NEPHROTIC SYNDROME Present Day Management

JWAHARLAL NEHRU HOSPITAL & RESEARCH CENTRE - BHILAI

Joint Director Medical & Health Services, HOD Pediatrics

Dr.G.Malini

EVALUATION AT ONSET

• History & exam

Pay attention to - secondary etiologies

- prior therapies

- edema

- blood pressure

- anthropometry

- infections

‘Nephrotic Range’ (Heavy Proteinuria)

protein excretion > 40 mg/m2/hr

>1gm / m2/ day Normal range <4 mg/ m2/hour

100mg/m2/day

First morning:spot urine alb/creatinine ratio (mg:mg)– Normal = <0.2 (0.5 if <2yr)– Nephrotic =2-3 : 1 (>2 )

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1801

Lab Investigations• Urine • Complete Blood Count • Renal parameters :– Spot Urine Protein : Creatinine ratio– Creatinine, urea, albumin, cholestrol

• Liver Function Test• Urine culture & sensitivity • PPD test & X- Ray chest

• C3 and ASO• ANA • Hepatitis B surface antigen• HIV testing

Additional Tests

Indications for Biopsy- (Bad Prognostic Factors)

• Age below 12 months >10yrs• Gross or persistent microscopic hematuria• Low blood C3• Sustained Hypertension• Renal failure not attributable to hypovolemia• Suspected secondary cause of nephrotic syndrome• Family history

After initial treatment• Diagnosis of steroid resistance• Before starting calcineurin inhibitors• SDNS and FRNS not responding to cytotoxic therapy.

Management- Initial EpisodeGoal: Remission & Reduce Risk Of Future Relapse

APN (German )regime 1993 – IPNG - IAP

Dose - 2mg/kg max of 60mg daily for 6 weeks

followed by 1.5mg/kg max 40mg for 6 weeks on alt days.

Agent – Prednisolone

longer remission and reduced relapse rate

*Cochrane Database system Rev2007;CD001533

Subsequent Course Of Disease• REMISSION by end of 2 weeks – usually.

• Minority respond after 4 weeks.

• Approximately 90-95% of children with MCNS respond to corticosteroid therapy.

• In contrast, only 20% of children with FSGS experience clinical remission with initial corticosteroid therapy

• >55% relapse multiple times• No relapse or a single relapse almost 40%

IJPP 2012;14(2) IJPAug(2012)79(8):1044

• RELAPSE = 3-4+ proteinuria + edema

Treatment of relapse

• Prednisolone 2mg/kg until remission foll by 1.5 mg/kg alt day for 4 weeks.

• Extend 2 more weeks if not in remission by 2 weeks.

• No remission by 4 weeks is late steroid resistance.

Protocols in Pediatric Nephrology 1st ed, by Arvind Bagga et al.

Brief Infection Related Proteinuria

• Proteinuria of 2+ is observed with a mild infection lasts for a week or so.

• Observe for a few days & defer treatment for relapse.

• If a child is already on alternate day prednisolone the dose of steroid may be doubled, but given on alternate day for a week or two.

• Such brief episodes may not be considered as relapse.

Pediatric Nephrology 5th ed, by RNShrivastava & Arvind Bagga.

Management Of Steroid-sensitive NS - FRNS & SDNS

Frequent relapses Two or more relapses within 6 months of initial response, or four or more relapses in any 12-month period

Steroid dependence Two consecutive relapses during corticosteroid therapy, or within 14 days of ceasing therapy

• All children referred for revaluation.

• Determine Steroid threshold.

• Low dose alternate day pred 0.3mg to 0.7mg/kg - 9 – 18 months

• Change from alt day dose to daily dose during infection.

Management Of Steroid-sensitive Nephrotic SyndromeFRNS Or SDNS. Addition Of Steroid Sparing Agents . Prednisolone Threshold >0.5 - 0.7mg/kg/Alt Day Or steroid toxicity

levamisole Levamisole failure

Frequent relapses or steroid dependance

cyclophosphamide

Mycophenolate mofetil

Calcineurin inhibitors

Rituximab

Step 1

Step 2

Step 3

Step 4

Step 5

Revised guidelines for management of steroid-sensitive nephrotic syndrome.Indian J Nephrol 2008;18:31-9

Investigations In Steroid Resistant Nephrotic Synd

• C3, ANA• Anti- HIV antibodies• Anti Parvovirus IgM• Free T3, T4, TSH• Renal histology by electron microscopy.• Genetic testing: sequencing of NPHS2, NPHS1, WTI & other genes

PATHOLOGY:

• FSGS, MCNS, Mesangioproliferative

• Treatment of membranous & membranoproliferative are different.

