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Journal club old

  1. 1. Dr Sidharth Kumar Sethi MD, FISN, FIPNA Journal Club
  2. 2. Efficacy and Safety of Treatment with Rituximab for Difficult Steroid-Resistant and Dependent Nephrotic Syndrome: Multicentric Report Ashima Gulati, Aditi Sinha, Stanley C. Jordan, Pankaj Hari, Amit K. Dinda, Sonika Sharma, Rajendra . Srivastava, Asha Moudgil, and Arvind Bagga Divisions of Pediatric Nephrology and Genetics, and Department of Pathology, AIIMS, New Delhi, India; Nephrology and Transplant Immunology, Cedars-Sinai Medical Center, Los Angeles; and Nephrology and Kidney Transplant, Children’s National Medical Center, Washington, DC
  3. 3. Nephrotic syndrome- why occurs? <ul><li>T cell disease </li></ul><ul><ul><li>Steroids, Immunosuppressives </li></ul></ul><ul><ul><li>Remission after Measles </li></ul></ul><ul><ul><li>Occurs in NHL </li></ul></ul><ul><li>Now a B cell disease too! </li></ul><ul><ul><li>Either a circulating permeability factor </li></ul></ul><ul><ul><li>Aberrant cross talk between B and T cells </li></ul></ul>Pediatr Nephrol (2009) 24:1433–1438
  4. 4. Evidence in support of B cell disease <ul><li>Recurrence after renal transplantation, </li></ul><ul><li>Total B-cell count reduction during remission </li></ul><ul><li>Remission by depletion of B-cells </li></ul>
  5. 5. Pro-B Pre-B1 Pre-B2 Immature B Mature B Plasma MHC II CD19 CD22 CD34 Ig  VpreB,  5 CD10 CD20
  6. 6. Rituximab and B cells <ul><li>Targets the CD-20 antigen </li></ul><ul><ul><li>NOT expressed on stem cells, plasma cells, dendritic cells, and other normal tissues </li></ul></ul><ul><li>CD20 act to signal phosphorylation or as a calcium channel in human B-lymphocytes </li></ul><ul><li>CD20 good target for monoclonal antibody therapy as it is highly expressed, not shed or internalized upon antibody binding, and is minimally present in soluble form. </li></ul>
  7. 7. Mechanism of Actions <ul><li>Depletion of B-cells </li></ul><ul><ul><li>In patients with NHL, circulating B-cells are depleted within the first three doses of Rituxan therapy </li></ul></ul><ul><ul><li>B-cells remain depleted for up to 6 to 9 months post-treatment </li></ul></ul><ul><ul><li>Recovery occurring at approximately 6 months after completion of treatment. </li></ul></ul><ul><ul><li>Median B-cell levels return to normal by 12 months following completion of treatment. </li></ul></ul>
  8. 9. Rituximab and Cell death <ul><li>Rituximab invokes cell death through </li></ul><ul><ul><li>antibody dependent </li></ul></ul><ul><ul><li>cell-mediated toxicity, </li></ul></ul><ul><ul><li>complement-dependent cytotoxicity, </li></ul></ul><ul><ul><li>induction of apoptosis, and </li></ul></ul><ul><ul><li>sensitivity to cytotoxic agents or corticosteroids </li></ul></ul>
  9. 10. Course of Nephrotic Syndrome 40% 10-15% ISKDC. J Am Soc Nephrol 8: 769–776, 1997 Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin J Am Soc Nephrol 4: 1593–1600, 2009
  10. 11. Difficult to manage <ul><li>Steroid dependents- risk of toxicity </li></ul><ul><li>Steroid resistants- </li></ul><ul><ul><li>Complicated course </li></ul></ul><ul><ul><li>Risk of ESRD </li></ul></ul><ul><li>Risk of complications </li></ul><ul><li>Immunosuppressive drugs </li></ul><ul><li>Progressive kidney injury </li></ul>Pediatr Nephrol 24: 1525–1532, 2009; Pediatr Nephrol 22: 215-221, 2007
