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

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.

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.

Where can one find a kidney?

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.

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

Lupus Nephritis Class ILupus Nephritis Class I

Lupus Nephritis Class IILupus Nephritis Class II

Lupus Nephritis Class IIILupus Nephritis Class III

Histology WHO Class IV: Diffuse Endocapillary Proliferation With Karyorrhexis and Focal Necrosis

Focal Necrosis Endocapillary Proliferation

Lupus Nephritis Class IVLupus Nephritis Class IV

Pre-Rx Post-Rx

Lupus Nephritis Class IVLupus Nephritis Class IV

Lupus Nephritis Class VLupus Nephritis Class V

End stage kidney due to chronic GN: Diffuse and global glomerulosclerosis, tubular atrophy & interstitial fibrosis

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.

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

RBC cast forms a mold of tubular lumen

Diffuse proliferative lupus nephritis: Diffuse and global mesangial and glomerular capillary wall positivity for IgG

Full house IF staining: IgG, IgM, IgA, C3, C1q

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.

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

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.

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

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

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.

ELNT - 10 year FU - ESRD

Houssiau FA et al. Ann Rheum Dis 2009,

ELNT - 10 year FU

Houssiau FA et al. Ann Rheum Dis 2009, Jan 20 (Epub ahead of print)

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

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

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.

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.

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.

http://www.google.com/url?sa=i&source=images&cd=&cad=rja&docid=mztR7ic0OP_UHM&tbnid=-hGEtRPvY_0PtM:&ved=0CAgQjRwwAA&url=http://www.medscape.org/viewarticle/523554&ei=jc92UrSyEcbJsQTMtoHABA&psig=AFQjCNG6M-vNKlQwsG32BhPN85Pf0mVadw&ust=1383604493347091

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

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

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

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

Bortezomib for NZB/W F1: Kidney Disease

Neubert Nat. Med. 2008

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

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

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.