Nephrotic Syndrome in

Children
Presenter

Dr. Dolon Rani Kuri

Maj Musrata Shaharin
Overview
• Definition
• Pathophysiology
• Classification of nephrotic syndrome
• Diagnostic evaluation
• Treatment options
• Issues involved in the treatment
• Natural history
• Key messages
Definition

Nephrotic syndrome is the clinical manifestation of glomerular

disease associated with
Heavy proteinuria
Hypo-albuminemia
Generalized edema and
Hyperlipidemia.

IPNA Guideline 2019

Definition (cont.)
Recent

Nephrotic-range proteinuria and either hypoalbuminemia (serum

albumin < 30 g/L) or edema when serum albumin is not available.

Ref: (IPNA guideline 2022)

Nephrotic range proteinuria

 Proteinuria ≥1000mg/m2/ day in a 24-hr urine sample

corresponding to 3 + (300–1000 mg/dL) or 4 + (≥ 1000 mg/dL) by
urine dipstick, or
 Urinary protein to creatinine ratio (uPCR)
≥200mg/mmol(2gm/gm) in a spot urine.
History
• 1827
Richard Bright showed that kidney
disease could cause dropsy (edema)
and some patient had low level of
albumin in their blood because it
was leaking from their kidney.
 1905
Friedrich Von Muller introduced the
term ‘Nephrosis’, meaning a non-
inflammatory kidney disease.
History (Cont..)
 Between (1930-1950)
The term ‘Nephrosis’ was
replaced by the word ‘Nephrotic
Syndrome’

 By 1949-1950
The first successful treatment of
nephrotic syndrome with newly
synthesis steroid hormone was
started
Epidemiology

 Commonest renal disease, 60% of all pediatric renal disease.

 Usually appear 2- 6 yrs of age. Peak at 3 years.
 25 times more common in children than adult
 Incidence 2 -7/ 100000 children.
 M:F - 2:1.
Filtration Barrier
 Fenestrated endothelium
 Glomerular basement
membrane
 Capsular epithelium
(Podocyte)
Filtration Barrier
 Fenestrated endothelium
• Pore size: 70 – 100 nm
• Negatively charged
Filtration
 Pressure gradient
Glomerular physiology

 Filtration
 Reabsorption
 Secretion
 Excretion
Pathophysiology
Immune dysfunctions- T & B cell abnormality

Release of cytokines like plasma soluble circulating substance

Visceral epithelial cell injury, diminished adhesion of visceral epithelial cell to glomerular
basement membrane (GBM)

Interference with polyanionic charge of glomeruli

Filtration of albumin- protein loss

Hypoalbuminaemia

Generalized edema
 What causes glomerular leakage of
protein?
 In MCNS - effacement of the Soluble plasma factors from T &
foot process of podocytes B cell
results increase in size of slit   Glomerular permeability due
diaphragm pore & allows to loss of charge selectivity
protein leak

Ref. Ref. Bagga A , Srivastava RN. Pediatric Nephrology 4th Edn Ndelhi:JP;2005. 161-200.
Dieter H et al.2009 ;24:1433-38.
Mechanism of edema
↓ Plasma oncotic pressure
Extravasation of plasma water
Contraction in plasma volume
Decrease in renal perfusion
Stimulation of the Renin-Angiotensin system (RAAS)
↑Synthesis of Aldosterone
↑Reabsorption of Na and water
Edema
Recent hypothesis of edema

 Vasopressin excess also contributes to the retention of water.

Ref. AAP. Pediatr. Rev.(2009) 30;94:105.

 Prolonged capillary refill
time(>3sec)
Cool periphery
Tachycardia
Hypotension
Oliguria
AKI
Abdominal pain
Reduced cardio-thoracic index
(CXR)
 Hypertension
Raised JVP
Cardiomegaly
Features of pulmonary
oedema
Mechanism of edema formation
Mechanism of hyperlipidemia

Hypoalbuminemia Proteinuria

Increased hepatic protein Loss of enzymes, eg.

synthesis(Lipoprotein) Lipoprotein lipase

Hyperlipidemia
Mechanism of hypercoagulability
A. Increase prothrombotic B. Decrease fibrinolytic factor :
factor :  Increase urinary loss of
 Haemoconcentration due to protien C,S, antithrombin III
hypovolumia, abuse of
diuretics, dehydration
 Increase fibrinogen
 Impaired fibrinogenolysis
 Thrombocytosis
 Relative immobilization
Classification
Etiological Classification:

