Lupus Nephritis ManagementMohammed Abdel GawadNephrology SpecialistKidney & Urology Center (KUC)AlexandriaThe Soft Evidence
Follow Onwww.nephrotube.blogspot.com&Facebook GroupNephroTube2
What is EvidenceBased Medicine?
Evidence vs LogicLogically both of us may be right,BUTWhat is the EVIDENCE for what will be better for us?
Evidence vs Judgement
Should We Followthe EvidenceBlindly?NO
Think CriticallyTo Evaluate The Available Evidence
Dose available evidence fit all patients?
For every treatment protocol in thislecture, I will:• Mention its evidence.• Appraise it.• When you appraise a study about...
For every treatment protocol in thislecture, I will:• Mention its evidence.• Appraise it.• When you appraise a study about...
Nomenclature and Description for RatingGuideline Recommendations
Lupus Nephritis ISN/RPS Classification
Lupus Nephritis ISN/RPS Classification
Class I LN is not associated with long-term impairment of kidney function.At present, there are no data to suggest thateve...
There are no evidence-based dataon the treatment of class II LN.While there have been noprospective studies of thetreatmen...
Lupus Nephritis ISN/RPS Classification
Class III & IV ManagementOverviewInitialTherapyMaintenanceTherapyThe objective is to rapidlydecrease kidneyinflammation by...
Treatment RegimensInitial Therapy - Class III & IVWidely used regimens Other regimensNIH(IV high dose Cyclophosphamide)Aza...
Treatment RegimensInitial Therapy - Class III & IVWidely used regimens Other regimensNIH(IV high dose Cyclophosphamide)Aza...
Widely used regimensInitial Therapy - Class III & IVThe dosing and duration of corticosteroids hasnever been subject to ev...
Widely used regimensInitial Therapy - Class III & IVThe dosing and duration of corticosteroids hasnever been subject to ev...
Widely used regimensInitial Therapy - Class III & IVThe dosing and duration of corticosteroids hasnever been subject to ev...
(A) NHI RegimenAustin III HA et al. N Engl J Med 1986; 314: 614–619.
(A) NHI RegimenAustin III HA et al. N Engl J Med 1986; 314: 614–619.With low dose prednisone
(A) NHI RegimenAustin III HA et al. N Engl J Med 1986; 314: 614–619.
(A) NHI RegimenTrials supporting Cyclophosphamide for initialtherapy• Boumpas DT, Austin III HA, Vaughn EM et al. Controll...
(B) Euro-Lupus RegimenHoussiau FA et al. Arthritis Rheum 2002; 46: 2121–2131
(B) Euro-Lupus RegimenHoussiau FA et al. Arthritis Rheum 2002; 46: 2121–2131
(B) Euro-Lupus RegimenHoussiau FA et al. Arthritis Rheum 2002; 46: 2121–2131
(B) Euro-Lupus RegimenHoussiau FA et al. Arthritis Rheum 2002; 46: 2121–2131
(B) Euro-Lupus RegimenHoussiau FA et al. Ann Rheum Dis 2010; 69: 61–64
(B) Euro-Lupus RegimenHoussiau FA et al. Ann Rheum Dis 2010; 69: 61–64
(B) Euro-Lupus RegimenHoussiau FA et al. Ann Rheum Dis 2010; 69: 61–64
(B) Euro-Lupus RegimenHoussiau FA et al. Ann Rheum Dis 2010; 69: 61–64
(B) Euro-Lupus RegimenDose it fit all patients?• Mild to moderate kidney disease. Few patientsin the Euro-Lupus trial had ...
Initial Therapy - Class III & IVNIH vs Euro-Lupus
(C) Oral Cyclophosphamide Regimen
(C) Oral Cyclophosphamide Regimen• Oral CYC vs IV CYC• Oral CYC vs MMF
(C) Oral Cyclophosphamide Regimen• Oral CYC vs IV CYC
(C) Oral Cyclophosphamide Regimenvs IV Cyclophosphamide• It has equivalent efficacy to i.v. cyclophosphamide inprospective...
(C) Oral Cyclophosphamide Regimenvs IV Cyclophosphamide• It has equivalent efficacy to i.v. cyclophosphamide inprospective...
(C) Oral Cyclophosphamide Regimen• Oral CYC vs IV CYC• Oral CYC vs MMF
(C) Oral Cyclophosphamide Regimen• Oral CYC vs IV CYC• Oral CYC vs MMF
(C) Oral Cyclophosphamide Regimenvs MMF• It has also been shown equivalent to MMF in Chinese patients.Chan TM et al. N Eng...
(C) Oral Cyclophosphamide Regimenvs MMF• It has also been shown equivalent to MMF in Chinese patients.Chan TM et al. N Eng...
