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Guidelines & Recommendations

in Pediatric Nephrology

IPNA - Best practices &

standards WG; December 2018

Francisco Cano MDTucuman 2019

The Nephrotic Syndrome

z Sumario

1. Incidencia

2. Breve Historia

3. Evolucion natural

4. Definiciones

5. Clasificacion

6. Tratamiento 1a linea

7. Tratamiento 2a linea

1-7. IPNA workshop

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INCIDENCIA

Noone D., Lancet 2018

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Arch Ar Pediatr 2014

zHistoria

Sindrome Nefrotico a través del tiempo

Arneil GC. Ped Clin North Am 1971

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ISKDC, Kidney Int 1978

Historia. Paradigmas

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Natural evolution of Idiopathic Nephrotic Syndrome.

15% single manifestation

25% infrequent relapses

35% frequent relapses

15% steroid dependent NS

10-20 % steroid resistant

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KDIGO, Kidney Int Suppl

2012

Definitions

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Idiopathic NephroticSyndrome

Immune dysregulation

Systemic circulating factors

Inherited structuralabnormalities of the podocyte

Classification

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Steroid Sensitive

Steroid Resistance

Classification

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First episode

SSNS

Long TermRemission

Tratamiento

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SHORT VERSUS STANDARD

PREDNISONE

THERAPY FOR INITIAL

TREATMENT OF

IDIOPATHIC NEPHROTIC

SYNDROME IN

CHILDREN

ARBEITSGEMEINSCHAFT FUR

PEDIATRISCHE

NEPHROLOGIE*

Tratamiento esteroidalprimer episodio

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SHORT VERSUS STANDARD

PREDNISONE

THERAPY FOR INITIAL

TREATMENT OF

IDIOPATHIC NEPHROTIC

SYNDROME IN

CHILDREN

ARBEITSGEMEINSCHAFT FUR PEDIATRISCHE

NEPHROLOGIE*

zFirst

episode

Noone D., Lancet 2018

Tratamiento primer episodio

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First episode

IRNS

SSNS

Long TermRemission

Tratamiento IRNS

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SSNS IRNS

Noone D., Lancet 2018

Tratamiento IRNS

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First episode

IRNS

FRNS/SDNS

SSNS

Long TermRemission

Tratamiento

zFRNS/SDNSSSNS

Noone D., Lancet 2018

Tratamiento SDNS

Tratamiento de las

recaídas frecuentes y

corticodependencia

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Correlation between relative risk for relapse andduration of therapy showing that relative risk for relapse

decreases with increase in duration of prednisonetherapy.

Hodson EM, Corticosteroid therapy for nephrotic syndrome in

children The Cochrane Collaboration. 2005

Tratamiento. Cuanto tiempo?

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Extending Prednisolone Treatment Does Not Reduce

Relapses in Childhood Nephrotic Syndrome. A CRT

Study in 150 children, The Netherlands.

Teeninga N., J Am Soc Nephrol 2013

Overall, relapses occurred in 48 (77%)of 62 patients who received 3 monthsof prednisolone and 51 (80%) of 64patients who received 6 months ofprednisolone

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Steroids in nephrotic syndrome: 2-month or 6-month treatment?

Yoshikawa N., Kidney Int 2015

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Steroids in nephrotic syndrome: 2-month or 6-month treatment?

Yoshikawa N., Kidney Int 2015

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First episode

1st Line Therapy. Steroidsparing agents

FRNS/SDNS

SSNS

Long TermRemission

Tratamiento

zFRNS/SDNS

KDIGO, Kidney Int Suppl 2012

Tratamiento SDNS

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Dorresteijn E., Ped Nephrol 2008

FRNS/SDNSMycophenolate Mofetil versus Cyclosporin A

in FRNS/SDNS and biopsy-proven MCD.

A multi-centre randomized controlled trial

• MMF 1200 mg/m2 • CsA 4–5 mg/kg/d• 12 months

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Mycophenolate Mofetil versus Cyclosporin A in Children with

Frequently Relapsing Nephrotic Syndrome. A 1-year,

randomized, multicenter, open-label, crossover study in 60 pts.

Gellermann J, JASN 2013

FRNS/SDNS

Target plasmamycophenolic acid trough level of

1.5– 2.5 mg/ml) ,

CsA (target trough level of 80–100 ng/ml)

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Gellermann J, JASN 2013

Mycophenolate Mofetil versus Cyclosporin A in

Children with Frequently Relapsing Nephrotic

Syndrome

Patients with a high MPA exposure (AUC . 50 m gz h/ml) had a

significantly longer time without relapse (P =0.03) than thosewith a

lower exposure. C0 showed a linear correlation with the MPAAUC (r2

=0.45; Figure 3E). ROC analysis showed that C0 concentrations had

no signifi cant predictive value for relapses

However, predose levels >3.5m g/ml were 100% predictive of an MPA-

AUC >50 mg/h/ml.

