Lupus and KidneyNaheed Ansari, MD FASN      10/15/12
Systemic Lupus Erythematosis• The term “Lupus Erythematosis” was introduced in  19th century to describe skin lesions• 100...
Lupus Nephritis• Multisystem involvement• Lupus patients are more at risk for development of  kidney disease than people w...
Lupus Nephritis• Defined as presence of abnormal elements in  the urine of patients with SLE              •   red blood ce...
Lupus Nephritis        Cameron et al:JASN 1999                                  5
Lupus Nephritis- Clinical              Features• History:• Patients usually experience other symptoms of active  SLE like ...
Lupus Nephritis- Clinical              Features• Physical Examination:• Evidence of rash, oral or nasal ulcers, joint swel...
Diagnosis of Lupus Nephritis• Blood tests           » BUN           » Serum Creatinine           » Laboratory tests for lu...
International Society of Nephrology/Renal     Pathology Society (ISN/RPS) 2003 classification of                       lup...
Lupus Nephritis- Biopsy           Findings                            Mesangioproliferative Lupus NephritisNorma Kidney- L...
Lupus Nephritis( Biopsy              Findings)Proliferative GN withnecrosis                Cellular Crescent
Lupus NephritisLupus Membranous- LM   Lupus Membranous- EM
Lupus NephritisLupus Podocytopathy-LM   Lupus Podocytopathy- EM
IF staining for IgGIgG-TBM deposits                         IgG vessel wall deposits
US NIH renal Pathology System for LupusNephritis
Treatment of Lupus Nephritis• Depends upon class of LN diagnosed on kidney biopsy along with  presence of extra-renal mani...
Kaplan–Meier survival curve for the development of renal involvement as a function of the use of                          ...
Treatment of Lupus Nephritis• Patients with proliferative classes of lupus  nephritis need immunomodulatory treatment  to ...
Induction Treatment• It is initial intense treatment given to induce  remission of active disease• Corticosteroids        ...
Cyclophosphamide• Efficacious when used in conjunction with  glucocorticoids• can be used intravenously or orally• Used in...
Standard “NIH protocol” dosing    Methylprednisolone and cyclophosphamide Alone or in Combination in                      ...
Kaplan-Meier Analysis of Failure of Therapy                                               Illei GG, et al. Ann Intern Med....
Long-term Follow-up of Protocol Completers in                   WHO Class IV LN                           50              ...
• Multicenter Prospective Clinical trial• Enrolled 90 patients from September 1996 – 2000 in 19  European centers• Objecti...
Euro Lupus Trial- Study Design                      90 Patients with LN Class                                III-V        ...
Euro Lupus Trial Treatment failure                           100                            90                            ...
Mycophenalate Mofetil-Cellcept
Efficacy of MMF vs sequential PO CYT-AZA in 42              patients with DPLN                                            ...
Multicenter Trial of MMF vs IV CTX for        Induction Therapy of Severe LN• Multicenter, randomized, non-blinded trial o...
Baseline Patient Characteristics                         MMF (n=71) IVC (n=69)Age ( yrs)               32.5 ± 10.0   31.0 ...
Remission Rates: MMF vs. IVC                        Intent to treat analysis                                           P=0...
• Multinational, Prospective, Randomized, Open label trial  comparing MMF to IV Cyclophosphamide• Background: Smaller stud...
ALMS TRIAL – RCT MMF vs IVC in Severe LN                      Appel , Contreras, Dooley et al JASN 2009                   ...
Figure 2. Response rates of study population and by racial groupAppel, G. B. et al. J Am Soc Nephrol 2009;20:1103-1112
Summary – Induction Phase     Therapy for Class III or IV LN• Multiple options  – Standard, NIH protocol IV CTX     • 0.75...
Treatment of Resistant LN• Some patients are challenging for induction• Plasmaphresis may be beneficial in some cases alth...
Maintenance Therapy for                  Proliferative LN• Up to 50% of patients with LN relapse during reduction in or ce...
Treatment of LN- Membranous             Nephropathy• Treatment with immunosuppressive drugs is indicated in patients      ...
Partial and Complete Remission Rates                     Membranous LNRadhakrishnan J, Moutzouris D, Ginzler E, and Appel ...
Prognostic Features- Lupus                   Nephritis•    End Stage Renal Disease can occur in some patients with lupus• ...
Treatment of LN- ESRD• Survival rate for individuals with LN after 10 years of diagnosis  of SLE is reduced to 88%.• This ...