(C) Oral Cyclophosphamide Regimen• More adverse effects have been reported withoral compared to i.v. cyclophosphamide, but...
(C) Oral Cyclophosphamide Regimen
(D) MMF Regimen
(D) MMF Regimen• MMF vs Oral CYC• MMF vs IV CYC
(D) MMF Regimen• MMF vs Oral CYC• MMF vs IV CYC
(D) Mycophenolate Regimen vs Oral CYC• MMF (maximum 3 g/d) for 6 months has been tested in an RCT in aChinese population, ...
(D) Mycophenolate Regimen vs Oral CYC• MMF (maximum 3 g/d) for 6 months has been tested in an RCT in aChinese population, ...
(D) MMF Regimen• MMF vs Oral CYC• MMF vs IV CYC
(D) MMF Regimen• MMF vs Oral CYC• MMF vs IV CYC
Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112(D) Mycophenolate Regimen vs IV CYCALMS Trial•370 patients with classI...
Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112(D) Mycophenolate Regimen vs IV CYCALMS TrialMMF had anequivalentrespo...
Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112(D) Mycophenolate Regimen vs IV CYCALMS TrialSimilar incidence ofadver...
Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112(D) Mycophenolate Regimen vs IV CYCALMS TrialBlack,Hispanic,Mixed
El-Shafey EM, Abdou SH, Shareef MM. Clin Exp Nephrol 2010;14: 214–221.(D) Mycophenolate Regimen vs IV CYC
El-Shafey EM, Abdou SH, Shareef MM. Clin Exp Nephrol 2010;14: 214–221.(D) Mycophenolate Regimen vs IV CYC
(D) Mycophenolate Regimen vs IV CYCGinzler EM et al. N Engl J Med 2005; 353: 2219–2228.
(D) Mycophenolate Regimen vs IV CYCGinzler EM et al. N Engl J Med 2005; 353: 2219–2228.In this 24-week trial,mycophenolate...
(D) Mycophenolate Regimen vs IV CYCGinzler EM et al. N Engl J Med 2005; 353: 2219–2228.In this 24-week trial,mycophenolate...
(D) Mycophenolate Regimen vs IV CYCGinzler EM et al. N Engl J Med 2005; 353: 2219–2228.
(D) Mycophenolate Regimen & LNSeverity• The patients in studies of MMF vs.cyclophosphamide generally had less severeLN, as...
Choice of Initial TherapyClass III & IV• In severe class III/IV LN, a cyclophosphamidecontaining protocol for initial ther...
Choice of Initial TherapyClass III & IV
Treatment RegimensInitial Therapy - Class III & IVWidely used regimens Other regimensNIH(IV high dose Cyclophosphamide)Aza...
Treatment RegimensInitial Therapy - Class III & IV
Treatment RegimensInitial Therapy - Class III & IV
Treatment RegimensInitial Therapy - Class III & IV
Does Rituximab have a role in initialtherapy of proliferative LN?• Because the kidney response rate for class III and IV L...
Does Rituximab have a role in initialtherapy of proliferative LN?Rovin BH et al. J Am Soc Nephrol 2009; 20: 77A.
Does Rituximab have a role in initialtherapy of proliferative LN?Rovin BH et al. J Am Soc Nephrol 2009; 20: 77A.
! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
Class III & IV ManagementOverviewInitialTherapyMaintenanceTherapyThe objective is to rapidlydecrease kidneyinflammation by...
Choice of Maintenance TherapyClass III & IV• MMF• AZA• Cyclosporine
Choice of Maintenance TherapyClass III & IV• MMF• AZA• Cyclosporine
Choice of Maintenance TherapyClass III & IV• A cohort of mainly black and Hispanic patients• Class III/IV LN• Treated with...
Choice of Maintenance TherapyClass III & IVContreras G et al. N Engl J Med 2004; 350: 971–980.Over 72 months, patientstrea...
Choice of Maintenance TherapyClass III & IVContreras G et al. N Engl J Med 2004; 350: 971–980.Over 72 months, patientstrea...
Choice of Maintenance TherapyClass III & IV - MMF vs AZA• Compared MMF with AZA as maintenance therapy in apredominantly C...
After at least 3 years offollow-up, this trialfound MMF andazathioprine to beequivalent.Houssiau FA et al. Ann Rheum Dis 2...
Choice of Maintenance TherapyClass III & IV - MMF vs AZA• ALMS trial extension phase.• Compared MMF and AZA as maintenance...
Choice of Maintenance TherapyClass III & IV - MMF vs AZADooley et al. N Engl J Med 2011; 365: 1886–1895.Over 3 years, thec...
Choice of Maintenance TherapyClass III & IV - MMF vs AZADooley et al. N Engl J Med 2011; 365: 1886–1895.Over 3 years, thec...
