Nephrotic Syndrome in ChildrenMODERATOR : DR. S. PRABHA, HOD PAEDIATRIC NEPHROLOGY, MEHTA CHILDREN’S HOSPITALPANELISTS: PEDIATRIC NEPHROLOGISTS DR. AMISH UDANI, BAI JERBAI WADIA HOSPITAL FOR CHILDREN, MUMBAI
DR. G. SANGEETHA, SRI RAMACHANDRA MEDICAL COLLEGE & RESEARCH INSTITUTE, CHENNAI
DR.SHWETA PRIYADARSHINI, APOLLO HOSPITAL, HYDERABAD
DR.VINOD KUMAR, NEOKIDS HOSPITAL, JODHPUR
Case history 1
4 yrs old boy presented with periorbital puffiness, abdominal distension, leg swelling and reduced urine output of 1 wk duration
No hematuria/fever/rash/arthralgia On examination Vitals – with in limits Periorbital puffiness, ascites and bilateral pitting pedal edema with normal system examination
Laboratory investigations
Urine routine – 4+ protein, RBCs - 3-4/HPF, PC – 3-4/HPF Spot urine protein creatinine ratio – 15.9mg/mg CBC, RFT and S.Electrolytes - Normal S.Albumin – 1.2g/dL ; S.Cholesterol – 349mg/dL X ray chest and Mantoux – Normal USG abdomen – Normal kidney sizes. Ascites and pleural effusion+
What is your diagnosis in this child?
How do you define this condition?
AU
Diagnosis
Nephrotic syndrome – 1st episode
Nephrotic Syndrome Definition
Heavy proteinuria 3+ or 4+ on urine routine
> 50 mg/kg/day or >40mg/m2/hr> 2.0 mg/mg UPCR
HypoalbuminemiaS. Albumin <2.5 g/dL
HyperlipidemiaS. Cholesterol >200 mg/dL
With edema
Management of SSNS: Revised Guidelines - Indian Pediatric Nephrology Group, IAP. Indian Pediatr 2008; 45: 203-214
What are the clinical features of nephrotic syndrome?
VK
Presentation of NS
Gradual onset of edema, oliguria, breathlessness Hematuria (Gross in <5%, microscopic in up to 20%) Hypertension (5%)
2 to 10yrs of age with male predominance(2:1)
What is the underlying cause for childhood nephrotic syndrome?
SP
Causes of Nephrotic Syndrome in ChildrenCauses Example
Idiopathic MCNS, FSGS, MPGN, MN
Infections Poststreptococcal, Hepatitis B, Hepatitis C, HIV, Malaria
Systemic diseases Henoch-Schönlein purpura, Systemic lupus erythematosus
Metabolic diseases Fabry disease, GSD, Mitochondrial cytopathies
Hematologic/oncologic disease Leukemia, Lymphoma, Sickle cell disease
Drugs Probenecid, Lithium, : Penicillamine, Captopril, NSAIDs
Others Bee stings, food allergies, obesity
What is the pathophysiology of nephrotic syndrome ?
SAN
Pathophysiology of Nephrotic Syndrome
Disruption of glomerular filtration barrier
T-cell dysfunction Production of circulating factors Genetic mutations B-cell involvement
GBM
FE
podocyte
GBM
FE
p
What is the mechanism of edema in children with nephrotic syndrome?
AU
Causes of edema in NS
Underfill theory Overfill theory
Edema - Sodium retention in Nephrotic Syndrome
Siddall EJ, Radhakrishnan J. The Pathophysiology of edema formation in the NS. KI2012 (86) 635-42
Do we have to do any other investigations apart from the already discussed lab tests?
VK
Second line investigations in NS
Complement C3, C4, antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) and ANCA
Hepatitis B and C (HBsAg, anti HCV), anti HIV antibodies Genetic mutation analysis Renal biopsy
Mandatory only in some specific situations
What are the indications for renal biopsy in nephrotic syndrome?
SP
Indications for Renal biopsy
At onset Age <1yr and > 10yrs Gross hematuria, persistent microscopic hematuria or low C3 Sustained hypertension Renal failure not attributable to hypovolemia Suspected secondary cause of NS
After initiating treatment Proteinuria despite 4 weeks of daily steroids Before initiating treatment with tacrolimus of cyclosporin A
What are the general supportive measures when we manage a child with nephrotic syndrome?