 Idiopathic/ Primary NS : 90%

 Secondary NS : 5%
 Congenital / Infantile NS : < 1 %

Clinical Classification:
SSNS (Steriod Sensitive Nephrotic Syndrome)
Difficult to treat
Steroid Resistant
Idiopathic Nephrotic Syndrome:
(90%)

 Minimal change nephrotic syndrome (85%)

 Focal segmental glomerulo-sclerosis (10%)
 Mesangial proliferation (2.3%)
 Membranous nephropathy (1.5%)
 Membrano-proliferative glomerulonephritis(7%)
Secondary Nephrotic Syndrome :
(10%)

 Infection : Hepatitis B & C, HIV, malaria, syphilis, toxoplasmosis,

cytomegalovirus(CMV)
 Drugs : Penicillamine, Gold, NSAIDS, Interferone, Lithium, Captopril,
Mercury
 Allergic Disorder : Bee sting, Food allergens
 Malignant Disease : Chronic lymphocytic leukaemia, Hodgkin’s
lymphoma
 Systemic disease : SLE, HSP, Amyloidosis, Polyarteritis , Diabetes
mellitus
Congenital Nephrotic Syndrome :
Rare
Finnish Type
Denys Drash Syndrome
Minimal Change Nephrotic
Syndrome

 In light microscopy: No appreciable glomerular pathology is

noted.
 Immunofluroscence microscopy : Typically negative.
 In electron microscopy: Effacement of foot processes of
podocytes in glomerular basement membrane.
 More than 95% response to steroid but high tendency to relapse.
Electron Microscopic view of MCNS
Mild fusion of podocyte foot
Normal glomerulus process
Minimal Change Nephrotic
Syndrome
Focal segmental glomerulosclerosis

 On light microscopy : shows mesangial proliferation & segmental

scarring.
 On immunofluroscence microscopy : shows IgM & C3 staining in
the area of segmental sclerosis.
 On electron microscopy : shows segmental scarring of
glomerulus tuft with the obliteration of the glomerular capillary
lumen.
Focal segmental glomerulosclerosis
(Cont.)
Mesengial Proliferation

 On light microscopy : shows diffuse increase in mesangial cell &

matrix.
 Immunofluroscence microscopy : shows slight deposition of IgM
in mesengial cell.
 Electron microscopy : shows increse number of mesengial cells
& matrix as well as effacement of the epithelial cell foot process.
Mesengial Proliferation (Cont.)
CONGENITAL NEPHROTIC
SYNDROME

 Nephrotic syndrome is present at birth or appears within three

months of life.
 Renal biopsy should be performed in all cases.
 The commonest form is the autosomal recessive Finnish
nephrotic syndrome due to defective production of Nephrin.
 There is no specific therapy, appropriate supportive care is
instituted.
CONGENITAL NEPHROTIC
SYNDROME (Cont.)
Causes of congenital nephrotic syndrome:
 Classic' Finnish 'type.
 Diffuse mesangial sclerosis -
• with pseudohermaphroditism (Denys-Drash syndrome).
• with microcephaly ,development delay and hiatal hernia(Galloway-Mowat
syndrome).
• idiopathic.
 Primary focal segmental glomerulosclerosis
 Congenital infections : cytomegalovirus, syphilis, rubella,
toxoplasma, hepatitis B.
Finnish type congenital nephrotic
syndrome

 The Finnish type congenital nephrotic syndrome is an autosomal

recessive disease.
 Infants with the Finnish type of congenital nephrotic syndrome
are born prematurely, often with large placenta.
 Nephrotic syndrome is present at or soon after birth.
Finnish type congenital nephrotic
syndrome (Cont.)

 Clinical presentation:
• Failure to thrive,
• Repeated infection,
• Delayed development,
• Ascites,
• Spontaneous vascular thrombosis.
 Biopsy shows cortical microcysts, representing dilated proximal
convoluted tubules, glomeruli may show mesangial proliferation
and increased mesangial matrix.
Finnish type congenital nephrotic
syndrome (Cont.)
Clinical manifestation
 Age: between 2-6 years of age
 Gradual onset
 Facial puffiness, Massive
periorbital swelling
 Generalized edema
 Scanty urination
Clinical manifestation(cont.)
 Ascites
 Edema-pitting edema, periorital edema, peripheral edema
Clinical manifestation(cont.)
 Loss of appetite but weight gain
 Shortness of breath
 Pallor
 Fever, rash, joint pain
 Irritability
 Flank pain
 Malaise
Criteria of MCNS vs Non MCNS

