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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. owe!er, because of the
great range of body sizes in children, the pediatric definition of nephrotic-range proteinuria is
Nephrotic-range proteinuria in children is protein excretion of more than "# mg$m
%"-hour urine collections are potentially unreliable and burdensome, especially in young
children, many pediatric nephrologists instead rely on a single, first-morning urine sample to
'uantify protein excretion by the ratio of protein to creatinine.
+he use of a first-morning urine sample eliminates the contribution of potentially
nonpathological orthostatic proteinuria, which might otherwise falsely ele!ate the protein le!el in
a urine sample collected while a patient is acti!e during the day. , urine protein$creatinine !alue
of more than %-3 mg$mg indicates nephrotic range proteinuria and correlates with results from
%"-hour urine collection.
Nephrotic syndrome is a constellation of clinical findings that is the result of massi!e renal
losses of protein. +hus, nephrotic syndrome is not a disease itself, but the manifestation of many
different glomerular diseases. +hese diseases might be acute and transient, such as postinfectious
glomerulonephritis, or chronic and progressi!e, such as focal segmental glomerulosclerosis
-./0/1. /till other diseases might be relapsing and remitting, such as minimal change nephrotic
+he glomerular diseases that cause nephrotic syndrome generally can be di!ided into primary
and secondary etiologies. Primary nephrotic syndrome -PN/1, also known as idiopathic
nephrotic syndrome -4N/1, is associated with glomerular diseases intrinsic to the kidney and not
related to systemic causes. +he subcategories of 4N/ are based on histological descriptions, but
clinical-pathological correlations ha!e been made.
, wide !ariety of glomerular lesions can be seen in 4N/. +hese include 23N/, focal segmental
glomerulosclerosis -./0/1, membranous nephropathy -2N1, membranoproliferati!e
glomerulonephritis -2P0N1, diffuse mesangial proliferation and others.
&y definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney.
/econdary causes of nephrotic syndrome include enoch-/ch5nlein purpura -/P1, systemic
lupus erythematosus, diabetes mellitus, syphilis, human immunodeficiency !irus -461
infection, hepatitis & and 3, malignancy, !asculitis, and drug exposure -eg, heroin, mercury1,
among many other causes -see 7tiology1.
Nephrotic syndrome may also be caused by genetic abnormalities. 4nfantile N/ -presenting
before age 3 mo1 and congenital N/ -presenting at age "-)% mo1 ha!e been associated with
defects in the nephrin gene -NPHS11, phospholipase 3 epsilon ) gene -PLCE11, and the 8ilms
tumor suppressor gene -WT11. 2utations in the podocin gene -NPHS21 are associated with a
familial, autosomal-recessi!e form of ./0/. 2utations in the 9-actinin-" gene -ACTN41 and the
gene TRPC6 are associated with autosomal-dominant forms of familial ./0/.
,dditionally, other genetic syndromes ha!e been associated with nephrotic syndrome, such as
Nail-Patella syndrome, Pierson syndrome, /chimke immuno-osseous dysplasia, and others. -/ee
Pathophysiology and 7tiology.1
4N/ is di!ided into steroid-sensiti!e -//N/1 and steroid-resistant nephrotic syndrome -/:N/1
because response to steroids has a high correlation with histological subtype and prognosis. +he
landmark study of nephrotic syndrome in children, the 4nternational /tudy of ;idney <isease in
3hildren -4/;<31, found that the !ast ma=ority of preadolescent children with 4N/ had 23N/
on kidney biopsy.
8hereas >#? of children with 23N/ responded to corticosteroid
treatment with remission of their nephrotic syndrome, only %#? of children with ./0/
responded to steroids.
+his article focuses on 4N/, primarily //N/ -which primarily consists of 23N/1. +he treatment
and prognosis of /:N/ -primarily ./0/ in children1 is briefly discussed. -see +reatment1. +he
discussion of congenital and secondary nephrotic syndrome is beyond the scope of this article.
Proteinuria and hypoaluminemia
+he hallmark of 4N/ is massi!e proteinuria, leading to decreased circulating albumin le!els. +he
initiating e!ent that produces proteinuria remains unknown. 4N/ is belie!ed to ha!e an immune
pathogenesis. /tudies ha!e shown abnormal regulation of +-cell subsets and expression of a
circulating glomerular permeability factor.
7!idence of the immune-mediated nature of 4N/ is demonstrated by the fact that
immunosuppressi!e agents, such as corticosteroids and alkylating agents, can result in remission
of nephrotic syndrome. .urthermore, nephrotic syndrome has been known to remit during
infection with the measles !irus, which suppresses cell-mediated immunity. owe!er, the precise
nature of the immune pathogenic process has yet to be defined.
, circulating factor may play a role in the de!elopment of proteinuria in 4N/. +his can be
demonstrated by the rapid de!elopment of proteinuria in recurrence of nephrotic syndrome after
kidney transplantation, the impro!ement in nephrotic syndrome in such patients after treatment
with plasmapheresis, and the experimental induction of proteinuria in animals by plasma from
patients with 4N/.
+he nature of this circulating factor is not known. 6arious cytokines and molecules ha!e been
implicated, including the following
• 4nterleukin -4A1B%, 4A-", 4A-)%, 4A-)3, 4A-)5, 4A-)C
• 4A-% receptor
• +umor growth factor -+0.1-E
• 6ascular permeability factor
• Nuclear factor -N.1-F&
• +umor necrosis factor -+N.1-9
+he association of allergic responses with nephrotic syndrome also illustrates the role of the
immune system in 4N/. Nephrotic syndrome has been reported to occur after allergic reactions to
bee stings, fungi, poison i!y, ragweed, house dust, =ellyfish stings and cat fur. .ood allergy might
play a role in relapses of 4N/G a reduced-antigenic diet was associated with impro!ed proteinuria
and complete remission in one study.
,dditionally, 4N/ is 3-" times more likely in children with human leukocyte antigen -A,1-
<:H. /teroid sensiti!e 4N/ has also been associated with A,-&C and the DQB1 gene of ,A-
<I8%. , greater incidence of 4N/ is also obser!ed in children with atopy and A,-&)%.
Perhaps the most exciting de!elopment in recent years in understanding the pathophysiology of
nephrotic syndrome has occurred in the area of podocyte biology -see the image below1.
/chematic drawing of the glomerular barrier. Podo K podocytesG
0&2 K glomerular basement membraneG 7ndo K fenestrated endothelial cellsG 7/A K endothelial
cell surface layer -often referred to as the glycocalyx1. Primary urine is formed through the
filtration of plasma fluid across the glomerular barrier -arrows1G in humans, the glomerular
filtration rate -0.:1 is )%5 mA$min. +he plasma flow rate -Ip1 is close to H## mA$min, with the
filtration fraction being %#?. +he concentration of albumin in serum is "# g$A, while the
estimated concentration of albumin in primary urine is " mg$A, or #.)? of its concentration in
plasma. :eproduced from araldsson et al, Physiol :e! CC@ "5)-"CH, %##C, and by permission of
the ,merican Physiological /ociety -www.the-aps.org1.
+he glomerular filtration barrier consists of the fenestrated capillary endothelium, the
extracellular basement membrane, and the intercalated podocyte foot processes, connected by
35-"5 nm slit diaphragms. Nephrotic syndrome is associated with the biopsy finding of fusion
-effacement1 of podocyte foot processes. +his effacement of the podocytes long was thought to
be a secondary phenomenon of nephrotic syndrome.
owe!er, theories ha!e shifted toward the podocyte as playing a primary role in the
de!elopment of proteinuria. +he understanding of the pathophysiology of proteinuria in renal
diseases has greatly expanded with insights into the molecular biology of the podocyte. 6arious
forms of 4N/ ha!e been described with mutations in podocyte genes, such as those associated
with the following
• /lit-diaphragm and podocyte cytoskeleton -NPHS1, NPHS2, TRCP6, CD2AP, ACTN4
• 0lomerular basement membrane -LAMB2
• 2itochondria -COQ2
• +ranscription factors -WT1, LMX1B
Nephrin is a transmembrane protein that is a ma=or structural element of the slit diaphragm and is
encoded by the NPHS1 gene on chromosome )>. 2utations in the NPHS1 gene are responsible
for autosomal recessi!e, congenital nephrotic syndrome of the .innish type -.N/1.
.N/ is characterized by massi!e proteinuria in the first year of life -usually within the first 3 mo1
and progression to end-stage kidney disease within the first decade of life, although milder forms
of the disease ha!e been described.
2utations in NPHS1 are usually associated with congenital
nephrotic syndrome, but Philipe and colleagues ha!e described NPHS1 mutations in children
aged J months to C years with later-onset /:N/.
/antin has described NPHS1 mutations in
patients with later childhood onset as well as adult-onset /:N/.
Podocin is another podocyte protein that interacts with nephrin and 3<%,P and is integral to the
assembly of the slit diaphragm. Podocin is encoded by the NPHS2 gene on chromosome ).
2utations in the NPHS2 gene were originally described in patients with autosomal recessi!e,
steroid-resistant 4N/ with ./0/ on biopsy. Podocin mutations account for approximately "5-
55? of familial and C-%#? of sporadic cases of /:N/.
9-,ctinin-", encoded by the gene ACTN4 on chromosome )>, cross-links actin filaments of the
podocyte cytoskeleton and anchors them to the glomerular basement membrane. +he TRPC6
gene on chromosome )) encodes for a calcium channel associated with the slit diaphragm.
<isruptions in either ACTN4 or TRPC6 are associated with autosomal dominant forms of ./0/.
CD2AP, which codes for a podocyte protein that associates with podocin and nephrin, has been
associated with the de!elopment of nephrotic syndrome in animal models. owe!er, the role it
plays in human nephrotic syndrome is unclear. 6arious case reports ha!e demonstrated
heterozygous mutations in CD2AP in patients with nephrotic syndrome and ./0/. Lne report
describes a single patient with a homozygous mutation in CD2AP and early onset of nephrotic
syndrome with ./0/ and diffuse mesangial sclerosis.
&ecause ,frican ,mericans ha!e a 3- to "-fold higher risk of end-stage kidney disease compared
with persons of 7uropean ancestry, genetic studies ha!e sought to explain this higher propensity
to kidney disease. 4n %##C, a strong association was found in ,frican ,mericans between
idiopathic and 46-related ./0/, as well as hypertensi!e end-stage kidney disease, and
mutations in the nonmuscle myosin hea!y chain > -2M>1. Nonmuscle 2M> is a podocyte
protein that binds to the podocyte actin cytoskeleton to perform intracellular motor functions.
owe!er, more recent studies ha!e demonstrated that the increased risk of kidney disease
pre!iously ascribed to 2M> was, in fact, more strongly associated with !ariations in the
neighboring apolipoprotein A) -APOL11 gene. 4nterestingly, these APOL1 !ariations, which are
more common in ,frican ,mericans but absent in whites, are able to lyse trypanosomes and may
confer resistance to ,frican sleeping sickness -Trypanosoma r!"#$ r%o&#s$#ns# infection1.
