ACTUALIZACIÓN EN EL TRATAMIENTO DE LAS 

ENFERMEDADES GLOMERULARESENFERMEDADES GLOMERULARES

2º Congreso de la Sociedad Gallega de g gNefrología

El Ferrol, 23‐24 de Octubre, 2015

GN PRIMARIAS. LESIONES MÍNIMASTRATAMIENTOPrednisona

(1-1.5 mg/Kg/día/2-4 semanas, con retirada gradual posterior durante 4-6 meses más)

Remisión Cortico-resistencia Córticodependencia RecaedoresCompleta (Biopsia renal) Frecuentes(>90%) (>3-4 al año)

Ciclos cortos (8 semanas)de Ciclofosfamida ó Clorambucil

No respuestaCiclosporinaCiclosporina

Ciclosporina-Dependencia

MicofenolatoMicofenolato

GN PRIMARIASGLOMERULOESCLEROSIS FOCAL

(HIALINOSIS SEGMENTARIA Y FOCAL)

ANATOMIA PATOLÓGICA

IF: Negativa ó Depósitos de IgM g p gME: Lesiones de esclerosis

GN PRIMARIAS. LESIONES MÍNIMASTRATAMIENTOPrednisona

(1-1.5 mg/Kg/día/2-4 semanas, con retirada gradual posterior durante 4-6 meses más)

Remisión Cortico-resistencia Córticodependencia RecaedoresCompleta (Biopsia renal) Frecuentes(>90%) (>3-4 al año)

Ciclos cortos (8 semanas)de Ciclofosfamida ó Clorambucil

No respuestaCiclosporina/TacrolimusCiclosporina/Tacrolimus

Ciclosporina-Dependencia

Mi f l RituximabMicofenolato. Rituximab

Box plot of the number of NS relapses over 1 year of follow-up after rituximab administration, and during the year before rituximab administration in the study group as a whole (overall),

and in different age (children versus adults) and diagnosis (MCD/MesG...g ( ) g (

Ruggenenti P et al. JASN 2014;25:850-863

©2014 by American Society of Nephrology

M A t l JASN 2012 23 1117 1124Magnasco A et al. JASN 2012;23:1117-1124

©2012 by American Society of Nephrology

Membranous Nephropathy. Therapeutic Strategy

Non-Nephrotic Proteinuria

Nephrotic syndrome (NS)Non Nephrotic Proteinuria

ACEI/ARBConservative Management/Observation in all the patients

(Except in those with renal function decline) Diet Diuretics Statins ACEI/ARBDiet, Diuretics, Statins. ACEI/ARB

Close Monitoring

Spontaneous Remission Renal function worsening Persistence of NS( %) ( %) ( %)(30%) (15%) (55%)

Membranous Nephropathy Therapeutic StrategyTherapeutic Strategy

328 PATIENTS without Immunosuppressive treatment

Spontaneous Remission in 104 (32 %)

JASN 2010

Polanco N et al, JASN 2010SPONTANEOUS REMISSION OF NEPHROTIC SYNDROME IN IDIOPATHIC MEMBRANOUS NEPHROPATHY

BaselineProteinuria (g/24h)

SpontaneousremissionsNo. (%)

Time toremission*(months)(g/24h) No. (%) (months)

<4 (n=64) 33 (51.5) 17.9±16( ) ( )

4-8 (n=169) 72 (42.6) 14.6±13.4

8-12 (n=91) 24 (26.3) 13.6±12.5

>12 (n=51) 11 (21.5) 14±10.7

SPONTANEOUS REMISSION OF NEPHROTIC SYNDROME IN IDIOPATHIC MEMBRANOUS NEPHROPATHY Polanco N et al, JASN 2010

10

12

6

8

10

(g/24h)

2

4

6

oteinu

ria 

0

0 4 8 12 20 30 42 54 66 78 90 102 114 132

Pro

MonthsMonths

Evolution of Proteinuria in Patients with Spontaneous Remission

Membranous Nephropathy. Therapeutic Strategy

Non-Nephrotic Proteinuria

Nephrotic syndrome (NS)Non Nephrotic Proteinuria

ACEI/ARBConservative Management/Observation in all the patients

(Except in those with renal function decline) Diet Diuretics Statins ACEI/ARBDiet, Diuretics, Statins. ACEI/ARB

Close Monitoring

Spontaneous Remission Renal function worsening Persistence of NS( %) ( %) ( %)(30%) (15%) (55%)

Immunosuppression for progressive membranousnephropathy: a UK randomised controlled trial.nephropathy: a UK randomised controlled trial.Howman A et al. Lancet 381: 744-751, 2013

Immunosuppression for progressive membranousnephropathy: a UK randomised controlled trial.Howman A et al Lancet 381: 744-751 2013Howman A et al. Lancet 381: 744-751, 2013

Conclusions: We conclude that six months’ therapy with prednisolone and chlorambucil is superior to cyclosporine or supportive therapy alone in patients with IMN whose renalfunction is deteriorating. This effect is maintained to at least 3 years.