MCNS NON MCNS

 Normotensive  Hypertension
 No hematuria  Hematuria
 Normal renal function  Impaired renal function
 Normal complement level  Hypocomplementemia
 Steroid sensitive
 Non response to therapy
 Off and on relapse &remission
 Prognosis is worst
 90% achieved remission at
puberty
Diagnostic Evaluation
Initial assessment at presentation
Diagnosis and detecting potential complications of nephrosis :
 History ,
 Physical examination
 Anthropometry
 Assessment of vitals
 Search for any features of infection
 Immunization history
Investigations

For Diagnosis:
 Urine boiling / dipstick test / RE- Massive proteinuria (+3 /+4)
 Spot urine protein creatinine ratio >2
 24 hours urinary total protein >1gm/m²/day
 Serum albumin : Hypoalbuminemia (<2.5 gm/dl)
 Serum cholesterol : >250 mg/dl
Investigations
For infection screening: Other investigation:
 CBC, CRP  Blood urea & serum
 Urine c/s, Blood c/s if needed creatinine, electrolyte
 Chest X-ray  Serum calcium
 Mantoux test  USG of KUB
 HBsAg, Anti HCV  C3,ANA, Anti Ds DNA if
needed
How to perform urinary boiling test
for detection of proteinuria?
 Collect an early morning mid stream urine sample in 2/3rd of a
clean test tube.
 Hold the test tube with a holder at its upper end and start to heat
on a spirit lamp very cautiously, withdraw immediately when
bubbles are coming.
 Continue 3 or 4 times. A white precipitate (ppt) will appear
following boiling, this is protein.
 Add a few drops of acetic acid in this boiled urine and boil again. If
white precipitate disappear, it is phosphate. If persists it is protein.
Heat & Acetic Acid Test
Asses the level of proteinuria

 Negative: 0 to < 15 mg/dl

 Trace : 15 to < 30mg/dl
 1+ :30mg to <100mg/dl
 2+ :100 to <300mg/dl
 3+ :300 to<1000mg/dl
 4+ : ≥ 1000mg/dl
Heat & Acetic Acid Test:
Interpretation
Do we need Renal Biopsy in NS?

 A kidney biopsy at diagnosis is not required routinely because

80% are SSNS.

Kidney Int. 1981 Dec; 20(6):765-71

When should we do Renal Biopsy in
NS?
 Age <1 year or >12 years
 Persistent hypertension not related to glucocorticoid or CNI therapy
 Impaired renal function for >1 week not attributable to volume
depletion.
 Persistent or gross hematuria
 Suspected secondary cause
 Low serum C3/ C4
 Steroid resistant NS, before treatment with Cyclosporine A or
Tacrolimus
Genetic tests

 Congenital NS
 Extrarenal features and/or family history suggesting syndromic /
hereditary SRNS
 All SRNS
 Infantile onset NS (age 3–12 months)
Terminology
Types of NS (IPNA 2022)
 SSNS: Complete remission within 4 weeks of PDN at standard
dose (60 mg/m²/day or 2 mg/kg/day, maximum 60 mg/day).
 Difficult to treat NS: FRNS , SDNS or significant steroid toxicity
with infrequent relapse and failure of acheiving remission with ≥
2 steroid sparing agents.
 SRNS : Lack of complete remission within 4 weeks of treatment
with PDN at standard dose.
 Remission

 Complete remission : UPCR (based on first morning void or 24

h urine sample) ≤ 20 mg/mmol (0.2 mg/mg) or < 100 mg/m² per
day, respectively, or negative or trace dipstick on three or more
consecutive day.
 Partial remission: UPCR (based on first morning void or 24 h
urine sample) > 20 but < 200 mg/mmol (> 0.2 mg/mg but < 2
mg/mg) and serum albumin ≥ 30 g/L.
Relapse

 Relapse: Urine dipstick ≥ 3 + (≥ 300 mg/dl) or UPCR ≥ 200

mg/mmol (≥ 2 mg/mg) on a spot urine sample on 3 consecutive
days, with or without reappearance of edema in a child who had
previously achieved complete remission.
 IRNS < 2 relapses in the 6 months following remission of the
initial episode or fewer than 3 relapses in any subsequent 12-
month period.
Definition- FRNS- SDNS

