Nephrotic Syndrome in

Children
3rd year
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.
 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.
 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.
 (5) systemic diseases such as diabetes mellitus, among many other causes
 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.
 Other genetic syndromes have been associated with nephrotic syndrome, such
as nail-patella syndrome, Pierson syndrome, Schimke immuno-osseous
dysplasia, and others.
 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.  
 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.
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.
 Podocyte biology and genetics
 New development in recent years in understanding the pathophysiology of
nephrotic syndrome.
 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 and is also associated with mutations.
 Alterations in the glomerular basement membrane also likely play a role in
the proteinuria of nephrotic syndrome.
 Edema
 Edema formation is as a result of the 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.
 This results in retention of sodium and water by the renal
tubules ,contributing to the extension and maintenance of edema.
 A more recent theory of edema formation suggests 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. 
 Therefore the precise cause of the edema and its persistence is uncertain.
 Various physiologic factors contribute to edema:
1. Decreased oncotic pressure
2. Increased activity of aldosterone and vasopressin
3. Diminished atrial natriuretic hormone
4. 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
1. very-low-density lipoprotein (VLDL),
2. intermediate-density lipoprotein (IDL),
3. low-density lipoproteins (LDL),
4. lipoprotein(a), with resultant increases in total cholesterol and LDL-
cholesterol.
 The level of high-density lipoprotein (HDL) cholesterol is normal or low.
 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. 
Etiology

 Causes of INS include the following:

 Minimal Change Nephrotic Syndrome (MCNS)
 Focal Segmental GlomeruloSclerosis (FSGS)
 Membrano ProliferativeGlomerulonephritis (MPGN)
 Membranous glomerulonephritis (MGN)
 C3 glomerulonephritis
 IgA nephropathy
 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:
 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
 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
Physical Examination

 The most common clinical finding is edema.

 The edema is pitting and is typically found in the lower extremities, face and
periorbital regions, scrotum or labia, and abdomen (ascites).
 In those children with marked ascites, mechanical restriction to breathing
may be present, and the child may manifest compensatory tachypnea.
 Pulmonary edema and effusions can also cause respiratory distress.
 Hypertension can be present and is more common in children with FSGS and
MPGN rather than MCNS.
 Physical findings can also be present due to complications of INS.
 Abdominal tenderness might indicate peritonitis.
 Hypotension and signs of shock can be present in children presenting with
sepsis.
 Thrombosis can cause various findings, including tachypnea and respiratory
distress (pulmonary thrombosis/embolism), hematuria (renal vein
thrombosis), and seizure (cerebral thrombosis).
Differential Diagnoses

 Acute Kidney Injury

 Acute Poststreptococcal Glomerulonephritis
 Angioedema
 Childhood Polyarteritis Nodosa
 Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)
 Crescentic Glomerulonephritis
 Denys-Drash Syndrome
 Diffuse mesangial sclerosis
 Finnish-type congenital nephrotic syndrome
 Focal Segmental Glomerulosclerosis
 Frasier syndrome
 Galloway-Mowat syndrome
 Granulomatosis with Polyangiitis (Wegener Granulomatosis)
 Henoch-Schonlein Purpura
 Henoch-Schönlein Purpura
 HIV-Associated Nephropathy and Other HIV-Related Renal Disorders
 IgA Nephropathy
 Lupus Nephritis
 Malaria
 Membranoproliferative Glomerulonephritis
 Membranous Glomerulonephritis
 Microscopic Polyangiitis
 Minimal-Change Disease
 Nail-Patella Syndrome
 Nephrotic Syndrome
 Oculocerebrorenal (Lowe) syndrome
 Pediatric Hepatitis B
 Pediatric Hepatitis C
 Pediatric HIV Infection
 Pediatric Hodgkin Lymphoma
 Pediatric IgA Nephropathy
 Pediatric Nephritis
 Pediatric Non-Hodgkin Lymphoma
 Pediatric Syphilis
 Pediatric Systemic Lupus Erythematosus
 Pierson syndrome
 Polyarteritis Nodosa
 Schimke immuno-osseous dysplasia
 Systemic Lupus Erythematosus (SLE)
 Toxoplasmosis
Approach Considerations

