2. Definitions
NEPHROTIC SYNDROME
• Heavy proteinuria
• Hypoalbuminaema ( sr.albumin <2.5g/dl )
• Hyperlipidaemia ( sr.cholestrol >200mg/dl)
• Edema
NEPHROTIC RANGE PROTEINURIA
• Early morning urine protein is 3+/4+(300-1000mg/dl) (on
dipstick or boiling test) for 3 consecutive days
• spot protein/creatinine ratio>2
• urine albumin excretion >40 mg/m2/hr
3.
4. EPIDEMIOLOGY
• Affects 1-3 per 1,00,000 children < 16 years of
age
• Age group- 2/3rd < 6 years
• boys:girls - 2:1
• 90% -idiopathic,10%-secondary causes
• Most common – sporadic
• Familial- 3-5%
ETHNICITY
African-American -FSGS
7. SSNS
• functional alteration in the barrier
In episodes of relapse in IDS,
Breakdown of charge selective barrier to
fitration
Massive selective proteinuria
SRNS
• In genetically related SRNS,Structural
alteration in the podocyte
8. ABNORMAL IMMUNE SYSTEM
Infection,Vaccine,allergen,lymphoma
dyregulated T cells
circulating glomerular permiablity factor
• interleukin 13
• Nuclear factor kappa-B,an element of IL - 13
• Low levels of i-kBa
• Imbalance between glomerular permeability
factors and its inhibitors like apolipoproteins
13. DIFFERENTIATING LOW AND HIGH INTRAVASCULAR VOLUME
LOW INTRAVASCULAR VOLUME
• Low FENa(<1%)
• Relative potassium excretion(UK/UK + UNa) >
60%
• Low intravascular volume correlates with
elevated RAAS
14. RECENT VIEW OF PATHOPHYSIOLOGY
OF EDEMA IN NS
SODIUM
RETENTION
Increased angiotensin
2 independent
afferent and efferent
arteriolar tone due to
increased sympathetic
nerve activity
Tubular resistance to
atrial natriuretic
peptide
Increased no of open
ENAC channels in CCD
due to proteolytic
activation by plasmin
Increased number and
activity of CCD
Na-K ATPase channels
17. HIGH RISK FACTORS FOR THROMBOSIS
• Age > 12 years
• Congenital nephrotic syndrome
• Severe proteinuria(>10 gms/day)
• Previous episodes of thrombosis,DVT
• Central line access
• SLE
22. CLINICAL FEATURES
HISTORY
• H/O preceding infections such as pharyngitis,URTI or skin
infections to exclude PSGN
• H/O erythematous rashes,arthralgia or arthritis
• Positive family history of NS suggests familial NS of FSGS
PRESENTATION
• A typical nephrotic child is a preschool boy,presenting with
puffiness of eyelids followed by slowly progressing generalised
edema.
• Some present with scrotal,labial edema n respiratory
compromise.rarely there is diarrhoea secondary to edema of
the bowel wall
• Occasionlly,NS presents critically ill due to
peritonitis,bacretemia,pneumonia or rarely due to thrombotic
episode
• Some may have hypotensive symptoms like abdominal
pain,persistent vomiting,dizziness and cold extremities
23. PHYSICAL EXAMINATION
• Assess the extent of edema
• Search for infections such as pneumonia or peritonitis
• Height,weight recorded and Check BP ,there may be hypo
or hypertension in sick children
• Skin examined for erythematous rashes,breaks n infection
• Small n big joints inspected for swelling or tenderness may
indicate collagen vascular disease
• Chest examination for pneumonia and pleural effusions
• Hepatospleenomegaly indicates a systemic disease
• Ascitis may be minimal or massive
• Children with abdominal pain checked for signs of
peritonitis like guarding,rigidity and absence of bowel
sounds
24. LABORATORY EVALUATION
Lab evaluation of the first episode includes
• Urine analysis
• Complete blood count
• Blood urea,creatinine
• Sr.electrolytes
• Sr.albumin and cholestrol
• Serum C3 and ASO done if there is gross or persistent
microscopic haematuria
• Appropriate tests are done,if necessary for associated
conditions(eg.chest X ray,tuberculin test,hepatitis B,C
,HIV,ANA).