Lther genetic forms of nephrotic syndrome continue to shed light on the pathogenesis of 4N/.
2utations in the de!elopmental regulatory gene WT1 are associated with forms of congenital
nephrotic syndrome associated with male pseudohermaphroditism, 8ilms tumor -<enys-<rash
syndrome1, and gonadoblastoma -.rasier syndrome1.
2utations in phospholipase 3 epsilon ) -PLCE11, a cytoplasmic enzyme re'uired for podocyte
maturation, ha!e been associated with as many as %C? of cases of congenital nephrotic
syndrome due to isolated -nonsyndromic1 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 46 collagen and the podocyte
proteins nephrin, podocin, and 3<%,P.
Pierson syndrome, characterized by microcoria, abnormal lens shape, cataracts, blindness, se!ere
neurological deficits, congenital nephrotic syndrome and progressi!e kidney failure, is caused by
a mutation in the LAMB2 gene that codes for laminin b%, which is found in glomerular basement
membrane, retina, lens and neuromuscular synapses.
+he role of alterations in the slit diaphragm in 23N/ has not been elucidated. Podocin appears
to be expressed normally in 23N/ but decreased in ./0/. 2utations in nephrin and podocin do
not at this time appear to play a role in steroid-sensiti!e nephrotic syndrome. owe!er, ac'uired
alterations in slit diaphragm architecture might play a role in 4N/ apart from actual mutations in
the genes encoding podocyte proteins. 6arious authors ha!e reported changes in expression and
distribution of nephrin in 23N/.
3oward et al demonstrated that nephrotic plasma induces translocation of the slit diaphragm
proteins nephrin, podocin, and 3<%,P away from the plasma membrane into the cytoplasm of
+hese 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 factor1 might be responsible for alterations in the
podocyte architecture and de!elopment of 4N/.
,part from the podocyte and slit diaphragm, alterations in the glomerular basement membrane
also likely play a role in the proteinuria of nephrotic syndrome. 4n 4N/, the glomerular capillary
permeability to albumin is selecti!ely increased, and this increase in filtered load o!ercomes the
modest ability of the tubules to reabsorb protein.
4n its normal state, the glomerular basement membrane is negati!ely charged because of the
presence of !arious polyanions along this surface, such as heparan sulfate, chondroitin sulfate,
and sialic acid. +his negati!e charge acts as a deterrent to filtration of negati!ely charged
proteins, such as albumin. 7xperimental models in which the negati!e charges are remo!ed from
the basement membrane show an increase in albuminuria. 3hildren with 23N/ ha!e been
reported to ha!e decreased anionic charges in the glomerular basement membrane.
+he classical explanation for edema formation is a decrease in plasma oncotic pressure, as a
conse'uence of low serum albumin le!els, causing an extra!asation of plasma water into the
interstitial space. +he resulting contraction in plasma !olume -P61 leads to stimulation of the
renin-angiotensin-aldosterone axis and antidiuretic hormone. +he resultant retention of sodium
and water by the renal tubules contributes to the extension and maintenance of edema.
8hile the classical model of edema -also known as the Nunderfill hypothesisN1 seems logical,
certain clinical and experimental obser!ations do not completely support this traditional concept.
.irst, the P6 has not always been found to be decreased and, in fact, in most adults,
measurements of P6 ha!e shown it to be increased. Lnly in young children with 23N/ ha!e
most -but not all1 studies demonstrated a reduced P6.
,dditionally, most studies ha!e failed to document ele!ated le!els of renin, angiotensin, or
aldosterone, e!en during times of a!id sodium retention. ,cti!e sodium reabsorption also
continues despite actions that should suppress renin effects -eg, as albumin infusion or
angiotensin-con!erting enzyme (,37* inhibitor administration1.
3oupled with these discrepancies is the fact that, in the steroid-responsi!e nephrotic, diuresis
usually begins before plasma albumin has significantly increased and before plasma oncotic
pressure has changed. /ome in!estigators ha!e demonstrated a blunted responsi!eness to atrial
natriuretic peptide -,NP1 despite higher-than-normal circulating plasma le!els of ,NP.
,nother model of edema formation, the No!erfill hypothesis,N postulates a primary defect in renal
sodium handling. , primary increase in renal sodium reabsorption leads to net salt and water
retention and subse'uent hypertension.
,NP might play a role is this mechanismG studies ha!e shown an impaired response to ,NP in
nephrotic syndrome. +his ,NP resistance, in part, might be caused by o!eracti!e efferent
sympathetic ner!ous acti!ity, as well as enhanced tubular breakdown of cyclic guanosine
Lther mechanisms that contribute to a primary increase in renal sodium retention include
o!eracti!ity of the Na
-,+Pase and renal epithelial sodium channel -:7Na31 in the cortical
collecting duct and shift of the Na
exchanger N73 from the inacti!e to acti!e pools in the
, more recent theory of edema formation posits that massi!e proteinuria leads to
tubulointerstitial inflammation and release of local !asoconstrictors and inhibition of
!asodilation. +his leads to a reduction in single-nephron glomerular filtration rate and sodium
and water retention.
+hus, the precise cause of the edema and its persistence is uncertain. , complex interplay of
!arious physiologic factors, such as the following, probably contribute@
• <ecreased oncotic pressure
• 4ncreased acti!ity of aldosterone and !asopressin
• <iminished atrial natriuretic hormone
• ,cti!ities of !arious cytokines and physical factors within the !asa recti
4N/ is accompanied by disordered lipid metabolism. ,polipoprotein -apo1-&Bcontaining
lipoproteins are ele!ated, including !ery-low-density lipoprotein -6A<A1, intermediate-density
lipoprotein -4<A1, low-density lipoproteins -A<A1, and lipoprotein-a1, with resultant increases in
total cholesterol and A<A-cholesterol. +he le!el of high-density lipoprotein -<A1 cholesterol is
normal or low. 7le!ations in triglyceride le!els occur with se!ere hypoalbuminemia.
+he traditional explanation for hyperlipidemia in 4N/ was the increased synthesis of lipoproteins
that accompany increased hepatic albumin synthesis due to hypoalbuminemia. owe!er, serum
cholesterol le!els ha!e been shown to be independent of albumin synthesis rates.
<ecreased plasma oncotic pressure may play a role in increased hepatic lipoprotein synthesis, as
demonstrated by the reduction of hyperlipidemia in patients with 4N/ recei!ing either albumin or
dextran infusions. ,lso contributing to the dyslipidemia of 4N/ are abnormalities in regulatory
enzymes, such as lecithin-cholesterol acyltransferase, lipoprotein lipase, and cholesterol ester
Patients with nephrotic syndrome are at increased risk for thrombosis. +he incidence rate of
thromboembolic complications -+731 is about ).C-5? but may be underestimated. Lne study
found the subclinical rate of pulmonary embolism to be %C? using scintigraphic pulmonary
!entilation and perfusion studies.
4ncidence is higher in adults and children with secondary
nephrotic syndrome. +he incidence is especially high in membranous nephrotic syndrome.
:enal !ein thrombosis, deep !ein thrombosis, and pulmonary embolism -P71 are the most
fre'uently encountered +73 in children. Lther !enous sites of thrombosis include the superior
sagittal sinus, other cerebral !enous sites, and the inferior !ena ca!a.
,rterial thrombosis, although less common than !enous +73, can occur and has been reported at
the axillary, subcla!ian, femoral, coronary, and mesenteric arteries.
6arious factors play a role in the increased incidence of thrombosis. ,bnormalities described in
4N/ include the following@
• 4ncreased platelet acti!ation and aggregation
• 7le!ation in le!els of factors 6, 644, 6444, and P444 and fibrinogen
• <ecreased antithrombin 444, proteins 3 and /, and factors P4 and P44
• 4ncreased acti!ities of tissue plasminogen acti!ator and plasminogen acti!ator inhibitor-)
+hese abnormalities in hemostatic factors, combined with potential hypo!olemia, immobility,
and increased incidence of infection, lead to a hypercoagulable state in 4N/.
Patients with 4N/ are at increased risk of infection. Peritonitis and sepsis are the most common
and serious infections. Peritonitis occurs at a rate of approximately %-J? and may be
accompanied by sepsis or bacteremia. +he predominant bacterial causes are S'r#p'o"o""!s
pn#!mon$a# and 0ram-negati!e enteric organisms such as Es"%#r$"%$a "o($)
6arious infections can also occur, including meningitis, cellulitis, !iral infections, and others.
6aricella is a particular concern in immunosuppressed patients and can be lethal. Prompt
recognition and treatment with acyclo!ir -or postexposure prophylaxis with !aricella-zoster
immune globulin (6Q40*1 is essential. :outine childhood !aricella immunization has alle!iated
some of the concern regarding this complication.
4nfection, !iral or bacterial, can trigger relapse of 4N/ and further complicate the course of the
:isk of infection may be increased in 4N/ because of low immunoglobulin -4g10 le!els, which
do not appear to be the result of urinary losses. 4nstead, low 4g0 le!els seem to be the result of
impaired synthesis, again pointing to a primary disorder in lymphocyte regulation in 4N/.
,dditionally, increased urinary losses of factor & are noted. +his is a cofactor of 33b in the
alternati!e pathway of complement, which plays an important role in the opsonization of
encapsulated organisms such as S pn#!mon$a#) 4mpaired +-cell function may also be present in
4N/, which contributes to the susceptibility to infection. .inally, the medications used to treat
4N/, such as corticosteroids and alkylating agents, further suppress the immune system and
increase the risk of infection.
&cute kidney %ailure
,cute kidney failure -,;.1 is a rare complication of 4N/, occurring in about #.C? of cases.
3auses include the following
• :apid progression of underlying disease -nephrotic syndrome other than 23N/,
secondary nephrotic syndrome1
• &ilateral renal !ein thrombosis
• ,cute interstitial nephritis -,4N1 due to drug therapy -eg, antibiotics, nonsteroidal anti-
inflammatory agents (N/,4<s*, diuretics1
• ,cute tubular necrosis -,+N1 due to hypo!olemia or sepsis
Rse of ,37 inhibitors or angiotensin 44 receptor blockers -,:&s1 in con=unction with !olume
depletion can also precipitate ,;..
