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![Page 1: SLE and Kidney Disease in 2014 GERALD APPEL, MD GERALD APPEL, MD Professor of Clinical Medicine Columbia University –College of Professor of Clinical Medicine.](https://reader037.fdocuments.net/reader037/viewer/2022110321/56649cec5503460f949b9401/html5/thumbnails/1.jpg)
SLE and Kidney Disease in 2014
GERALD APPEL, MD
Professor of Clinical Medicine Columbia University –College of Physicians and Surgeons NY-Presbyterian Hospital New York, New York
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
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Where can one find a kidney?
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
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ISN/RPS Classification of LN• Class I Minimal mesangial LN• Class II Mesangial proliferative LN• Class III Focal LN III (A): Active lesions: focal proliferative LN III (A/C): Active and chronic lesions III (C): Chronic inactive lesions with scars• Class IV Diffuse LN IV-S (A): Active lesions: diffuse segmental proliferative LN IV-G (A): Active lesions: diffuse global proliferative LN IV-S (A/C): Active and chronic lesions IV-G (A/C): Active and chronic lesions IV-S (C): Chronic inactive lesions with scars IV-G (C): Chronic inactive lesions with scars • Class V Membranous LN• Class VI Advanced sclerotic LN
ISN = International Society of Nephrology; RPS = Renal Pathology Society
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Lupus Nephritis Class ILupus Nephritis Class I
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Lupus Nephritis Class IILupus Nephritis Class II
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Lupus Nephritis Class IIILupus Nephritis Class III
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Histology WHO Class IV: Diffuse Endocapillary Proliferation With Karyorrhexis and Focal Necrosis
Focal Necrosis Endocapillary Proliferation
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Lupus Nephritis Class IVLupus Nephritis Class IV
Pre-Rx Post-Rx
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Lupus Nephritis Class IVLupus Nephritis Class IV
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Lupus Nephritis Class VLupus Nephritis Class V
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End stage kidney due to chronic GN: Diffuse and global glomerulosclerosis, tubular atrophy & interstitial fibrosis
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
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Case 3: Saleswoman with rash and arthritis
•A 29 year old saleswoman develops arthritis
multiple joints, fever•Exam: Lymphadenopathy, and a malar rash.•Labs:
–Urinalysis 3+ protein, 18-20 rbc’s–Creatinine 1.2 mg/dl–24 hr. protein 1.8 g per day –Complement 18% (normal 50-150%)–ANA positive, Anti-DNA antibody positive
KIDNEY BIOPSY PERFORMED
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RBC cast forms a mold of tubular lumen
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Diffuse proliferative lupus nephritis: Diffuse and global mesangial and glomerular capillary wall positivity for IgG
Full house IF staining: IgG, IgM, IgA, C3, C1q
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• What happened with SLE Kidney disease ( lupus nephritis )in
the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
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Event Cy Therapy
(n = 21)Combination Therapy
(n = 20)
n/n n/n
Hypertension 10/20 10/20
Ischemic heart disease 1/19 4/19
Hyperlipidemia 7/20 8/19
Valvular heart disease 9/19 7/21
Avascular necrosis 6/21 6/20
Osteoporosis 4/18 3/19
Premature menopause 9/16 10/18
Major infections 7/21 9/20
Herpes zoster infection 6/21 5/20
Side Effects of Cyclophosphamide in the past
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
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MMF +
glucocorticoids (e.g. pulse methylprednisolone)
CYC +
Glucocorticoids(e.g. pulse methylprednisolone)
or
EURO LUPUSLow-dose CYC
NIH studyHi-dose CYC
or
6 months 6 months
INDUCTION
Proliferative LN ACR- KDIGO Treatment guidelines –
CONFIDENTIALAnti-MIF & LN Ad Board, July 13, 2011
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Proliferative Lupus Nephritis – Maintenance TreatmentACR – KDIGO Treatment guidelines
IMPROVED NOT IMPROVED
MMFinduction
MMF1-2g/dor
AZA 2 mg/kg/d ± lo dose daily GC
CYC (lo- or hi-dose)
+pulse GC then
daily GC 6 m
onth
s
CYCinduction
IMPROVED NOT IMPROVED
MMF1-2g/dor
AZA 2 mg/kg/d ± lo dose daily GC
MMF 2-3g/d x 6 months
+pulse GC then daily
GC 6 m
onth
s
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
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ELNT - 10 year FU - ESRD
Houssiau FA et al. Ann Rheum Dis 2009,
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ELNT - 10 year FU
Houssiau FA et al. Ann Rheum Dis 2009, Jan 20 (Epub ahead of print)
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ALMS TRIAL Primary Endpoint: Responders at Month 6
56.2% 53.0%
0
20
40
60
80
100
Prop
ortio
n of p
atien
ts rep
ondin
g (%
)
Response judged by blinded Clinical Endpoint Committee:
Decrease in proteinuria to <3g if baseline nephrotic (≥3g/d) , or by ≥50% in patients ith subnephrotic (<3g/d) proteinuria
and
Stabilization of serum creatinine level (24-week level ± 25% of baseline),or improvement
MMF was not superior to IVC (p = 0.575)
MMF
IVC
Appel , Contreras, Dooley et al JASN 2009
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0
20
40
60
80
100
120
140
160
Seru
m c
reati
nin
e (μ
mol/
L,
SD
)IVCMMF
ALMS Trial - Renal Variables
0
1
2
3
4
5
6
7
8
9
Baseline 4 8 12 16 20 24 Endpoint
24
ho
ur
uri
ne p
rote
in (
g/
day,
SD
)
Week
Serum creatinine and urine protein levels improved in both the MMF and IVC groups
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
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Rituximab:Anti-CD20 Monoclonal Antibody
Rituximab - FDA approved for the treatment of relapsed or refractory, CD20-positive B-cell NHLymphomas
• Approved for Rheumatoid Arthritis – used in 240,000 patients > 10 yrs
• Approved for ANCA+ glomerulonephritis since 2010
• Chimeric murine/human monoclonal antibody
Davies B, Shaw T. Presented at EULAR 2004.