Choice of Maintenance TherapyClass III & IV - MMF vs AZAAfter at least 3 years of follow-up,this trial found MMF andazathi...
Choice of Maintenance TherapyClass III & IV - MMF vs AZAAfter at least 3 years of follow-up,this trial found MMF andazathi...
Choice of Maintenance TherapyClass III & IV• MMF• AZA• Cyclosporine
Choice of Maintenance TherapyClass III & IV• MMF• AZA• Cyclosporine
Choice of Maintenance TherapyClass III & IV - CyclosporineMoroni G et al. Clin J Am Soc Nephrol 2006; 1: 925–932.A pilot R...
Duration of Therapy• Few patients reach complete remission by 6 months, (andkidney biopsies after 6 months of initial ther...
Duration of Therapy• We suggest that immunosuppressive therapy shouldusually be slowly tapered after patients have been in...
• Decisions to alter therapy should not be basedon urine sediment alone. A repeat kidneybiopsy may be considered if kidney...
Monitoring Therapy• The progress of LN therapy is monitored with serial measurements of:– proteinuria (In LN, as in other ...
Lupus Nephritis ISN/RPS Classification
There are no convincing data to treatclass V LN and subnephrotic proteinuriawith immunosuppression; however,given the adve...
The justifications to treat class V LN and nephrotic proteinuriawith immunosuppression are as follows:1. Decreased GFR occ...
Class V – Nephrotic RangeCyclosporine vs CYCAustin III HA et al. J Am Soc Nephrol 2009; 20: 901–911.
Austin III HA et al. J Am Soc Nephrol 2009; 20: 901–911.Both cyclophosphamide andcyclosporine significantlyincreased respo...
Austin III HA et al. J Am Soc Nephrol 2009; 20: 901–911.Relapse after stoppingtherapy was much more likelyin those treated...
Class V – Nephrotic RangeMMF & AZA• There have been small uncontrolled retrospective, oropen-label, studies of MMF and aza...
Class V – Nephrotic RangeMMFSpetie DN et al. Kidney Int 2004; 66: 2411-2415.
Class V – Nephrotic RangeMMFSpetie DN et al. Kidney Int 2004; 66: 2411-2415.
Class V – Nephrotic RangeAzathioprineSpetie DN et al. Kidney Int 2004; 66: 2411-2415.
Class V – Nephrotic RangeAzathioprineSpetie DN et al. Kidney Int 2004; 66: 2411-2415.
Class V – Nephrotic RangeTacrolimusSzeto CC et al. Rheumatology (Oxford) 2008; 47: 1678–1681.
Class V – Nephrotic RangeTacrolimusSzeto CC et al. Rheumatology (Oxford) 2008; 47: 1678–1681.
Relapse - Diagnosis
• A fall in levels of serum complementcomponents and a rise in anti–doublestranded DNA antibody titers also support adiagn...
Relapse - Incidence• In subjects with LN who had participated in RCTs (1):– 40% of complete responders experienced a kidne...
Lupus Nephritis ISN/RPS Classification
There is low-quality evidence that hydroxychloroquinemay protect against the onset of LN, against relapsesof LN, ESRD, vas...
When to Biopsy?
Post card sent from Ed Lewis to Mel Schwrtzwhile Ed Lewis was at the 1980 ISKDC Meeting
Anyone WHO ISN’t confused really doesn’tunderstand the situation.Edward R. Murrow
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Thank YouGawad
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
Lupus Nephritis Management (The Soft Evidence)
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Lupus Nephritis Management (The Soft Evidence)

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  1. 1. Lupus Nephritis ManagementMohammed Abdel GawadNephrology SpecialistKidney & Urology Center (KUC)AlexandriaThe Soft Evidence
  2. 2. Follow Onwww.nephrotube.blogspot.com&Facebook GroupNephroTube2
  3. 3. What is EvidenceBased Medicine?
  4. 4. Evidence vs LogicLogically both of us may be right,BUTWhat is the EVIDENCE for what will be better for us?
  5. 5. Evidence vs Judgement
  6. 6. Should We Followthe EvidenceBlindly?NO
  7. 7. Think CriticallyTo Evaluate The Available Evidence
  8. 8. Dose available evidence fit all patients?
  9. 9. For every treatment protocol in thislecture, I will:• Mention its evidence.• Appraise it.• When you appraise a study about LN you have to considerthe following points:• Nnumber of patients.• Ethnicity.• Severity of the LN in study.• Duration of the study.• Remmision & relapse.• Side effects.
  10. 10. For every treatment protocol in thislecture, I will:• Mention its evidence.• Appraise it.• When you appraise a study about LN you have to considerthe following points:• Nnumber of patients.• Ethnicity.• Severity of the LN in study.• Duration of the study.• Remmision & relapse.• Side effects.