• Urine culture is not necessary unless the child has clinical
features suggestive of UTI
25. Imaging studies
• Chest X ray to identify pleural effusion in children with marked ascitis
and respiratory compromise
• USG abdomen identifies anatomical site,size,parenchymal changes
suggesting nature and duration of disease
• Kidneys in nephrotic syndrome show NEPHROMEGALY WITH
NORMAL ECHOTEXTURE
• Increase in echotexture and loss of corticomedullary differentiation
indicates severe renal involvement
• Small contracted disease suggests chronic nature of the disease
26. TREATMAENT OF STEROID SENSITIVE
NS
AIM:
• The aim of therapy is to induce and
maintain remission from active NS,while
minimising the side effects of the medication
27. TREATMENT OF INITIAL EPISODE(ISPN)
MEDICATION:
Prednisone or prednisolone is administered after
meals to reduce its GI side effects.
REGIMEN:
Prednisolone at a dose of 2mg/kg/day(maximum
60mgs) in single or divided doses for 6 weeks
1.5mg/kg/day (maximum 40mgs) in single
morning dose on alternate days for next 6 weeks
28. PROTOCOL BY INTERNATIONAL STUDY OF KIDNEY
DISEASE IN CHILDREN(ISKDC):
• Daily prednisolone for 4 weeks followed by 4 weeks
intermittent therapy
ARBEITSGEMEINSCHAFT FUR PADIATRISCHE
NEPHROLOGIE(APN) REGIME:
• Initial therapy for 6 weeks of daily prednisolone at a dose
of 60mgs/m2/day(2 mg/kg) in single or divided doses
followed y 40mgs/m2/day(1.5mg/kg) on alternate days for
next 6 weeks
29. SUMMARY OF DIFFERENCES IN
RECCOMENDATIONS BY KDIGO FROM ISPN
• In children with presumed MCNS,
prednisolone administered as a single daily dose
of 60mgs/m2/day(2 mg/kg) to a maximum of
60mgs/day for 4-6 weeks
alternate day prednisolone starting at a dose of
40mgs/m2 qod or 1.5mgs/kg qod for 8 wk to 5
months with tapering of the dose
30. Cont..
CORTICOSTEROID THERAPY FOR FREQUENTLY RELAPSING (FR) AND STEROID-
DEPENDENT (SD) SSNS:
• Relapses in children with FR or SD SSNS be treated with daily prednisone until the
child has been in remission for at least 3 days, followed by alternate-day prednisone for
at least 3 months in the lowest possible dose without any major adverse effects
•If alternate day prednisolone cannot maintain remission,daily prednisolone is given in
the lowest possible dose
TREATMENT OF FR AND SD SSNS WITH CORTICOSTEROID-SPARING AGENTS
•chlorambucil (0.1–0.2 mg/kg/d) may be given for 8 weeks (maximum cumulative
dose 11.2 mg/kg) as an alternative to cyclophosphamide.