  11. 12. Rituximab <ul><li>Approved for Non Hodgkin’s Lymphoma </li></ul><ul><li>Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin’s B-cell lymphoma. Biochem Soc Trans 25: 705–708, 1997 </li></ul><ul><li>Also used successfully in </li></ul><ul><ul><li>rheumatoid arthritis, </li></ul></ul><ul><ul><li>systemic lupus erythematosus, </li></ul></ul><ul><ul><li>vasculitis, and </li></ul></ul><ul><ul><li>nephrotic syndrome </li></ul></ul>Semin Arthrit Rheum 36: 71–81, 2006 Pediatr Nephrol 24: 1433–1438, 2009
  12. 13. Rituximab in Nephrotic Syndrome <ul><li>Previous reports </li></ul><ul><li>Immediate Outcome </li></ul><ul><li>No data on Long term outcome </li></ul><ul><li>Rituximab in refractory nephrotic syndrome. Pediatr Nephrol 25: 461–468, 2010 </li></ul><ul><li>Single infusion of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome after long-term cyclosporine. Pediatr Nephrol 25:539–544, 2010 </li></ul><ul><li>Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356: 2751–2752, 2007 </li></ul><ul><li>Bagga A, Sinha A, Moudgil A: Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356: 2751–2752, 2007 </li></ul>
  13. 15. Material and Methods <ul><li>Records reviewed </li></ul><ul><li>SDNS; SRNS (Early/ Late) </li></ul><ul><li>Jan 2006- Feb 2009 </li></ul><ul><li>Minimum Follow up 12 months </li></ul><ul><li>Centres </li></ul><ul><ul><li>AIIMS, India, </li></ul></ul><ul><ul><li>CNMC, Washington DC, </li></ul></ul><ul><ul><li>CSMC, Los Angeles </li></ul></ul>
  14. 16. Definitions <ul><ul><li>Steroid Resistance (Early/ Late) </li></ul></ul><ul><ul><li>Lack of remission to Prednisone 2 mg/kg X 4 wks </li></ul></ul><ul><ul><li>Initial SRNS screened for NPHS1 and NPHS2, sequencing </li></ul></ul><ul><li>Steroid Dependence </li></ul><ul><ul><li>relapses on two occasions while receiving prednisone on alternate days or within 14 days of its discontinuation. </li></ul></ul>
  15. 17. Methods <ul><li>Clearances </li></ul><ul><ul><li>Ethical committee </li></ul></ul><ul><ul><li>DCGI </li></ul></ul><ul><li>Parental consent </li></ul><ul><ul><li>Information on Efficacy </li></ul></ul><ul><ul><li>Off Label use </li></ul></ul><ul><ul><li>Potential side effects </li></ul></ul>
  16. 18. Rituximab Therapy in SRNS <ul><li>Lack of remission despite therapy with </li></ul><ul><li>intravenous cyclophosphamide (500 mg/m 2 monthly for 6 months) and/or </li></ul><ul><li>calcineurin inhibitors (cyclosporine 5 to 6 mg/kg per day; tacrolimus 0.1 to 0.15 mg/kg per day for 6 months), </li></ul><ul><li>disease recurrence after stopping prolonged (3-yr) calcineurin inhibitor therapy, or </li></ul><ul><li>Presence of nephrotoxicity (striped pattern of </li></ul><ul><li>interstitial fibrosis or tubular atrophy and/or </li></ul><ul><li>arteriolar medial hyalinosis) </li></ul>
  17. 19. Rituximab therapy in SDNS <ul><li>Lack of steroid sparing effect (inability to sustain remission at a prednisone dose of 0.5 mg/kg every other day) or </li></ul><ul><li>Presence of steroid toxicity (cataract, or body mass index 95 th percentile for age), </li></ul><ul><ul><li>despite treatment with oral cyclophosphamide (2 mg/kg per day X 12 wks), levamisole (2.5 mg/kg X 6 mths), mycophenolate mofetil (MMF; 1000 mg/m 2 X 6 mths), and calcineurin inhibitors. </li></ul></ul><ul><li>Patients with relapses after prolonged (3 yrs) therapy with Calcineurin inhibitors or those showing nephrotoxicity </li></ul>
