Klinik für Nieren- und Hochdruckkrankheiten

Jürgen Floege

STOP-IgAN Studie: Konsequenzen für die Praxis

juergen.floege@rwth-aachen.de

Wenn Sie in 2016 mein Patient mit IgA Nephropathie wären…

„Kein Problem“

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011

Geringe Urinbefunde, GFR nl, Normotonus

1-2-jährliche Kontrollen über mindestens 10 Jahre

„Achtung!“

AKI (Makro-Hämaturie o. andere Ätiol.)

Nephrot. Syndrom

oder RPGN

Akuter o. schneller GFR Verlust

Supportive Therapie

+ Immun-suppression

Supportive Therapie

Lv J, et al, J Am Soc Nephrol 2013; 24: 2118-2125

Vasculitic IgAN (RPGN-variant)IgAN

>50% glomerular crescents and RPGN course

113 chinese patients

At time of biopsy: • 66±16% crescents• Crea 4.3±3.4 mg/dl

Cum

ulat

ive

rena

l sur

viva

l[%

]

Months

All patients

Aggressive immuno-

suppression(n = 43)

Noimmunosuppr.(n = 70)

„Kein Problem“

Geringe Urinbefunde, GFR nl, Normotonus

1-2-jährliche Kontrollen über mindestens 10 Jahre

„Risiko stratifizieren!“

Supportive Therapie 3-6 Monate optimieren

Proteinurie >0,5-1 g/d ±GFR reduz. ± Hypertonie

GFR >50 ml/min

Protein-urie

<1 g/d +GFR =

Sup-portiv

Protein-urie ≥1 g/die

± GFR ò

+ 6 Monate Kortiko-steroid

Sup-portiv

„Achtung!“

AKI (Makro-Hämaturie o. andere Ätiol.)

Nephrot. Syndrom

oder RPGN

Akuter o. schneller GFR Verlust

Supportive Therapie

+ Immun-suppression

Supportive Therapie

Wenn Sie in 2016 mein Patient mit IgA Nephropathie wären…

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011

KDIGO CLINICAL PRACTICE GUIDELINEFOR GLOMERULONEPHRITIS

IgA Nephropathy10.2.1: … long-term ACEi or ARB treatment when proteinuria is >1 g/d. (1B)10.2.2: … ACEi or ARB treatment if proteinuria is between 0.5 to 1 g/d. (2D)10.3.1: We suggest that patients with persistent proteinuria ≥1 g/d despite 3-6

months of optimized supportive care and GFR >50 mL/min receive 6 month corticosteroid therapy. (2C)

10.4.1: We do not suggest treatment with corticosteroids combined with cyclophosphamide or azathioprine in IgAN patients (unless there is crescentic IgAN with rapidly deteriorating renal function). (2D)

10.4.2: We suggest not using immunosuppressive therapy in patients with GFR <30 mL/min unless there is crescentic IgAN with rapidly deteriorating renal function. (2C)

10.4.3: We do not suggest the use of MMF in IgAN. (2C)

0

20

40

60

80

100

0 2 4 6 8

…mit Enalapril

Praga et al., JASN 2003

Kein ACE-H./ARBEnalapril

100

80

60

40

20

00 2 4 6 8

[Jahre]

<50% S-Krea Anstieg [%]

p < 0,05

10

p = 0,0003

Steroid-Therapie

<100% S-Krea Anstieg [%]

[Jahre]

…mit Kortikosteroiden

Pozzi et al. JASN 2004

Kein SteroidKortikosteroid

Therapie der IgA Nephropathie…

Patients: IgAN, moderate histological damage, proteinuria ≥1 g/d, eGFR ≥ 50 mL/min

Steroids + Ramipril (n=48)

• Start with ramipril 2.5 mg/d• Uptitration 1.25 mg• Target BP < 120/80 mmHg• Target proteinuria < 1 g/d

• Ramipril identical• plus oral prednison 6 months

- initially 1 mg/kg/d for 2 months- reduction 0.2 mg/kg/d per month

Ramipril (n=49)

