome include the following:

  • Systemic lupus erythematosus
  • Malignancy - Lymphoma, leukemia
  • Vasculitis - Wegener granulomatosis (granulomatosis with polyangiitis), Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis), polyarteritis nodosa, microscopic polyangiitis, Henoch-Schönlein purpura (HSP)
  • Immune-complex–mediated - Poststreptococcal (postinfectious) glomerulonephritis
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Epidemiology

In the United States, the reported annual incidence rate of nephrotic syndrome is 2-7 cases per 100,000 children younger than 16 years. The cumulative prevalence rate is approximately 16 cases per 100,000 individuals.[28] The 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.[3, 29]

A study from New Zealand found the incidence of nephrotic syndrome to be almost 20 cases per million children under age 15 years.[30] In specific populations, such as those of Finnish or Mennonite origin, congenital nephrotic syndrome may occur in 1 in 10,000 or 1 in 500 births, respectively.[31]

Some studies have suggested a change in the histology of INS over the past few decades, although the overall incidence of INS has remained stable. The frequency of FSGS associated with INS appears to be increasing. A review of the literature suggested a 2-fold increase in the incidence of FSGS in recent decades.[32] However, another study found no evidence of an increasing incidence of FSGS.[33]

Race-, sex, and age-related demographics

Black and Hispanic children appear to have an increased risk of steroid-resistant nephrotic syndrome and FSGS.[33, 34] An increased incidence of INS is reported in Asian children, (6 times the rate seen in European children). An increased incidence of INS is also seen in Indian, Japanese, and Southwest Asian children.

Primary, SSNS is rare in Africa, where nephrotic syndrome is more likely to be secondary or steroid-resistant. These variations in ethnic and geographic distribution of INS underscore the genetic and environmental influences in the development of PNS.[1]

In children younger than 8 years at onset, the ratio of males to females varies from 2:1 to 3:2 in various studies. In older children, adolescents, and adults, the male-to-female prevalence is approximately equal. ISKDC data indicate that 66% of patients with either MCNS or FSGS are male, whereas 65% of individuals with MPGN are female.

Of patients with MCNS, 70% are younger than 5 years. Only 20-30% of adolescents with INS have MCNS on biopsy findings. In the first year of life, genetic forms of INS and secondary nephrotic syndrome due to congenital infection predominate.[28]

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Prognosis

Since the introduction of corticosteroids, the overall mortality of INS has decreased dramatically from over 50% to approximately 2-5%. Despite the improvement in survival, INS is usually a chronic, relapsing disease and most patients experience some degree of morbidity, including the following:

  • Hospitalization, in some instances
  • Frequent monitoring both by parents and by physician
  • Administration of medications associated with significant adverse events
  • A high rate of recurrence (relapses in >60% of patients)
  • The potential for progression to chronic kidney failure and end-stage kidney failure (ESKD)

Additionally, INS is associated with an increased risk of multiple complications, including edema, infection, thrombosis, hyperlipidemia, acute kidney failure, and possible increased risk of cardiovascular disease.

The prognosis varies, depending on whether the nephrotic syndrome is steroid responsive or steroid resistant.

Steroid-responsive nephrotic syndrome

Patients who remain responsive to steroids with remission of proteinuria, even with frequent relapses, generally have a good prognosis. The ISKDC found that in 93% of children with INS who responded to steroids, kidney biopsy revealed MCNS.[4] In contrast, 75% of patients who did not initially respond to steroids had histology other than MCNS.

About 90% of children with MCNS (but only 20% of children with focal segmental glomerulosclerosis [FSGS]) achieve remission after the initial course of steroid treatment.

Despite the generally favorable prognosis in patients who respond to steroids, the ISKDC reported a 60% rate of subsequent relapses, which can lead to complications, increased morbidity, and decreased quality of life.[4] A longer course of initial steroid treatment (12 wk rather than the original ISKDC protocol of 8 wk) may reduce the rate of subsequent relapse to 36%,[35] which still represents a large number of patients who undergo repeated courses of immunosuppression, with possible hospitalizations, edema, infections, medication side effects, and other comorbidities.

A long-term study of 398 children with INS found that the percentage of children who became free of relapses during the course of their disease rose from 44% one year after diagnosis to 69% at 5 years and 84% 10 years after diagnosis.[28, 36] Although most children with INS who respond to steroids achieve long-term remission, relapses may continue into adulthood.