  11. 11. Nomenclature and Description for RatingGuideline Recommendations
  12. 12. Lupus Nephritis ISN/RPS Classification
  13. 13. Lupus Nephritis ISN/RPS Classification
  14. 14. Class I LN is not associated with long-term impairment of kidney function.At present, there are no data to suggest thatevery patient with lupus requires a kidneybiopsy, or that treatment of class I LN isclinically necessary.
  15. 15. There are no evidence-based dataon the treatment of class II LN.While there have been noprospective studies of thetreatment of nephrotic-rangeproteinuria in class II LN, it isreasonable to treat suchpatients as for MCD/FSGS incase of nephrotic syndrome,or if proteinuria cannot becontrolled using RAS blockade.
  16. 16. Lupus Nephritis ISN/RPS Classification
  17. 17. Class III & IV ManagementOverviewInitialTherapyMaintenanceTherapyThe objective is to rapidlydecrease kidneyinflammation by initialintensive treatment,and thenconsolidate treatmentover a longer time.At the end of initialtherapy, remission maynot be achieved.Remissions continue tooccur well into themaintenance phase.The evolution of initial therapy in proliferativeLN has been to reduce toxicity whilemaintaining efficacy.
  18. 18. Treatment RegimensInitial Therapy - Class III & IVWidely used regimens Other regimensNIH(IV high dose Cyclophosphamide)AzathioprineEuro-Lupus(IV low dose Cyclophosphamide)CyclosporineOral CyclophosphamideCombination of Tacrolimus and MMF(‘‘multitarget’’ therapy).MMF ProtocolAll the above regimens are in addition of Corticosteroids.
  19. 19. Treatment RegimensInitial Therapy - Class III & IVWidely used regimens Other regimensNIH(IV high dose Cyclophosphamide)AzathioprineEuro-Lupus(IV low dose Cyclophosphamide)CyclosporineOral CyclophosphamideCombination of Tacrolimus and MMF(‘‘multitarget’’ therapy).MMF ProtocolAll the above regimens are in addition of Corticosteroids.
  20. 20. Widely used regimensInitial Therapy - Class III & IVThe dosing and duration of corticosteroids hasnever been subject to evaluation by RCTs.
  21. 21. Widely used regimensInitial Therapy - Class III & IVThe dosing and duration of corticosteroids hasnever been subject to evaluation by RCTs.
  22. 22. Widely used regimensInitial Therapy - Class III & IVThe dosing and duration of corticosteroids hasnever been subject to evaluation by RCTs.
  23. 23. (A) NHI RegimenAustin III HA et al. N Engl J Med 1986; 314: 614–619.
  24. 24. (A) NHI RegimenAustin III HA et al. N Engl J Med 1986; 314: 614–619.With low dose prednisone
  25. 25. (A) NHI RegimenAustin III HA et al. N Engl J Med 1986; 314: 614–619.
  26. 26. (A) NHI RegimenTrials supporting Cyclophosphamide for initialtherapy• Boumpas DT, Austin III HA, Vaughn EM et al. Controlled trial of pulsemethylprednisolone versus two regimens of pulsecyclophosphamide in severe lupus nephritis. Lancet 1992; 340:741–745.• Donadio Jr JV, Holley KE, Ferguson RH et al. Treatment of diffuseproliferative lupus nephritis with prednisone and combinedprednisone and cyclophosphamide. N Engl J Med 1978; 299: 1151–1155.• Gourley MF, Austin III HA, Scott D et al. Methylprednisolone andcyclophosphamide, alone or in combination, in patients with lupusnephritis. A randomized, controlled trial. Ann Intern Med 1996; 125:549–557.
  27. 27. (B) Euro-Lupus RegimenHoussiau FA et al. Arthritis Rheum 2002; 46: 2121–2131
  28. 28. (B) Euro-Lupus RegimenHoussiau FA et al. Arthritis Rheum 2002; 46: 2121–2131
  29. 29. (B) Euro-Lupus RegimenHoussiau FA et al. Arthritis Rheum 2002; 46: 2121–2131
  30. 30. (B) Euro-Lupus RegimenHoussiau FA et al. Arthritis Rheum 2002; 46: 2121–2131
  31. 31. (B) Euro-Lupus RegimenHoussiau FA et al. Ann Rheum Dis 2010; 69: 61–64
  32. 32. (B) Euro-Lupus RegimenHoussiau FA et al. Ann Rheum Dis 2010; 69: 61–64
  33. 33. (B) Euro-Lupus RegimenHoussiau FA et al. Ann Rheum Dis 2010; 69: 61–64
  34. 34. (B) Euro-Lupus RegimenHoussiau FA et al. Ann Rheum Dis 2010; 69: 61–64
  35. 35. (B) Euro-Lupus RegimenDose it fit all patients?• Mild to moderate kidney disease. Few patientsin the Euro-Lupus trial had severe kidneydisease (defined as rapidly progressive kidney failure andtypically with widespread (>50%) segmental glomerularnecrosis or crescents).• RCT in Caucasians.Therefore, it is not certain whether thisprotocol will be effective in patients of otherancestry, or in patients with more severe classIII/IV LN.
