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    Journal club old Journal club old Presentation Transcript

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