03 10 2016 IgAN Heidelberg...IgA Nephropathy 10.2.1: … long-term ACEi or ARB treatment when...
Transcript of 03 10 2016 IgAN Heidelberg...IgA Nephropathy 10.2.1: … long-term ACEi or ARB treatment when...
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Klinik für Nieren- und Hochdruckkrankheiten
Jürgen Floege
STOP-IgAN Studie: Konsequenzen für die Praxis
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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
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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)
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„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
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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)
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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…
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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
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….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
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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)
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„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
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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
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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
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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
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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
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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)
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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
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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
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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
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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)
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-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
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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
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„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
?
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EinpaarAnsätze,dieSienichterwägensollten……
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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)
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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
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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
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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
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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
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Alsonurnochsupportiv füralle??
Vielleichtgibt‘snochAlternativen……
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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
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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
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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
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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
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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*
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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
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„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?? ?