Hemodialysis• Patient survival with either hemodialysis or CAPD appears to be similar in  patients with ESRD ( 5 year surv...
Peritoneal Dialysis• Peritoneal dialysis and kidney transplantations lower among African-  Americans, uninsured, and unemp...
Kidney Transplantation• Under utilized in patients with LN• Only 3% of LN patients undergo renal transplantation• Graft su...
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Dialysis and Transplant for Lupus Nephritis

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  • 83% of patients enrolled in the study completed the full 24-week course of treatment. Inclusion criteria Age 12–75 years Diagnosis of SLE per American College of Rheumatology (ACR) 1997 criteria Kidney biopsy within the 6 months prior to first randomization Lupus nephritis (International Society of Nephrology/Renal Pathology Society [ISN/RPS] 2003 classification) class III, IV-S, or IV-G, (A) or (A/C), or V, alone or in combination with class III or IV Exclusion criteria Continuous dialysis for more than 2 weeks before randomization and/or expected 8 weeks Pancreatitis, GI hemorrhage within 6 months, active peptic ulcer within 3 months Severe viral infection Severe cardiovascular disease Bone marrow insufficiency, with cytopenias not attributable to SLE Current infection requiring intravenous antibiotics Maintenance phase: Double-blind, double-dummy, randomized (re-randomized), MMF orally 2 g/day or oral azathioprine 2 mg/kg/day with corticosteroids to a maximum of 10 mg/day, to treatment failure (or up to 3 years for last patient)
  • Dialysis and Transplant for Lupus Nephritis

    1. 1. Lupus and KidneyNaheed Ansari, MD FASN 10/15/12
    2. 2. Systemic Lupus Erythematosis• The term “Lupus Erythematosis” was introduced in 19th century to describe skin lesions• 100 years later, it was realized that it is a systemic disease and it is causes by some aberrant autoimmunity• Prevalence- 1 case per 2000 population• Currently, US 322,000 have SLE• Incidence higher in African Americans,Hispanics, and Asian ancestry• 4 year survival rate- 50% in 1950s• 15 year survival rate- 80% in 2012
    3. 3. Lupus Nephritis• Multisystem involvement• Lupus patients are more at risk for development of kidney disease than people who do not have lupus• Kidney involvement can occur in upto 50% of patients with SLE. It usually occurs within first 5 years of diagnosis of SLE.• Renal involvement can occur before ACR criterion for SLE is made• Patients with SLE can also develop kidney disease due to other medical problems like Diabetes Mellitus
    4. 4. Lupus Nephritis• Defined as presence of abnormal elements in the urine of patients with SLE • red blood cells, white blood cells • Red blood cell casts in urine• Presence of protein >0.5gm/Day• Elevated serum creatinine reflecting kidney damage• occurs both in children and• adults 4
    5. 5. Lupus Nephritis Cameron et al:JASN 1999 5
    6. 6. Lupus Nephritis- Clinical Features• History:• Patients usually experience other symptoms of active SLE like rash, fatique, arthritis,serositis or clinical CNS disease• Some patients are asymptomatic usually with mesangial/membranous lupus nephritis.• Some patients experience swelling of the body due to proteinuria. Some are hypertensive along with proteinuria.• Some have symptoms associated with hypertension like dizziness,headaches and heart failure
    7. 7. Lupus Nephritis- Clinical Features• Physical Examination:• Evidence of rash, oral or nasal ulcers, joint swelling, brown or foamy urine and changes in amount of urine• Patients with active lupus nephritis have hypertension, peripheral edema, and occasionally heart failure• With membranous nephropathy, signs of nephrotic syndrome( peripheral edema, ascites, pericardial effusion and pleural effusions can be seen.