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First episode

SRNS

1st Line Therapy

Kdbiopsy

GENETIC (CsA)

Long TermRemission

SRNS

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First episode

SRNS

2nd LineTherapy

1st LineTherapy

Kdbiopsy

GENETIC

Long TermRemission

SRNSGuidelines & Recommendations in Pediatric

Nephrology

IPNA - Best practices & standards WG; December 2018

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SRNS GENETIC

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Genetic diagnosis made in 333 of 1,294 SRNS subjects (25.7%)

Mutation detection rate:

41% familial cases

36% sporadic but consanguineous cases

19% sporadic, non-consanguineous cases

SRNS GENETIC

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Genetic Screening Results

Pts tested Pts w/causative

mutations

% positive

NPHS2 1198 145 12.1

WT1 994 53 5.2

NPHS1 406 47 11.6

SMARCAL1 253 16 6.3

ADCK4 251 13 5.2

PLCE1 258 11 4.3

INF2 279 10 3.6

LAMB2 268 8 3.0

PTPRO 254 8 3.2

LMX1B 237 5 2.1

MYO1E 250 5 2.0

COQ6 258 4 1.6

COQ2 263 2 0.8

TRPC6 278 1 0.4

Total 1,294 333 25.7

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Renal Survival

ADCK4 PodocinWT1 Nephropathy

Korkmaz et al. JASN 2015

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KDIGO, Kidney Int (2012)

SRNS Kd

biopsy

4.2.1: We recommend using a calcineurin inhibitor(CNI) as initial therapy for children with SRNS.

4.2.1.1: We suggest that CNI therapy be continuedfor a minimum of 6 months andthen stopped if a partial or complete remission ofproteinuria is not achieved.

4.2.1.2: We suggest CNIs be continued for aminimum of 12 months when at least a partialremission is achieved by 6 months.

4.2.1.3: We suggest that low-dose corticosteroidtherapy be combined withCNI therapy.

1st Line

Therapy

Guidelines & Recommendations in Pediatric

Nephrology

IPNA - Best practices & standards WG; December 2018

GENETIC

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Cyclosporin significantly increased the number ofchildren with SRNS who achieved completeremission compared with placebo or no treatment.

Ponticelli C., Kidney Int 1993

SRNS

CsA, 6 mg/kg: 13/22

Placebo 3/19

C0 CsA 250 - 600 ng/mI

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A randomized 6-m, double-blind placebo-controlled

trial of cyclosporine in steroid-resistant idiopathic

focal segmental glomerulosclerosis in children.

Lieberman K., J Am Soc Nephrol. 1996

SRNS

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KDIGO, Kidney Int (2012)

SRNSKd

biopsy

4.2.3: In children who fail to achieveremission with CNI therapy:

4.2.3.1:We suggest that mycophenolatemofetil , high-dose corticosteroids , or acombination of these agents beconsidered in children who fail to achievecomplete or partial remission with CNIsand corticosteroids.

4.2.3.2: We suggest cyclophosphamide notbe given to children with SRNS.

2nd Line

Therapy

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Mycophenolate mofetil therapy in 24 children

with steroid-resistant nephrotic syndrome

Li Z, Ped Nephrol 2010

SRNS

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Efficacy of intravenous pulse cyclophosphamide

treatment versus combination of intravenous

dexamethasone and oral cyclophosphamide

treatment in steroid-resistant nephrotic syndrome

Mantan M., Ped Nephrol 2008

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Efficacy and safety of immunosuppressive medications for steroid-resistant nephrotic

syndrome in children: a systematic review and network meta-analysis

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Efficacy and safety of immunosuppressive medications for steroid-resistant nephrotic

syndrome in children: a systematic review and network meta-analysis

Complete remission Partial remission Complete + partial remission

cyclosporin (88.7%)

tacrolimus (86.4%)

rituximab-cyclosporin (82.8%)

MMF (59.8%)

iv cyclophosphamide (44.8%)

leflunomide (31.5%)

chlorambucil (28.6%)

azathioprine (28.6%)

placebo / no treatment (24.5%)

oral cyclophosphamide (24.2%)

tacrolimus (74.1%)

cyclosporin (71.7%)

MMF (65.9%)

oral cyclophosphamide (41.1%)

iv cyclophosphamide (37.6%)

azathioprine (33.5%)

placebo / no treatment (26.1%)

tacrolimus (91.5%)

cyclosporin (87.8%)

MMF (65.7%)

placebo / no treatment (29.2%)

iv cyclophosphamide (28.1%)

azathioprine (28.1%)

oral cyclophosphamide (19.6%)

Li S., Oncotarget 2017

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First episode

SRNS

2nd LineTherapy

1st LineTherapy

1st LineTherapy

Kdbiopsy

FRNS/SDNS

SSNS

Long TermRemission

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Rituximab for childhood-onset, complicated,

frequently relapsing nephrotic syndrome or steroid-

dependent nephrotic syndrome: a multicentre,

double-blind, randomised, placebo-controlled trial

2nd Line

Therapy

Iijima K, The Lancet 2014

RTX, 1/sem/4 dosis, 375 mg/m2,

267 days, 95% CI 223–374

101 days, 70–155

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Short-Term Effects of Rituximab in Children with

Steroid- and Calcineurin-Dependent Nephrotic

Syndrome: A Randomized Controlled Trial in 54 pts2nd Line

Therapy

Ravani P., Clin J Am Soc Nephrol 2011

50% of RTX cases were in stable remissionwithout drugs after 9 months

Rituximab (Mabthera; 375 mg/m2) was given

intravenously once, or twice (at randomization

and after 2 weeks in the presence of toxicity).

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Magnasco A., JASN 2012

Rituximab in Children with Resistant Idiopathic

Nephrotic Syndrome. RCT Trial in 31 children with

idiopathic nephrotic syndrome unresponsive to the

combination of calcineurin inhibitors and prednisone

2nd Line

Therapy

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First episode

SRNS

RTX

CsA/MMF/Tacro

Ciclofosfamide

Kdbiopsy

GENETIC (CsA)

IRNS: Pred

FRNS/SDNS

SSNS: Prednisone

Long TermRemission

CNIs/MMF

CNIsCPH

zGracias…