STEROID-RESISTANT NEPHROTIC SYNDROME:
• a minimum of 8 weeks treatment with corticosteroids to define steroid resistance
•cyclophosphamide not be given to children with SRNS
31. TREATMENT OF RELAPSE
Treatment of infection
NO SPONTANEOUS REMISSION
Prednisolone at a dose of 2mgs/kg/day untill urine
protein is trace or nil for 3 consecutive days
NO REMISSION
REMISSION IN 2 WEEKS IN 2 WEEKS
predisolone is tapered to continue prednisolone
1.5mgs/kg on alternate days for 2 more weeks
for 4 weeks REMISSION NO REMISSION
refered for evaluation
32. INFREQUENT RELAPSERS
• Patients who have 3 or less relapses a year and
respond promptly to prednisolone
• Such children have low risk for developing
steroid toxicity
FREQUENT RELAPSERS AND STEROID
DEPENDENCE
• Should be managed in consultation with a
pediatric nephrologist
• It is usually not necessary to perform a renal
biopsy in these cases
35. IMMUNOMODULATORS
LEVAMISOLE:
PATIENT SELECTION:
Has modest steroid sparing property and is the initial choice in patients
with FRNS and steroid dependence
2-2.5mgs/kg alternate days for 12-24 months
+
prednisolone 1.5mgs/kg on alternate days for 4 week
prednisolone dose gradually reduced 0.15-0.25mg/kg every
4 weeks to a maintainence dose of
0.25-0.5 mg/kg that is continued for 6 or > months
ADVERSE EFFECTS:
chief side effect:leucopenia
others:flu like symptoms,liver toxicity,convulsions,skin rash
MONITORING:
leukocyte count every 12-16 weeks
36. CYCLOPHOSPHOMIDE
Therapy started preferably following remission of proteinuria.
2-2.5mgs/kg/day for 8 - 12 weeks
+
prednisolone 1.5mgs/kg on alternate days for 4 week
Prednisolone 1mgs/kg for next 8 weeks
tapered and stopped in next 2-3 months
ADVERSE EFFECTS:
• Leucopenia,infections,alopecia,haemorrahagic
cystitis,nausea,vomiting,gonadal toxicity,malignancies
• Increased risk of overwhelming varicella infection
37. MONITORING
•Cumulative dose should not exceed 168mgs/kg
•Leucocyte count monitered every 2
weeks.Therapy is discontinued if < 4000/mm^3
•Fluid intake should be increased and patients
encouraged to void frequently
PATIENT SELECTION
•Significant steroid toxicity
•Severe relapses with episodes of hypovolemia or
thrombosis
•Poor compliance or difficult follow up
38. CYCLOPHOSPHOMIDE Cont..
• Various studies show that IVCP monthly for 6
months(500 mgs/m2/month) along with alternate
day steroids(1mg/kg) for 1 year has been better in
inducing remission(73%)
• Chlorambucil,because of its toxicity is not
recommended by ISPN
• When steroid dependent children have not
achieved prolonged remission after
cyclophosphomide therapy,renal biopsy should be
performed
40. MYCOPHENOLATE MOFETIL
• 800-1200mgs/m2/day or 20mgs/kg/day BID
along with tapering doses of prednisolone for
12-24 months
ADVERSE EFFECTS:
GI discomfort,diarrhoea,leucopenia
MONITORING:
• leucocyte counts monitored every 1-2 months
• Stopped if < 4000/mm^3
41. CALCINEURIN INHIBITORS
PATIENT SELECTION:
patients with steroid dependence that fails to benefit with
levamisole,cyclophosphomide or MMF
CYLOSPORINE: 4-5mgs/kg/day daily for 12-24 months
TACROLIMUS: 0.1-0.2mgs/kg daily for 12-24 months
+
+
prednisolone 1.5 on alternate days for 2-4 weeks
prednisolone dose gradually reduced 0.15-0.25mg/kg every 4
weeks to a maintainence dose of
0.25-0.5 mg/kg that is continued for 6 or > months
ADVERSE EFFECTS:
CsA:nephrotoxicity,Hypomagnesemia,
hirsuitism,gumhypertrophy,hypertention,
Hypercholesterolemia and elevated transaminases
TACROLIMUS:hyperglycaemia,diarrhoea and rarely
neurotoxicity(seizures n headache)
42. MONITORING:
• Estimation of trough levels of CsA in patients with suspected
non compliance,unsatisfactory response or
nephrotoxicity(increase in sr.creatinine by 30% or more from