    8. 8. Diagnosis of Lupus Nephritis• Blood tests » BUN » Serum Creatinine » Laboratory tests for lupus disease activity like complement level, antibodies to DNA, ESR,CRP etc• Urine tests » Urinalysis- presence of blood or protein in the urine as well as presence of red blood cell casts » Spot urine for protein/creatinine ratio » 24 hour urine for creatinine clearance and protein• Kidney biopsy
    9. 9. International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis• Class I Minimal mesangial lupus nephritis• Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence• Class II Mesangial proliferative lupus nephritis• Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits• Class III Focal lupus nephritis• Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations – A=active lesions, C=chronic lesions• Class IV Diffuse lupus nephritis• Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving >50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. – This class is divided into diffuse segmental(IV-S) lupus nephritis when 50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when 50% of the involved glomeruli have global lesions. – A=active lesions, C=chronic lesions• Class V Membranous lupus nephritis• Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations – Class V lupus nephritis may occur in combination with class III or IV in which case both will be diagnosed
    10. 10. Lupus Nephritis- Biopsy Findings Mesangioproliferative Lupus NephritisNorma Kidney- Light Micro
    11. 11. Lupus Nephritis( Biopsy Findings)Proliferative GN withnecrosis Cellular Crescent
    12. 12. Lupus NephritisLupus Membranous- LM Lupus Membranous- EM
    13. 13. Lupus NephritisLupus Podocytopathy-LM Lupus Podocytopathy- EM
    14. 14. IF staining for IgGIgG-TBM deposits IgG vessel wall deposits
    15. 15. US NIH renal Pathology System for LupusNephritis
    16. 16. Treatment of Lupus Nephritis• Depends upon class of LN diagnosed on kidney biopsy along with presence of extra-renal manifestations of SLE• Goal of treatment is to normalize kidney function, reduce proteinuria, and prevent progressive loss of kidney function.• Conservative (Non-immunomodulatory) treatment is appropriate for Class I and II LN• RAAS Blockade with ACE/ARB delays progression of Lupus Nephritis• (Durán-Barragán S et al. Rheumatology 2008;47:1093-1096)• Spironolactone significantly reduces proteinuria and lowers levels of anti ds DNA and anti ss DNA• (Role of aldosterone blockade in murine lupus nephritis Arthritis Res Ther 2008;10:R5)
    17. 17. Kaplan–Meier survival curve for the development of renal involvement as a function of the use of ACE inhibitors. Durán-Barragán S et al. Rheumatology 2008;47:1093-1096
    18. 18. Treatment of Lupus Nephritis• Patients with proliferative classes of lupus nephritis need immunomodulatory treatment to turn off the immune system. • Induction: usually Corticosteroids with either Cyclophosphamide or Mycophenalate are used for first six months • Maintenance: usually with lowest and best tolerated immunosuppressive medication. Azathioprine or Mycophenalate are used based on recent clinical trials
    19. 19. Induction Treatment• It is initial intense treatment given to induce remission of active disease• Corticosteroids » PO or IV » 3 day Pulse( 7mg/kg/day) followed by 1mg/kg/day ( not exceeding 60mg/day) for 8 weeks and then taper » Glucocorticoids alone is significantly less effective• Immunosuppressive agents » Cyclophosphamide (Cytoxan) given IV » Mycophenalate Mofetil (cellcept) administered orally » Azathioprine( Imuran)
    20. 20. Cyclophosphamide• Efficacious when used in conjunction with glucocorticoids• can be used intravenously or orally• Used in dose of 0.5- 1.0gm/m2 monthly for six months and then quarterly for at least two years• Can be given in biweekly doses of 500mg/m2• Toxicity remains an issue
    21. 21. Standard “NIH protocol” dosing Methylprednisolone and cyclophosphamide Alone or in Combination in Patients w LN• Randomized Controlled Trial in 85 Pts• Treatment Remission• IV Cyt x 6 mo + q 3rd mo 13/21 62%• Methylpred 1 g/m2 x 1yr 7/24 29%• Combined Therapy 17/20 85%• Gourly MF, et al. Ann Int Med. 125:549, 1996
    22. 22. Kaplan-Meier Analysis of Failure of Therapy Illei GG, et al. Ann Intern Med. 2 001 1.0 Cy + MP Cy alone 0.9 MP alone 0.8 Probability That Therapy 0.7 Would Not Fail 0.6 0.5 0.4 Patients at Risk 0.3 27 25 25 24 23 22 18 18 17 11 7 Cy 0.2 28 27 27 26 23 23 20 20 17 15 12 Cy + MP 27 23 23 19 17 13 11 10 10 8 6 MP 0 24 48 72 96 120 Months From Study Entry
    23. 23. Long-term Follow-up of Protocol Completers in WHO Class IV LN 50 Dialysis Doubling SCr 40 50% Rise SCr Patients (%) 30 20 10 0 MP alone CY alone MP + CY (n = 24*) (n = 21) (n = 20)*14 of 24 patients received CY after study completionIllei GG, et al. Ann Intern Med. 2001;135:248-257.