 FRNS : ≥ 2 relapses in the first 6-months following remission of

the initial episode or ≥ 3 relapses in any 12 months.
 SDNS : A patient with SSNS who experiences 2 consecutive
relapses during recommended PDN therapy for the first
presentation or relapse within 14 days of its discontinuation.
 Management of
Nephrotic Syndrome
Management:
 General management
 Lifestyle and nutrition.
 Management of volume status, edema, and blood pressure.
 Treatment of infection

 Specific treatment
 Treatment of complication
 Immunization
 Parent and patient councelling
Lifestyle and nutrition

DIET
 Healthy nutrition (avoiding high fat and/ or high caloric food)
while on steroids is recommended.
 Normal calories, low saturated fats, no refined sugars.
• Protein: 10-14%
• Poly and mono-unsaturated fats: 40-50%
• Carbohydrates: 40-50%
Lifestyle and nutrition (Cont.)

Salt restriction:
 No added salt is allowed.
 Low salt diet (max dose of 2–3 meq/kg/day, 2000 mg/day in
larger children) during relapse with moderate or severe edema,
 Normal salt intake while in remission.
Lifestyle and nutrition (Cont.)

Regular physical activity:

 To prevent thromboembolic events during relapses.
 To prevent weight gain on prednisolone treatment.
Management of volume status,
edema:

 We should evaluating the volume status of a child in the acute

nephrotic state.
 No routine fluid restriction.
 Fluid restriction in case of hyponatraemia(<130meq/L) and/or
severe oedema.
Common Infections
 Peritonitis  Pyogenic infection of bone &
 Cellulitis joints
 UTI, diarrhohea  Varicella
 Pneumonia  Measles
 Meningitis  Fungal infection
 Hepatitis B
 TB
Factors contributing to infections

 Low IgG
 Low properdin factor causes impaired opsonization
 Impaired lymphocyte transformation
 Drug induced immuno suppression eg steroid.
Prevention and treatment of viral
and bacterial infections:
 Antibiotic prophylaxis should not be given routinely.
 Prompt antibiotic treatment in the case of a suspected bacterial
infection.
 About 30 to 50% of infections are due to pneumococcal
infection, with the rest due to gram-negative bacteria principally
Escherichia coli)
 In peritonitis with IV antibiotics targeting Streptococcus
pneumoniae (cephalosporin or high doses of amoxicillin).
 IVIG useful to treat child with low plasma IgG level.
Treatment of infection (Cont.)
Infection Clinical features Common Treatment
organisms
UTI Asymptomatic, gm─ve organisms Oral:Ciprofloxacin/Cotrimoxazole/Cefixime/
fever, dysuria, E.coli, Nitrofurantoin 7 to 10 days
hematuria pseudomonas, IV: Amikacin, gentamicin, Ceftriaxone,
Klebsiella, Meropenem 7 to 10 days

Peritonitis Abdominal pain, S.pneumonae, IV:

tenderness, E.coli, S.pyogenes. i.Ampicillin+aminoglycoside 7 to 10 days
distension, > 100 ii. Ceftriaxone/ cefotaxime 7 to 10 days
diarrhea, leucocytes/mm2
vomiting, fever and >50%
lymphocytes
Treatment of infection (Cont.)
TB MT +ve without evidence of TB: INH prophylaxis for 6 months. Active TB: 2HRZ+4HR.

Hep B Patients with nephrotic syndrome who are hepatitis B surface antigen positive
infection should be investigated for disease activity by doing HBV DNA, anti HBcIgM, HBeAg.
If in active state then treatment with lamivudin (3mg/kg for at least 1 year) or
interferon should be started first along with anti proteinuric drugs ACEi and or ARBs
and albumin if severely edematous.
Treatment of infection (Cont.)
Pneumonia Fever, cough, S.pneumonie, Oral: amoxicillin/Amoxiclav/erythromycin,
tachypnoea,crep H. influenzae, IV:
itations S.aureus. i.Ampicillin+aminoglycoside
ii. Ceftriaxone/ cefotaxime for 7 to 10days

Cellulitis Cutaneouseryth Staphylococcus, Oral :Cefixime/Amoxyclav/Flucloxacillin. In

ema, induration, Group A severe case- IV: Flucloxacillin + Ceftriaxone
tenderness Streptococci, H. Duration: 7 to 10 days.
influenzae, 20% I/V infusion with frusemide.
Treatment of infection
Fungal Pulmonary infiltrate, Organisms: Systemic: Amphotericin for 14 to 21
infection persistent fever Candida, days.
unresponsive to Aspergillus spp. Skin, mucosa: Oral fluconazole for 10
antibiotics, sputum and days.
urine shows
septatehyphae