Membranous Nephropathy. Therapeutic Strategy

Non-Nephrotic Proteinuria

Nephrotic syndrome (NS)Non Nephrotic Proteinuria

ACEI/ARBConservative Management/Observation in all the patients

(Except in those with renal function decline) Diet Diuretics Statins ACEI/ARBDiet, Diuretics, Statins. ACEI/ARB

Close Monitoring

Spontaneous Remission Renal function worsening Persistence of NS( %) ( %) ( %)(30%) (15%) (55%)

7. 3: Initial Therapy of IMN

7.3.1: We recommend that initial therapy consist of a 6 month course f lt ti thl l f l d i t ti t idof alternating monthly cycles of oral and intravenous corticosteroids

and oral alkylating agents.(1B)

Steroids+Clorambucil St id +C l h h idSteroids+Clorambucil Ponticelli et al Kidney Int 1995

Steroids+CyclophosphamideJha et al, JASN 2007

100

P<0 001 P<0.001

60

80

ION

S

P<0.001

P<0.001

8

P 0.001

40

60

RE

MIS

SI

1

36

P<0.001

3

20

%R

8

1

11

2

11

4

311

3

37

5

0T C T C T C T C T C

2 12

1

4 3

MONTHS 2 6 12 18 30

2

MONTHS 2 6 12 18 30

Kidney International 71: 924-930, 2007.

JASN 2012;23:1416-1425

©2012 by American Society of Nephrology

RCT with Rituximab (RTx)• MENTOR: Cyclosporin vs RTx• STARMEN: Ponticelli Regimen g

(Corticosteroids+Cyclophosphamide) vs Tacrolimus-RTx

Decline in Renal Function in Patients Treated with Prednisone for Idiopathic Membranous Nephropathy and in Controls.

Cattran DC et al. N Engl J Med 1989;320:210-215.

Membranous Nephropathy. Therapeutic Strategy

Non-Nephrotic Proteinuria

Nephrotic syndrome (NS)Non Nephrotic Proteinuria

ACEI/ARBObservation Period in all the patients

(Except in those with renal function decline) T t t f NS Di t di ti t ti ACEI/ARBTreatment of NS: Diet, diuretics, statins. ACEI/ARBClose Monitoring

Spontaneous Remission Renal function worsening Persistence of NS( %) ( %) ( %)(30%) (15%) (55%)

Anti-PLA2RMonitoringMonitoring

Beck LH, Salant DJ. Membranous nephropathy: recent travels and new road ahead. Kidney Int 2010.

Type 1 MPGN

• DDD (type 2)• Dysregulation of the alternative

CComplement Pathway

Isolated C3 deposits on IF

Type 3 MPGN

Kidney Int 2012

Proposed evaluation scheme for MPGN based on the presence or absence of immunoglobulins by immunofluorescence.

Sethi S et al. CJASN 2011;6:1009-1017

To summarize, we present a case of severe crescen‐tic and necrotizing GN associated with a novel muta‐tic and necrotizing GN associated with a novel mutation in CFH and the presence of 2 copies of the H402allele of CFH and 2 copies of the G102 and 1 copy ofthe L314 alleles of C3. Crescentic and necrotizing GNwith extensive glomerular C3 staining on immunoflu‐with extensive glomerular C3 staining on immunofluorescence studies warrants an in‐depth evaluation ofthe alternative pathway.

C3 G. Pathogenesis

S SSethi S et al Kidney Int 2012

C3 GlomerulonephritisSpanish Group for the Study of Glomerular Diseases (GLOSEN)Spanish Group for the Study of Glomerular Diseases (GLOSEN)

• Age : 37 (13-57); Gender: 34 M, 26 F

• Renal Biopsy: Membranoproliferative GN 74% Mesangioproliferative GN 14% Endocapillar proliferatioin GN 8%Focal segmental glomerulosclerosis 2%Extracapillar proliferation 2%Extracapillar proliferation 2%

• Clinical presentationNephrotic syndrome (NS): 50%Nephrotic syndrome (NS): 50%Nephritic syndrome (NephS): 33%Asymptomatic urinary abnormalities (AUA): 17%y p y ( )

• Low C3 serum levels: 63%

Reich, H. N. et al. J Am Soc Nephrol 2007;18:3177-3183Renal survival by category of TA-proteinuria

Copyright ©2007 American Society of Nephrology

Tratamiento de la Nefropatía IgA.-IECA/ARA a cualquier paciente con proteinuria> 0.5-1 g/24 h, independientemente de la TA y preferentemente cuando la función renal es normales normal.