 The first step in evaluating the child with edema is to establish whether
nephrotic syndrome is present, because hypoalbuminemia can occur in the
absence of proteinuria (such as from protein-losing enteropathy).
 edema can occur in the absence of hypoalbuminemia (for example, in
angioedema, capillary leak, venous insufficiency, congestive heart failure).
 In order to establish the presence of nephrotic syndrome, laboratory tests
should confirm
 (1) nephrotic-range proteinuria,
 (2) hypoalbuminemia,
 (3) hyperlipidemia.
 Initial laboratory testing should include the following:
 Urinalysis
 Urine protein quantification (by first-morning urine protein/creatinine or 24-
hour urine protein)
 Serum albumin
 Lipid panel
 Once the presence of nephrotic syndrome has been established, the next task
is to determine whether the nephrotic syndrome is primary (idiopathic) or
secondary to a systemic disorder
 If idiopathic nephrotic syndrome (INS) has been determined,establish whether
signs of chronic kidney disease, kidney insufficiency, or other signs exclude
the possibility of MCNS.
 Therefore, in addition to the above tests, the following should be included in
the workup:
 Complete blood count (CBC)
 Metabolic panel (Serum electrolytes, BUN and creatinine, calcium,
phosphorus, and ionized calcium levels) Testing for HIV, hepatitis B and C
 Complement studies (C3, C4)
 Antinuclear antibody (ANA), anti–double-stranded DNA antibody
 Other tests and procedures in selected patients may include the following:
 Genetic studies
 Kidney ultrasonography
 Chest radiography
 Mantoux test
 Kidney biopsy
 Age plays an important role in the diagnostic evaluation of nephrotic
syndrome.
 Children presenting with nephrotic syndrome younger than 1 year of age
should be evaluated for congenital/infantile nephrotic syndrome.
 In addition to the above tests, infants should have the following tests:
1. Congenital infection (syphilis, rubella, toxoplasmosis, cytomegalovirus, HIV)
2. Kidney biopsy
3. Genetic tests
 Urine studies:
 Microscopic hematuria is present in 20% of cases of INS and cannot be used to
distinguish between minimal change nephrotic syndrome (MCNS) and other
forms of glomerular disease.
 RBC casts, if present, are suggestive of acute glomerulonephritis, such as
postinfectious nephritis, or a nephritic presentation of chronic
glomerulonephritis, such as membranoproliferative glomerulonephritis
(MPGN).
 Granular casts may be present and are non-specific to etiology
 The presence of macroscopic (gross) hematuria is unusual in MCNS and
suggests another cause, such as MPGN, or a complication of idiopathic
nephrotic syndrome (INS), such as renal vein thrombosis.
 Urine protein quantification
 First morning urine protein/creatinine is more easily obtained than 24-hour
urine studies, is possibly more reliable, and excludes orthostatic proteinuria.
 A urine protein/creatinine ratio of more than 2-3 mg/mg is consistent with
nephrotic-range proteinuria.
 A 24-hour urine protein level of more than 40 mg/m2/h also defines
nephrotic-range proteinuria.
 Blood Studies
 Serum albumin levels in nephrotic syndrome are generally less than 2.5 g/dL.
Values as low as 0.5 g/dL are not uncommon.
 Lipid panel findings are typically as follows:
 Elevated total cholesterol, low-density lipoprotein (LDL)-cholesterol
 Elevated triglycerides with severe hypoalbuminemia
 High-density lipoprotein (HDL)-cholesterol (normal or low)
 The patient with INS, even MCNS, can present with acute kidney failure due
to intravascular volume depletion and/or bilateral renal vein thrombosis.
 In the absence of the above, elevated BUN and creatinine levels and signs of
chronic kidney failure (such as poor growth, anemia, acidosis, hyperkalemia,
hyperphosphatemia, elevated parathyroid hormone) suggest a chronic
glomerular disease other than MCNS, such as one of the following:
1. Focal segmental glomerulosclerosis (FSGS)
2. Membranous nephropathy (MN)
3. MPGN
4. Immunoglobulin (Ig)A nephropathy
 Serum sodium levels are low in patients with INS because of hyperlipidemia
(pseudohyponatremia), as well as dilution due to water retention.
 Total calcium levels are low because of hypoalbuminemia, but ionized
calcium levels are normal.
 On the CBC, an increased hemoglobin and hematocrit indicate
hemoconcentration and intravascular volume depletion.
 The platelet count is often increased.
 HIV infection, hepatitis B, and hepatitis C are important secondary causes of
nephrotic syndrome.
 Consequently, screening for these viruses should be performed in all patients
presenting with nephrotic syndrome.
 Consider checking liver enzymes, such as alanine aminotransferase (ALT) and
aspartate aminotransferase (AST), when screening for liver disease.
 Low complement levels (C3, C4) are found in postinfectious nephritis, MPGN,
and lupus nephritis.
 ANA and anti–double-stranded DNA antibody assays are used to screen for
collagen-vascular disease in patients with systemic symptoms (fever, rash,
weight loss, joint pain) or any patient with nephrotic syndrome presenting in
later school-age or adolescent years when lupus has a higher incidence.
 Genetic Testing
 Imaging Studies
 Kidney ultrasonography
 Kidney ultrasonography findings are usually nonspecific. The kidneys are usually
enlarged due to tissue edema. Increased echogenicity is usually indicative of chronic
kidney disease other than MCNS, in which echogenicity is usually normal. A finding of
small kidneys indicates chronic kidney disease other than MCNS and often accompanied
by elevated serum creatinine levels.
 Chest radiography
 Chest radiography is indicated in the child with respiratory symptoms. Pleural
effusions are common, although pulmonary edema is rare.