-8

-6

-4

-2

0

-6.17

Mea

n G

FR-lo

ss/y

ear (

ml/m

in) Ramipril

-0.56

Steroids+

Ramipril

Design: prospective, randomized, open-label

ACE-inhibitors + steroids vs ACE-inhibitors alone in IgAN patients

Manno C et al., Nephrol Dial Transplant. 2009

….We feel that the major limitation of both trials istheir design, which required the patients todiscontinue any prior ACEI or ARB therapy and then,in the combination groups, to start simultaneousACEI and a corticosteroid treatment…..

Nature Reviews Nephrology May 2010

105

(1/s

erum

crea

tinin

e) l

x µm

ol-1

Monate

Nierenfunktion (Steigung von 1/Kreatinin)

1xKM-Suppression1xSteroid-Diabetes

Controlled Prospective Trial of Prednisolone and Cytotoxics in Progressive IgA Nephropathy

Ballardie et al., J Am Soc Nephrol 2002; 13:142

38 IgAN Patienten mit progredientem S-Krea-Anstieg (max 3 mg/dl)

N = 19 supportive Therapie

Monate

N = 19 Prednisolon + Cyclophos-phamid / Azathioprin (bis Jahr 6)

„Kein Problem“

Geringe Urinbefunde, GFR nl, Normotonus

1-2-jährliche Kontrollen über mindestens 10 Jahre

„Risiko stratifizieren!“

Supportive Therapie 3-6 Monate optimieren

Proteinurie >0,5-1 g/d ±GFR reduz. ± Hypertonie

GFR >50 ml/min GFR 30-50 ml/min

Protein-urie

<1 g/d +GFR =

Sup-portiv

Protein-urie ≥1 g/die

± GFR ò

+ 6 Monate Kortiko-steroid

Sup-portiv

Supportive Therapie

Immunsuppression kritisch abwägen

„Achtung!“

AKI (Makro-Hämaturie o. andere Ätiol.)

Nephrot. Syndrom

oder RPGN

Akuter o. schneller GFR Verlust

Supportive Therapie

+ Immun-suppression

Supportive Therapie

Wenn Sie in 2016 mein Patient mit IgA Nephropathie wären…

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011

VALIGA-Konsortium: Kortikosteroide in der IgANTesar V et al, J Am Soc Nephrol 2015; 26: im Druck

1147 Europäer der VALIGA KohorteRetrospektive Analyse (incl. propensity score match) von Steroid-Effekten

Patienten ohne

Ereignis(50% GFR-Reduktion

oder GFR<15 ml/min)

Baseline-GFR ≤50 ml/min Baseline-GFR >50 ml/min

RAS-Blocker alleinSteroid + RAS-Blocker

p = 0.01

p = 0.25

Optimale supportive Therapie(ACEi, ARB, Ziel-RR < 125/75 mm Hg, Statin, etc.)

Baseline nach 6 Monaten: RR, Proteinurie, GFR

Optimal supportiv (n=74)

ResponderProteinurie <0,75 g/d

optimale supp. Therapie;periodisch Proteinurie

Non-ResponderProteinurie >0,75 g/d

Run

-in P

hase

(6 M

onat

e)St

udie

n-Ph

ase

(3 J

ahre

)

IgAN, 18-70 Jahre alt, GFR > 30 ml/min, Proteinurie > 0,75 g/dplus Hypertonie oder GFR < 90 ml/min

Optimal supportiv + Immunsuppression

(n=74)

Drop-OutProteinurie > 3,5 g/dGFR-Verlust > 20%

Proteinurie>0,75 g/d

Randomisierung

Studiendesign

Supportive Therapy of IgA NephropathyLevel 1 Recommendations• Control blood pressure (sitting systol. BP in the 120s)• ACEI or ARB therapy (uptitrate + maybe combine)• Avoid dihydropyridine type calciumchannel-blockers• Control protein intake