-Si respuesta antiproteinúrica no satisfactoria:Combinación IECA + ARA; Añadir unCombinación IECA + ARA; Añadir un Antialdosterónico

-Si pese a ello la proteinuria tiende a subir y/o la función renal tiende a empeorar:función renal tiende a empeorar:

Esteroides ( ciclo de 6 meses)

Tratamiento de la Nefropatía IgA.-IECA/ARA a cualquier paciente con proteinuria> 0.5-1 g/24 h, independientemente de la TA y preferentemente cuando la función renal es normales normal.

-Si respuesta antiproteinúrica no satisfactoria:Combinación IECA + ARA; Añadir unCombinación IECA + ARA; Añadir un Antialdosterónico

-Si pese a ello la proteinuria tiende a subir y/o la función renal tiende a empeorar:función renal tiende a empeorar:

Esteroides ( ciclo de 6 meses)Esteroides+Micofenolato Mofetil (12 meses)Esteroides+Micofenolato Mofetil (12 meses)

Not randomized:•Randomization criteria not met (n=37)

Not enrolled:•Screening failure (n=87)•Withdrawal of consent (n=2)•Not in patient’s interest (n=1)

297 screened

•Randomization criteria not met (n 37)•Withdrawal of consent (n=4)•Immunosuppressive/corticosteroid treatment (n=3)•Lost to follow-up/did not return to clinic (n=2)•(S)AE (n=2)•Pregnancy/ intention of becoming pregnant (n=1)•Other (n=5)

p ( )207 enrolled into run-in

153 randomized

TRF-budesonide 16 mg/day, n=51

R i d i t ti R i d i t ti

TRF-budesonide 8 mg/day, n=51Placebo, n=51

Intervention not received:•Randomization criteria not met (n=2)

Received intervention

Intervention not received:•Randomization criteria not met (n=1)

Received intervention, (safety set) n=51

Received intervention, (safety set) n=49

FASa, n=50 FASa, n=51 FASa, n=48

Received intervention, (safety set) n=50

Withdrawn:•Inability to swallow tablets (n=1)

Discontinued study medication:•(S)AE (n=1)•(S)AE and subsequent immunosuppressive/systemic corticosteroid treatment (n=1)•Initiation of immunosuppressive/systemic

Discontinued study medication:•(S)AE (n=10)•((S)AE and subsequent immunosuppressive/systemic corticosteroid treatment (n=1)•Withdrawal of consent (n=1)•Personal reasons (n=1)

Discontinued study medication:•(S)AE (n=5)•(S)AE and subsequent immunosuppressive/systemic corticosteroid treatment (n=1)•CTP violation (n=4)•Other (pregnancy/intention of b i ) ( 1)

Completed study as planned, n=46

Completed study as planned, n=40

Completed study as planned, n=34

corticosteroid treatment (n=1)•Inability to tolerate ACEIs/ARBs) (n=1)

•Other (travelling distance) (n=1)

becoming pregnant) (n=1)

20 p=0 0096 p=0 006

5

10

15

20

m baseline

p=0.0066p=0.009

0

2

4

rom baseline

p=0.001

p=0.003p=0.006

15

‐10

‐5

0

in UPC

R from

‐6

‐4

‐2

eGFR

 CKD

‐EPI f

‐30

‐25

‐20

‐15

an % cha

nge i

‐12

‐10

‐8

ean % change in 

‐40

‐35Mea

TRF‐budesonide16+8mg/day combined

Placebo TRF‐budesonide16mg/day

TRF‐budesonide8mg/day

‐16

‐14

Me

TRF‐budesonide16+8mg/day combined

Placebo TRF‐budesonide16mg/day 

TRF‐budesonide8mg/day 

combined 16mg/day  8mg/day 

Title: The NEFIGAN Trial: NEFECON, a Novel Targeted Release Formulation of Budesonide, reduces proteinuria and stabilizes eGFR in IgA Nephropathy Patients at Risk of ESRD 

 Bengt C. Fellstrom*, Rosanna Coppo, John Feehally, Jürgen Floege, Johan W. De Fijter, Alan G. Jardine, Francesco Locatelli, Bart D. Maes, Alex Mercer, Fernanda Ortiz, Manuel Praga, Soren Schwartz Sorensen and Vladimir Tesar. 1Uppsala Univ Hospital; 2Univ Turin; 3Univ Leicester; 4RWTH Univ Aachen; 5LeidenUnivMedical Center; 6UnivGlasgow; 7OspedaleAManzoni; 8AZDeltaUniv Aachen;  Leiden Univ Medical Center;  Univ Glasgow;  Ospedale A Manzoni;  AZ Delta Roeselare; 9Pharmalink; 10Helsinki Univ Hospital; 11Hospital 12 de Octubre, Madrid; 12Rigshospitalet, Copenhagen and 13Charles Univ, Prague.  