  18. 20. Rituximab not used <ul><li>Estimated GFR <60 ml/min per 1.73 m2, </li></ul><ul><li>infantile onset of nephrotic syndrome, </li></ul><ul><li>underlying hepatitis B or HIV positivity, Systemic lupus erythematosus, amyloidosis, Henoch Schonlein purpura, IgA nephropathy, membranoproliferative glomerulonephritis or membranous nephropathy, </li></ul><ul><li>more than one episode of serious infections (e.g., peritonitis, lower respiratory infection, cellulitis) in the past 12 months, or </li></ul><ul><li>current or previous therapy for tuberculosis. </li></ul>
  19. 21. Rituximab Therapy <ul><li>Dose 375 mg/m 2 weekly 4 doses SRNS and 2 doses SDNS. </li></ul><ul><li>Dissolved in normal saline (concentration 2 mg/ml), infused over 3 to 4 hours after 30-minute premedication with oral acetaminophen and diphenhydramine ; intravenous hydrocortisone (4 mg/kg) </li></ul><ul><li>SDNS, rituximab was given during corticosteroid-induced remission, not possible in SRNS. </li></ul><ul><li>Monitored for infusion-related reactions and </li></ul><ul><li>Screened at each visit for infections. </li></ul>
  20. 22. Concomitant therapy <ul><li>Oral prednisone was given every other day at a dose of 1.5 mg/kg for 2 weeks, 1 mg/kg for 4 weeks, 0.75 mg/kg for another 4 weeks, and then 0.5 mg/kg </li></ul><ul><li>Calcineurin inhibitor dose reduced to 50% at 3 months, with cessation, if possible, at 6 months. </li></ul><ul><li>Other immunosuppressive agents discontinued before treatment with rituximab, except in two adult patients with SRNS who received long-term therapy with MMF. </li></ul><ul><li>Enalapril 0.5 mg/kg per day all SRNS; SDNS with hypertension. </li></ul><ul><li>Furosemide if indicated. </li></ul><ul><li>SRNS and blood LDL-cholesterol >130 mg/dl atorvastatin </li></ul>
  21. 23. Follow-Up <ul><li>Daily urine albumin testing with a dipstick. </li></ul><ul><li>Spot urine protein/creatinine ratio (Up/Uc) in the first morning sample was done at 1, 3, 6, and 12 months after the last dose of rituximab. </li></ul><ul><li>Complete blood counts and levels of creatinine, albumin, and cholesterol were obtained at baseline and every 3 months thereafter. </li></ul>
  22. 24. Results <ul><li>n=57 </li></ul><ul><ul><li>24 SDNS </li></ul></ul><ul><ul><li>33 SRNS (3 Adults) </li></ul></ul>
  23. 26. SRNS patients <ul><li>Rituximab mean dose of 410 + 26.6 mg/wk for 4 weeks (except 5) </li></ul><ul><ul><li>(one dose in 3 adults and 1 child; 2 doses in 1 child). </li></ul></ul><ul><li>Cotrimoxazole prophylaxis to the first 16 patients for 6 months </li></ul><ul><ul><li>As no increased risk of infections </li></ul></ul><ul><ul><li>Normal levels of IgG </li></ul></ul><ul><ul><li>Discontinued. </li></ul></ul>
  24. 27. <ul><li>Median time to response was 32 days (range, 8 to 60 days) after the last dose of rituximab. </li></ul><ul><li>Prednisone continued in all patients at 0.5 mg/kg every other day, </li></ul><ul><li>Calcineurin inhibitors were stopped in 2, and </li></ul><ul><ul><li>and tapered to 50% in 2 patients. </li></ul></ul>
  25. 28. Longer follow up <ul><li>At a mean follow-up of 21.5 + 11.5 months (range, 12 to 48 months), remission was sustained in 15 patients (complete in 7 and partial in 8); no response was seen in 18 patients. </li></ul><ul><li>Nine patients (all non responders) had an estimated GFR 60 ml/min per 1.73 m 2 at 12 months, including five with CKD stage 5. </li></ul><ul><li>On multivariate logistic regression , none associated with response to rituximab therapy: </li></ul><ul><li>duration of nephrotic syndrome; initial or late resistance; renal histology, tubulointerstitial damage and calcineurin inhibitor nephrotoxicity; and prior response and duration of treatment with calcineurin inhibitors. </li></ul>
