NEPHROTIC SYNDROME AND ITS TREATMENT PROTOCOLS

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

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

ETIOLOGY

PATHOGENESISLoss of glomerular filtration barrier or Abnormal

immune system

SSNS• functional alteration in the barrier In episodes of relapse in IDS, Breakdown of charge selective barrier to

fitration Massive selective proteinuriaSRNS• In genetically related SRNS,Structural

alteration in the podocyte

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

PATHOPHYSIOLOGYHypoproteinemia in

EDEMA

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

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

HYPERCHOLESTER0LEMIA

HYPOALBUMINAEMIA

Generalised increase in hepatic synthesis of

LIPOPROTEINS

Reduced activity of lipopropein lipase in NS

THROMBOSIS

THROMBOSIS

ALTERATION IN FIBRINOLYTIC SYSTEM

WITH DECREASED PLASMINOGEN AND INCREASED PLASMIN

INDIRECT ROLE OF INCREASED HCT WITH

SEVERE VOLUME CONTRACTION,HYPERLIPIDEMIA AND RBC

HYPERAGGREGATION

INCREASED SYNTHESIS OF CLOTTING FACTORS

1,5,7,8,9,10

SPONTANEOUS PLATELET AGGREGATION TO

COLLAGEN AND ADP

DECREASED LEVEL OF ANTITHROMBIN FACTORS

LIKE ANTITHROMBIN 3,HEPARIN

COFACTOR,PROTEIN C AND PROTEIN S

INDWELLING CATHETERS,AGGRESSIVE USE OF DIURETICS

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

INFECTIONS

INFECTIONS

Urinary loss of IgG and FACTOR

B

Impaired lymphocyte

function due to CIRULATING

FACTORS

Hypercholesterolemia

Steroids and immunosuppress

ive therapy

Classification

• As renal biopsy is not done in all children with NS,

STEROID RESPONSE yes no

SSNS SRNS

PATHOLOGY

CLINICAL FEATURESHISTORY• 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 FSGSPRESENTATION• 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

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

LABORATORY EVALUATIONLab 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

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

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

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

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

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

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

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

INFREQUENT RELAPSERS• Patients who have 3 or less relapses a year and

respond promptly to prednisolone• Such children have low risk for developing

steroid toxicityFREQUENT 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

Indications for referral to a paediatric nephrologist

IMMUNOMODULATORSLEVAMISOLE: 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 > monthsADVERSE EFFECTS: chief side effect:leucopenia others:flu like symptoms,liver toxicity,convulsions,skin rashMONITORING: leukocyte count every 12-16 weeks

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 monthsADVERSE EFFECTS:• Leucopenia,infections,alopecia,haemorrahagic

cystitis,nausea,vomiting,gonadal toxicity,malignancies• Increased risk of overwhelming varicella infection

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

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

Indications for renal biopsy

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,leucopeniaMONITORING:• leucocyte counts monitored every 1-2 months• Stopped if < 4000/mm^3

CALCINEURIN INHIBITORSPATIENT SELECTION: patients with steroid dependence that fails to benefit with

levamisole,cyclophosphomide or MMFCYLOSPORINE: 4-5mgs/kg/day daily for 12-24 monthsTACROLIMUS: 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 transaminasesTACROLIMUS:hyperglycaemia,diarrhoea and rarely neurotoxicity(seizures n headache)

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 avoidedRISK FACTORS FOR DEVELOPING CsA TOXICITY:• Age> 5 years,CsA treatment >3 years • Heavy proteinuria persisting at the end of 1 month of therapy

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

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

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%

STEROID RESISTANT NEPHROTIC SYNDROME

DEFINITION: Absence of remission despite 4 weeks of daily

prednisolone therapy at 2mg/kg/dayTYPES:INITIAL NON RESPONDER(INR) A child who does not respond to initial 4 weeks of SPTSUBSEQUENT NON-RESPONDER(SNR) A child who was steroid responsive earlier fails to

respond to subsequent 4 weeks course of SPT

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

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

The options for treatment in SRNS include

CALCINEURIN INHIBITORS:

Treatment with CsA or tacrolimus results in complete or partial remission in 60-85% of children

Studies from various trials suggest thatCYCLOSPORINE:• 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 dependentTACROLIMUS:• 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

CYCLOPHOSPHOMIDE:

Oral cyclophosphomide has limited efficacy in inducing remission while iv cyclophosphomide has modest success

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

MENDOZA PROTOCOLIntensive therapy with bolus doses of corticosteroids in

combination with alkylating agentsHowever,they are associated with significant risks of hypertention,serious infection and delayed growth

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

Other drugs

• The efficacy of Rituximab,MMF,mizoribine in SRNS remains poor

• ACEI appear to benefit in treatment of SRNS

NEWER THERAPIES

• SAQUINAVIR• PLASMAPHERESIS• GALACTOSE• ORAL ZINC SUPPLEMENTATION IN SSNS

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

CONGENITAL NEPHROTIC SYNDROME• Presents in first 3 months of lifeEtiology:heterogenous Finnish form –NPHS1 mutation, AR NPHS2,PLCE 1 mutation intrauterine infectionsCLINICAL FEATURES: anasarca,hypoalbuminaemia,oliguriaHISTOLOGY: microcystic dilatation of proximal tubules in NPHS1AN SREENING: Elevated levels of AFP in maternal serum and amniotic fluidCOMPLICATIONS: FTT,recurrent infections,hypothyroidism and progression to renal failure by 2-3

years Treatment: supportive

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

EDEMA

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/kgPNEMACOCCAL 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 PPV23VARICELLA VACCINE• 12 months – 12 years: one dose • 13 years and older :2 doses separated by 4 weeks apart

INFECTIONS

THROMBOSIS• venous thrombosis and rarely arterial thrombosis

occursTreatment 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

HYPERTENTION• Treated with ACE inhibitors,CCB,beta blockers to keep

the percentile< 90HYPERLIPIDAEMIA• 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

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

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