Level 2 Recommendations• Restrict NaCl- and fluid-intake, diuretics• Non-dihydropyridine type calciumchannel-blockers• Control all components of the metabolic syndrome• Aldosteronantagonist, ß-blocker• Stop smoking• Allopurinol• Empiric NaHCO3 therapy, independent of metabolic acidosis

Other measures to retard progression• Avoid NSAIDs (max. 1-2 tbl. per week)• Avoid severe, prolonged hypokalemia• Avoid phosphate-containing laxatives• Ergocalciferol to correct vitamin-D deficiency• Control hyperphosphatemia and hyperparathyroidism

ALL

As manymeasuresas possible

Floege & Eitner, JASN 2011 Floege & Feehally Nat Rev Nephrol 2013

Prednisolon 0,5 mg/kg p.o./48h

0 2 4 12 24 36Monat

6

Pozzi et al. Lancet 1999; 353: 883

GFR ≥ 60 ml/min

Immunsuppression

Cyclo-phosphamid 1,5

mg/kg/d p.o.

Prednisolon·initial 40 mg/d·Reduktion auf 7,5 mg/d nach 6 Monaten

Azathioprin1,5 mg/kg/d

0 1 2 3 12 24Monat

36

Ballardie et al., J Am Soc Nephrol 2002; 13:142

GFR 30-59 ml/min

Baseline Charakteristika

Run-In Phase(N=337)

Female sex (%) 24Smoker (%) 18Age (years) 43.7 (12.8)Body mass index (kg/m2) 27.9 (5.3)Blood pressure (mmHg)

Systolic 131 (14.0)Diastolic 81 (9.9)

Serum creatinine (mg/dl) 1.5 (0.6)eGFR (CKD-Epi; ml/min) 61.5 (27.3)Creatinine clearance (ml/min) 76.0 (34.7)Proteinuria (g/d) 2.2 (1.8)Cholesterol (mg/dl) 210.1 (48.3)

Screening(n=379)

Start of Run-In(n=337)

End of Run-In(n=309)

Screen Failures(n=42)

Lost during Run-In(n=28)

Non-Responder(n=177)

n=165

Drop Outs(n=38)

n=12Responder(n=106)

34% der Patienten mit Proteinurie<0,75 g/d

nach 6 Monaten

15% optimal

25% normal

30% hochnormal

27% HTN I°

3% HTN II°

21% optimal

49% normal

21% hochnormal

8% HTN I°

1% HTN II°

Run-in Phase: Blutdruck

Start Run-In

Non-Responder (Proteinurie ≥0,75 g/d nach 6 Monaten)

< 140/90: 70% 91%

Ende Run-In

Klinische Vollremission (prot. < 0.2 g/g plus eGFR loss < 5 ml/min/1.73 m2)

WCS 4/80 14/82 4.82 (1.43-16.3) 0.011

ACA 4/68 14/66 5.33 (1.54-18.5) 0.008

OR (95%-CI) p-value

0 1 2 3

Pro Supportiv Pro Immunsuppression

3-Jahres Studienphase: primäre Endpunkte

ln-1

ACA 16/72 14/68 0.91 (0.40-2.05) 0.817

WCS 24/80 28/82 1.20 (0.61-2.33) 0.602

eGFR Verlust ≥ 15 ml/min/1.73 m²

0-1 1 2

Pro Immunsuppression Pro Supportiv

ln

SUP IMMevents/total

CorticosteroidMonotherapyvsCombinedImmuno-suppressioninIgAN:InsightsfromSTOP-IgAN

FloegeJetal,ASNKongress 2015

Full clinical remission (proteinuria < 0.2 g/g plus eGFR loss < 5 ml/min/1.73 m2)

eGFR loss ≥ 15 ml/min/1.73 m²

GFR > 60 ml/minIMM (n=55) vs. SUP (n=54)

GFR 30-59 ml/minIMM (n=27) vs. SUP (n=26)

OR 5.23 (95%-CI 1.29 – 21.15)p=0.020

OR 2.77 (95%-CI 0.38 – 32.29)p=0.319

GFR > 60 ml/minIMM (n=55) vs. SUP (n=54)