SAN
Management –General supportive measures
Normal salt with balanced diet and adequate protein (1.5 to 2g/kg)
Fluid restriction to insensible water loss in severe edema and previous day’s output + insensible water loss in moderate edema
Diuretics in moderate to severe edema (> 7 to 10% of body wt)
Albumin infusion in diuretic resistant edema(0.5 to 1g/kg 20%albumin)
Treatment of associated infections
Allow them to have full activity unless they are sick
ENaC
NKCC
NCCT
Aldosterone antagonist
Amiloride
Loop diuretic
ThiazideDiuretics
Question 1
4years old male child has been diagnosed to have nephrotic syndrome 1 st episode. How will you treat this child as per ISPN guidelines?
a. 4 weeks daily + 4 weeks alternate day steroidsb. 6 weeks daily + 6 weeks alternate day steroidsc. 6 weeks daily + 6 weeks alternate day steroids + tapering over next few weeksd. 2 weeks daily + 4 weeks alternate day steroids
Question 1
4years old male child has been diagnosed to have nephrotic syndrome 1 st episode. How will you treat this child as per ISPN guidelines?
a. 4 weeks daily + 4 weeks alternate day steroidsb. 6 weeks daily + 6 weeks alternate day steroidsc. 6 weeks daily + 6 weeks alternate day steroids + tapering over next few weeksd. 2 weeks daily + 4 weeks alternate day steroids
How will you manage a child with first episode nephrotic syndrome? (Specific management)
AU
Specific Management of Nephrotic syndrome 1st episode – ISPN Guidelines
2mg/kg/day prednisolone (maximum 60 mg/day) as single or in divided doses for 6 wks, followed by 1.5mg/kg/day on alternate days (maximum 40 mg/day) for next 6 weeks
Taper and stop it over next 2 or more weeks (APN regime/ KDIGO guidelines)
Check for remission at the end of 2 and 4 weeks
Case history
This boy attained remission after 2 weeks of initiating steroids, completed 6 weeks daily and 6 weeks of alternate day steroids
He presents after 2 months with recurrence of symptoms, precipitated by LRI Urine albumin 4+, UPCR 14, S.albumin 1.3g/dL, S.Cholesterol – 278mg/dL
What is your diagnosis now? How will you treat this child?
VK
Diagnosis – Nephrotic syndrome relapse I
Treat the infection with appropriate antibiotics Treat with daily dose steroids(2mg/kg/day) till
he attains remission followed by 1.5mg/kg/day on alternate days for 4 weeks
Case history
He developed 3 episodes of relapses in 1 year duration
Will the management change here? Do you want to modify the diagnosis now?
With the frequency of relapses do we use any other terminologies?
SP
Diagnosis - Frequently relapsing nephrotic syndrome
Definitions
Frequently Relapsing Nephrotic Syndrome (FRNS) Two or more relapses in initial six months or more than three relapses in any 12 months
Steroid Dependent Nephrotic Syndrome (SDNS) Two consecutive relapses when on alternate day steroids or within 14 days of its discontinuation
Steroid Resistant Nephrotic Syndrome(SRNS) Absence of remission despite therapy with daily Prednisolone 2 mg/kg/day for 4 weeks
Management of SSNS: Revised Guidelines - Indian Pediatric Nephrology Group, IAP. Indian Pediatr 2008; 45: 203-214
Definitions
Congenital nephrotic syndrome – onset < 3 months of age
Infantile nephrotic syndrome – 4 months to 1yr of age
How will you manage these children? Role of low dose steroids in nephrotic syndrome
SAN
Management of FRNS and SDNS
Slow tapering of steroids and maintain on low dose steroids of 0.5 to 0.7mg/kg on alternated days for 9 to 18 months If steroid threshold exceeds > 0.7mg/kg, start on alternative immuno suppressive therapy Monitor for adverse effects Children on steroids for >3 months - supplement oral calcium (500 to 800mg/day) and vitamin D (400 to 1000 IU/day)
Question 2
10years old male child presented with steroid resistant nephrotic syndrome. Renal biopsy revealed FSGS. What is the treatment of choice in him?a. Levamisoleb. Mycophenolate mofetilc. Cyclophosphamided. Calnineurin inhibitors
Question 2
10years old male child presented with steroid resistant nephrotic syndrome. Renal biopsy revealed FSGS. What is the treatment of choice in him?a. Levamisoleb. Mycophenolate mofetilc. Cyclophosphamided. Calnineurin inhibitorsAns : d
What are the other alternative drugs available to treat nephrotic syndrome?