Diarrhoea ORS, in case of severe dehydration or unable to drink - IV Cholera saline + FFP/
Albutein,
Antibiotic: if necessary, Ciprofloxacin oral/ IV (If invasive diarrhoea)
Duration: 5 to 7 days
Treatment of infection (Cont.)
Varicella  Susceptible (unimmunized /no H/O inf./ exposed ):
infection VZIG (125 u/10 kg body wt, minimum 125u, maximum 625u )within 72 hrs of
exposure - single dose, Or IVIG(400mg/kg).
 Active infection – 7 days Rx
I/V Acyclovir (150mg/m2/day) – 8 hourly Or Oral acyclovir (20 mg/kg/dose – 6 hrly)
for 7 days
Prednisolone - taper to ≤0.5 mg/kg/day during infection.

Measles  Isolation.
 Stop steroid during infection.
 Supportive care.
Specific treatment
Ref-KDIGO guideline 2025
Treatment of initial episode
Oral prednisolone
 4 weeks at 2mg/kg or 60mg/m² (maximum 60 mg/day)daily,
followed by 1.5mg/kg or 40mg/m² (maximum 40 mg) on
alternate day OR
 6 weeks at 2mg/kg or 60mg/m² (maximum 60 mg/day) daily,
followed by 1.5 mg/kg or 40mg/m² (maximum 40 mg) on
alternate day.
Ref-IPNA guideline 2022
Recommendation
 Infant ˃3 months and children 1-18 years should receive
prednisolone(PDN) as primary immunosuppressive.
 Oral PDN as a single morning dose.
 Tapering schedule during alternate day dosing should be avoided.
 Calculating the prednisolone dose according to estimated dry
weight.

Ref-IPNA guideline 2022

SOURCE-IPNA GUIDELINE 2022
Primary immunosuppressive
treatment

 Prednisolone
 Prednisone
 Deflazacort
 Methylprednisolone
Primary immunosuppressent
(Cont.)

Prednisolone
 Synthetic steroid.
 Inhibit B and T lymphocyte.
 Oral, intravenous form.
 Excreted through urine.
Primary immunosuppressent cont.

Prednisone
 Is a prodrug of prednisolone.
 Conversion occurs in liver.
 Not affected by impaired liver function.
 Dose is equivalent to prednisolone.
Primary immunosuppressent
(Cont.)

High dose steroid definition

• Oral prednisolone at a daily dose of 2mg/kg/day for at least one
week Or at a daily dose of 1mg/kg/day for one month
Low dose steroids definition
 Oral prednisolone at a daily dose of 2mg/kg/day for less than one
week
 Or a daily dose of 1mg/kg/day or alternate day regime for less than
one month
Primary immunosuppressent cont.

Patients receiving prednisolone at a dose of 2mg/kg/day or

greater, or total 20mg/day or greater for more than 14 days are
considered immunocompromised.
Deflazacort

 Synthetic glucocorticoid oxazoline derivatives of prednisolone.

 6mg equivalent to 5mg prednisolone.
 No difference in achieving remission between prednisolone and
deflazacort.

[ Singhal R et al.,(2015), Agarwal IGJ et al.,(2010)]

Treatment of relapsing nephrotic
syndrome(IFRNS)

 Relapse should be treated with single daily dose of PDN(2mg/kg

or 60mg/m², max 60 mg) until complete remission and then
decreased to alternate day PDN (1.5mg/kg or 40 mg/m², max
40mg) for 4 weeks.

Ref-IPNA guideline 2022

Recommendation
 Tapering Schedule during alternate day dosing should be
avoided.
 Short course of low dose daily prednisolone (≤0.25 mg/kg, max
10 mg) at the onset of upper respiratory tract infection for
prevention of relapses in not recommended.
 Who are already taking low dose alternate day PDN,
recommendation is to consider a short course of daily low dose
PDN schedule.