3auses of 4N/ include the following@
• 2embranous glomerulonephritis -20N1
• 4g, nephropathy
• 4diopathic crescentic glomerulonephritis
3auses of genetic or congenital nephrotic syndrome include the following@
• .innish-type congenital nephrotic syndrome -NPHS1, nephrin1
• <enys-<rash syndrome -WT11
• .rasier syndrome -WT11
• <iffuse mesangial sclerosis -WT1, PLCE11
• ,utosomal recessi!e, familial ./0/ -NPHS2, podocin1
• ,utosomal dominant, familial ./0/ -ACTN4, 9-actinin-"G TRPC61
• Nail-patella syndrome -LMX1B1
• Pierson syndrome -LAMB21
• /chimke immuno-osseous dysplasia -SMARCAL11
• 0alloway-2owat syndrome
• Lculocerebrorenal -Aowe1 syndrome
4nfections that can cause secondary nephrotic syndrome include the following@
• 3ongenital syphilis, toxoplasmosis, cytomegalo!irus, rubella
• epatitis & and 3
• 46$ac'uired immunodeficiency syndrome -,4</1
<rugs that can cause secondary nephrotic syndrome include the following@
• Nonsteroidal anti-inflammatory drugs -N/,4<s1
/ystemic diseases that can cause secondary nephrotic syndrome include the following@
• /ystemic lupus erythematosus
• 2alignancy - Aymphoma, leukemia
• 6asculitis -8egener granulomatosis, 3hurg-/trauss syndrome, polyarteritis nodosa,
microscopic polyangiitis, enoch-/ch5nlein purpura -/P1
• 4mmune-complexBmediated - Poststreptococcal glomerulonephritis
4n the Rnited /tates, the reported annual incidence rate of nephrotic syndrome is %-H cases per
)##,### children younger than )J years. +he cumulati!e pre!alence rate is approximately )J
cases per )##,### indi!iduals.
+he 4/;<3 found that HJ.J? of children with 4N/ had 23N/
on kidney biopsy findings, with H? of cases associated with ./0/ on biopsy findings.
, study from New Qealand found the incidence of nephrotic syndrome to be almost %# cases per
million children under age )5 years.
4n specific populations, such as those of .innish or
2ennonite origin, congenital nephrotic syndrome may occur in ) in )#,### or ) in 5## births,
/ome studies ha!e suggested a change in the histology of 4N/ o!er the past few decades,
although the o!erall incidence of 4N/ has remained stable. +he fre'uency of ./0/ associated
with 4N/ appears to be increasing. , re!iew of the literature suggested a %-fold increase in the
incidence of ./0/ in recent decades.
owe!er, another study found no e!idence of an
increasing incidence of ./0/.
'ace-( se)( and age-related demographics
&lack and ispanic children appear to ha!e an increased risk of steroid-resistant nephrotic
syndrome and ./0/.
,n increased incidence of 4N/ is reported in ,sian children, -J times
the rate seen in 7uropean children1. ,n increased incidence of 4N/ is also seen in 4ndian,
Sapanese, and /outhwest ,sian children.
Primary, //N/ is rare in ,frica, where nephrotic syndrome is more likely to be secondary or
steroid-resistant. +hese !ariations in ethnic and geographic distribution of 4N/ underscore the
genetic and en!ironmental influences in the de!elopment of PN/.
4n children younger than C years at onset, the ratio of males to females !aries from %@) to 3@% in
!arious studies. 4n older children, adolescents, and adults, the male-to-female pre!alence is
approximately e'ual. 4/;<3 data indicate that JJ? of patients with either 23N/ or ./0/ are
male, whereas J5? of indi!iduals with 2P0N are female.
Lf patients with 23N/, H#? are younger than 5 years. Lnly %#-3#? of adolescents with 4N/
ha!e 23N/ on biopsy findings. 4n the first year of life, genetic forms of 4N/ and secondary
nephrotic syndrome due to congenital infection predominate.
/ince the introduction of corticosteroids, the o!erall mortality of 4N/ has decreased dramatically
from o!er 5#? to approximately %-5?. <espite the impro!ement in sur!i!al, 4N/ is usually a
chronic, relapsing disease and most patients experience some degree of morbidity, including the
• ospitalization, in some instances
• .re'uent monitoring both by parents and by physician
• ,dministration of medications associated with significant ad!erse e!ents
• , high rate of recurrence -relapses in TJ#? of patients1
• +he potential for progression to chronic kidney failure and end-stage kidney failure
,dditionally, 4N/ is associated with an increased risk of multiple complications, including
edema, infection, thrombosis, hyperlipidemia, acute kidney failure, and possible increased risk of
+he prognosis !aries, depending on whether the nephrotic syndrome is steroid responsi!e or
*teroid-responsive nephrotic syndrome
Patients who remain responsi!e to steroids with remission of proteinuria, e!en with fre'uent
relapses, generally ha!e a good prognosis. +he 4/;<3 found that in >3? of children with 4N/
who responded to steroids, kidney biopsy re!ealed 23N/.
4n contrast, H5? of patients who did
not initially respond to steroids had histology other than 23N/.
,bout >#? of children with 23N/ -but only %#? of children with focal segmental
glomerulosclerosis (./0/*1 achie!e remission after the initial course of steroid treatment.
<espite the generally fa!orable prognosis in patients who respond to steroids, the 4/;<3
reported a J#? rate of subse'uent relapses, which can lead to complications, increased
morbidity, and decreased 'uality of life.
, longer course of initial steroid treatment -)% wk
rather than the original 4/;<3 protocol of C wk1 may reduce the rate of subse'uent relapse to
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.
, long-term study of 3>C children with 4N/ found that the percentage of children who became
free of relapses during the course of their disease rose from ""? one year after diagnosis to J>?
at 5 years and C"? )# years after diagnosis.
,lthough most children with 4N/ who respond
to steroids achie!e long-term remission, relapses may continue into adulthood.
Llder studies suggested that more than >#? of children achie!e long-term remission without
further relapses by puberty. owe!er, this has recently been challenged by sur!eys indicating a
rate of relapse during adulthood as high as %H-"%?.
4n a retrospecti!e study, 6i!arelli et al reported that the length of time between initiation of
steroid treatment and syndrome remission is an early prognostic indicator for children with 4N/.
4n study patients who did not suffer relapse or who relapsed infre'uently, the median time
from treatment onset to remission was less than H days. 4n patients who had fre'uent relapses or
who de!eloped steroid-dependent nephrotic syndrome, the median time to remission was more
than H days.
, study of "% adult patients with a history of childhood 4N/ found that 33? of patients
continued to relapse into adulthood. .ortunately, o!erall morbidity -eg, bone disease, infections,
malignancies, cardio!ascular complications1 remained low, and patients had normal adult height,
body mass index -&241, 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, cyclophosphamide1.
*teroid-resistant nephrotic syndrome
,pproximately )#? of patients o!erall with 4N/ do not respond to an initial trial of steroids -%?
of patients with 23N/ do not respond to steroids1. ,dditionally, about )-3? of patients who
initially do respond to steroids later become resistant to treatment -Nlate non-respondersN1.
2ost patients who do not achie!e remission of proteinuria with steroids ha!e kidney biopsy
findings other than 23N/. +he most common diagnosis in these patients is ./0/.
2ore than J#? of patients with nephrotic syndrome and ./0/ who fail to achie!e remission
with any treatment progress to end-stage kidney disease -7/;<1. 4n contrast, only )5?
progression to 7/;< is obser!ed in patients with ./0/ who achie!e remission by any
0ipson et al reported a >#? lower risk of progression to 7/;< in patients with 4N/
who achie!ed remission.
+hus, patients with steroid-resistant 4N/ ha!e a good prognosis if remission of proteinuria can be
achie!ed by other medications. .ailure to respond to treatment -ie, failure to achie!e remission1
and kidney insufficiency at presentation are predictors of poor outcome and progression to
/oon after nephrotic syndrome is diagnosed, the patient and family should be educated about the
disease, its management, and its expected course. +he family should participate in therapeutic
decisions and should be encouraged to adhere to the medical regimen.
,s with all chronic illnesses, many psychosocial issues may need to be addressed, including -but
not limited to1 the following@
• ,dherence to medication
• ,de'uate parental$caretaker super!ision
• 2edical insurance
• 2issed work and school due to hospitalizations and outpatient !isits
3onsultation with social workers and mental health care workers may be useful.
Ainks to resources for parents can be found at the 8eb sites for the ,merican /ociety of
Pediatric Nephrology -,/PN1 and the National ;idney .oundation.
7dema is the presenting symptom in about >5? of children with nephrotic syndrome. 7arly on,
the edema is intermittent and insidious, and its presence may not be appreciated. , common
story is for the child to present to a primary care practitioner repeatedly for periorbital edema,
which is ascribed to NallergiesN until the edema progresses.
7dema usually appears first in areas of low tissue resistance -eg, the periorbital, scrotal, and
labial regions1. 4t can progress rapidly or slowly. Rltimately, it becomes generalized and can be
massi!e -anasarca1. +he edema is pitting and typically dependent in nature, being more
noticeable in the face in the morning and predominantly in lower extremities later in the day.
, history of a respiratory tract infection immediately preceding the onset of nephrotic syndrome
is fre'uent, but the rele!ance to causation is uncertain. Rpper respiratory infections, otitis media,
and other infections are often associated with relapses of idiopathic nephrotic syndrome -4N/1 as
well. ,pproximately 3#? of children ha!e a history of allergy. , hypersensiti!ity e!ent, such as
a reaction to bee sting or poison i!y, has been reported to precede the onset of 4N/ in some
3hildren with nephrotic syndrome occasionally present with gross hematuria. +he fre'uency of
macrohematuria depends on the histological subtype of nephrotic syndrome. 4t is more common
in patients with membranoproliferati!e glomerulonephritis -2P0N1 than in other causes, but its
fre'uency in minimal change nephrotic syndrome -23N/1 has been reported to be as high as 3-
"? of cases.
/tatistically, a higher percentage of patients with focal segmental glomerulosclerosis -./0/1
ha!e microhematuria than those with 23N/, but this is not helpful in differentiating between
types of nephrotic syndrome in the indi!idual patient.
0i!en the risk of thrombosis in 4N/, renal !ein thrombosis must be considered in patients with
significant hematuria. :arely, a child can present with other symptoms secondary to thrombosis,
such as seizure caused by cerebral thrombosis.
, child might be brought to medical attention for symptoms of infection, such as fe!er, lethargy,
irritability, or abdominal pain due to sepsis or peritonitis. Peritonitis can be mistaken for
appendicitis or other cause of acute abdomen unless the childUs proteinuria and edema are
,norexia, irritability, fatigue, abdominal discomfort, and diarrhea are common. 04 distress can
be caused by ascites, bowel wall edema, or both. :espiratory distress can occur, due to either
massi!e ascites and thoracic compression or frank pulmonary edema, effusions, or both.