AU
Management of FRNS and SDNS - Levamisole
Levamisole(Immuno modulator) 2.0-2.5 mg/kg alternate days for 12-24 months
Prednisolone Induce remission. 1.5 mg/kg/EOD for 4 weeks, taper by 0.15-0.25mg/kg
every 4 weeks and stop at the end of 9 to 12 monthsAdverse effects of Levamisole Leukopenia, flu-like symptoms, liver toxicity, convulsions and skin rash Check TC and liver enzymes every 12-16 wks
Management of SSNS: Revised Guidelines - Indian Pediatric Nephrology Group, IAP. Indian Pediatr 2008; 45: 203-214
Management of FRNS & SDNS- Cyclophosphamide
Cyclophosphamide(Alkylating agent and cytotoxic drug) 2.0-2.5 mg/kg/day for 12 weeks (Should not exceed > 168mg/kg/cycle)Prednisolone Induce remission. 1.5 mg/kg/EOD for 4 weeks, followed by tapering over next 3
to 7monthsAdverse effects of Cyclophosphamide Monitor TC once in 2 weeks If TC is < 4000/mm3 - Discontinue cyclophosphamide Hemorrhagic cystitis, alopecia, nausea, vomiting and gonadal toxicity
Management of SSNS: Revised Guidelines - IPNG, IAP. Indian Pediatr 2008; 45: 203-214Long-term outcome after CYP treatment in children with SD & FR MCNS. Am J Kidney Dis 2007; 49: 592-97.
Management of FRNS and SDNS - MMF
Mycophenolate Mofetil (MMF) (IMP inhibitor) 800-1200 mg/m2 12-24 months
Prednisolone Induce remission. 1.5 mg/kg/EOD for 4 weeks, taper by 0.15-0.25mg/kg every 4 weeks and stop at the end of 9 to 12 months Adverse effects of MMF GI discomfort, diarrhea and leucopenia TC should be done every 4 to 8 weeks Treatment is withheld if count falls <4000/mm3
Management of SSNS: Revised Guidelines - IPNG, IAP. Indian Pediatr 2008; 45: 203-214KDIGO
What is the role of calcineurin inhibitors?
VK
Role of Calcineurin inhibitors
Prevents T‑ cell activation through inhibition of calcineurin-induced IL-2 gene expression
CNI’s also stabilizes the podocyte actin cytoskeleton Indications: FRNS, SDNS (Levamisole, CYP and MMF failed) and SRNS Dose: Tacrolimus - 0.1-0.2 mg/kg daily for 12-24 months Cyclosporin – 6mg/kg daily for 12–24 months Monitor RFT, electrolytes, sugar, magnesium and drug trough levels Adverse effects: Hyperglycaemia, hypertension, nephrotoxicity, hyperkalemia, neurotoxicity, hirsutism and gum hypertrophy Tacrolimus is preferred over cyclosporine because of lack of cosmetic side effects Greenbaum, L. A. et al. Childhood NS -current and future therapies. Nat. Rev. Nephrol. 2012,8; 445–458
Role of Rituximab in nephrotic syndrome
SP
Rituximab
Anti-CD20 monoclonal antibody that selectively targets CD20-positive B cells Restoration of T‑ regulatory (TREG) cell populations and upregulation of their functions decrease proteinuria and prevent the production of cytokines, suppresses circulating permeability factors Indications: Difficult SDNS, FRNS and SRNS unresponsive to CNI’s
Dosage: 375 mg/m2 once a week for two or more doses, to achieve CD19 levels < 1% of leukocytes
Side effects: Infusion reactions: Flu-like symptoms, infections, restrictive lung disease and progressive multifocal leukoencephalopathy
Sinha A et al. Rituximab therapy in NS: implications for patients’ management. Nat. Rev. Nephrol. 2013; 9: 154–169.
What are the complications of nephrotic syndrome?
SAN
Drug induced complications Steroids, diuretic & other alternative drugs side effects
Disease related complications
Edema Infections Hypocalcemic tetany Hypercoagulable states Hypovolemia
Case 1
3 yrs old child with nephrotic syndrome relapse presented with abdominal pain, fever of 4 days. On examination has severe tenderness. Ascitic fluid tapping showed 300cells/HPF. Diagnosis of peritonitis was made. This child also has patchy consolidation of right lower zone. How will you treat?