  36. 36. Initial Therapy - Class III & IVNIH vs Euro-Lupus
  37. 37. (C) Oral Cyclophosphamide Regimen
  38. 38. (C) Oral Cyclophosphamide Regimen• Oral CYC vs IV CYC• Oral CYC vs MMF
  39. 39. (C) Oral Cyclophosphamide Regimen• Oral CYC vs IV CYC
  40. 40. (C) Oral Cyclophosphamide Regimenvs IV Cyclophosphamide• It has equivalent efficacy to i.v. cyclophosphamide inprospective observational studies.Austin III HA et al. N Engl J Med 1986; 314: 614–619./
  41. 41. (C) Oral Cyclophosphamide Regimenvs IV Cyclophosphamide• It has equivalent efficacy to i.v. cyclophosphamide inprospective observational studies.Mok CC et al. Am J Kidney Dis 2001; 38: 256–264.
  42. 42. (C) Oral Cyclophosphamide Regimen• Oral CYC vs IV CYC• Oral CYC vs MMF
  43. 43. (C) Oral Cyclophosphamide Regimen• Oral CYC vs IV CYC• Oral CYC vs MMF
  44. 44. (C) Oral Cyclophosphamide Regimenvs MMF• It has also been shown equivalent to MMF in Chinese patients.Chan TM et al. N Engl J Med 2000; 343:1156–1162
  45. 45. (C) Oral Cyclophosphamide Regimenvs MMF• It has also been shown equivalent to MMF in Chinese patients.Chan TM et al. N Engl J Med 2000; 343:1156–1162
  46. 46. (C) Oral Cyclophosphamide Regimen• More adverse effects have been reported withoral compared to i.v. cyclophosphamide, butthis is not a consistent finding.Austin III HA et al. N Engl J Med 1986; 314: 614–619.
  47. 47. (C) Oral Cyclophosphamide Regimen
  48. 48. (D) MMF Regimen
  49. 49. (D) MMF Regimen• MMF vs Oral CYC• MMF vs IV CYC
  50. 50. (D) MMF Regimen• MMF vs Oral CYC• MMF vs IV CYC
  51. 51. (D) Mycophenolate Regimen vs Oral CYC• MMF (maximum 3 g/d) for 6 months has been tested in an RCT in aChinese population, and was equivalent in achieving remission to RegimenC; patients with severe LN were excluded from this study.Chan TM et al. J Am Soc Nephrol 2005; 16: 1076–1084
  52. 52. (D) Mycophenolate Regimen vs Oral CYC• MMF (maximum 3 g/d) for 6 months has been tested in an RCT in aChinese population, and was equivalent in achieving remission to RegimenC; patients with severe LN were excluded from this study.Chan TM et al. J Am Soc Nephrol 2005; 16: 1076–1084
  53. 53. (D) MMF Regimen• MMF vs Oral CYC• MMF vs IV CYC
  54. 54. (D) MMF Regimen• MMF vs Oral CYC• MMF vs IV CYC
  55. 55. Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112(D) Mycophenolate Regimen vs IV CYCALMS Trial•370 patients with classIII, IV, and V LN•Randomized to IV CYCpulses for 6 months orMMF 3gm/d target dosefor 6 months
  56. 56. Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112(D) Mycophenolate Regimen vs IV CYCALMS TrialMMF had anequivalentresponse rate toi.v.cyclophosphamideat 6 months
  57. 57. Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112(D) Mycophenolate Regimen vs IV CYCALMS TrialSimilar incidence ofadverse events includingserious infections anddeaths.
  58. 58. Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112(D) Mycophenolate Regimen vs IV CYCALMS TrialBlack,Hispanic,Mixed
  59. 59. El-Shafey EM, Abdou SH, Shareef MM. Clin Exp Nephrol 2010;14: 214–221.(D) Mycophenolate Regimen vs IV CYC
  60. 60. El-Shafey EM, Abdou SH, Shareef MM. Clin Exp Nephrol 2010;14: 214–221.(D) Mycophenolate Regimen vs IV CYC
  61. 61. (D) Mycophenolate Regimen vs IV CYCGinzler EM et al. N Engl J Med 2005; 353: 2219–2228.
  62. 62. (D) Mycophenolate Regimen vs IV CYCGinzler EM et al. N Engl J Med 2005; 353: 2219–2228.In this 24-week trial,mycophenolate mofetilwas more effective thanintravenouscyclophosphamide ininducing remission oflupus nephritis and had amore favorable safetyprofile.
