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