the baseline)
• 12 hours trough levels should be kept between CsA 80-
120ng/ml, tarolimus 3-7ng/ml
• RBS,RFT every 3 months
• Lipid profile annually
• Repeat kidey biopsy after 2 years if therapy is extended beyond
2 years
• Drugs interfering with P450 should be avoided
• Diet like grape juice should be avoided
RISK FACTORS FOR DEVELOPING CsA TOXICITY:
• Age> 5 years,CsA treatment >3 years
• Heavy proteinuria persisting at the end of 1 month of therapy
43. FAILURE OF ALTERNATIVE MEDICATION:
If the patient has 2 or more relapses over 6
months while on treatment with any of the
above medication,its replacement with an
alternative medication should be considered
RELAPSES DURING TREATMENT:
Daily steroids followed by tapering doses of
steroids on alternate days
44. RITUXIMAB
• An anti-CD20 monoclonal antibody ,recently shown to
be useful in SDNS
• 2 to 4 weekly infusions(375 mgs/m2/week) induced
remission associated with B cell depletion in 75% of
children
ADVERSE EFFECTS:
Neutropenia,hypogammaglobinemia,cytokine
shock syndrome and infections
45. OUTCOME AND PROGNOSIS
• If response to steroids< 9 days and relapse
free in the first 6 months after treatment,they
tend to have no or infrequent relapses
• Progression to ESRD < 0.3-0.5%
• Active NS in adulthood 25%
• Risk of recurrence of IDS after transplant is
20% to 30%
46. STEROID RESISTANT NEPHROTIC
SYNDROME
DEFINITION:
Absence of remission despite 4 weeks of daily
prednisolone therapy at 2mg/kg/day
TYPES:
INITIAL NON RESPONDER(INR)
A child who does not respond to initial 4 weeks
of SPT
SUBSEQUENT NON-RESPONDER(SNR)
A child who was steroid responsive earlier fails
to respond to subsequent 4 weeks course of SPT
47. GENETICS:
• Mutations of nephrin(NPHS1),podocin(NPHS2),
AATN 4 and WT 1
• SRNS and steroid responsive nephrotic syndrome
are associated with MHC markers
• MHC class-1 antigens,specifically HLA B-12 &
• DR-7 in MHC class 2 confer higher risk for SRNS
48. MANAGEMENT
• Treatment failure co-relates with poor long
term prognosis for renal function
• Children with MCD or late resistance respond
better to immunosuppressive gents than those
with FSGS or with initial resistance
• The aim of treatment is inducing and
maintaining remission while avoiding
medication related toxicity
51. Studies from various trials suggest that
CYCLOSPORINE:
• It is more efficacious than IVCP
• However,it has more serious side effects such as
hypertention,hyperkalemia,reversible acute renal insufficiency
• Its nephrotoxicity causes progressive interstitial fibrosis and tubular atrophy not
resulting from evolution of FSGS.hence monitoring is mandatory
• FSGS without NPHS2 homozygous or heterozygous mutations,77% achieved
remission with CsA & prednisolone with or without pulse methylprednisolone
• Most patients who respond do so in 2-3 months of initiating treatment
• Therapy should therefore be considered not effective and discontinued in patients
showing persistent proteinuria beyond 6 months
• Those who show complete or partial remission should receive treatment for 2-3
years ,the dose of CI tapered to lowest effective possible dose for another 1 to 2
years
• Some children who respond to CsA relapse on its discontinuation while
reintroduction is not always effective and some tend to be CsA dependent
TACROLIMUS:
• Has less cosmetic side effects
• Some studies showed that children not achieved remission with CsA responded to
tacrolimus
• Monitoring is mandatory as it is also nephrotoxic
53. Studies from various trials suggest that
• As compared to oral CYP,IVCP produces more
sustained remission,fewer side effects at 60% of the
total dose
• The risk of chronic renal insufficiency or ESRD
decreased in patients with SRNS who were CYP