Protocols in Pediatric Nephrology 1st ed, by Arvind Bagga et al.

Management of Steroid Resistant Nephrotic SyndromeAgent Dose Duration Efficacy Calcineurin inhibitors

Cyclosporin 4-5mg/kg/ D 12-36 months 50-80%

Tacrolimus 0.1- 0.2mg/ kg/D 12-36 months 70-85%

Cyclophosphamide

Intravenous

Oral

500-750mg/m2 6 pulses 40-50%

2-2.5mg/kg/D 12weeks 20-25%

High dose steroids & cyclophosphamide

Methylprednisolone Or Dexamethasone

20-30mg/kg/dose

4-5mg/kg/dayAD x6, weekly x8, monthly x 8Fortnightly x 4, bimonthly x 4

30-50%

Prednisolone Tapering dose 18 months

Cyclophosphamide 2-2.5mg/kg/D 12weeks

Adjunctive Therapy Steroid Resistant Nephrotic Syndrome

• Prednisolone is a component of all regimens

• Initially 1mg/kg on alternate days for 1 to 3 months.Then tapered .

• If sustained remission is present for 6 to 12 months then may be discontinued .

• ACE inhibitors & angiotensin receptor blockers.

COMPLICATIONS OF NS Infections

Thromboembolism (LMW heparin, heparin, then oral)

Hypovolemia: (NS bolus, 5% alb 10-15 ml/k ,20% alb 0.5-1g/kg)

Edema

Loss of various binding proteins, (Thyroxine and vit D)

Hyperlipidemia. (statins)

Complicaions of treatment

Evidence of hypovolemia

Oral frusemide 1-3mg/kg

Add spironolactone 2-4mg/kg

Increase Frusemide 4-6mg/kg

No

Add hydrochlorthiazide or metolazone

Frusemide IV bolus or infusion

20% albumin 1Gm/kg followed by IV frusemide

No response

No response

No response

No response

No response

MANAGEMENT OF EDEMA

Head out water immersion & ultrafiltration

• Peritonitis-abd.pain, vomiting, diarrhoea.

• Pneumonia, cellulitis, fungal infections.

• Varicella-single dose of VZIG within 96 hrs of exposure (125U min to 625U max) or IVIG 400mg/kg single dose & Acyclovir.

• MT positive with no TB-INH Px for 6 mths evidence of active TB- AKT.

INFECTIONS

Complications

• Hypertension- ACEI, CCB, B blockers. • Steroid toxicity BP, growth, yearly eye exam, oral Ca and Vit D

supplements.

• Behavior/sleep changes• Weight gain & obesity• Acne & hirsuitism• Adrenal suppression• Acute pancreatitis• Growth arrest & pubertal

delay• Osteoporosis

• Increased susceptibility to infection.

• Impaired glucose metabolism

• Hypertension• Cataract • Risk of ulcer• Hyperlipidemia

• High dose steroids >2wk - in past 1 year

• Stress= req IV fluids, during surgery, severe infections etc.

• Hydrocortisone 30-50 mg/m2 for duration of stress, (IV hydrocortisone 2-4 mg/k/d) tapered by 50% of its dose daily after that.

• Or followed by Oral prednisolone- 0.3-1 mg/kg/d

tapered rapidly.

Stress Dose of Steroids

Immunization

• On Prednisolone >2mg/kg for more than 2weeks should not receive live viral vaccine.

• Hib, HB, Pneumococcal-given but response blunted.

• (MMR, Varicella, OPV) avoided till 4 weeks after.

• Siblings - IPV

Take Home Message

• Treat the initial episode adequately

• Prednisolone only for initial episode.

• Steroid responsiveness - Prognostic indicator.

• Parent education – essential.

Prognosis• The proportion of MCNS that became non-relapsers rose from

44% at 1 year

69% at 5 years,

84% at 10 years.

Mortality <1%

• Steroid-resistant FSGS – 30 to 50% progress to ESRD by 15 years

ultimate treatment - renal transplantation

recurs in about 25% of renal allografts.

• Mesangioproliferative 50% progress to ESRD over 10 years