Results: Baseline data were similar across groups; BP was 127‐128/78‐80  mmHg, UPCR 0.76–0.83 g/g, and eGFR 72‐85 mL/min/1.73m2. Primary endpoint was met at the pre‐specified interim analysis. Mean UPCR decreased by 24% (NEFECON 8+16 mg/d) vs 3% increase (placebo) at 9 mo y y ( g ) (p )(p=0.007); reduction in the 16 mg/d group was 27% (p=0.009). At final analysis, mean absolute change in eGFR was ‐4.7 mL/min/1.73m2 for placebo compared with 0.32 and 1.95 mL/min/1.73m2 for NEFECON 8 and 16 mg/d, respectively; difference in mean percentage change in eGFR achieved 

i i l i ifi f 8 /d ( 0 006) d 16 /d ( 0 003) Ad hi hstatistical significance for 8 mg/d (p=0.006) and 16 mg/d (p=0.003). Adverse event rates were higher in NEFECON groups (75–82%) than placebo (66%). Two serious adverse events were assessed as possibly related to NEFECON; deteriorated renal function (in follow‐up) and deep vein thrombosis. 

Conclusions: NEFECON reduced UPCR and maintained eGFR in patients with primary IgAN at risk of progression to ESRD despite optimized RAS blockade. Treatment was generally well‐tolerated 

Presentaciones Atípicas de la IgAPresentaciones Atípicas de la IgA

• Síndrome Nefrótico, muy parecido en manifestaciones clínicas y en respuesta a y plos esteroides a las lesiones mínimas

• HTA maligna• HTA maligna• Proliferación extracapilar masiva (>50%

de los glomérulos)

FRA en los Brotes de HematuriaMacroscópica de la IgA

Acute worsening of renal function during episodes of macroscopic hematuria in IgA nephropathy”M. Praga, et al Kidney Int 28: 69-74, 1985

NEFROPATÍA IgA – BROTES DE HMgCorrelación entre la duración del BHM y la creatinina final

-Edad > 50 años

- BHM > 10 días.

F ió l b l- Función renal basal

- Grado de necrosis tubular

Gutiérrez E. et al. Clin J Am Soc Nephrol 2007; 2, 51-57

Table 2. Clinical syndromes at presentation.Abbreviations: AKI, acute kidney injury.

Variable All,

(n=2872)

<16 years

(n=210)

65. years

(n=2388)

>65 years

(n=274)

p

Nephrotic syndrome % 13 1 11 3 12 7 17 7 0 000Nephrotic syndrome, % 13.1 11.3 12.7 17.7 0.000

Nephritic syndrome, % 6.9 8.9 6.6 7.9 0.000

A t ti i 37 7 34 40 1 18 8 0 000Asymptomatic urinary

disorders, %

37.7 34 40.1 18.8 0.000

AKI, % 11.6 4.9 9.5 35.3 0.000,

Chronic renal failure, % 16.7 1.5 18.1 16.5 0.000

Figure 2. Response rates of study population and by racial group

Appel, G. B. et al. J Am Soc Nephrol 2009;20:1103-1112

Copyright ©2009 American Society of Nephrology

Kaplan–Meier Curves for Time to Treatment Failure and Time to Renal Flare.

Dooley MA et al. N Engl J Med 2011;365:1886-1895

From: Multitarget Therapy for Induction Treatment of Lupus Nephritis: A Randomized TrialMultitarget TherapyFrom: Multitarget Therapy for Induction Treatment of Lupus Nephritis: A Randomized TrialMultitarget Therapy for Induction Treatment of Lupus Nephritis

Ann Intern Med. 2015;162(1):18-26. doi:10.7326/M14-1030

Study flow diagram.IVCY = intravenous cyclophosphamide.

Figure Legend:

Date of download: 9/28/2015 Copyright © American College of Physicians. All rights reserved.