7xcept in rare cases of familial 4N/, no significant family history of kidney disease or 4N/ is
usually noted. 3hildren are typically healthy prior to onset of 4N/ and, except for the history of
allergy and atopy noted abo!e, do not usually ha!e a significant past medical history related to
+he most common clinical finding is edema. +he edema is pitting and is typically found in the
lower extremities, face and periorbital regions, scrotum or labia, and abdomen -ascites1. 4n 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. ypertension can be present and is more common in children with ./0/
and 2P0N rather than 23N/.
Physical findings can also be present due to complications of 4N/. ,bdominal tenderness might
indicate peritonitis. ypotension and signs of shock can be present in children presenting with
sepsis. +hrombosis can cause !arious findings, including tachypnea and respiratory distress
-pulmonary thrombosis$embolism1, hematuria -renal !ein thrombosis1, and seizure -cerebral
,cute kidney failure -,;.1 is a rare complication of idiopathic nephrotic syndrome. .e!er, rash,
arthralgia and eosinophilia with a NblandN urinalysis -minimal cellular elements1 in the presence
of ,;. are typical for acute interstitial nephritis. owe!er, ob!ious clinical symptoms may be
absent except for the ,;. and unremarkable urinalysis. 0ross hematuria, flank pain, and
thrombocytopenia may be signs of renal !ein thrombosis. emoconcentration in the patient with
anasarca might indicate intra!ascular !olume depletion.
• ,cute Poststreptococcal 0lomerulonephritis
• ,cute :enal .ailure
• <enys-<rash /yndrome
• enoch-/ch5nlein Purpura
• 46-,ssociated Nephropathy
• 2inimal-3hange <isease
• Nail-Patella /yndrome
• /ystemic Aupus 7rythematosus -/A71
+he first step in e!aluating the child with edema is to establish whether nephrotic syndrome is
present, because hypoalbuminemia can occur in the absence of proteinuria -such as from protein-
losing enteropathy1, and edema can occur in the absence of hypoalbuminemia -eg, in
angioedema, capillary leak, !enous insufficiency, congesti!e heart failure1.
4n order to establish the presence of nephrotic syndrome, laboratory tests should confirm -)1
nephrotic-range proteinuria, -%1 hypoalbuminemia, and -31 hyperlipidemia. +herefore, initial
laboratory testing should include the following@
• Rrine protein 'uantification -by first-morning urine protein$creatinine or %"-hour urine
• /erum albumin
• Aipid panel
Lnce the presence of nephrotic syndrome has been established, the next task is to determine
whether the nephrotic syndrome is primary -idiopathic1 or secondary to a systemic disorder and,
if idiopathic nephrotic syndrome -4N/1 has been determined, whether signs of chronic kidney
disease, kidney insufficiency, or other signs exclude the possibility of 23N/. +herefore, in
addition to the abo!e tests, the following should be included in the workup@
• 3omplete blood count -3&31
• 2etabolic panel -/erum electrolytes, &RN and creatinine, calcium, phosphorus, and
ionized calcium le!els1
• +esting for 46, hepatitis & and 3
• 3omplement studies -33, 3"1
• ,ntinuclear antibody -,N,1, antiBdouble-stranded <N, antibody -in selected patients1
Patients with 4N/ lose !itamin <Bbinding protein, which can result in low !itamin < le!els, and
thyroid binding globulin, which can result in low thyroid hormone le!els. 3onsideration should
be gi!en, especially in the child with fre'uently relapsing or steroid-resistant nephrotic
syndrome, to testing for %5-L-!itamin <G ),%5-di-L1-!itamin <G free +"G and thyroid-
stimulating hormone -+/1.
Lther tests and procedures in selected patients may include the following@
• 0enetic studies
• ;idney ultrasonography
• 3hest radiography
• 2antoux test
• ;idney biopsy
,ge plays an important role in the diagnostic e!aluation of nephrotic syndrome. 3hildren
presenting with nephrotic syndrome younger than ) year of age should be e!aluated for
congenital$infantile nephrotic syndrome. 4n addition to the abo!e tests, infants should ha!e the
• 3ongenital infection -syphilis, rubella, toxoplasmosis, cytomegalo!irus, 461
• ;idney biopsy -see Procedures1
• 0enetic tests for NPHS1, NPHS2,WT1, and LAMB2 mutations as guided by biopsy
findings and clinical presentation
• No routine surgical care is indicated for this condition.
Lccasionally, a patient with nephrotic syndrome either presents with or de!elops clinical signs of
an acute abdomen, which is fre'uently due to peritonitis. +he diagnosis can usually be made
clinically and confirmed by bacteriologic examination of the peritoneal fluid aspirate. +he
organism most often responsible for the peritonitis is S'r#p'o"o""!s pn#!mon$a#G howe!er,
enteric bacteria may also cause peritonitis. +reatment is medical rather than surgical.
2icroscopic hematuria is present in %#? of cases of 4N/ and cannot be used to distinguish
between minimal change nephrotic syndrome -23N/1 and other forms of glomerular disease.
:&3 casts, if present, are suggesti!e of acute glomerulonephritis, such as postinfectious
nephritis, or a nephritic presentation of chronic glomerulonephritis, such as
membranoproliferati!e glomerulonephritis -2P0N1.
0ranular casts may be present and are non-specific to etiology
+he presence of macroscopic -gross1 hematuria is unusual in 23N/ and suggests another cause,
such as 2P0N, or a complication of idiopathic nephrotic syndrome -4N/1, such as renal !ein
-rine protein .uanti%ication
.irst morning urine protein$creatinine is more easily obtained than %"-hour urine studies, is
possibly more reliable, and excludes orthostatic proteinuria. , urine protein$creatinine ratio of
more than %-3 mg$mg is consistent with nephrotic-range proteinuria.
, %"-hour urine protein le!el of more than "# mg$m
$h also defines nephrotic-range proteinuria.
/erum albumin le!els in nephrotic syndrome are generally less than %.5 g$dA. 6alues as low as
#.5 g$dA are not uncommon.
Aipid panel findings are typically as follows@
• 7le!ated total cholesterol, low-density lipoprotein -A<A1-cholesterol
• 7le!ated triglycerides with se!ere hypoalbuminemia
• igh-density lipoprotein -<A1-cholesterol -normal or low1
+he patient with 4N/, e!en 23N/, can present with acute kidney failure due to intra!ascular
!olume depletion and$or bilateral renal !ein thrombosis. 4n the absence of the abo!e, ele!ated
&RN and creatinine le!els and signs of chronic kidney failure -such as poor growth, anemia,
acidosis, hyperkalemia, hyperphosphatemia, ele!ated parathyroid hormone1 suggest a chronic
glomerular disease other than 23N/, such as one of the following@
• .ocal segmental glomerulosclerosis -./0/1
• 2embranous nephropathy -2N1
• 4mmunoglobulin -4g1, nephropathy
/erum sodium le!els are low in patients with 4N/ because of hyperlipidemia
-pseudohyponatremia1, as well as dilution due to water retention. +otal calcium le!els are low
because of hypoalbuminemia, but ionized calcium le!els are normal.
Ln the 3&3, an increased hemoglobin and hematocrit indicate hemoconcentration and
intra!ascular !olume depletion. +he platelet count is often increased.
46 infection, hepatitis &, and hepatitis 3 are important secondary causes of nephrotic
syndrome. 3onse'uently, screening for these !iruses should be performed in all patients
presenting with nephrotic syndrome. 3onsider checking li!er enzymes, such as alanine
aminotransferase -,A+1 and aspartate aminotransferase -,/+1, when screening for li!er disease.
Aow complement le!els -33, 3"1 are found in postinfectious nephritis, 2P0N, and lupus
,N, and antiBdouble-stranded <N, antibody assays are used to screen for collagen-!ascular
disease in patients with systemic symptoms -fe!er, rash, weight loss, =oint pain1 or any patient
with nephrotic syndrome presenting in later school-age or adolescent years when lupus has a
WT1 testing is indicated for patients with pseudohermaphroditism, 8ilms tumor,
gonadoblastoma, and diffuse mesangial sclerosis on biopsy. NPHS1 testing is indicated in
patients with biopsy and clinical findings consistent with .innish-type nephrotic syndrome
&ecause congenital N/ has been reported with mutations in NPHS2, analysis of this gene should
also be considered. 4nfants with nephrotic syndrome and neurological or !isual disturbances
should be considered candidates for LAMB2 testing -Pierson syndrome1.
4n patients initially or subse'uently unresponsi!e to steroid treatment, in addition to kidney
biopsy, consideration should be gi!en to testing for mutations in podocin -NPHS21, ACTN4 and
;idney ultrasonography might help to distinguish between 23N/ and other chronic kidney
disease, but findings are usually nonspecific. 4n all cases of nephrotic syndrome, the kidneys are
usually enlarged due to tissue edema. 4ncreased echogenicity is usually indicati!e of chronic
kidney disease other than 23N/, in which echogenicity is usually normal. , finding of small
kidneys indicates chronic kidney disease other than 23N/ and is usually accompanied by
ele!ated serum creatinine le!els.
3hest radiography is indicated in the child with respiratory symptoms. Pleural effusions are
common, although pulmonary edema is rare.
3hest radiography also should be considered prior to steroid therapy to rule out tuberculosis -+&1
infection, especially in the child with positi!e or pre!iously positi!e 2antoux test or prior
treatment for +&.
2antoux test -purified protein deri!ati!e (PP<*1 should be performed prior to steroid treatment
to rule out +& infection.
2antoux testing can be performed concurrent to starting steroid treatment, as treatment with
steroids for "C hours prior to reading the PP< does not mask a positi!e result and the risk
associated with % days of steroids is minimal -if tests results are positi!e, steroids should be
4n children with a positi!e PP<, pre!iously positi!e PP<, or prior treatment for +&, chest
radiography should be performed.
, kidney biopsy is not indicated for first presentation of PN/ in the child )-C years of age unless
the history, physical findings, or laboratory results indicate the possibility of secondary nephrotic
syndrome or primary nephrotic syndrome other than 23N/. ;idney biopsy is indicated in
patients younger than ) year when genetic forms of congenital nephrotic syndrome are more
common, and in patients older than C years, when chronic glomerular diseases such as ./0/
ha!e a higher incidence.
4n select preadolescent patients older than C 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. /ome authors ha!e recommended performing a kidney
biopsy in patients older than )% years.