  26. 29. SRNS- Retreatment <ul><li>A repeat course (2 doses each)- 3 patients </li></ul><ul><ul><li>2 patients with complete and </li></ul></ul><ul><ul><li>1 patient with partial remission, </li></ul></ul><ul><li>12 to 24 months after the first course. </li></ul><ul><li>At follow-up of 9 to 18 months, </li></ul><ul><ul><li>2 patients partial remission </li></ul></ul><ul><ul><li>1 no response. </li></ul></ul>
  27. 31. SDNS patients <ul><li>Rituximab given at a mean dose of 400 + 20.7 mg/wk for 2 weeks; </li></ul><ul><ul><li>four patients concomitant therapy with calcineurin inhibitors. </li></ul></ul><ul><li>Relapse Rates at 12 Months </li></ul><ul><li>Sustained remission in 20 (83.3%) </li></ul><ul><ul><li>The time to first relapse was 11.2 + 2.7 months; (range, 8 to 14 months). </li></ul></ul><ul><li>Mean number of relapses </li></ul><ul><ul><li>before therapy was 4.0 + 0.4 episodes/patient per year </li></ul></ul><ul><ul><li>Reduced significantly to 0.2 + 0.3 episodes/patient per year in the next 12 months (mean difference, 3.9; 95% CI, 3.6, 4.1; P 0.000, ANOVA). </li></ul></ul><ul><li>At a mean follow-up of 16.8 + 5.9 months (range, 12 to 38 months), </li></ul><ul><ul><li>Sustained remission 17 (71%) patients </li></ul></ul>
  28. 32. SDNS patients <ul><ul><li>One or more immunosuppressive medications withdrawn in 12 </li></ul></ul><ul><ul><ul><li>In 8 additional patients, dose of prednisone tapered to 0.3 to 0.5 mg/kg every other day. </li></ul></ul></ul><ul><ul><ul><li>One patient multiple relapses 11 months after the first course of treatment. Received two additional doses of rituximab and is in remission 10 months later. </li></ul></ul></ul>
  29. 33. SDNS Patients
  30. 35. B-Cell (CD19) Depletion <ul><li>Data available in 14 patients </li></ul><ul><li>(5 SRNS and 9 SDNS). </li></ul><ul><li>Baseline CD 19 12.6 + 3.4% TLC </li></ul><ul><ul><li>After therapy, CD19 levels after two and four doses in patients with SDNS and SRNS, respectively. </li></ul></ul><ul><ul><li>0.2 + 0.1 % </li></ul></ul><ul><ul><li>0.3 + 0.2% </li></ul></ul>
  31. 36. Side Effects <ul><li>3 with SRNS and 1 with SDNS </li></ul><ul><ul><li>mild infusion-related reactions </li></ul></ul><ul><ul><li>(3- chills; 1-myalgia). </li></ul></ul><ul><li>No differences in TLC at baseline or 6 and 12 months after therapy. </li></ul><ul><li>None had peritonitis, cellulitis, thrombosis, or any other serious infection or adverse event on follow-up. </li></ul>
  32. 37. Discussion <ul><li>Efficacy of rituximab in difficult nephrotic syndrome; remission </li></ul><ul><ul><li>48.5% patients SRNS </li></ul></ul><ul><ul><li>95% reduction relapse frequency SDNS. </li></ul></ul><ul><li>Mostly SRNS or SDNS with unsatisfactory response to multiple immunosuppressive agents </li></ul><ul><li>Demonstration of complete or partial remission in 16 of 33 patients with SRNS valuable. </li></ul><ul><li>Similar outcomes </li></ul><ul><ul><li>initial and late resistance </li></ul></ul><ul><li>Trend toward better response rates in patients with steroid-resistant MCD compared with FSGS </li></ul>