 Chest radiography also should be considered prior to steroid therapy to rule out
tuberculosis (TB) infection, especially in the child with positive or previously positive
Mantoux test or prior treatment for TB.
 Mantoux Test
 Mantoux test (purified protein derivative [PPD]) should be performed prior to
steroid treatment to rule out TB infection.
 Mantoux testing can be performed concurrent to starting steroid treatment,
as treatment with steroids for 48 hours prior to reading the PPD does not
mask a positive result and the risk associated with 2 days of steroids is
minimal (if tests results are positive, steroids should be immediately
stopped).
 In children with a positive PPD, previously positive PPD, or prior treatment for
TB, chest radiography should be performed.
 Kidney Biopsy
 A kidney biopsy is not indicated for first presentation of INS in the child 1-8
years of age unless the history, physical findings, or laboratory results
indicate the possibility of secondary nephrotic syndrome or primary nephrotic
syndrome other than MCNS.
 Kidney biopsy is indicated in patients younger than 1 year, when genetic
forms of congenital nephrotic syndrome are more common, and in patients
older than 8 years, when chronic glomerular diseases such as FSGS have a
higher incidence.
 In select preadolescent patients older than 8 years, empirical steroid
treatment can be considered prior to kidney biopsy, but this should occur only
under the care of a pediatric nephrologist experienced with nephrotic
syndrome.
 Some authors have recommended performing a kidney biopsy in patients
older than 12 years. 
 Kidney biopsy should also be performed when history, examination, or
laboratory findings indicate secondary nephrotic syndrome or kidney disease
other than MCNS.
 Thus, a kidney biopsy is indicated if patients have any of the following:
1. Symptoms of systemic disease (e.g., fever, rash, joint pain)
2. Laboratory findings indicative of secondary nephrotic syndrome (e.g., positive
ANA findings, positive anti–double-stranded DNA antibody findings, low
complement levels)
3. Elevated creatinine levels unresponsive to correction of intravascular volume
depletion
4. A relevant family history of kidney disease
5. Finally, in patients who are initially or subsequently unresponsive to steroid
treatment, kidney biopsy should be performed, because steroid unresponsiveness
has a high correlation with prognostically unfavorable histology findings such as
FSGS or MGN.
 Histologic Findings
 If a kidney biopsy is performed, various histologic findings can be present,
depending on the etiology of the nephrotic syndrome.
 The most common histological types of INS are as follows.
 Minimal change nephrotic syndrome
 MCNS indicates glomerular morphology that on light microscopic examination
is little different from normal. Minimal mesangial hypercellularity may be
present.
 The only significant change seen on electron microscopy (EM) is flattening and
fusion of the podocyte foot processes (effacement). 
 Diffuse mesangial proliferation
 Diffuse mesangial proliferation (DMP) refers to increased mesangial matrix and increased
mesangial hypercellularity. IF findings are negative and EM reveals the typical foot process
effacement of MCNS. Patients with DMP have an increased incidence of steroid resistance,
although whether these patients are at increased risk for progression to kidney failure is
unclear. [43]
 Focal glomerulosclerosis
 FSGS describes a lesion in which, as seen on LM, discrete segments of the glomerular tuft reveal
sclerosis (segmental); some glomeruli are involved, and others are spared (focal).
 Adhesion of the glomerular tuft to Bowman capsule (synechiae) is observed. Glomerular
hypertrophy is common. Interstitial fibrosis and tubular atrophy are often present and correlate
with the severity of disease.
 Membranoproliferative glomerulonephritis
 MPGN is also known as mesangiocapillary glomerulonephritis. Glomeruli are typically
lobulated in appearance on LM findings and demonstrate mesangial proliferation.
Silver stain may reveal characteristic duplication of the glomerular basement
membrane ("tram-track" appearance).
 Three types of MPGN are recognized and can be distinguished by electron
microscopy findings
1. Type 1 is subendothelial;
2. Type 2 has ribbon-like, dense intramembranous deposits;
3. Type 3 is subendothelial and subepithelial.
 Some controversy surrounds the existence of type 3 MPGN as a distinct entity or a
variant of type 1. 
 Membranous nephropathy
 MN is a rare finding in INS of childhood, comprising only approximately 1% of
biopsies.
 Light microscopy typically reveals thickening of the glomerular basement
membrane. Silver stain may reveal characteristic "spikes," resulting from
protrusion of basement membrane around immune deposits.
Treatment & Management

 Approach Considerations
 A trial of corticosteroids is the first step in treatment of idiopathic nephrotic syndrome (INS) in which kidney
biopsy is not initially indicated.
 Thus, patients may be considered for steroid treatment prior to kidney biopsy if they meet all of the
following criteria:
1. Age 1-8 years
2. Normal kidney function
3. No macroscopic (gross) hematuria
4. No symptoms of systemic disease (fever, rash, joint pain, weight loss)
5. Normal complement levels
6. Negative antinuclear antibody (ANA) assay
7. Negative viral screens (ie, HIV, hepatitis B and C)
8. No family history of kidney disease
 Hyperlipidemia
 Lipid abnormalities generally resolve when nephrotic syndrome is in
remission.
 Dietary modification does not appear to be effective in limiting
hyperlipidemia during active nephrotic syndrome. 
 Treat complications accordingly