    24. 24. • Multicenter Prospective Clinical trial• Enrolled 90 patients from September 1996 – 2000 in 19 European centers• Objective: To evaluate efficacy and safety of low dose IV CYC for remission induction followed by AZA
    25. 25. Euro Lupus Trial- Study Design 90 Patients with LN Class III-V Low Dose IV CYC High Dose IV CYC 44 46 (6 pulses of 500mg (6 monthly pulses and 2 q2wks) quaterly pulses) 40 Remained in the study 38 Remained in the study
    26. 26. Euro Lupus Trial Treatment failure 100 90 LD Free of Failure (%) 80 HD 70 60 50 HD LD 0 0 12 24 36 48 60 Follow-up (months) Houssiau et al., Arthritis Rheum, 2002
    27. 27. Mycophenalate Mofetil-Cellcept
    28. 28. Efficacy of MMF vs sequential PO CYT-AZA in 42 patients with DPLN Group 1: MMF (2 g x 6 mo, then 1 g x 6 mo) + prednisone (0.8 mg/kg) Group 2: POCY (2.5 mg/kg/d x 6 mo), then AZA (1.5-2.0 mg/kg/d) + prednisone Pts (%) Chan TM et al. New Engl J Med 2000; 343:1156-62.
    29. 29. Multicenter Trial of MMF vs IV CTX for Induction Therapy of Severe LN• Multicenter, randomized, non-blinded trial of induction RX for severe active LN• Designed as equivalence trial • Calculated sample size: 64/ Rx arm• Hypothesis: MMF has equivalent efficacy with superior toxicity/tolerability profile vs. IVC•• Ginzler et al. N Eng J Med 2005
    30. 30. Baseline Patient Characteristics MMF (n=71) IVC (n=69)Age ( yrs) 32.5 ± 10.0 31.0 ± 9.0Female 61 (86%) 65 (94%)Black 43 (61%) 36 (52%)Duration of SLE, mo. 43.72 ± 66.88 58.70 ± 80.64Screatinine, mg/dL 1.06 ± 0.52 1.08 ± 0.49Urine protein, g/24 hr 4.06 ± 3.14 4.41 ± 3.51Urine sediment RBC/hpf 24.1 ± 50.3 33.2 ± 115.5 WBC/hpf 12.6 ± 23.5 10.3 ± 17.3Salbumin, g/L 2.81 ± 0.95 2.69 ± 0.56
    31. 31. Remission Rates: MMF vs. IVC Intent to treat analysis P=0.009Percent Responding P=0.005 P=NS
    32. 32. • Multinational, Prospective, Randomized, Open label trial comparing MMF to IV Cyclophosphamide• Background: Smaller studies have shown that MMF may offer advantages over IV Cyclophosphamide for treatment of Lupus Nephritis but there is no large International Randomized control trial• Objective: To assess the efficacy and safety of MMF as Induction therapy in Lupus Nephritis• Hypothesis: More patents with Lupus Nephritis would respond to MMF than IV Cyclophosphamide during 24 weeks
    33. 33. ALMS TRIAL – RCT MMF vs IVC in Severe LN Appel , Contreras, Dooley et al JASN 2009 Randomized (n = 370) MMF Open-label treatment IVC Allocated to MMF Allocated to IVC (n = 185) (n = 185)Received MMF (n = 184) Received IVC (n = 180) Withdrawals (n = 35) Withdrawals (n = 29) Due to adverse event (n = 24) Consent withdrawn (n = 6) Due to adverse event (n = 13) Other reason (n = 5) Consent withdrawn (n = 5) Other reason (n = 11) Primary endpoint: responders in randomized population (n = 370) Responders Maintenance phase Double-blind re-randomization to corticosteroids plus MMF or azathioprine for up to 3 years
    34. 34. Figure 2. Response rates of study population and by racial groupAppel, G. B. et al. J Am Soc Nephrol 2009;20:1103-1112
    35. 35. Summary – Induction Phase Therapy for Class III or IV LN• Multiple options – Standard, NIH protocol IV CTX • 0.75-1.0 g/m2 IV q4 weeks for 6 doses – Eurolupus IV CTX • 500 mg IV q2 weeks for 6 doses – MMF • 2000-3000 mg/day for 6 months• All should be given alongside standard steroid regimen – 3 days pulse (7 mg/kg) followed by PO steroids at 1 mg/kg/day (not exceeding 60 mg) for 8 weeks, then taper
    36. 36. Treatment of Resistant LN• Some patients are challenging for induction• Plasmaphresis may be beneficial in some cases although randomized controlled trials showed no benefit• Tacrolimus can by used• Rituximab - FDA approved for the treatment of relapsed or refractory, CD20-positive B-cell NH Lymphomas and Rheumatoid Arthritis• Chimeric murine/human monoclonal antibody• Used in many glomerular diseases in uncontrolled trials• LUNAR study showed that induction of complete or partial remission is higher with rituximab as compared to placebo Rovin et al LUNAR study Arth Rheu 2012 Lewis et al NEJM 1992 Euler et al Arth Rheum 1994