  63. 63. (D) Mycophenolate Regimen vs IV CYCGinzler EM et al. N Engl J Med 2005; 353: 2219–2228.In this 24-week trial,mycophenolate mofetilwas more effective thanintravenouscyclophosphamide ininducing remission oflupus nephritis and had amore favorable safetyprofile.
  64. 64. (D) Mycophenolate Regimen vs IV CYCGinzler EM et al. N Engl J Med 2005; 353: 2219–2228.
  65. 65. (D) Mycophenolate Regimen & LNSeverity• The patients in studies of MMF vs.cyclophosphamide generally had less severeLN, assessed by level of proteinuria and kidneyfunction, than the patients in some of theRCTs of cyclophosphamide.• However, a subset of patients in the ALMS trialdid have severe LN and responded to MMF, somore data are required (!!!!).
  66. 66. Choice of Initial TherapyClass III & IV• In severe class III/IV LN, a cyclophosphamidecontaining protocol for initial therapy may bepreferred.• In patients with less severe proliferative LN, aninitial regimen not containingcyclophosphamide should be considered.
  67. 67. Choice of Initial TherapyClass III & IV
  68. 68. Treatment RegimensInitial Therapy - Class III & IVWidely used regimens Other regimensNIH(IV high dose Cyclophosphamide)AzathioprineEuro-Lupus(IV low dose Cyclophosphamide)CyclosporineOral CyclophosphamideCombination of Tacrolimus and MMF(‘‘multitarget’’ therapy).MMF ProtocolAll the above regimens are in addition of Corticosteroids.
  69. 69. Treatment RegimensInitial Therapy - Class III & IV
  70. 70. Treatment RegimensInitial Therapy - Class III & IV
  71. 71. Treatment RegimensInitial Therapy - Class III & IV
  72. 72. Does Rituximab have a role in initialtherapy of proliferative LN?• Because the kidney response rate for class III and IV LN with any ofthe initial therapies so far discussed is only about 60% at 6–12months, an RCT adding rituximab or placebo to MMF pluscorticosteroids for initial LN therapy was undertaken to determine ifremission rates could be improved.• At 12 months, there were no differences between the rituximaband placebo groups in terms of complete or partial remissions.Thus, rituximab cannot be recommended as adjunctive initialtherapy.Rovin BH et al. J Am Soc Nephrol 2009; 20: 77A.
  73. 73. Does Rituximab have a role in initialtherapy of proliferative LN?Rovin BH et al. J Am Soc Nephrol 2009; 20: 77A.
  74. 74. Does Rituximab have a role in initialtherapy of proliferative LN?Rovin BH et al. J Am Soc Nephrol 2009; 20: 77A.
  75. 75. ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
  76. 76. Class III & IV ManagementOverviewInitialTherapyMaintenanceTherapyThe objective is to rapidlydecrease kidneyinflammation by initialintensive treatment,and thenconsolidate treatmentover a longer time.At the end of initialtherapy, remission maynot be achieved.Remissions continue tooccur well into themaintenance phase.The evolution of initial therapy in proliferativeLN has been to reduce toxicity whilemaintaining efficacy.
  77. 77. Choice of Maintenance TherapyClass III & IV• MMF• AZA• Cyclosporine
  78. 78. Choice of Maintenance TherapyClass III & IV• MMF• AZA• Cyclosporine
  79. 79. Choice of Maintenance TherapyClass III & IV• A cohort of mainly black and Hispanic patients• Class III/IV LN• Treated with monthly i.v. cyclophosphamide for up to sevencycles, followed by azathioprine or MMF,• And compared to patients treated with 6-monthlycyclophosphamide pulses followed by quarterlycyclophosphamide pulses for 1 year beyond remission.Contreras G et al. N Engl J Med 2004; 350: 971–980.
  80. 80. Choice of Maintenance TherapyClass III & IVContreras G et al. N Engl J Med 2004; 350: 971–980.Over 72 months, patientstreated with maintenanceazathioprine or MMF weresignificantly less likely toreach the composite end-point of death or CKD thanthe CTX maintenance group,and to experience feweradverse effects.
  81. 81. Choice of Maintenance TherapyClass III & IVContreras G et al. N Engl J Med 2004; 350: 971–980.Over 72 months, patientstreated with maintenanceazathioprine or MMF weresignificantly less likely toreach the composite end-point of death or CKD thanthe CTX maintenance group,and to experience feweradverse effects.
  82. 82. Choice of Maintenance TherapyClass III & IV - MMF vs AZA• Compared MMF with AZA as maintenance therapy in apredominantly Caucasian population after initialtreatment with low-dose (Regimen B) cyclophosphamide.• The primary end-point was time to kidney relapse.Houssiau FA et al. Ann Rheum Dis 2010; 69: 2083–2089.