GFR 30-59 ml/minIMM (n=27) vs. SUP (n=26)

OR 0.65 (95%-CI 0.27 – 1.56)p=0.333

OR 1.62 (95%-CI 0.49 – 5.61)p=0.428

Intention-to-treat analysis (worst case scenario)

-8

-6

-4

-2

0

-6.17M

ean

eGFR

loss

/yea

r (m

l/min

)

-0.56

RamiprilSteroid

+Ramipril

Manno et al. (2009)

-8

-6

-4

-2

0-1.6

Mea

n eG

FR lo

ss/y

ear (

ml/m

in)

-1.5

SUP IMM

STOP-IgAN

3-Year Trial Phase: Annual GFR Loss

SUP (n=80)

IMM(n=82)

Patienten mit min. 1 SAE 20 25

Gesamte SAEs 27 30

Alle infektiösen Ereignisse 111 182

Infektiöse SAEs 3 8

Todesfälle 1 (Unfall) 1 (Sepsis)

Malignome 0 2

Gestörte Glukosetoleranz / Diabetes 1 9

Gewichtszunahme ≥ 5 kg im 1. Jahr 5 14

3-Jahres Studienphase: Nebenwirkungen

„Kein Problem“

Geringe Urinbefunde, GFR nl, Normotonus

1-2-jährliche Kontrollen über mindestens 10 Jahre

„Risiko stratifizieren!“

Supportive Therapie 3-6 Monate optimieren

Proteinurie >0,5-1 g/d ±GFR reduz. ± Hypertonie

GFR >50 ml/min GFR 30-50 ml/min

Protein-urie

<1 g/d +GFR =

Sup-portiv

Protein-urie ≥1 g/die

± GFR ò

+ 6 Monate Kortiko-steroid

Sup-portiv

Supportive Therapie

Immunsuppression kritisch abwägen

„Achtung!“

AKI (Makro-Hämaturie o. andere Ätiol.)

Nephrot. Syndrom

oder RPGN

Akuter o. schneller GFR Verlust

Supportive Therapie

+ Immun-suppression

Supportive Therapie

Wenn Sie in 2016 mein Patient mit IgA Nephropathie wären…

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011

?

EinpaarAnsätze,dieSienichterwägensollten……

KDIGO CLINICAL PRACTICE GUIDELINEFOR GLOMERULONEPHRITIS

IgA Nephropathy10.2.1: … long-term ACEi or ARB treatment when proteinuria is >1 g/d. (1B)10.2.2: … ACEi or ARB treatment if proteinuria is between 0.5 to 1 g/d. (2D)10.3.1: We suggest that patients with persistent proteinuria ≥1 g/d despite 3-6

months of optimized supportive care and GFR >50 mL/min receive 6 month corticosteroid therapy. (2C)

10.4.1: We do not suggest treatment with corticosteroids combined with cyclophosphamide or azathioprine in IgAN patients (unless there is crescentic IgAN with rapidly deteriorating renal function). (2D)

10.4.2: We suggest not using immunosuppressive therapy in patients with GFR <30 mL/min unless there is crescentic IgAN with rapidly deteriorating renal function. (2C)

10.4.3: We do not suggest the use of MMF in IgAN. (2C)

Therapy of IgA-Nephropathy- Combination Steroid + Azathioprine -

Pozzi C et al. J Am Soc Nephrol 2010

0

0

20

40

60

80

100

1 2 3 4 5 6 7Follow-up (years)

Renal function(% patients without 50% increase of s-creatinine)

Steroid+Aza n=101

Steroidn=106

84%

83%88%

89%

6 months „Pozzi“-schemeadditionally azathioprine(1.5 mg/kg)

6 months „Pozzi“-scheme

• No difference in proteinuria• Markedly higher side effects of combination therapy

SHP Therapy of Henoch Schönlein PurpuraCombination steroid + cyclophosphamide

Pillebout E et al, Kidney Int 2010; 78: 495-502

eGFR

[ml/m

in/1

,73

m²]

Steroid-monotherapy Steroid + Cyclophosphamide

Mycophenolate Mofetil Therapy in IgA Nephropathy

Country MMFPlacebo

S-Crea Protein-uria

Histo ACE-I.AT-1 Bl.