sensitive
• Compared to IV methyl prednisolone,it has shorter
duration of treatment(6 months),at fraction of total
cost and with minimal side effects
54. MENDOZA PROTOCOL
Intensive therapy with bolus doses of corticosteroids in
combination with alkylating agents
However,they are associated with significant risks of
hypertention,serious infection and delayed growth
55. CORTICOSTEROIDS:
• Important part of all therapeutic protocols in
combination with other agents in SRNS
• Intiated in daily doses along with an
alternative agent and dose is decreased to
alternate day to minimise steroid side effects
1.5mgs/kg on alternate days for 4 weeks
1.25mgs/kg for next 4 weeks
1mg/kg for 4 months
0.5-0.75mg/kg for 12-18 months
56. Other drugs
• The efficacy of Rituximab,MMF,mizoribine in
SRNS remains poor
• ACEI appear to benefit in treatment of SRNS
59. PROGNOSIS AND OUTCOME
• Increasing evidence of FSGS and decreasing
incidence of MCNS
• The most important factor predictive of
remission in SRNS: IVCP therapy and evidence
of MCNS
• The risk of development of ESRD > 40% in 5
years in SRNS
60. CONGENITAL NEPHROTIC SYNDROME
• Presents in first 3 months of life
Etiology:heterogenous
Finnish form –NPHS1 mutation, AR
NPHS2,PLCE 1 mutation
intrauterine infections
CLINICAL FEATURES:
anasarca,hypoalbuminaemia,oliguria
HISTOLOGY:
microcystic dilatation of proximal tubules in NPHS1
AN SREENING:
Elevated levels of AFP in maternal serum and amniotic fluid
COMPLICATIONS:
FTT,recurrent infections,hypothyroidism and progression to renal
failure by 2-3 years
Treatment:
supportive
61. SUPPORTIVE CARE AND MANAGEMENT
OF COMPLICATIONS
DIET:
• If Persistent proteinuria, 2-2.5gms/kg of daily
protein
• Not more than 30% calories from fat and no
saturated fat
• If persisitent edema,salt reduction 1-2 gms/day,fluid
restriction and no added salt
• Adequate physical activity and preventing excessive
weight gain
63. IMMUNISATION
• some vaccines like hepatitis b,mmr,meningococcal vaccine
can precipitate a relapse
• Live vaccines are administered once the child is of the
immunosuppressive medications for 4 weeks
• If there is a need,can be given while the child is on
prednisolone< 0.5mg/kg
PNEMACOCCAL VACCINE
• <2 yrs : 2-4 doses of PCV
• Unimmunised 2-5 yrs : one dose of PCV followed by PPV23 8
weeks later
• > 5 years :one dose of PPV23
VARICELLA VACCINE
• 12 months – 12 years: one dose
• 13 years and older :2 doses separated by 4 weeks apart
65. THROMBOSIS
• venous thrombosis and rarely arterial thrombosis
occurs
Treatment includes
• Correction of dehydration and other complications
• IV heparin or LMW heparin initially followed by oral
anti-coagulants on long term
• No role for prophylactic anti-coagulants
• Some trials recommend prophylactic use of
warfarin if sr.albumin < 2g/dl,fibrinogen>6g/dl,
anti-thrombin < 70% of normal
66. HYPERTENTION
• Treated with ACE inhibitors,CCB,beta blockers to
keep the percentile< 90
HYPERLIPIDAEMIA
• Patients with SRNS may show persistent
dyslipidaemia that requires treatment with
atorvastatin(10-20mgs/kg)
HYPOVOLEMIA
15-20ml/kg of rapid bolus of normal saline
no response
1 more bolus repeated
no response
albumin infusion
67. Steroids during stress
• Supplementation of steroids during
surgery,anaesthesia and serious infections
• IV hydrocortisone 2-4mg/kg/day followed by
oral prednisolone 0.3-1 mg/kg/day during
stress and then tapered
68. Parent education
• Parental motivation and involvement is
essential
• Provide information about disease,course and
complications
• They should maintain a diary,recording the
protein excretion,intake of medications and
intercurrent illnesses
• Ensure normal activity and school attendance
• Appropriate immunisations should be done
