Pediatric Nephrotic Syndrome

Ashraf Beharrie, M.D.

Pediatric Nephrologist
Chris Evert Childrens Hospital
Broward Health Medical Center
Definition/Background
Pediatric Nephrotic Syndrome (nephrosis) defined as :

Nephrotic range proteinuria 40mg/m/hr

~1gm/m2/day
semiquantitative Urine P/C value > 2mg/mg (first morning urine sample)

Hypoalbuminemia: (serum albumin < 2.5 g/dl)

Edema: ( Anasarca > 10 % increase body weight)

Nephrotic syndrome:
constellation of features due to massive protein loss not a disease itself
manifestation of glomerular injury
Etiology
Causes of INS include the following:
MCNS
FSGS
MPGN
Membranous glomerulonephritis (MGN)
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, -actinin-4; TRPC6)
Nail-patella syndrome (LMX1B)
Pierson syndrome (LAMB2)
Schimke immuno-osseous dysplasia (SMARCAL1)
Galloway-Mowat syndrome
Oculocerebrorenal (Lowe) syndrome
Etiology (contd.)
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
Etiology (contd.)

Systemic diseases that can cause secondary nephrotic syndrome

include the following:
Systemic lupus erythematosus
Malignancy - Lymphoma, leukemia
Vasculitis -Wegener granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa,
microscopic polyangiitis, Henoch-Schnlein purpura (HSP)
Immune-complexmediated - Poststreptococcal glomerulonephritis
Classification of glomerular disease

Primary / Idiopathic Nephrotic Secondary Nephrotic Syndrome

Syndrome
Usually refers to systemic etiology
Usually intrinsic kidney disease extrinsic to the kidneys
without systemic causes SLE
Based on histopathology HIV
MCD Syphilis
FSGS Hepatitis B, C
MN Henoch-Schonlein purpura
MPGN Malignancy
Diffuse mesangial proliferation Drugs
Vasculitis
Classification

Genetic abnormalities

Infantile NS ( present< 3 months of age)

Congenital NS ( present 4-12 months of age)
associated defects/mutations :
Nephrin gene ( NPHS1)
Wilms tumour suppressor gene ( WT1)
Podocin gene ( NPHS2)- familial AR FSGS
Alpha actinin 4 gene( ACTN-4)
TRPC6 gene - familial AD FSGS
Myosin heavy chain 9 ( MYH-9)FSGS African-Americans
Classification

Clinical responses-
Steroid sensitive nephrotic syndrome ( SSNS)
Steroid resistant nephrotic syndrome (SRNS)

Landmark study childhood nephrosis ( ISKDC)

Vast majority preadolescent INS had MCNS
90% respond to steroid
FSGS biopsy proven only 10-20% steroid responder
Response to steroid is the prognosticator, regardless of histopathology
Nephrotic
Syndrome

Typical Features are Nephrosis Classification

likely steroid
Typical Features Atypical Features
responders and
likely MCD Age 1-10 years <1 yrs, > 10yrs

Atypical Features Normotensive Hypertensive

likely steroid
resistant and likely Normal Renal Function Elevated Creatinine

FSGS
+/- microscopic hematuria Macroscopic Haematuria
Epidemiology

USA Annual incidence rate 2-7cases per 100, 000 < 16 yrs
Prevalance rate 16 case per 100,000
ISKDC 76% children MCNS
7% children FSGS
Black and Hispanic children at increased risks for SRNS/FSGS
Asian Children has increased incidence INS x 6 fold compared with
European children
Children < 8 years Male;Female 2:1
Older children male = female
MCNS 70% < 5yrs old
20-30% adolescent
Pathophysiology

Initiating event that produces proteinuria remains unknown

INS believed to have immune pathogenesis
Studies show abnormal T-Cell subset regulation and expression of circulating
permeability factor

Indirect evidence of immune mediated INS

Corticosteroids/ alkalating agents causes remission
Nephrotic syndrome remits during measles infection, which suppresses cell mediated
immunity
Circulating factor-rapid development of proteinuria in transplanted kidney
improvement after plasmapheresis
Experimental induction of proteinurea in animals by plasma from patient with INS
Pathophysiology
Various cytokines implicated
Interleukins IL-2, IL-4, IL-12, IL-13
Interferon gamma
Tumor growth factor (TGF-Beta)
Tumor necrosis factor (TNF-alpha)
Vascular permeability factor

Association of allergic response to NS

Bee stings, jellyfish stings, poison ivy, ragweed pollen etc....
INS associated 3 to 4 times more likely with;
HLA-DR7
HLA-B8
HLA-B12 (atopy)
Pathophysiology
Recent Developments
Podocyte biology now forefront of pathophysiology of NS
Intercalated podocyte foot process connected 35-45 nm slit diaphragm
(integral part GBM)
Biopsy shows effacement foot processes long thought to be secondary
phenomenon
Theories now shift towards podocyte molecular biology playing primary role
in development of proteinuria
Numerous mutations podocyte genes
Slit diaphragm cytoskeleton NPHS1, NPHS2, TRCP6, ACTN4 and MYH9
Glomerular basement membrane- LAMB2
Transcription factors WT1
Edema Formation

Classic Hypothesis (underfill theory)

Overfill Hypothesis
Recent Theory (interstitial inflammation/intrarenal
vasoconstriction)
Combination of all of the above
Edema Formation
Hyperlipidemia

Increase liver
synthesis
Decrease
function of
regulatory
enzymes
Decrease
clearance of
cholesterol in
the periphery
Complications of NS
Hypovolemia- children usually intravascular depleted
Cool periphery, tachycardia
Increase hematocrit
Hypotension (late)
Hypertension (paradoxical)
Low FeNa