SAN
Infection Clinical features Common organisms Antibiotics and duration
Peritonitis Abdominal pain, tenderness, distension; diarrhea, vomiting;, ascitic fluid >100 leukocytes/mm3; >50% neutrophils for 7-10 days
S. pneumoniae, S. pyogenes, E. coli
Cefotaxime or ceftriaxone for 7-10 days
Pneumonia Fever, cough, tachypnea, intercostal retractions, crepitations
S. pneumoniae, H. influenzae, S. aureus
Oral: amoxicillin, co-amoxiclavParenteral : cefotaxime/ceftriaxonefor 7-10 days
Cellulitis Cutaneous erythema, induration, tenderness
Staphylococci, Group A streptococci, H. influenzae
Cloxacillin and ceftriaxone for 7-10 days
Case history
3years old boy presented with nephrotic syndrome relapse. He also has persistent vomiting, lethargy and intermittent periods of drowsiness. On examination, his HR – 130/min, BP was 70/50mmHg. He also has bilateral papilledema. He did not have any meningeal signs or focal neurological Deficit. History of diuretics intake for edema.
How will you manage this child?
AU
Differential diagnosis1.Sepsis and Hypovolemic shock 2.Hyponatremia3.Cerebral venous thrombosis
This child had Superior sagittal sinus thrombosis with intra cranial hypertension Management Correction of hypovolemiaStarted on LMW heparin, followed by warfarin for 3 months
Question 3
When will you say that a child is immunocompromised when on steroids? 1. >10mg/day steroid for >4 weeks2. >20mg/day steroid for >4 weeks3. >2mg/kg/day or >20mg/day of steroid for >4 weeks4. >2mg/kg/day or >20mg/day of steroid for >2 weeks
Question 3
When will you say that a child is immunocompromised when on steroids? 1. >10mg/day steroid for >4 weeks2. >20mg/day steroid for >4 weeks3. >2mg/kg/day or >20mg/day of steroid for >4 weeks4. >2mg/kg/day or >20mg/day of steroid for >2 weeks
Ans : 4
What is stress dose steroids?
How does it help in this children?
VK
Stress dose steroids in NS
Children on >20 mg or 2 mg/kg of steroids in last 1 year for > 2 weeks are susceptible to adrenal crisis during stress like surgery or infections
IV hydrocortisone 2-4 mg/kg or oral prednisolone 0.5 to 1 mg/kg should be given till the period of stress and then tapered rapidly
Immunization in nephrotic syndrome – Do they need any specific advice?
SAN
Immunization in Nephrotic syndrome
Live vaccines are contraindicated when the child is on steroids
Oral polio vaccine should not be given to siblings of children with active nephrotic syndrome
Killed/adjuvant vaccines when in remission or on alternate day steroids of 0.5 mg/kg
Annual influenza vaccine
Pneumococcal conjugate vaccine
Children aged 24 to 71 months who received 3 doses previously - administer 1 dose of PCV13 Received < 3 doses of PCV 13 - 2 doses of PCV13 (Both are followed by PCV 23) 6 to 18 yrs, previously unvaccinated children- a single dose of PCV13 & PCV23 at 8 weeks apart Varicella 2 doses at 3 months interval
IAP Guidebook on Immunization 2013–14
How will be the prognosis in children with nephrotic syndrome?
SP
Long term care and outcome
SSNS prognosis is good. Normal growth and development, schooling and social adjustments ensured
Long term course of the disorder and response to specific drugs – variable and unpredictable especially with non minimal change disease
SRNS management is challenging, often frustrating for the family with poor prognosis as they may go for chronic kidney disease
“When will the child be cured?” - cannot be answered
Referral to a Paediatric Nephrologist – when is it needed?
AU
Referral to a Paediatric Nephrologist
Nephrotic syndrome at extremes of age( <1 yr and >10yrs) Difficult to manage SDNS and FRNS Familial nephrotic syndrome Steroid resistant nephrotic syndrome(Primary and late steroid non
responder) Suspected secondary causes like SLE and HSP
Ongoing care of these children is always a collaborative effort between the Paediatric Nephrologist and the primary Paediatrician
To summarize