Ref-IPNA guideline 2022

FRNS and SDNS
Maintenance treatment with PDN in all patients with FRNS or SDNS.
Patients with FRNS:

 Either introduction of a steroid-sparing agent

or
 Low-dose maintenance PDN given as an alternate-day (<0.5
mg/kg/day,max20mg)
or
 A daily dose PDN (0.25 mg/kg/day,max 10 mg /day)
Ref-IPNA guideline 2022
Second line immunosuppressive
agent

Indication:
 Patient are not controlled on therapy.
 Patient suffer a complicated relapse.
 SDNS children.
 Steroid toxicity
 Steroid Sparing agent

 Levamisole
 Cyclophosphamide
 Mycophenolate mofetil
 Calcineurin inhibitor
• Cyclosporine
• Tacrolimus
 Rituximab
Levamisole
It is an immunomodulatory agent
Dose
 2-2.5 mg/kg/alternate day (maximum dose 150 mg).
 Duration 12 months.
Monitoring
Neutropenia, elevated
 Quarterly: CBC, LFTs transaminase level,
arthritis, vasculitic rash
 Twice-yearly: ANCA titers (also at baseline)
Cyclophosphamide
 2 mg/kg per day (maximum dose 150 mg) over 12 weeks or
3mg/kg per day (maximum dose 150 mg) over 8 weeks.
 Single morning dose preferable.
 No more than a single course (max TCD 168 mg/kg)
 With alternate day oral PDN.
 Start after achieving remission.
 CBC every 14 days during therapy.
M/A of cyclophosphamide
Cyclophosphamide (cont.)

Adverse effects
 Leukopenia
 Alopecia
 Severe infection
 Seizure
 Hemorrhagic cystitis
 Gonadal toxicity
Prevention of hemorrhagic cystitis

 Adequate hydration
 Frequent voiding
 Use Mesna in case of large dose
Calcineurin Inhibitor(CNI)
Cyclosporine & Tacrolimus
Specific and reversible inhibitor of T helper cells

Inhibit production and release of lymphokines(IL-2)

Maintain integrity of glomerular membrane and podocyte functions

Cyclosporin A

Dose
 Start: 3–5 mg/kg per day (maximum dose 250 mg) in 2 divided
dose
 Target: C0 is 60–100 ng/ml or C2 300–550 ng/ml.

Duration: at least 12 months

Adverse effects
 Acute and chronic nephrotoxicity
 Hypertension
 Hypertrichosis
 Tremor
 Hirsutism
 Gum hypertrophy  S. Creatinine, CBC, eGFR, S. Electrolyte,
Fasting lipid profile- 3 monthly
 Hyperkalemia
 After 2-3 years- Kidney biopsy
Tacrolimus
Dose
Start:0.1–0.2mg/kg per day (maximum dose 10 mg) in 2 divided
doses
Target: c0 level between 3 – 7 ng/ml (aiming for the lowest
possible dose to maintain remission)

Duration
at least one year.
Adverse effects

 Nephrotoxicity
 Hypertension
 Diabetes mellitus
 Hypomagnesemia

S. Creatinine, RBS, S.
Magnesium level- 3 monthly
Rituximab

 Anti-CD20 monoclonal antibody.

 It acts by depleting B lymphocyte.
 Children with FRNS or SDNS who are not controlled on therapy
after a course of treatment with at least one other steroid-
sparing agent at adequate dose.
 In case of non-adherence.
Rituximab (Cont.)
Dose
 375 mg/m² for 1–4 doses per course (maximum single dose 1000 mg) at
weekly intervals aim for CD19 depletion (<5 cell/mm² or <1% total
lymphocyte)
 Dose given during remission.
Side effects
 Infusion reaction
 Infections(viral, bacterial, fungal, TB)
 Activation of latent virus
 Transient or persistent IgG deficiency.
Rituximab (Cont.)

Monitoring
 CBC
 LFTs
 CD19 b lymphocyte(before & after rituximab infusion).
 Serum IgG level.
Steroid Resistant Nephrotic
Syndrome
 Management is difficult and challenging
 Defined by unresponsiveness to steroid for a minimum of 6
weeks
 All patients with SRNS should receive treatment with ACE
inhibitors and or Angiotensin receptor blockers
SRNS- Specific Treatment
 Calcineurin inhibitors: Cyclosporin/tacrolimus with tapering
doses of alternate day steroids
 Cyclophosphamide with tapering doses of alternate day steroids
 High dose intravenous steroids (dexamethasone,
methylprednisolone) with oral cyclophosphamide and tapering
alternate day steroids
SRNS- Mendoza Protocol
 I/V methylprednisolone (30 mg/kg)
 Every alternate day 6 doses
 Weekly for 8 weeks 8 doses
 1× every 2 weeks 4 doses
 Monthly 8 doses
 Every other month for 6month 4 doses
 In association with oral prednisone
 Alkylating agent added if complete/ partial remission not achieved
by 2 wks
SRNS Mendoza Protocol

 Combination of IV corticosteroids, oral alkylating agents and

prednisolone show remission in 30-70% cases
Methylprednisolone

 4mg is equivalent to 5mg prednisolone.