  83. 83. After at least 3 years offollow-up, this trialfound MMF andazathioprine to beequivalent.Houssiau FA et al. Ann Rheum Dis 2010; 69: 2083–2089.Choice of Maintenance TherapyClass III & IV - MMF vs AZA
  84. 84. Choice of Maintenance TherapyClass III & IV - MMF vs AZA• ALMS trial extension phase.• Compared MMF and AZA as maintenance therapies afterthe 6-month initial treatment period (Regimen D).• Patients entered this extension phase only if they achieveda complete or partial remission after initial therapy.Dooley et al. N Engl J Med 2011; 365: 1886–1895.
  85. 85. Choice of Maintenance TherapyClass III & IV - MMF vs AZADooley et al. N Engl J Med 2011; 365: 1886–1895.Over 3 years, thecomposite treatmentfailure end-point (death,ESRD, kidney flare,sustained doubling of SCr,or requirement for rescuetherapy) was reached in16% of MMF-treatedpatients compared to 32%of azathioprine-treatedpatients.
  86. 86. Choice of Maintenance TherapyClass III & IV - MMF vs AZADooley et al. N Engl J Med 2011; 365: 1886–1895.Over 3 years, thecomposite treatmentfailure end-point (death,ESRD, kidney flare,sustained doubling of SCr,or requirement for rescuetherapy) was reached in16% of MMF-treatedpatients compared to 32%of azathioprine-treatedpatients.
  87. 87. Choice of Maintenance TherapyClass III & IV - MMF vs AZAAfter at least 3 years of follow-up,this trial found MMF andazathioprine to be equivalent.Over 3 years, the compositetreatment failure was reachedin 16% of MMF-treatedpatients compared to 32% ofazathioprine-treated patients.
  88. 88. Choice of Maintenance TherapyClass III & IV - MMF vs AZAAfter at least 3 years of follow-up,this trial found MMF andazathioprine to be equivalent.Over 3 years, the compositetreatment failure was reachedin 16% of MMF-treatedpatients compared to 32% ofazathioprine-treated patients.
  89. 89. Choice of Maintenance TherapyClass III & IV• MMF• AZA• Cyclosporine
  90. 90. Choice of Maintenance TherapyClass III & IV• MMF• AZA• Cyclosporine
  91. 91. Choice of Maintenance TherapyClass III & IV - CyclosporineMoroni G et al. Clin J Am Soc Nephrol 2006; 1: 925–932.A pilot RCT in 69 patients withclass III/IV LN suggested that 2years of cyclosporine may be aseffective as 2 years of azathioprinefor maintenance, after initialtreatment with prednisone andoral cyclophosphamide, in termsof relapse prevention andreduction of proteinuria.
  92. 92. Duration of Therapy• Few patients reach complete remission by 6 months, (andkidney biopsies after 6 months of initial therapy haveshown that, while active inflammation tends to improve,complete resolution of pathologic changes is unusual). (1)• Consistent with this finding, clinical improvement in classIII/IV LN continues well beyond 6 months and into themaintenance phase of therapy. (2)• There is no evidence to help determine the duration ofmaintenance therapy. The average duration ofimmunosuppression was 3.5 years in seven RCTs. (3)(1) Traitanon O et al. Lupus 2008; 17: 744–751.(2) Grootscholten C et al. Kidney Int 2006; 70: 732–742.(3) Houssiau FA et al. Ann Rheum Dis 2010; 69: 61–64.
  93. 93. Duration of Therapy• We suggest that immunosuppressive therapy shouldusually be slowly tapered after patients have been incomplete remission for a year.• If a patient has a history of kidney relapses it may beprudent to extend maintenance therapy.• Immunosuppression should be continued for patients whoachieve only a partial remission. (However, the strategy oftrying to convert a partial remission to a completeremission by increasing corticosteroids or using alternativeimmunosuppressive agents is not supported by evidence).
  94. 94. • Decisions to alter therapy should not be basedon urine sediment alone. A repeat kidneybiopsy may be considered if kidney function isdeteriorating.Duration of Therapy
  95. 95. Monitoring Therapy• The progress of LN therapy is monitored with serial measurements of:– proteinuria (In LN, as in other proteinuric GN, resolution of proteinuria is thestrongest predictor of kidney survival; thus, effective treatment is expected todecrease proteinuria over time).– SCr.– Urine sediment (However, hematuria may persist for months even if therapy isotherwise successful in improving proteinuria and kidney dysfunction).– It is desirable to see serologic markers of lupus activity, such as complementand double-stranded DNA antibody levels, normalize with treatment.(However, C3 and C4, and anti–double-stranded DNA antibodies have lowsensitivity (49–79%) and specificity (51–74%) in relationship to LN activity).