Maloney DG, et al. J Clin Oncol. 1997;15(10):3266-3274.
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Rituxilup Trial
• MPred + MMF + Rituximab vs MP + MMF + steroids ( ALMS regimen )
• 19 Adult + 4 Peds Centers in UK; Europe 12 Centers in 3 networks; US Centers.
• Non-inferiority Trial of 252 LN patients • Primary endpoint complete remission at 1 yr.• Secondary Endpoints – Time to CR, Partial
remissions, PR with histologic response, serious infections, SAEs, SRI score etc.
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Navarra, et al. Lancet. 2011;377(9767):721-31Furie, et al. Arthritis Rheum. 2011;63(12):3918-30
1 mg/kg belimumab
60
40
20
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52Visit Week
SR
I R
esp
on
der
s (%
)
+ + +*
+*
+*
+*
+*
+*
+*
* p<0.05 + p<0.05
10 mg/kg belimumabPlacebo
50
40
30
20
10
0
0 4 8 16 24 32 40 48 52 60 68 76
Visit Week
% S
RI
Res
po
nd
ers *
Belimumab – FDA Approved for SLE
p<0.05
SRI, SLE Responder Index
IMNL-SCT-019799
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Abatacept ( CTLA4Ig Co-Stimulatory Blocker ) Study in 300 LN PTS
Background Rx: MMF up to 3 g/day plus corticosteroids
Primary Outcome Measure: Time to complete response
Abatacept 10/1010 mg/kg days 1,15, 29, then Q 28 days
Abatacept 30/1030 mg/kg x4, then 10 mg/kg Q 28 days
Placebo
Days 1 and 15(1st and 2nd dose)
Day 337Final dose
Dose every 28 days
Randomization1:1:1
Courtesy of D Wofsy
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Treatment of LN with Abatacept and Low-Dose Pulse Cyclophosphamide: The ACCESS TrialBrad H. Rovinon behalf of the ACCESS Trial Group
• EuroLupus Low dose Cyclophosphamide and prednisone starting at 60 mg (tapering to 10 mg by week 12 )
• Azathioprine 2 mg/kg/day PO maintenance
• Abatacept 500 mg or 1000 mg at 0, 2, 4, then Q4 wk until week 24 vs Placebo
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Proteasome Inhibitors
NH
HN BO
OHOH
O
N
N
Bortezomib
( Velcade™)
Carfilzomib
(Kyprolis)
Manufacturer Takeda Onyx/Amgen
Status Approved Approved
Indications Myeloma & Mantle Cell Lymphoma Myeloma & Solid Tumors
Class Boronic Acid Ketoepoxide
Active Sites Targeted
b5/LMP7/LMP2 b5/LMP7
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Bortezomib for NZB/W F1: Kidney Disease
Neubert Nat. Med. 2008
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An Open Label Randomized Phase IV Study of the Safety and Efficacy of ACTHAR GEL in Patients with Membranous
(Class V) Lupus NephritisPrincipal Investigator: Brad H. Rovin MD, Ohio State University
SCRN 0 1 2 3 4 5 6 9 12
Study Month
ARM 1. Acthar Gel 80 IU administered subcutaneously 2 times per week, 12 patients
ARM 2. Acthar Gel 80 IU administered subcutaneously 3 times per week, 13 patients
Administration of Acthar Follow-Up
Primary Objectives: • To determine the safety and tolerability of Acthar Gel in patients with Class V lupus
nephritis• To determine the efficacy of Acthar Gel in patients with Class V lupus nephritis as
CRR+PRR
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Treatment of Severe LN in the Future
• Treatment will still be divided into an induction and maintenance phase.
• Induction therapy will consist of Cyclophosphamide (usually IV ) or MMF or Newer regimens e.g. older drugs combined with CNI’s, ACTH, proteosome inhibitors, or corticosteroid free Rituximab regimens.
• Maintenance therapy will consist of MMF or AZA or rituximab or other newer agents .
• Use of combinations of immunosuppressives will increase.• One Regimen Will Not Fit All
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Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.