OutcomeMMF vs.Control

Baseline

Belgium n=21n=12 76% 1.5±0.1

1.4±0.11.9±0.31.3±0.4

grade II-IVChurg

No MMFbenefit

USA n=17n=15 85% 2.6±1.2

2.2±0.72.7±1.62.7±1.4

70% grade VHaas

No MMFbenefit

China n=20n=20 30% 1.5±0.2

1.7±0.21.8±0.21.9±0.3

85% grade II-IIIHaas

Proteinuriareduced

GFR stable

China n=31n=31(steroid)

?Proteinuriareduced +crea stable

Maes B et al, Kidney Int 2004

Frisch G et al, NDT 2005

Tang S et al, Kidney Int 2005 and Kidney Int 2010

? ? ? ?Chen X et al, Zhonghua Yi Xue Za Zhi 2005

Modified after Floege J, Nat Clin Pract Nephrol 2006; 2: 16

USA n=27n=25 62% Mean

eGFR105

MeanUP/Cr1.8 g/g

MEST scoremildHogg R et al, Am J Kidney Dis 2015

No MMFbenefit

0tandard

0tandard

0tandard

0tandard

0tandard

0tandard

0tandard

0tandard

0tandard

0tandard

0tandard

Baseline Day91 Day168 Day258 Day352Time(day)

24hrProteinuriainRitumab Group(N=17)

0tandard0tandard0tandard0tandard0tandard0tandard0tandard0tandard0tandard0tandard0tandard

Baseline Day91 Day168 Day258 Day352Time(day)

24hrProteinuriainControlGroup(N=17)

A randomized controlled study of

rituximab for patients with advanced IgA nephropathy

(2x1 g Month 0 and 6)

Fervenza F et al, ASN Congress 2015

Alsonurnochsupportiv füralle??

Vielleichtgibt‘snochAlternativen……

Patie

nten

ohn

e Er

eign

is(5

0% G

FR-R

eduk

tion

oder

GFR

<15

ml/m

in)

RAS-Blocker alleinSteroid + RAS-Blocker

p = 0.97

p = 0.001

p = 0.03

Mittlere Proteinurie vor Studienbeginn [g/d]< 1 1- <3 ≥3

VALIGA-Konsortium: Kortikosteroide in der IgANTesar V et al, J Am Soc Nephrol 2015; 26: im Druck

RUN-INPHASE6months

TREATMENTPHASE9months

FOLLOW-UPPHASE3months

OptimizeRASBlockade*

2weekplacebotapering

2weektaperingat8mg/day

2weekplacebotaperingMainInclusioncriteria:

• ≥18years• Biopsy-verifiedIgAN• UPCR≥0.5g/gORUrineprotein≥0.75g/day

• eGFR≥45mL/min/1.73m2

NEFECON8mg/day

NEFECON16mg/day

PLACEBO

*Optimized RASBlockadethroughoutTreatmentandFollow-upPhases

FellstromBetal,ASNKongress2015

NEFIGANTrial:design

Variable NEFECON 16mg(n=48)

NEFECON 8mg(n=51)

Placebo(n=50)

Age,years 37.5(11.9) 40.6(13.0) 38.9(12.0)Malegender,n(%) 33(68.8) 37(72.5) 35(70.0)BMI,kg/m2 27.8(5.2) 26.5(4.4) 27.5(5.4)Weight,kg 86.7(16.9) 80.9(14.5) 85.2(18.9)Race,n(%)AsianCaucasianOther

1(2.1)47(97.9)0(0.0)

0(0.0)49(96.1)2(3.9)

1(2.0)48(96.0)1(2.0)