Older studies suggested that more than 90% of children achieve long-term remission without further relapses by puberty. However, this has recently been challenged by surveys indicating a rate of relapse during adulthood as high as 27-42%.

In a retrospective study, Vivarelli et al reported that the length of time between initiation of steroid treatment and syndrome remission is an early prognostic indicator for children with INS.[37] In study patients who did not suffer relapse or who relapsed infrequently, the median time from treatment onset to remission was less than 7 days. In patients who had frequent relapses or who developed steroid-dependent nephrotic syndrome, the median time to remission was more than 7 days.

A study of 42 adult patients with a history of childhood INS found that 33% of patients continued to relapse into adulthood. Fortunately, overall morbidity (eg, bone disease, infections, malignancies, cardiovascular complications) remained low, and patients had normal adult height, body mass index (BMI), and kidney function. Predictors of adult relapse included the number of relapses during childhood and the use of immunosuppressant medications other than steroids (ie, cyclosporine, chlorambucil, cyclophosphamide).[38]

Steroid-resistant nephrotic syndrome

Approximately 10% of patients overall with INS do not respond to an initial trial of steroids (2% of patients with MCNS do not respond to steroids). Additionally, about 1-3% of patients who initially do respond to steroids later become resistant to treatment ("late non-responders").[1]

Most patients who do not achieve remission of proteinuria with steroids have kidney biopsy findings other than MCNS. The most common diagnosis in these patients is FSGS.

More than 60% of patients with nephrotic syndrome and FSGS who fail to achieve remission with any treatment progress to end-stage kidney disease (ESKD). In contrast, only 15% progression to ESKD is observed in patients with FSGS who achieve remission by any treatment.[39] Gipson et al reported a 90% lower risk of progression to ESKD in patients with INS who achieved remission.[40]

Thus, patients with steroid-resistant INS have a good prognosis if remission of proteinuria can be achieved by other medications. Failure to respond to treatment (ie, failure to achieve remission) and kidney insufficiency at presentation are predictors of poor outcome and progression to ESKD.[41]

General complications

Complications are discussed in detail in previous sections (see Pathophysiology and History). Complications of INS include:

  • Edema
  • Hyperlipidemia
  • Thrombosis (renal vein thrombosis, deep vein thrombosis, and pulmonary embolism are the most frequently encountered TEC in children. Other venous sites of thrombosis include the superior sagittal sinus, other cerebral venous sites, and the inferior vena cava.)
  • Infection (spontaneous bacterial peritonitis, sepsis, cellulitis)
  • Acute kidney failure
  • Medication adverse effects (steroids, diuretics, albumin, steroid-sparing agents). (see Side-effects of drug therapy under Treatment)
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Patient Education

Soon after nephrotic syndrome is diagnosed, the patient and family should be educated about the disease, its management, and its expected course. The family should participate in therapeutic decisions and should be encouraged to adhere to the medical regimen.

As with all chronic illnesses, many psychosocial issues may need to be addressed, including (but not limited to) the following:

  • Behavior
  • Adherence to medication
  • Adequate parental/caretaker supervision
  • Medical insurance
  • Missed work and school due to hospitalizations and outpatient visits

Consultation with social workers and mental health care workers may be useful.

Links to resources for parents can be found at the Web sites for the American Society of Pediatric Nephrology (ASPN) and the National Kidney Foundation.

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Contributor Information and Disclosures
Author

Jerome C Lane, MD Associate Professor of Pediatrics, Northwestern University, The Feinberg School of Medicine; Attending Physician, Department of Pediatrics, Division of Kidney Diseases, Ann & Robert Lurie Children's Hospital of Chicago

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children's Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, International Society of Nephrology

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Raptor Pharmaceuticals; Eli Lilly and Company; Dicerna<br/>Received grant/research funds from NIH for none; Received grant/research funds from Raptor Pharmaceuticals, Inc for none; Received grant/research funds from Alexion Pharmaceuticals, Inc. for none; Received consulting fee from DiCerna Pharmaceutical Inc. for none.

Acknowledgements

Laurence Finberg, MD Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine and Stanford University School of Medicine

Laurence Finberg, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Adrian Spitzer, MD Clinical Professor Emeritus, Department of Pediatrics, Albert Einstein College of Medicine

Adrian Spitzer, MD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Pediatric Society, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).
 
 
 
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