Infections INS at increased risk

Low IgG levels (impaired synthesis, ? Urinary loss)
Low complements (urinary loss)
Decreased opsonization of capsulated organisms
Impaired T-Cell function
Drugs such as corticosteroids/ cyclophosphamide suppress immune system
Peritonitis/sepsis are most serious and not that uncommon (2-6%)- Pneumococcus,
E.Coli
Other infections such as meningitis, cellulitis and viral infections
Varicella of concern- Can be lethal in the immunosuppressed- treatment with
Acyclovir and Post exposure prophylaxis with VZIG
Routine Childhood vaccination for varicella and pneumococcus has helped
Complications of NS

Thrombosis- 2-5% of cases

Worse in membranous nephropathy (greater protein loss)
Renal vein thrombosis, deep vein thrombosis, cerebral sinus
thrombosis, pulmonary embolism.
Arterial thrombosis less common
Imbalance in procoagulation/ anticoagulation factors
Complications of NS
Acute renal failure
Rare complication - ~1% of cases
Initial Investigations

Do all the following tests in new onset nephrotics

CBC, CMP, C3, C4, Lipid Profile, ASO titer, ANA, HIV, RPR, Hepatis B, C
profile
Urinalysis, urine electrolytes
24 hr urine collection for protein/creatinine, or early am urine for P/C ratio
Renal ultrasound
PPD to be placed
Check on varicella status
Referral to pediatric nephrologist for atypical presentation
age <1 yr or > 10 to 12 yrs, persistent hypertension, macroscopic hematuria, low
complements, or failure to respond to steroids within 4 weeks
Patient Education

Soon after NS is diagnosed patient and family should be educated about

the disease, its management, and expected course. Family should
participate in therapeutic decisions, and encourage to adhere to
medical regimen.
Psychosocial issues to be addressed
Behavior
Adherence to medication
Adequate parental/ caretaker supervision
Medical insurance
Missed work and school due to hospitalization and outpatient visits
Social worker may be needed
Terminology
Steroid responder- patient goes into remission on prednisolone usually
within 10-14 days (trace or negative proteinuria for three consecutive
days)
Steroid resistance- after 4 weeks of prednisolone, patient persists with
proteinuria
Relapse nephrosis- > 2+ proteinuria on 3 consecutive days
Frequent relapser- 2 or more relapse in the first 6 months of
presentation or 4 or more relapse within any 12 months
Steroid dependency- relapse during the tapering phase of
prednisolone or less than 2 weeks after stopping prednisolone
Late responder- patient goes into remission at about 4 weeks of
prednisolone
Late nonresponder patient who initially went into remission on
steroid but became resistant at a later date
Treatment
For typical features prednisolone is the first line drug
For atypical features consider a renal biopsy first
Predisolone course 8 weeks vs 12 weeks
Use Ranitidine for the entire steroid course and use calcium carbonate and
vitamin D supplement
Side effects of steroids should be discussed
Albumin- indications, include clinical hypovolemia and symptomatic edema
No added salt diet
Fluid restriction ~1 liter per day
Penicillin prophylaxis- no consensus
Vaccinations
Pneumococcal polysaccharide vaccine, varicella vaccine

See algorithm
Relapsing NS

70-80% of children of steroid responders will

have one or more relapse
Treatment-prednisolone 60mg/m/per day, until
trace or negative proteinuria for 3 days
Taper treatment 40mg/m/q other day for 4
weeks, and wean off over another 4 weeks
Can also use low-dose alternate day
prednisolone 10-15mg qod x 6 months
Relapsing NS

Other meds
Levamisole is beneficial for occasional relaspes/steroid
dependency. Check for neutropenia

Cyclophosphmide/ Chlorambucil- useful for frequent relapser,

steroid sensitive patients. Usually, 8-12 week course. Monitor for
neutropenia and small risk of gonadol toxicity and malignancy

Cyclosporine- third line drug for steroid sensitive frequent relapser

or in steroid resistant post biopsy. The dose is 5 mg/ kg/ day x 1
year . Aim for a trough 70-150. Be aware of the side effects eg.
Hypertension, decreased renal function

Mycophenolate mofetal (MMF) Third or Fourth line drug for both

steroid sensitive frequent relapser or steroid resistant ( FSGS) .
Dose 600mg/m/day. Side effects include gastritis and leucopenia
Prognosis

NS is usually a chronic relapsing disease

with some degree of morbidity
Hospitalization, medication side effects, relapses,
and potential progression to ESRD.
Since introduction of corticosteroids, INS mortality
has decreased dramatically from >50% to ~2%
Prognosis varies depending on steroid sensitive
vs. steroid resistant.
Prognosis

Steroid sensitive nephrotic syndrome (SSNS)

Good prognosis
93% of responders to steroids will have MCD
75% who did not respond will have a
histopathology other than MCD
Despite favorable progress- relapse is the rule
Longer initial course of steroids 12 week vs. 8
week decreases subsequent relapse by 36%
Length of time between steroid treatment and
remission is early prognostic indicator
Prognosis

Most SSNS will eventually achieve long term

remission
Percent of patients free of relapse
44% 1 year after diagnosis
69% 5 years after diagnosis
84% 10 years after diagnosis

Overall 90% of children achieve long term

remission by puberty
Some studies show 20-30% can relapse into adulthood
Prognosis

Steroid resistant nephrotic syndrome ( SRNS)

10% of INS do not respond to steroids
Only 2% of MCNS do not respond
1-3% initial responders to steroids, evolve to late non responder
Nonresponders usually have FSGS
More than 60% of NS/ FSGS who fail to achieve remission,
progress to ESRD
In contrast, FSGS who achieve remission, only 15% progress to
ESRD
Even steroid resistant INS have a relative good prognosis if
remission can be achieved with a second/third line medication
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