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
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
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
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.
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
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.
33 SRNS (3 Adults)
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
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.
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.
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
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.
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%
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.
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.
initial and late resistance
Trend toward better response rates in patients with steroid-resistant MCD compared with FSGS
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
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 .
Includes ethnically different populations,
Uniform inclusion and exclusion criteria.
Therapies for SRNS and SDNS similar.
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.
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
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
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
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.