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SLE and Kidney Disease in 2014 GERALD APPEL, MD

Learn about the kidneys, SLE involvement, diagnosing kidney problems, patterns of LN, historical perspective, current treatment options, success rates, and future innovations in treating lupus nephritis.

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SLE and Kidney Disease in 2014 GERALD APPEL, MD

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  1. 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

  2. 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.

  3. 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.

  4. Where can one find a kidney?

  5. 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.

  6. 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

  7. Lupus Nephritis Class I

  8. Lupus Nephritis Class II

  9. Lupus Nephritis Class III

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

  11. Lupus Nephritis Class IV Post-Rx Pre-Rx

  12. Lupus Nephritis Class IV

  13. Lupus Nephritis Class V

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

  15. 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.

  16. 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

  17. RBC cast forms a mold of tubular lumen

  18. Diffuse proliferative lupus nephritis: Diffuse and global mesangial and glomerular capillary wall positivity for IgG Full house IF staining: IgG, IgM, IgA, C3, C1q

  19. 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.

  20. Side Effects of Cyclophosphamide in the past

  21. 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.

  22. Proliferative LN ACR- KDIGO Treatment guidelines – INDUCTION CYC + Glucocorticoids (e.g. pulse methylprednisolone) MMF + glucocorticoids (e.g. pulse methylprednisolone) or EURO LUPUS Low-dose CYC NIH study Hi-dose CYC or 6 months 6 months Anti-MIF & LN Ad Board, July 13, 2011 CONFIDENTIAL

  23. Proliferative Lupus Nephritis – Maintenance TreatmentACR – KDIGO Treatment guidelines MMF induction CYC induction IMPROVED NOT IMPROVED IMPROVED NOT IMPROVED MMF1-2g/d or AZA 2 mg/kg/d ± lo dose daily GC MMF1-2g/d or AZA 2 mg/kg/d ± lo dose daily GC CYC (lo- or hi-dose) + pulse GC then daily GC MMF 2-3g/d x 6 months + pulse GC then daily GC 6 months 6 months

  24. 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.

  25. ELNT - 10 year FU - ESRD Houssiau FA et al. Ann Rheum Dis 2009,

  26. ELNT - 10 year FU Houssiau FA et al. Ann Rheum Dis 2009, Jan 20 (Epub ahead of print)

  27. ALMS TRIAL Primary Endpoint: Responders at Month 6 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 IVC MMF was not superior to IVC (p = 0.575) Appel , Contreras, Dooley et al JASN 2009

  28. ALMS Trial - Renal Variables IVC MMF Serum creatinine and urine protein levels improved in both the MMF and IVC groups

  29. 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.

  30. 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.

  31. 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.

  32. Belimumab – FDA Approved for SLE IMNL-SCT-019799 Placebo 1 mg/kg belimumab 10 mg/kg belimumab +p<0.05 *p<0.05 + + + + + + + + + * * * * * * * 60 50 * 40 40 30 % SRI Responders SRI Responders (%) p<0.05 20 20 10 0 0 0 4 8 16 32 24 40 52 76 48 60 68 12 0 4 8 16 20 24 28 32 36 40 44 48 52 Visit Week Visit Week Navarra, et al.Lancet. 2011;377(9767):721-31 Furie, et al.Arthritis Rheum. 2011;63(12):3918-30 SRI, SLE Responder Index

  33. Abatacept ( CTLA4Ig Co-Stimulatory Blocker ) Study in 300 LN PTS Abatacept 30/10 30 mg/kg x4, then 10 mg/kg Q 28 days Abatacept 10/10 10 mg/kg days 1,15, 29, then Q 28 days Randomization 1:1:1 Placebo Dose every 28 days Day 337 Final dose Days 1 and 15 (1st and 2nd dose) Background Rx: MMF up to 3 g/day plus corticosteroids Primary Outcome Measure: Time to complete response Courtesy of D Wofsy

  34. 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

  35. Proteasome Inhibitors O O H H N N B N O H H O N

  36. Bortezomib for NZB/W F1: Kidney Disease Neubert Nat. Med. 2008

  37. An Open Label Randomized Phase IV Study of the Safety and Efficacy of ACTHAR GEL in Patients with Membranous (Class V) Lupus Nephritis SCRN 0 1 2 3 4 5 6 9 12 Study Month Principal Investigator: Brad H. Rovin MD, Ohio State University • 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 Administration of Acthar Follow-Up • 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

  38. 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

  39. 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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