From: Multitarget Therapy for Induction Treatment of Lupus Nephritis: A Randomized TrialMultitarget TherapyFrom: Multitarget Therapy for Induction Treatment of Lupus Nephritis: A Randomized TrialMultitarget Therapy for Induction Treatment of Lupus Nephritis

Ann Intern Med. 2015;162(1):18-26. doi:10.7326/M14-1030

Complete remission incidence at 24 weeks in all patients with LN and per pathologic class subgroup, by treatment (MT regimen or IVCY).Bars represent 95% CIs LN = l p s nephritis MT = m ltitarget IVCY = intra eno s c clophosphamide

Figure Legend:

Date of download: 9/28/2015

Bars represent 95% CIs. LN = lupus nephritis; MT = multitarget; IVCY = intravenous cyclophosphamide.

Copyright © American College of Physicians. All rights reserved.

Ann Rheum Dis 2014

Tratamiento Nefritis Lúpica Nefrología, Hospital 12 de Octubre

I d ió E id ( á id d ió ) Mi f l• Inducción: Esteroides (rápida reducción)+Micofenolato. Hidroxicloroquina

• Mantenimiento: Esteroides retirados en 1.5-2 años, muy gradualmente. Micofenolato retirado en 2-3 años, gradualmente

• Casos refractarios: Adición de Tacrolimus (primera opción) o cambio a Ciclofosfamida

• Casos recaedores: Micofenolato prolongada o indefinidamente

TRATAMIENTO DE LAS VASCULITIS ANCA +Tratamiento de Inducción

-Esteroides ( choques i v si FRA semilunas )-Esteroides ( choques i.v. si FRA, semilunas…)-Esteroides via oral, 1 mg/Kg/dia 3-4 semanas, después pauta

descendente hasta dosis de mantenimiento

Oral (1.5-2 mg/kg/día)Ciclofosfamida

Ch I V i di (0 5 1 / 2/ )Choques I.V. periodicos (0.5-1 g/m2/mes)

Remisión completa en 80-90% de casos a los 9-12 meses

Preferibles Choques IV (similar eficacia, menos efectos d i M i id i d íd ?)secundarios.... ¿Mayor incidencia de recaídas?)

IMPROVE Trial: Micophenolate versus Azatioprina for maintenance

o 155 con vasculitiso 155 con vasculitis ANCA + en remisión

o MMF 2g/díao MMF 2g/día

o Aza 2 mg/kg/día

o Recidivas 12 meses

Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis

N Engl J Med363(3):211-220, 2010

Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis

N Engl J Med363(3):221-232, 2010

Conclusion

• Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

Original ArticleOriginal Article

Rituximab versus Azathioprine for Maintenance in ANCA-Associated Vasculitis

Loïc Guillevin, M.D., Christian Pagnoux, M.D., M.P.H., Alexandre Karras, M.D., Ph.D., Chahera Khouatra, M.D., Olivier Aumaître, M.D., Ph.D., Pascal Cohen, M.D.,

François Maurier, M.D., Olivier Decaux, M.D., Ph.D., Jacques Ninet, M.D., Pierre Gobert, M.D., Thomas Quémeneur, M.D., Claire Blanchard-Delaunay, M.D., Pascal Godmer, M.D., Xavier Puéchal, M.D., Ph.D., Pierre-Louis Carron, M.D., Pierre-Yves Hatron M D Ph D Nicolas Limal M D Mohamed Hamidou M D Ph D MaizeHatron, M.D., Ph.D., Nicolas Limal, M.D., Mohamed Hamidou, M.D., Ph.D., Maize

Ducret, M.D., Eric Daugas, M.D., Ph.D., Thomas Papo, M.D., Bernard Bonnotte, M.D., Ph.D., Alfred Mahr, M.D., Ph.D., Philippe Ravaud, M.D., Ph.D., Luc

Mouthon, M.D., Ph.D., for the French Vasculitis Study Group

N Engl J MedVolume 371(19):1771-1780

November 6, 2014

Kaplan–Meier Curves for the Probability of Remaining Free of Relapse According to Treatment Group.

More patients with ANCA-associatedMore patients with ANCA associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine.

Guillevin L et al. N Engl J Med 2014;371:1771-1780;

Figure 5 Presumed order of occurrence of MYH9 and APOL1 variants inFigure 5 Presumed order of occurrence of MYH9 and APOL1 variants in human evolutionary history

Rosset S et al (2011)Rosset, S. et al. (2011)The population genetics of chronic kidney disease: insights from the MYH9–APOL1 locus

Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.52

Figure 4 Contour maps of allele frequency distributions of identified APOL1 riskFigure 4 Contour maps of allele frequency distributions of identified APOL1 risk variants in a number of African countries

Rosset, S. et al. (2011) The population genetics of chronic kidney disease: insights from the MYH9–APOL1locus Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.52