 Patient is unable to tolerate oral steroid.
 Can be used for short duration.
Some other recommendation

 Combination of more than one steroid sparing agent is in a

clinical trial
 Other steroid sparing agents mizoribine, azithromycin,
azathioprine or adrenocorticotropic hormone (ACTH) not be used
to treat children with SSNS

Ref-IPNA guideline 2022

Common complications
 Infection
 Thromboembolism
 Hypovolemia
 Hyperlipidemia, atherosclerosis
 Acute Kidney Injury/ CKD
 Malnutrition
 Growth retardation
 Reduced bone mineral density
 Steroid toxicity
Management of blood pressure:

 Prevalence of hypertension between 7 and 34%.

 The etiology is multifactorial:
• Medication side effects(gluco-corticoids and CNIs)
• Fluid overload due to inappropriate use of albumin infusion during
relapses.
Treatment
 Intravenous furosemide
 Antihypertensive medications:
• Nifedipin
• Calcium channel blockers
• Intravenous labetalol infusion
(Use of ACEI and ARB has not been shown to be beneficial in NS
due to risk of AKI and hyperkalemia).
Prevention of thrombosis:

 The incidence of symptomatic thromboembolic events, mainly

diagnosed within 3 months after disease onset.
 It is about 3% in all forms of NS with peaks in infancy and
adolescence, is much lower than in adults (27%).
 The incidence is lower in children with SSNS (1.5%) than in
complicated NS/SRNS (3.8%).
Associated risk factors include

 The disease-related hypercoagulability

 Hypovolemia
 Immobilization
 Infections with hospitalization
 Indwelling central venous lines and
 Underlying hereditary thrombotic predisposition
Sites

Cerebral venous thrombosis, DVT, pulmonary embolism, arterial

infarction.
(The majority of children have deep venous thrombosis rather
than arterial thrombosis)
Specific treatment of a thrombotic
event

 Low molecular weight heparin (0.5-1.5 mg/kg/day, 12 hourly)

 Oral warfarin (0.1-0.2 mg/kg daily)
 Surgical thrombectomy or nephrectomy(Renal vein thrombosis)
Prevention

 Avoiding immobilization
 Maintenance of hydration
 Preventive anticoagulation is needed, based on the individual
clinical risk profile.
 No recommendation for routine prophylactic anticoagulation or
antiplatelet treatment.
Preservation of bone health
 Avoid prolong steroid exposure
 Ensure adequate dietary calcium intake in all children with SSNS
 Oral calcium supplementation in those with insuffcient calcium
intake.

 Glucocorticoid induced osteoporosis is prevented by:

• Administering the minimum effective dose,
• Changing to alternate-day therapy while in remission after relapses,
• Limiting the duration, and
• Considering steroid-sparing agents in case of emerging toxicity.
Intermittent endocrine and metabolic
changes during the acute nephrotic state
Hypothalamic–pituitary–adrenal axis suppression:
Risk factors:
 Daily steroid therapy for more than a few weeks,
 Evening/bedtime doses for more than a few weeks, and
 Any patient who has a Cushingoid appearance (also NS
diagnosed before age 5 years and steroid dependence.
Prevention measures for transient
adrenal insuffciency include

 Shortening the duration and lowering the dose of PDN as much

as possible,
 In the case of prolonged use of PDN associated with steroid
toxicity, slow tapering of PDN, and
 Informing patients and families of the risks and symptoms of
adrenal insufficiency and crisis.
Steroid during stress

 Patients who have received high dose steroids (2 mg /kg/day) for >2
weeks are at risk of suppression of the hypothalamo-pituitary-adrenal
axis.
 These children requires supplementation of steroids during surgery,
anaesthesia, or serious infection. Hydrocortisone are supplemented at
a dose of 2-4 mg/kg/day during this period of stress, followed by oral
prednisolone at 0.3-1mg/kg/day and then tapered rapidly.
 Administration of 5 days daily corticosteroids at 0.5 mg/kg at the onset
of an upper respiratory tract infection reduce the frequency of relapses.
Immunization