  96. 96. Lupus Nephritis ISN/RPS Classification
  97. 97. There are no convincing data to treatclass V LN and subnephrotic proteinuriawith immunosuppression; however,given the adverse effects of proteinuriaon the kidney, it is reasonable to treatthese patients with antiproteinuric andantihypertensive medications
  98. 98. The justifications to treat class V LN and nephrotic proteinuriawith immunosuppression are as follows:1. Decreased GFR occurs in about 20% of cases of class V LN, and ESRD inabout 8–12% after 7–12 years. (1)2. One study reporting death or ESRD in 28% of patients at 10 years. (2)3. Spontaneous remission of heavy proteinuria occurs in only a minority ofclass V LN.(3)4. The adverse effects of sustained, heavy proteinuria includehyperlipidemia and atherosclerosis, contributing to cardiovascularmorbidity and mortality, (4) and hypercoagulability with arterial andvenous(1) Mok CC et al. Lupus 2009; 18: 1091–1095.(2) Sloan RP et al. J Am Soc Nephrol 1996; 7: 299–305.(3) Gonzalez-Dettoni H, Tron F. Adv Nephrol Necker Hosp 1985; 14: 347–364.(4) Wilmer WA et al. J Am Soc Nephrol 2003; 14: 3217–3232.Class V – Nephrotic Range
  99. 99. Class V – Nephrotic RangeCyclosporine vs CYCAustin III HA et al. J Am Soc Nephrol 2009; 20: 901–911.
  100. 100. Austin III HA et al. J Am Soc Nephrol 2009; 20: 901–911.Both cyclophosphamide andcyclosporine significantlyincreased responseClass V – Nephrotic RangeCyclosporine vs CYC
  101. 101. Austin III HA et al. J Am Soc Nephrol 2009; 20: 901–911.Relapse after stoppingtherapy was much more likelyin those treated withcyclosporine compared tocyclophosphamide (norelapse in 48 months).Class V – Nephrotic RangeCyclosporine vs CYC
  102. 102. Class V – Nephrotic RangeMMF & AZA• There have been small uncontrolled retrospective, oropen-label, studies of MMF and azathioprine with orwithout corticosteroids in class V LN.• In general, these studies have shown completeremission rates of 40–60% at 6–12 months.
  103. 103. Class V – Nephrotic RangeMMFSpetie DN et al. Kidney Int 2004; 66: 2411-2415.
  104. 104. Class V – Nephrotic RangeMMFSpetie DN et al. Kidney Int 2004; 66: 2411-2415.
  105. 105. Class V – Nephrotic RangeAzathioprineSpetie DN et al. Kidney Int 2004; 66: 2411-2415.
  106. 106. Class V – Nephrotic RangeAzathioprineSpetie DN et al. Kidney Int 2004; 66: 2411-2415.
  107. 107. Class V – Nephrotic RangeTacrolimusSzeto CC et al. Rheumatology (Oxford) 2008; 47: 1678–1681.
  108. 108. Class V – Nephrotic RangeTacrolimusSzeto CC et al. Rheumatology (Oxford) 2008; 47: 1678–1681.
  109. 109. Relapse - Diagnosis
  110. 110. • A fall in levels of serum complementcomponents and a rise in anti–doublestranded DNA antibody titers also support adiagnosis of relapse but will not necessarily bepresent.Relapse - Diagnosis
  111. 111. Relapse - Incidence• In subjects with LN who had participated in RCTs (1):– 40% of complete responders experienced a kidneyrelapse within a median of 41 months after remission,– 63% of partial responders had a kidney flare within amedian of 11.5 months after response.• The strongest risk factor for relapse is failure toachieve complete remission. (2)(1) Illei GG et al. Arthritis Rheum 2002; 46: 995–1002.(2) Chan TM et al. Lupus 2005; 14: 265–272.
  112. 112. Lupus Nephritis ISN/RPS Classification
  113. 113. There is low-quality evidence that hydroxychloroquinemay protect against the onset of LN, against relapsesof LN, ESRD, vascular thrombosis, and that it has afavorable impact on lipid profiles.Ruiz-Irastorza G et al. Ann Rheum Dis 2010; 69: 20–28.
  114. 114. When to Biopsy?
  115. 115. Post card sent from Ed Lewis to Mel Schwrtzwhile Ed Lewis was at the 1980 ISKDC Meeting
  116. 116. Anyone WHO ISN’t confused really doesn’tunderstand the situation.Edward R. Murrow
  117. 117. Follow Onwww.nephrotube.blogspot.com&Facebook GroupNephroTube139
  118. 118. Thank YouGawad

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