    37. 37. Maintenance Therapy for Proliferative LN• Up to 50% of patients with LN relapse during reduction in or cessation of immunosuppressive therapy• Relapse rate is 5-15 per 100 patient years with an average of 8 per 100 patient years for first 5 years of follow up.• Treatment is usually continued for 24 months to prevent progressive kidney disease• Usually treatment with cellcept or azathioprine is continued to keep patient in remission and prevent relapses• Cyclosporine is not used due to high risk of relapse upon withdrawl of drug• Low dose oral prednisone is continued in most patients receiving maintenance therapy with goal to prevent extrarenal symptoms. Usually a dose of 0.05 to 0.2mg/kg/day is used Houssiau et al Maintain Trial 2010 Chan et al JASN 2005 Contreras et al NEJM 2004
    38. 38. Treatment of LN- Membranous Nephropathy• Treatment with immunosuppressive drugs is indicated in patients » Severe symptomatic nephrotic syndrome » Rising serum creatinine » Mixed membranous and proliferative lesions on renal biospy » Non immunosuppressive treatment is continued in these patients along with immunosuppressive drugs• Various drugs can be used in patients with class V lupus nephritis, usually Mycophenalate is used for remission of nephrotic syndrome because of its safety and better tolerance.•• IV cyclophosphamide and cyclosporine can be used as alternative when MMF cannot be used.• Non immunosuppressive agents include use of ACEI, statins, aspirin, non dihydropyridine calcium channel blockers
    39. 39. Partial and Complete Remission Rates Membranous LNRadhakrishnan J, Moutzouris D, Ginzler E, and Appel GBKidney Int 77:152-160, 2009.
    40. 40. Prognostic Features- Lupus Nephritis• End Stage Renal Disease can occur in some patients with lupus• Histological Predictors• Class IV (diffuse proliferative LN)• High activity and chronicity on Biopsy• Crescents• Interstitial fibrosis• Segmental necrotizing lesions• Clinical Predictors• Hypertension• Anemia• High baseline serum creatinine• Higher baseline proteinuria• Delay in therapy• Epidemiologic Predictors• African American Race• Low socioeconomic status
    41. 41. Treatment of LN- ESRD• Survival rate for individuals with LN after 10 years of diagnosis of SLE is reduced to 88%.• This survival rate is further reduced in African Americans• 15-20% of patients with lupus nephritis start renal replacement therapy if End Stage Renal Disease occurs• USRDS data shows that 1.4% of ESRD due to LN » Hemodialysis » Peritoneal Dialysis » Kidney Transplantation Appel et al: AJKD 1987: 83-877 Ortega LM et al: Lupus 2010: 19-557
    42. 42. Hemodialysis• Patient survival with either hemodialysis or CAPD appears to be similar in patients with ESRD ( 5 year survival rate is 90%)• Most lupus nephritis patients with end-stage renal disease opt for hemodialysis therapy(82%)• Increased risk of death during the first three months of dialysis due to sepsis and other complications of high dose of steroids. Cheigh et al AJKD 1993: 21:2 Devlin et al Arth Care & Resear 2011
    43. 43. Peritoneal Dialysis• Peritoneal dialysis and kidney transplantations lower among African- Americans, uninsured, and unemployed• Only 12.2% of LN patients started PD between 1995-2006• Patients on PD do better than HD after kidney transplantation• There may be high risk of peritonitis and non catheter related Infections in PD. Huang et al PDI 2001 21:143 Siu YP et al NDT 2005 20:2797 Kasiske et al J Transp 2001
    44. 44. Kidney Transplantation• Under utilized in patients with LN• Only 3% of LN patients undergo renal transplantation• Graft survival rates at 5 and 10 years in patients with lupus are similar to those in patients with other diseases.• Rate of recurrent disease is low ( 2-9% in LN patients)• Patients with rapidly progressive renal disease• Should undergo dialysis before kidney transplant• Measurement of serologic marker such as titres of• DNA and complement levels do not help predict• disease recurrence• Kidney transplant recipients with lupus and• Antiphospholipid antibodies are at increased• Risk for thrombotic events. Stone et al Semin Arth Rheu 1997 Choy et al Am J Transplant 2006
    45. 45. Thank You
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