 Parent should be advised regarding the need for completing the

primary immunization.
Vaccinations

 Vaccination with inactivated vaccines should follow the

recommended schedule for healthy children.
 Administration of inactivated infuenza vaccine annually is
recommended
Immunosuppresion No vaccination within

Steroid pulse 3 months

Rituximab 1 year

Live vaccines Non-live vaccines

MMF/CNIs/Cyclophosphamide/ 3 months after

azathioprine cessation

High dose of corticosteroid given as a daily dose or on 1 month after cessation

alternate days for >14 days:
• >2mg/kg if body weight <10kg
• ≥20mg if body weight ≥ 10kg
Pneumococcal vaccine
 <2 year: 2-4 doses of heptavalent conjugate vaccine, 4 weeks
interval
 2-5 year: 1st dose of conjugate vaccine
• 1 dose of 23 valent polysaccharide vaccine, 8 weeks interval
 >5 year: 1 dose of 23 valent polysaccharide vaccine
 Varicella immunization:

 Varicella infection may lead to life-threatening disease in children

receiving immunosuppressive medications.
 Varicella immunization is safe and effective in children with
nephrotic syndrome.
 Varicella vaccine:
• 1year-12year: 1 dose
• >12 year: 2 doses, 4 weeks apart
Patient & parent education
 Assurance & adequate counselling to the parent about the
natural history of the disease
 Discuss about the available treatment options with probable
drug toxicity
 Dietary advice
 How to do urinary boiling test/ dipstick test
 Maintenance of nephrotic diary
 Importance of regular follow up
Issues involved in the treatment of
MCNS with FRNS & SDNS
Atopy URTI
30% 30-50%

Complications:
Refractory ascitesControl of
infection & Infection, thrombosis
atopy
Break through Steroid threshold
relapse

Steroid toxicity Ref: Indian Pediatric Nephrology Group, Indian Academy of

Growth retardation Pediatrics. Management of Steroid Sensitive Nephrotic

Syndrome: Revised Guidelines.
Recommendation for referral to
Pediatric nephrologist
 Atypical features not consistent with idiopathic NS
 Positive family history for NS
 Congenital or infantile onset NS
 Age at onset of NS above 12 years
 Secondary NS
 SRNS
 SSNS late responder
 FRNS or SDNS
 SSNS patient with drug toxicities
 Complicated relapse
Monitoring during acute phase and
follow up

Bed side urine boiling/dipstick test

 Daily until remission
 Twice weekly when patient is on remission
 Daily during any episode of acute illness or fever
 Suspected relapse
Follow up (cont.)
Frequency of follow up visit
 Every 3 monthly within the first year.
 More frequent visit during relapse.
Clinical evaluation
Patient complaints(at every visit)
 Fever
 Abdominal pain, edema
 Weight gain, sleep disturbance
Follow up (cont.)
Physical examination(at every visit)
 Blood pressure
 Assessment of volume status
 Drug toxicity
 Ophthalmological evaluation
Anthropometry
 Height/length Monitor in every visit
 Weight Monitor in every visit
 OFC (˂ 2 years) Monitor in every visit
Monitor yearly
 BMI and annual height velocity
Follow up(cont.)
Biochemistry
 Spot urine
 protein creatinine ratio(in every visit)
Blood
 CBC
 S. Creatinine
 S. Electrolyte
 S. Albumin
 S. Vitamin D level.
Natural History

70-80% IRNS
85% steroid
sensitive
50 % FRNS/ SDNS

10-30% adult NS

Mortality 40% Infection,

Thrombosis, AKI, CKD
Ref. IPNA Guideline 2022
Prognosis
STEROID RESISTANT NEPHROTIC
STEROID RESPONSIVE NS SYNDROME
 have repeated relapse  Most often caused by FSGS
 Frequency decrease as child  Have much poor prognosis
grows older  Develop progressive renal
 Unlikely to develop CKD insufficiency ultimately ESRD
 Who respond rapidly to require dialysis or kidney
steroid,no relapse during first transplant
6 months follows an  Recurrent NS occours in 30-
infrequently relapsing course 50% of transplant recepient
Take home massage
 Serum albumin level can varies in different lab according to
different reagent use.
 Fluid and salt restriction is not recommended until severe
edema.
 ACEi & ARB should be avoided.
 In FRNS and SDNS children a steroid sparing agent should be
added along with tapering alternate day steroid.
 Patient with complicated relapse should be referred to pediatric
nephrologists.
Any
Question?