Bloodpressure,mmHgSystolicDiastolic

126.7(11.6)78.1(9.6)

127.7(13.6)80.3(10.1)

128.1(11.9)80.2(10.1)

Median(range)24-hprotein, g 1.32(0.86-2.14) 1.14(0.87-1.83) 1.23(0.98-3.19)eGFR CKD-EPI,ml/min/1.73m2 83.8(25.9) 74.1(25.8) 76.5(23.2)Patients previouslytreatedwithimmunosuppress/CS,n(%)

6(12.5) 14(27.5) 7(14.0)

Dataare presentedasmean(SD)unlessotherwisestatedBaselinecharacteristicsatrandomization

FellstromBetal,ASNKongress2015

NEFIGANTrial:PatientDemographics

FellstromBetal,ASNKongress2015

NEFIGANTrial:Primaryendpoint(proteinuriaat9months)

20

10

0

-10

-20

-30

-40

Mean(SEM

)%cha

ngefrom

baselineinUPC

R

1 3 6 9 12 Month

Treatmentperiod Follow-upperiod

NEFECON16mg/dNEFECON8mg/dPlacebo

6

NEFECON16mg/d

NEFECON8mg/d

Placebo

Month1 3 6 9 12Follow-upperiodTreatmentperiod

4

0

2

-6

-4

-2

-8

-10

Mean(SEM

)cha

ngefrom

baselineineGFR

(mL/min/1.73m

2 )

*eGFR estimatedwithCKD-EPIequationusingserumcreatinine

FellstromBetal,ASNKongress2015

NEFIGANTrial:eGFR*

Preferredterm;n(%)ofpatientsNEFECON16mg

(n=49)NEFECON8mg

(n=51)Placebo(n=50)

AnyAE, 43 (87.8) 48(94.1) 42(84.0)

Nasopharyngitis 9(18.4) 6(11.8) 10(20.0)Acneb 8(16.3) 7(13.7) 3(6.0)Jointswelling 8(16.3) 8(15.7) 2(4.0)Cushingoidb 8(16.3) 5(9.8) 3(6.0)Insomniab 8(16.3) 6(11.8) 2(4.0)Diarrhoea 5(10.2) 1(2.0) 7(14.0)Dyspepsiaa 7(14.3) 2(3.9) 4(8.0)Headache 6(12.2) 3(5.9) 3(6.0)Alopeciab 4(8.2) 4(7.8) 2(4.0)Backpain 3(6.1) 6(11.8) 1(2.0)Moodswingsb 5(10.2) 3(5.9) 2(4.0)Oedemaperipheral 6(12.2) 2(3.9) 2(4.0)

a Gastrointestinal-related AEs solicited by questionnaire at every visit.b Glucocorticoid-related AEs solicited by questionnaire at every visit.

FellstromBetal,ASNKongress2015

NEFIGANTrial:Treatmentemergentadverseeffects

„Kein Problem“

Geringe Urinbefunde, GFR nl, Normotonus

1-2-jährliche Kontrollen über mindestens 10 Jahre

„Risiko stratifizieren!“

Supportive Therapie 3-6 Monate optimieren

Proteinurie >0,5-1 g/d ±GFR reduz. ± Hypertonie

GFR >50 ml/min GFR 30-50 ml/min GFR ≤30 ml/min

Protein-urie

<1 g/d +GFR =

Sup-portiv

Protein-urie ≥1 g/die

± GFR ò

+ 6 Monate Kortiko-steroid

Sup-portiv

Supportive Therapie

Ø Immunsuppression (Ausnahme RPGN)

Supportive Therapie

Immunsuppression kritisch abwägen

„Achtung!“

AKI (Makro-Hämaturie o. andere Ätiol.)

Nephrot. Syndrom

oder RPGN

Akuter o. schneller GFR Verlust

Supportive Therapie

+ Immun-suppression

Supportive Therapie

Wenn Sie in 2016 mein Patient mit IgA Nephropathie wären…

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011

• HochproteinurischePatienten?

• Nefecon?? ?