;idney biopsy should also be performed when history, examination, or laboratory findings
indicate secondary nephrotic syndrome or kidney disease other than 23N/. +hus, a kidney
biopsy is indicated if patients ha!e any of the following@
• /ymptoms of systemic disease -eg, fe!er, rash, =oint pain1
• Aaboratory findings indicati!e of secondary nephrotic syndrome -eg, positi!e ,N,
findings, positi!e antiBdouble-stranded <N, antibody findings, low complement le!els1
• 7le!ated creatinine le!els unresponsi!e to correction of intra!ascular !olume depletion
• , rele!ant family history of kidney disease
.inally, in patients who are initially or subse'uently unresponsi!e to steroid treatment, kidney
biopsy should be performed, because steroid unresponsi!eness has a high correlation with
prognostically unfa!orable histology findings such as ./0/ or 20N.
4f a kidney biopsy is performed, !arious histologic findings can be present, depending on the
etiology of the nephrotic syndrome. , detailed discussion of the !arious types of 4N/ and
histological findings is beyond the scope of this article. &riefly, the most common histological
types of 4N/ are as follows.
1inimal change nephrotic syndrome
23N/ indicates glomerular morphology that on light microscopic examination is little different
from normal. 2inimal mesangial hypercellularity may be present. 4mmunofluorescent
microscopy -4.1 usually re!eals no presence of immune deposits.
Lccasionally, mesangial 4g2 deposition may be seen on 4.. /ome consider the presence of 4g2
to indicate a separate entity -4g2 nephropathy1, whereas others consider this to be a !ariant of
23N/. +he presence of 4g2 may indicate a more difficult course of nephrotic syndrome, with
fre'uent relapses, steroid dependence, or steroid resistance, although the o!erall prognosis is still
usually fa!orable. +he only significant change seen on electron microscopy -721 is flattening
and fusion of the podocyte foot processes -effacement1.
+i%%use mesangial proli%eration
<iffuse mesangial proliferation -<2P1 refers to increased mesangial matrix and increased
mesangial hypercellularity. 4. findings are negati!e and 72 re!eals the typical foot process
effacement of 23N/. Patients with <2P ha!e an increased incidence of steroid resistance,
although whether these patients are at increased risk for progression to kidney failure is unclear.
./0/ describes a lesion in which, as seen on A2, discrete segments of the glomerular tuft re!eal
sclerosis -segmental1G some glomeruli are in!ol!ed, and others are spared -focal1.
,dhesion of the glomerular tuft to &owman capsule -synechiae1 is obser!ed. 0lomerular
hypertrophy is common. 4nterstitial fibrosis and tubular atrophy are often present and correlate
with the se!erity of disease.
4. re!eals 4g2 and 33 trapped in the sclerotic areas. ,s in 23N/, 72 re!eals effacement of the
podocyte foot processes. ,dditionally, 72 re!eals obliteration of capillary lumens by fine
granular and lipid deposits.
, subtype of ./0/, in which the glomerular tufts demonstrate collapse of capillaries -collapsing
glomerulopathy1 on A2, has a poorer prognosis and high rate of progression to end-stage kidney
./0/ is not a specific disease but a histopathological finding that can be associated with 4N/ but
can also be found in a wide !ariety of other conditions, including 46 nephropathy, heroin
nephropathy, reflux nephropathy, obstructi!e uropathy, renal hypoplasia, hypertension, obesity,
and ,lport syndrome.
,s always, clinical and histopathological correlations must always be made when considering
the findings e!ident on kidney biopsy.
2P0N is also known as mesangiocapillary glomerulonephritis. 0lomeruli are typically lobulated
in appearance on A2 findings and demonstrate mesangial proliferation. /il!er stain may re!eal
characteristic duplication of the glomerular basement membrane -Ntram-trackN appearance1. 4.
findings re!eal characteristic capillary deposition of 33.
+hree types of 2P0N are recognized and can be distinguished by electron microscopy findings
according to the location of immune deposits. +ype ) is subendothelialG type % has ribbonlike,
dense intramembranous depositsG and type 3 is subendothelial and subepithelial. /ome
contro!ersy surrounds the existence of type 3 2P0N as a distinct entity or a !ariant of type ).
2N is a rare finding in 4N/ of childhood, comprising only approximately )? of biopsies,
whereas in adult 4N/, 2N can be found in %5-"#? of cases. Aight microscopy typically re!eals
thickening of the glomerular basement membrane. /il!er stain may re!eal characteristic Nspikes,N
resulting from protrusion of basement membrane around immune deposits. 4. re!eals fine
granular 4g0 and complement staining along the periphery of the glomerular capillary wall. 72
re!eals subepithelial electron-dense deposits.
+he reader is referred to other articles regarding histology of congenital nephrotic syndrome, and
secondary forms of nephrotic syndrome due to lupus, !asculitis, and other etiologies.
6arious staging schemes are recognized for the different histological lesions of 4N/. 4n general,
when referring to kidney biopsy, the se!erity and chronicity of the disease is determined by the
extent of tubulointerstitial fibrosis. +he greater the extent of fibrosis, the greater the
irre!ersibility of the disease and the poorer the prognosis, regardless of histological subtype.
, trial of corticosteroids is the first step in treatment of idiopathic nephrotic syndrome -4N/1 in
which kidney biopsy is not initially indicated. +hus, patients may be considered for steroid
treatment prior to kidney biopsy if they meet all of the following criteria@
• ,ge )-C years
• Normal kidney function
• No macroscopic -gross1 hematuria
• No symptoms of systemic disease -fe!er, rash, =oint pain, weight loss1
• Normal complement le!els
• Negati!e antinuclear antibody -,N,1 assay
• Negati!e !iral screens -ie, 46, hepatitis & and 31
• No family history of kidney disease
;idney biopsy should be performed prior to any immunosuppressi!e treatment, including
steroids, in patients who meet one or more of the following criteria@
• ,ge younger than ) year or older than C years
• Presence of recurrent gross hematuria
• :ele!ant family history of kidney disease
• /ymptoms of systemic disease
• Positi!e !iral screens
,dditional criteria are laboratory findings possibly indicati!e of secondary nephrotic syndrome
or 4N/ other than minimal change nephrotic syndrome -23N/1, such as the following@
• /ustained ele!ation in serum creatinine le!els
• Aow 33$3" le!els
• Positi!e ,N, findings
• Positi!e antiBdouble-stranded <N, antibody assay
4n these cases, histology guides treatment, and steroids may or may not be indicated depending
on the underlying etiology.
4n selected preadolescent patients older than C years -V)% y1, empirical steroid treatment can be
considered prior to kidney biopsyG howe!er, this should occur only under the care of a pediatric
nephrologist experienced with nephrotic syndrome. 3hildren older than )% years re'uire a kidney
biopsy due to the rising incidence of focal segmental glomerulosclerosis -./0/1 and other
causes of nephrosis in that age range.
+he treatment of steroid-sensiti!e 4N/, steroid-dependent and fre'uently-relapsing 4N/, steroid-
resistant nephrotic syndrome -/:N/1 and ./0/ are discussed in detail below. +he treatment of
membranoproliferati!e glomerulonephritis -2P0N1, membranous nephropathy -2N1, congenital
nephrotic syndrome, and secondary nephrotic syndrome -eg, lupus nephritis and !asculitis1 are
beyond the scope of this article.
Aipid abnormalities generally resol!e when nephrotic syndrome is in remission. <ietary
modification does not appear to be effecti!e in limiting hyperlipidemia during acti!e nephrotic
3hronic hyperlipidemia has been linked to increased risk of atherosclerosis and coronary artery
3hronic hyperlipidemia has also been associated with progression of renal disease.
owe!er, the small studies to date of lipid-lowering agents in pediatric 4N/ ha!e not shown an
impro!ement in proteinuria or progression of renal disease.
<yslipidemias in adults with nephrotic syndrome ha!e been successfully treated with the
• /tatins -sim!astatin, lo!astatin1
• .ibrates -gemfibrozil1
• &ile-acid binding resins -cholestyramine1
3hildren with 4N/ ha!e been effecti!ely treated with probucol, but this agent has been associated
with prolonged I+ inter!al and is not a!ailable in the Rnited /tates. 0emfibrozil has also been
shown to be effecti!e in childhood nephrotic syndrome in small studies.
/mall studies ha!e shown that sim!astatin and lo!astatin are well tolerated and effecti!e in
childhood 4N/. +otal cholesterol, triglycerides, and A<A cholesterol were reduced by "%?, ""?,
and "J?, respecti!ely. No changes in proteinuria, hypoalbuminemia, or progression of renal
disease were noted.
(5, "#, ")*
4n order to monitor for treatment-associated rhabdomyolysis, children treated with statins should
ha!e creatine kinase measured prior to initiating therapy and e!ery J-)% weeks during treatment.
Patients and families should be instructed to report muscle soreness, tenderness, or pain.
,spartate aminotransferase -,/+1 and alanine aminotransferase -,A+1 le!els should be
measured before initiating treatment and about e!ery 3 months thereafter to monitor for li!er
Aong-term safety studies regarding statins in pediatrics are lacking, and routine use of statins
were not recommended by an expert panel in %##". +he only drugs recommended at this time by
the panel were bile acid se'uestrants.
4nitial treatment of thromboembolic complications includes thrombolysis with anticoagulants
-such as heparin1 and$or fibrinolytic agents -ie, tissue plasminogen acti!ator, streptokinase,
.or secondary pre!ention, warfarin is often prescribed for a period of as long as J
7mpiric prophylactic anticoagulation is not routinely indicated in 4N/. /ome practitioners
ad!ocate the use of long-term, low-dose aspirin in patients with chronic nephrotic syndrome -eg,
fre'uently relapsing nephrotic syndrome, /<N/, /:N/1. owe!er, ade'uate controlled trials
examining the use of aspirin ha!e not been performed.
&cute kidney %ailure
,cute kidney failure may rarely result from complications of 4N/, from the underlying disease,
or from drug therapy. 4n most cases, acute kidney failure is re!ersible with remission of
nephrotic syndrome, correction of intra!ascular !olume contraction, and$or -in patients with
acute interstitial nephritis1 remo!al of inciting agent.
7xclude acti!e infection or other contraindications before starting steroid therapy.
+he original 4nternational /tudy of ;idney <isease in 3hildren -4/;<31 protocol recommended
induction therapy with oral prednisone or prednisolone at J# mg$m
$d -% mg$kg$d1, with a
maximum of J# mg, daily for " weeks. +raditionally, the total daily dose was split into two
doses. owe!er, a single daily dose of steroids has efficacy e'ual to split dosing and fewer side
/ubse'uent studies ha!e shown that a longer period of initial steroid treatment -J weeks rather
than " weeks1 reduces the subse'uent rate of relapse. +hus, the general consensus now is to
prescribe the initial daily steroids for J weeks.