  33. 38. SDNS patients <ul><li>Favorable long-term </li></ul><ul><li>Sustained remission 83.3% </li></ul><ul><li>Steroid-sparing effect 75% at 12 months. </li></ul><ul><li>Potential role in difficult SDNS. </li></ul>
  34. 42. Sustained remission in 19 patients (86.3%),
  35. 43. <ul><li>An international, multicenter report </li></ul><ul><li>28 patients with SDNS, 27 patients with SRNS, and 15 patients with post-transplant recurrence </li></ul><ul><li>variable severity </li></ul><ul><li>heterogeneity regarding treatment regimens and the dose </li></ul><ul><li>At a median follow-up of 5 months, 44% of patients with refractory SRNS showed reduction of proteinuria with normalization of serum albumin. </li></ul><ul><li>No difference in response based on underlying histology. </li></ul><ul><li>Although the authors found satisfactory initial response in 82% patients with SDNS, only 40% had sustained remission at a follow-up of 4.5 months . </li></ul>
  36. 45. Critical Appraisal <ul><li>Includes ethnically different populations, </li></ul><ul><li>Uniform inclusion and exclusion criteria. </li></ul><ul><li>Therapies for SRNS and SDNS similar. </li></ul><ul><li>Follow up: </li></ul><ul><ul><li>SRNS 21.5 + 11.5 months </li></ul></ul><ul><ul><li>SDNS 16.8 + 5.9 months </li></ul></ul><ul><li>Extended follow-up of SDNS emphasizes the impact of rituximab in </li></ul><ul><ul><li>causing sustained remission and marked corticosteroid sparing. </li></ul></ul><ul><li>Also confirms previous experience </li></ul><ul><ul><li>satisfactory short-term results 5 patients with difficult SRNS. </li></ul></ul>
  37. 46. Side Effects <ul><li>Multicentric French report </li></ul><ul><ul><li>transient adverse effects 45% </li></ul></ul><ul><ul><li>1 P. carinii pneumonia </li></ul></ul><ul><li>Prytula et al </li></ul><ul><ul><li>acute reactions in 27% patients </li></ul></ul><ul><ul><li>high incidence severe side effects including anaphylaxis and serious infections. </li></ul></ul><ul><li>Reversible cytokine shock and neutropenia </li></ul>
  38. 47. New Fatal Side Effects
  39. 48. Limitations <ul><li>Lack of a control group. </li></ul><ul><li>Prospective controlled trials necessary to confirm the efficacy </li></ul><ul><li>Obtaining CD19 counts, serial monitoring not done. </li></ul><ul><li>Number of doses of rituximab used based on experience rather than targeting specific CD19 levels, dose? </li></ul><ul><li>Potential urinary losses of rituximab, more doses used in SRNS </li></ul>
  40. 49. Conclusions <ul><li>Might be a bias for reporting favorable outcomes </li></ul><ul><li>Rituximab benefits a proportion of patients with difficult SDNS or SRNS. </li></ul><ul><li>Trend toward better response in MCD </li></ul><ul><li>Future studies needed to analyze clinical, histologic,and other features associated with a satisfactory response </li></ul>
  41. 50. Conclusions <ul><li>Expensive (500 mg rituximab costs approximately $800–1200 in India and $8000 in the United States) </li></ul><ul><li>Need for a RCT comparing the efficacy and safety of rituximab to a calcineurin inhibitor (e.g., tacrolimus) </li></ul><ul><li>Relative safety profile and lack of nephrotoxicity, might be preferred to long term therapy with calcineurin inhibitors. </li></ul><ul><li>Until then, consider in patients with SRNS and SDNS refractory to other medications or show evidence of calcineurin inhibitor nephrotoxicity. </li></ul>