Lriginal guidelines recommended that induction therapy be followed with maintenance therapy
with oral prednisone or prednisolone at "# mg$m
-or ).5 mg$kg1, with a maximum of "# mg,
gi!en as a single dose on alternate days for " weeks. /ubse'uent studies demonstrated that a
longer alternate-day maintenance period of J weeks resulted in a lower rate of relapse.
+hus, the general consensus now is daily induction steroid treatment for J weeks, followed by
alternate-day maintenance therapy for another J weeks.
,fter J weeks of alternate day
treatment, steroids may be stopped or slowly tapered o!er a !ariable length of time.
Aonger duration of alternate-day steroid treatment may further reduce the number of children
with subse'uent relapses. , meta-analysis concluded that, after the initial daily steroid induction
phase, continuation of alternate day steroids for J months could reduce the subse'uent relapse
rate by 33? compared with shorter alternate-day treatment. No ad!erse effects were noted with
the longer steroid treatment, although the authors cautioned the ade'uate randomized controlled
trials comparing shorter !ersus long-term alternate day steroid treatment still needed to be
#reatment o% relapses
.or infre'uent relapses, steroids are resumed, although for a shorter duration than treatment
during initial presentation. Prednisone, % mg$kg$d -J# mg$m
$d1, is gi!en as a single morning
dose until the patient has been free of proteinuria for at least 3 days.
.ollowing remission of proteinuria, prednisone is reduced to ).5 mg$kg -"# mg$m
1 gi!en as a
single dose on alternate days for " weeks. /teroids may then be stopped or gradually tapered.
<iuretic therapy may be beneficial, particularly in children with symptomatic edema. Aoop
diuretics, such as furosemide -starting at )-% mg$kg$d1 may impro!e edemaG their administration,
howe!er, should be handled with care because plasma !olume contraction may already be
present, and hypo!olemic shock has been obser!ed with o!erly aggressi!e therapy.
2etolazone may be beneficial in combination with furosemide for resistant edema. Patients must
be monitored carefully on this regimen. 4f the child is sent home on diuretic therapy, the family
must ha!e clear guidelines about discontinuing therapy when edema is no longer present and
careful communication with the family should continue.
8hen a patient presents with anasarca and signs of intra!ascular !olume depletion -such as a
high hematocrit, indicati!e of hemoconcentration1, consideration should be gi!en to
administration of %5? albumin, although this is contro!ersial. :apid administration of albumin
can result in pulmonary edema.
+he authorUs practice has been to administer %5? albumin at a dose of ) g$kg body weight gi!en
as a continuous infusion o!er %" hours. 4ntra!enous albumin may be particularly useful in
diuretic-resistant edema and in patients with significant ascites and$or scrotal, penile or labial
,ntihypertensi!e therapy should be gi!en when hypertension is present and particularly if it
persists, but caution should be exercised. 4n some patients, the hypertension will respond to
diuretics. ,ngiotensin-con!erting enzyme -,371 inhibitors or angiotensin 44 receptor blockers
-,:&s1 may also contribute to reducing proteinuria but should be used cautiously in the presence
of acute kidney failure or !olume depletion because they can worsen kidney function in these
,37 inhibitors and ,:&s 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.
3alcium channel blockers and beta-blockers may also be used as first-line agents for
ome monitoring of urine protein and fluid status is an important aspect of management. ,ll
patients and parents should be trained to monitor first morning urine proteins at home with urine
dipstick. Rrine testing at home is also useful in monitoring response -or nonresponse1 to steroid
8eight should be checked e!ery morning, as well, and a home logbook should be kept recording
the patientWs daily weight, urine protein le!els, and steroid dose if being treated. .amilies and
patients are instructed to call for any edema, weight gain, or proteinuria of %O or more for more
than % days.
2re.uently 'elapsing and *teroid-+ependent +isease
.re'uently-relapsing nephrotic syndrome -.:N/1 is defined as steroid-sensiti!e nephrotic
syndrome -//N/1 with % or more relapses within J months or more than 3 relapses within a )%-
month period. /teroid-dependent nephrotic syndrome -/<N/1 is defined as //N/ with % or more
consecuti!e relapses during tapering or within )" days of stopping steroids.
.or .:N/ and /<N/, the clinical e!idence is inade'uate to support a preferred method of
treatment. +herefore, practitioners must rely on their clinical experience and discuss the potential
ad!antages and disad!antages of each treatment with families and patients.
complexity of management in these cases and the importance of clinical experience, patients
should be referred to a pediatric nephrologist if this has not already been done.
,lkylating agents -eg, cyclophosphamide (3MP*, chlorambucil, nitrogen mustard1 offer the
benefit of possible sustained remission after a defined course of treatment, although with the
possible risk of infertility and other side effects -see /ide 7ffects of <rug +herapy1.
,n increased risk of seizures is noted with chlorambucil.
,dditionally, a higher incidence of
infections and leukopenia may be seen with chlorambucil compared with 3MP.
these risks, and the need to gi!e nitrogen mustard intra!enously, 3MP has generally been the
preferred alkylating agent.
/teroids -prednisone % mg$kg$d in single dose, max J# mg1 are usually started prior to
administration of 3MP in order to induce remission of proteinuria before starting 3MP. ,fter
initiation of 3MP, if proteinuria remains in remission, prednisone is reduced to ).5 mg$kg on
alternate days for " weeks, then slowly tapered o!er " weeks.
3MP -% mg$kg daily1 is gi!en orally for C-)% weeks. ,n influential study found that a )%-week
course was more effecti!e than an C-week course in producing sustained remission of nephrotic
owe!er, a subse'uent randomized trial did not reach this same conclusion,
the optimal duration of 3MP treatment is still unclear at this time.
Patients must ha!e weekly complete blood counts to monitor for leukopenia. Patients must also
maintain ade'uate hydration and take 3MP in the morning -not at bedtime1 to limit the risk of
hemorrhagic cystitis. .amilies must be counseled to report gross hematuria, fe!er, or se!ere
3alcineurin inhibitors -eg, cyclosporin , (3/,*, tacrolimus (+,3*1 are useful steroid-sparing
agents. +hese agents can also be used in those children who fail to respond to, or subse'uently
relapse after, treatment with 3MP, or in children whose families ob=ect to the use of 3MP.
3alcineurin inhibitors ha!e disad!antages@ prolonged courses of treatment are needed, nephrotic
syndrome tends to recur when treatment is stopped, and nephrotoxic in=ury may occur.
3onsideration should be gi!en to kidney biopsy after prolonged treatment to monitor for
calcineurin inhibitorBinduced nephrotoxicity and fibrosis.
Aimited studies are a!ailable regarding the effecti!eness of +,3 compared with 3/,. , single-
center study by 3houdhry et al in ") patients with idiopathic /:N/ found that +,3 -#.)-#.%
mg$kg$d1 or 3/, -5-J mg$kg$d1 ha!e similar efficacy in inducing remission in patients with
idiopathic /:N/ at J months and ) year when combined with alternate-day low-dose
corticosteroids and enalapril.
:elapse was significantly greater with 3/, than with +,3G in addition, +,3 decreased blood
cholesterol le!els to a greater extent and resulted in fewer incidents of nephrotoxicity that
necessitated discontinuance than 3/,. 3osmetic ad!erse effects -eg, hypertrichosis, gum
hypertrophy1 were significantly more fre'uent with 3/,.
+hus, +,3 therapy is a promising
alternati!e to 3/, because of the lower relapse risk and lack of cosmetic ad!erse effects.
3/, treatment is started at 3-5 mg$kg$d di!ided e!ery )% hoursG doses are ad=usted for trough
concentrations of 5#B)%5 ng$mA. owe!er, trough le!els correlate poorly with area-under-the-
cur!e -,R31 pharmacokinetics and may not represent true exposure to 3/,. le!els obtained %
hours after administration -3%1 ha!e better correlation with ,R3.
;idney function and drug le!els must be carefully monitored due to the risk of 3/,-induced
Aow-dose steroids are continued for a !ariable length of time. ,s many as "#? of patients may
need to remain on steroids during 3/, treatment to maintain remission.
+,3 is started at a dose of #.) mg$kg daily di!ided e!ery )% hours and ad=usted to keep trough
le!el about 5-)# ng$mA.
Lur practice is to use the lowest possible dose that sustains remission
and to aim for a trough le!el of around 3-5 ng$mA. +,3 trough le!els correspond better to ,R3
than 3/,, allowing better determination of dosing and exposure with +,3 than with 3/,.
with 3/,, continuing low-dose steroids is often necessary to maintain remission, although some
patients may e!entually be able to discontinue steroid treatment.
Ae!amisole is an anthelmintic drug that has immune-modulating effects and can be effecti!e in
reducing the relapse rate in .:N/. owe!er, it is una!ailable in the Rnited /tates. /ide effects
include leukopenia, hepatic dysfunction, agranulocytosis, !asculitis, and encephalopathy.
Ae!amisole is prescribed at a dose of %.5 mg$kg gi!en on alternate days.
,lthough small studies ha!e shown mycophenolate mofetil -22.1 to be effecti!e in reducing
the number of relapses in .:N/ and /<N/, ade'uate randomized controlled trials still need to
be performed. Lne study of 33 patients, using a J-month course of 22. with tapering dose
alternate day steroids, achie!ed a H5? remission rate, which persisted in %5? of patients after
discontinuation of 22.. ,dditionally, this study demonstrated an impro!ement in relapse rate
from once e!ery % months to once e!ery )".H months.
+hus, 22. might be a useful steroid-sparing agent in stable patients -without excessi!e edema,
need for hospitalizations and without other serious complications1 whose families wish to a!oid
the possible side effects of 3MP, 3/,, or +,3. owe!er, response to 22. !aries and is less
reliable than other treatments.
22. is started at a dose of J## mg$m
twice daily. 3omplete blood counts should be monitored
for bone marrow suppression, and li!er function tests should occasionally be performed to
monitor for hepatic toxicity.
*teroid-'esistant +isease and 2ocal *egmental /*
,de'uate randomized controlled trials ha!e not yet been reported to gi!e sufficient e!idence to
guide treatment of steroid-resistant nephrotic syndrome -/:N/1.
, current National 4nstitutes
of ealth -N41-sponsored, multicenter, randomized clinical trial has recently concluded
enrollment and will compare 3/, !ersus 22. for treatment of focal segmental
+he most fre'uently recommended treatment for ./0/ and /:N/ is 3/,. ,pproximately 3J?
of children with /:N/ may achie!e remission with this agent.
3/, is dosed as for .:N/ and
/<N/. owe!er, higher doses and trough le!els may be re'uired to achie!e remission in /:N/
+,3 may be effecti!e as well, although studies are limited at this time.
studies to date ha!e shown no clear benefit to the use of alkylating agents in ./0/ and /:N/.
4n a nonrandomized study of in children with /:N/, approximately half responded to 22.. Lf
3" patients treated with 3/, prior to 22., %#? achie!ed complete remission, 3>? achie!ed
partial remission, and ")? had no response. ,mong )C patients treated only with 22., %H?
achie!ed complete remission, 33? partial remission, and "#? had no response.
regimen used in this study was 5##-J## mg$m
body surface area$d or )C mg$kg$d (maximum )
g* for a minimum of J mo.
+he histology in these patients consisted of 23N/, ./0/, 2P0N, crescentic
glomerulonephritis, and membranous nephropathy1. .urther studies are needed on the use of
22. in /:N/ and ./0/.
, contro!ersial treatment in!ol!es high-dose, intra!enous methylprednisolone tapered o!er HC
weeks, in combination with alternate-day oral prednisoneG 3MP or chlorambucil is added if
remission is not achie!ed in the first )# weeks. +he authors reported a 5%? remission rate in
owe!er, subse'uent studies using this protocol ha!e not duplicated the initial success.
+he risk of steroid toxicity and infection, as well as lack of sufficient e!idence for the
effecti!eness of this protocol, ha!e dampened enthusiasm for this treatment.
+he use of an ,37 inhibitor -eg, enalapril1, either alone or in combination with an ,:& -eg,
losartan1, has been shown to reduce proteinuria in ./0/$/<N/ and should be considered in all
patients, e!en in the absence of hypertension. ,ccordingly, ,37 inhibitors and ,:& should be
considered as preferred agents in patients with hypertension. ,37 inhibitor and ,:& treatment
may also ha!e a renoprotecti!e effect and slow progression of renal disease by inhibiting
pathways of fibrosis.
+he following treatments ha!e been studied in nephrotic syndrome, but cannot be routinely
:ituximab -:ituxan1 is a chimeric, anti-3<%# antibody that results in depletion of & cells.
4solated reports and small studies ha!e examined the use of rituximab in /<N/ and /:N/.
, prospecti!e trial of )% patients with /<N/, who were gi!en a single dose of rituximab -3H5
body surface area1 demonstrated a reduction in the number of relapses and use of steroids.
owe!er, H5? of patients relapsed within ) year, and H patients were gi!en a second dose of
rituximab. No serious ad!erse effects were reported.
, multicenter trial in which %% patients with /<N/ or 3/,-dependent nephrotic syndrome were
gi!en %-" weekly doses of rituximab -3H5 mg$m
1 demonstrated complete remission in all )5
patients, who were free of proteinuria at the time of rituximab administration. Lnly 3 of H
patients who were still nephrotic at the time of administration achie!ed remission.
,n open-label, randomized, controlled, noninferiority trial was recently performed, in which 5"
children with steroidB and$or calcineurin inhibitorBdependent 4N/ were randomized to either
standard treatment -prednisone$calcineurin-inhibitor1 or rituximab in addition to low-dose
prednisone and calcineurin inhibitor. +hree months after randomization, proteinuria was H#?
lower in patients treated with rituximab compared with standard therapyG relapse occurred in
)C.5? in the rituximab group and "C? in the standard treatment group. ,t 3 months, J3? of the
rituximab group was drug free, compared with "? in the standard treatment group. 4t was
concluded that rituximab with low-dose prednisone and calcineurin inhibitor was noninferior to
standard therapy in maintaining short-term remission in children with steroidB and calcineurin
Lnly a small number of patients with /:N/ treated with rituximab ha!e been reported in the
literature to date. 4n these " small studies, rituximab was administered in )-" weekly doses -3H5
1 with resultant remission of proteinuria in some patients.
owe!er, these studies are too
small to draw any general conclusions about the use of rituximab in /:N/.
, recent nonrandomized cohort study examined the efficacy of rituximab in pediatric patients
with /<N/ and /:N/. Patients were treated with %-" doses of intra!enous rituximab. 4n %"
patients with /<N/, sustained remission of proteinuria was achie!ed in C3? at )% months and
H)? at approximately )H months of follow-up. 4n 33 patients with /:N/, at J months of follow-
up, %H? had complete remission, %)? had partial remission, and 5)? had no response. ,t
approximately %% months of follow-up, %)? of patients with /:N/ had complete remission and
%"? had partial remission.
:ituximab has been associated with fatal pulmonary interstitial fibrosis.
:ituximab has also
been associated with hypogammaglobulinemia and a subse'uent need for intra!enous
immunoglobulin administration. ,dditionally, progressi!e multifocal leukoencephalopathy has
been reported in a patient with lupus nephritis treated with rituximab.
0i!en the lack of ade'uate, controlled trials and the potential for se!ere ad!erse conse'uences,
routine use of rituximab cannot be recommended at this time. .urther studies are needed to
examine the safety and efficacy of rituximab.
&ecause of the e!idence of immunological mechanisms and presumed circulating factors in the
pathophysiology of nephrotic syndrome, plasmapheresis has been attempted in patients with
treatment-resistant ./0/ and /:N/. +o date, a few case reports and small series ha!e showed
some efficacy in reducing proteinuria in patients with ./0/ or /:N/ treated with
plasmapheresis or immunoadsorption.
:outine use of plasmapheresis or immunoadsorption in /:N/ and ./0/ cannot be
recommended at this time. owe!er, e!idence suggests that plasmapheresis might be effecti!e in
treating recurrence of proteinuria in patients with ./0/ who ha!e recei!ed a kidney transplant.
/ome patients with ./0/ ha!e been found to ha!e an incompletely characterized circulating
permeability factor -./P.1 that has been associated with recurrence of ./0/ after kidney
transplantation. 0alactose has a high affinity for ./P.. ,n adult patient with ./P.-positi!e
./0/ who was treatment-resistant was placed on galactose -)# g orally twice daily1.
achie!ed complete remission of proteinuria within H months and, % years later, remained in
complete remission -on a higher dose of )5 g orally twice daily1.
.urther studies are needed before routine use of galactose can be recommended, and safety and
efficacy in children is unknown.
, study examined oral zinc supplementation -)# mg daily1 of children with //N/.
found a trend in reduction of relapse fre'uency and an increase in remission length. owe!er,
the study was underpowered to show statistical significance.
.urther studies are needed before routine use of zinc supplementation can be recommended.
*ide !%%ects o% +rug #herapy
&eha!ioral changes, increased appetite, and 3ushingoid signs -rounded, or NmoonN facies1 are
common during the first J weeks of daily therapy but usually begin to subside during the
alternate-day maintenance therapy period and, if steroids are successfully discontinued, usually
disappear completely within 3-J months
4f longer periods of steroid therapy are re'uired, the risk of complications increases.
3omplications of long-term steroid therapy may include the following@
• 0rowth delay
• ,!ascular necrosis of the hip
Nutritional counseling and an exercise regimen may help to limit weight gain during steroid
therapy. 3onsideration should be gi!en to monitoring of bone density by dual energy P-ray
absorptiometry -<7P,1 in patients on long-term steroids.
Aoop diuretics -furosemide, bumetanide1 commonly cause hypokalemia and contraction
alkalosis. /erum electrolytes should be monitored and electrolyte abnormalities treated as
2etolazone may augment these side effects. +he use of potassium-sparing diuretics
-spironolactone, amiloride1 may help to limit hypokalemia.
4nfusion of %5? albumin can result in pulmonary edema and congesti!e heart failure. 4t should
be used cautiously, sparingly, and only in those patients with hemoconcentration and$or diuretic-
resistant edema. 4n the authorUs experience, slow infusion of ) g$kg as a continuous infusion o!er
%" hours helps to limit complications.
3/, and +,3 can cause increased susceptibility to infection, direct nephrotoxicity,
hyperkalemia, and hypertension. 3/, can also cause hirsutism and gingi!al hyperplasia,
whereas +,3 can cause impaired glucose tolerance and o!ert diabetes.
3MP, chlorambucil, and nitrogen mustard can cause dose-related infertility -including
azoospermia, oligospermia, and amenorrhea1, nausea, and hair loss. . +he risk of infertility rises
abo!e a cumulati!e 3MP dose of %## mg$kg . air loss, when it occurs, is usually mild and not
cosmetically significant in the doses used for most types of 4N/.
,lkylating agents can also cause myelosuppression and increased susceptibility to infection.
3MP can cause hemorrhagic cystitis and increased incidence of bladder malignancy.
/ide effects of 22. include cramps, diarrhea, 04 distress, myelosuppression, and increased
susceptibility to infection.
/ide effects of blood pressure medications are numerous and can include the following@
• yperkalemia and acute kidney failure -,37 inhibitors, ,:&s1
• &radycardia -beta-blockers1
• /edation -clonidine1
• 7lectrolyte disturbances -diuretics1
$ndications %or "ospital &dmission
,dmitting all patients with new-onset nephrotic syndrome to the hospital is not necessary.
4ndi!idually address the decision on whether to admit the child or to in!estigate and initiate
treatment on an outpatient basis.
Possible medical indications for admission include the following@
• ,nasarca, especially when resistant to outpatient therapy and$or accompanied by
respiratory compromise, massi!e ascites or scrotal$perineal or penile edema
• /ignificant hypertension
• ,nuria or se!ere oliguria
• Peritonitis, sepsis, or other se!ere infection
• /ignificant respiratory infection
• /ignificant azotemia
ospital admission may be necessary because of social reasons and often is useful on initial
presentation of idiopathic nephrotic syndrome -4N/1 in order to pro!ide intensi!e education of
the family regarding 4N/ and long-term management at home.
+iet and &ctivity
, sodium-restricted diet should be maintained while a patient is edematous and until proteinuria
remits. +hereafter, a normal diet can be followed. <uring se!ere edema, careful and modest fluid
restriction may be appropriate, but the patient must be monitored closely for excessi!e
intra!ascular !olume depletion.
Protein restriction is not indicated, except in cases of acute or chronic kidney failure when se!ere
azotemia is present. 7!en then, protein restriction should be done carefully as to a!oid impaired
, normal acti!ity plan is recommended. &ecause !iral respiratory illnesses are often associated
with relapses of nephrotic syndrome, keeping children with 4N/ away from those who ha!e
ob!ious respiratory tract infections may be beneficial. owe!er, children should not be kept out
of school and should ha!e as normal a routine as possible.
Mearly influenza !accination is recommended to pre!ent serious illness in the
immunocompromised patient, as well as to pre!ent this possible trigger of relapse.
Pneumococcal !accination should be administered to all patients with 4N/ upon presentation.
6accination should be repeated e!ery 5 years while the patient continues to ha!e relapses.
:outine childhood !accines with li!e !irus strains are contraindicated during steroid therapy and
for a minimum of ) month afterward.
3are must be taken in administering li!e !iral !accines
to children in remission from .:N/, who might need to restart steroid therapy shortly after
&ecause of the high risk of !aricella infection in the immunocompromised patient, postexposure
prophylaxis with !aricella-zoster immune globulin is recommended in the nonimmune patient.
Patient with !aricella-zoster infection should be treated with acyclo!ir and carefully monitored.
6aricella immunization is safe and effecti!e in patients with 4N/ who are in remission and off
steroid treatment -with the usual precautions for administering li!e !iral !accines to patients who
ha!e recei!ed steroids1.
:outine nonli!e !iral !accines should be administered according to their recommended
schedules. <espite the former belief that routine immunization can trigger relapse of nephrotic
syndrome, no solid e!idence supports this, and the risk of these pre!entable childhood illnesses
exceeds the theoretical, unpro!en risk for triggering relapses.
,onsultations and 3ong-#erm 1onitoring
&ecause of the complexity of care of 4N/ in all but the simplest of cases, the lack of strong
clinical e!idence supporting treatment options, and the great deal of experience re'uired in
successfully managing these patients, care of the patient with 4N/ should always be performed in
consultation with a pediatric nephrologist.
4n cases that ha!e initially been managed by the primary care specialist, referral to a pediatric
nephrologist is mandatory in cases of .:N/, /<N/, /:N/, secondary nephrotic syndrome, and
situations in which a kidney biopsy is necessary.
:eferral to a pediatric nephrologist is mandatory for all children with nephrotic syndrome whose
symptoms fail to respond to initial therapy -complete remission of proteinuria1G in most of these
patients, a percutaneous renal biopsy is indicated, and an alternati!e treatment plan may be
,s with all chronic illnesses, many psychosocial issues may need to be addressed, including
beha!ior, adherence to medication, ade'uate parental$caretaker super!ision, medical insurance,
missed work and school due to hospitalizations and outpatient !isits, and many other important
issues. 3onsultation with social workers and mental health care workers may be useful.
,mbulatory monitoring of the childUs condition and response to treatment is a !ery important
aspect of the o!erall management of nephrotic syndrome.
ome monitoring of urine protein and fluid status is an important aspect of management. Parents
and$or caregi!ers should be trained to monitor first morning urine proteins at home with urine
dipstick. 8eight should be checked e!ery morning as well and a home logbook should be kept
recording the patientWs daily weight, urine protein, and steroid dose if the child is recei!ing
.amilies and patients are instructed to call for any edema, weight gain, or urine testing %O or
more for protein for more than % days. :apid detection of relapse of proteinuria by home testing
of urine can allow early initiation of steroid treatment before edema and other complications
de!elop. Rrine testing at home is also useful in monitoring response -or nonresponse1 to steroid
Prednisone is the first-line therapy for children with nephrotic syndrome. Lther
immunosuppressi!e medications may be useful in those whose symptoms fail to respond to
standard corticosteroid therapy or in those who ha!e fre'uent relapses.
Prednisone is the first-line therapy for children with nephrotic syndrome. Lther
immunosuppressi!e medications may be useful in those whose symptoms fail to respond to
standard corticosteroid therapy or in those who ha!e fre'uent relapses.
,ll glucocorticoids are effecti!eG howe!er, prednisone or prednisolone is used most commonly.
+heir specific mode of action in nephrotic syndrome is unknown.
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+osing 2orms 6 *trengths
delayed- release tablet
#.5-% mg$kg$day PL '<ay or di!ided &4<G not to exceed C# mg$day
X)% years@ % mg$kg$day PL '<ay or di!ided &4< for 3-)# daysG not to exceed J# mg$day
)% years or older@ "#-J# mg PL '<ay or di!ided &4< for 3-)# days
% mg$kg PL '<ayG not to exceed C# mg$day
Prednisone is a delta)-deri!ati!e of naturally occurring adrenocortical steroids. 4t suppresses key
components of the immune system.
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Prednisolone 89rapred( Pediapred( Prelone:
Prednisolone is a delta)-deri!ati!e of the naturally occurring adrenocortical steroids. 4t
suppresses key components of the immune system.
<iuretics promote excretion of water and electrolytes by the kidneys. +hese agents are used to
treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention has
resulted in edema or ascites.
6iew full drug information
.urosemide is used when symptomatic edema occurs. 4t increases excretion of water by
interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and
chloride reabsorption in the ascending loop of enle and distal renal tubule.
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+osing 2orms 6 *trengths
4nitial@ )-% mg$kg 46$42$PL once
4ncrease by )-% mg$kg 'J-Chr -PL1 L: by) mg$kg '%hr -46$421, no more than J mg$kg$day
Neonates -X%C days old1
• #.5-) mg$kg 46$42 'C-%"hrG no more than % mg$kg$dose L:
• #.5-) mg$kg PL 'C-%"hrG no more than J mg$kg$day
3ontinuous 4nfusion@ #.#5 mg$kg$hr 46, titrate to effect
1echanism o% &ction
Aoop diureticG inhibits reabsorption of NaO and 3l- at proximal and distal renal tubules and loop
of enle. &y interfering with the chloride binding cotransport system, it cuases an increase in
water, calcium, magnesium, sodium, and chloride.
alf-Aife elimination@ 3#-)%# min -normal renal function1G > hr -end stage renal disease1
7xcretion@ Rrine -J#->#?1, .eces -including bile1 -)3-)C?1
,bsorption@ J#-C#? -PL1
&ioa!ailability@ "H-J"? -PL1
Protein &ound@ >)->>?
6d@ #.% A$kg
2etabolism@ Ai!er -Y)#?1
2etabolite@ (0lucuronide, %-amino-"-chloro-5-sulfamoyl anthranilic acid, Z saluamine* -acti!ity
:enal 3learance@ % mA$min$kg
<ialyzable@ Not remo!ed by peritoneal or hemo-dialysis
• 46@ % hr
• PL@ J-C hr
• 4nitial effect@ 3#-J# min -PL, /A1G 3# min -421G 5 min -461
• 2ax effect@ X)5 min -461G )-% hr -PL1
2etolazone increases excretion of sodium, water, potassium and hydrogen ions by inhibiting
reabsorption of sodium in the distal tubules. 2etolazone may be used to augment diuretic
response during treatment with furosemide.
+his agent is used to supplement diuresis in patients with edema. 4t increases oncotic pressure
and thereby promotes a fluid shift from interstitial tissues.
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-sual +osing /uidelines
Neonates -X%C days old1$infants@ )#-%# mA$kg 46 of 5? solution
5##-)### mg$kg 46 infusion
Not to exceed %5# g$"C hr or J g$kg$day
/ee 46 4nfo for infusion rate
3hoice of 5? 6s %5? depends on whether patient re'uires primarily !olume -5?1 or primarily
protein$oncotic pressure -%5?1
1echanism o% &ction
:eplacement of plasma proteinG increases intra!ascular oncotic pressure, mobilize fluids from
interstitial into intra!ascular space
7limination alf-life@ )5-%# days
<istribution@ plasma compartment@ 3#-"#?, extra!ascular compartments@ JH?
alf-life, <istribution@ )J hr, in!ersely proportional to plasma albumin concentrations
2etabolism@ 2inimally in the li!er, main site is unknown
7xcretion@ 4ntestinal mucosa, not !ia kidney
&lumin 8&luminar( Buminate( 2le)umin( Plasumin:
,lbumin raises oncotic pressure and thus supplements the diuretic effect of furosemide.
+his agent is used to supplement diuresis in patients with edema. 4t increases oncotic pressure
and thereby promotes a fluid shift from interstitial tissues.
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3yclophosphamide is a cyclic polypeptide that suppresses some humoral acti!ity. 4t is
chemically related to nitrogen mustards. 4n the li!er, this agent is biotransformed by the
cytochrome P-"5# system to its acti!e metabolite, "-hydroxycyclophosphamide, which alkylates
the target sites in susceptible cells in an all-or-none type reaction. ,s an alkylating agent, the
mechanism of action of the acti!e metabolites may in!ol!e cross-linking of <N,, which may
interfere with growth of normal and neoplastic cells.
+he mechanism of action of cyclophosphamide in autoimmune diseases is thought to in!ol!e
immunosuppression due to destruction of immune cells !ia <N, cross-linking.
4n high doses, cyclophosphamide affects & cells by inhibiting clonal expansion and suppression
of production of immunoglobulins. 8ith long-term low-dose therapy, it affects + cell functions.
3yclophosphamide has been successfully used in conditions that re'uire immunosuppression. 4t
is highly effecti!e for fre'uently relapsing steroid-sensiti!e nephrotic syndromeG half of the
children enter a prolonged remission. :esearchers ha!e formulated !arious protocols for
different renal pathological lesions.
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,yclosporine 8*andimmune( 7eoral( /engra%:
3yclosporine is an ))-amino acid cyclic peptide and natural product of fungi that suppresses
some humoral immunity and, to a greater extent, cell-mediated immune reactions -eg, delayed
hypersensiti!ity, allograft re=ection, experimental allergic encephalomyelitis, and graft-!s-host
disease1 for !arious organs.
+his agent is a specific modulator of +-cell replication and acti!ity. 4t depresses cell-mediated
immune responses by inhibiting helper +-cell function. 4t may produce preferential and
re!ersible inhibition of + lymphocytes in 0# or 0) phase of the cell cycle. 2aximum
suppression of +-lymphocyte proliferation re'uires that drug be present during first %" h of
antigenic exposure. +his agent has minimal acti!ity against & cells.
3yclosporine binds to cyclophilin, an intracellular protein, which in turn pre!ents formation of
interleukin % and the subse'uent recruitment of acti!ated + cells.
+he bioa!ailability of cyclosporine a!erages about 3#?, but this !aries markedly between
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+acrolimus is an immunomodulator produced by the bacterium /treptomyces tsukubaensis. 4ts
mechanism of action is similar to that of cyclosporine. +his agent is primarily used in transplant
recipients, but is also used in &eh[et disease to treat u!eitis.
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1ycophenolate mo%etil 8,ell,ept( 1y%ortic:
+his agent inhibits inosine monophosphate dehydrogenase -42P<1 and suppresses de no!o
purine synthesis by lymphocytes, thereby inhibiting their proliferation. 4t inhibits antibody
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