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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 5  |  Page : 973-978
Rituximab in treatment of idiopathic glomerulopathy


1 Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait
2 Department of Medicine, Al-Amiri Renal Center, Ministry of Health, Kuwait
3 Department of Immunology, Faculty of Medicine, Kuwait University, Kuwait

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Date of Web Publication13-Sep-2012
 

   Abstract 

The aim of our study was to assess the role of rituximab (Mabthera) in the treatment of patients with corticosteroid-resistant and calcineurin-inhibitors ± cellcept refractory idiopathic nephrotic syndrome (INS). A total of 83 patients who had required the previous treatment for a minimum of two years were included in the study. Our protocol included the use of rituximab in four-weekly slow infusions. Five patients were excluded as they could not tolerate rituximab infusion for allergic reaction. As expected, none of the patients had a decline in the total circulating lymphocyte counts yet all had achieved decline of their initially normal CD20 to < 0.5% one month after infusion. The decline persisted for eight to ten months later. In the minimal change disease (MCD) group, 31 of the 32 patients had complete remission (CR) and were off any immunosuppressive therapy and one of the previous non-responders (NR) did not respond. Excluding two patients who had required retreatment, the others remained in CR (17 up to 28 months and six up to 36 months). Treatment with rituximab resulted in amelioration of NS in 17 of the 18 patients with focal segmental glomerulosclerosis (FSGS), while only one patient remained NR. Although renal function remained stable, proteinuria reappeared by eight to 12 months. Retreatment with rituximab resulted in a similar response with stable kidney function. In the 28 patients with membranous glomerulopathy (MG), 24 had achieved CR. Two patients failed to respond and two had partial remission. By 12 months, all patients relapsed. The response was within one month following treatment in patient with MCD, but was gradual within three months in FSGS and MG. Relapsers in all groups responded in a similar pattern to repeat dosing with the drug subsequently. Our prospective study represents an adequate number of patients with biopsy-proven subgroups of INS in both children and adults with long-term follow-up of treatment with rituximab. The drug is effective and safe for treatment of patients refractory to the conventional agents.

How to cite this article:
El-Reshaid K, Sallam HT, Hakim AA, Al-Attiyah R. Rituximab in treatment of idiopathic glomerulopathy. Saudi J Kidney Dis Transpl 2012;23:973-8

How to cite this URL:
El-Reshaid K, Sallam HT, Hakim AA, Al-Attiyah R. Rituximab in treatment of idiopathic glomerulopathy. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Jul 11];23:973-8. Available from: http://www.sjkdt.org/text.asp?2012/23/5/973/100878

   Introduction Top


Idiopathic nephrotic syndrome (INS) is a disease of the glomeruli characterized by nephrotic range proteinuria, hypoalbuminemia, generalized edema (up to anasarca) and hypercholesterolemia without an obvious underlying etiology. [1] It is the most common cause of chronic renal disease in our area, approaching a prevalence of 32% [2] and an annual incidence of 34.5 patients per 100,000 populations. [3] Minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous glomerulopathy (MG) are the most prevalent histopathological lesions. [4] INS is associated with high morbidity and mortality due to its symptomatic anasarca, bacterial infections, venous and arterial thromboembolism as well as the inherent complications of immunosuppressive therapy. [1] Moreover, FSGS and MG have a tendency for progressive renal disease and are major causes of end-stage renal disease. [1] Traditional therapy consisted of 12 weeks of corticosteroids (60 mg/m 2 /day with a maximum of 80 mg/day), which were sufficient for steroid-sensitive INS, and the course can be used for future infrequent relapses. The frequently relapsing and steroid-dependent INS were treated with 12 weeks of oral cyclophosphamide (CTX) or chlorambucil with adequate remission up to two years. [5] In the past few years, large amount of research has supported the use of cyclosporin A (CyA), and even tacrolimus (prograf), in the treatment of patients who had relapses after adequate corticosteroid or cytotoxic therapy and even in those who had steroid resistance at the start. [6],[7] Unfortunately, a large percentage of such patients were rendered CyA-dependent with the inherent risk of its long-term nephrotoxicity [8],[9] or were found to be CyA-resistant with a prevalence as high as 50% in steroid-resistant FSGS. [10] Previously, we had introduced a new protocol of combination of immunosuppressive agents added sequentially to improve the response of steroid and CyA refractory or resistant-INS to minimize the long-term side-effects of single agent's treatment. [11] At this stage, we would like to report on our experience with the use of rituximab as a single long-acting immunosuppressive agent in this field.


   Patients and Methods Top


Selection criteria

During the period 1 January 2009 and 31 December 2011, 32 patients with MCD, 18 with FSGS and 28 with MG were selected for the study. Patients were included if they satisfied the following criteria:

a) histological diagnosis was made by adequate renal histology during their initial nephrotic presentation.

b) secondary causes of NS were excluded after clinical, laboratory, radiological and appropriate serological testing.

c) NS was resistant to four-month treatment with corticosteroid (1 mg/kg/day) and refractory (frequently relapsing or dependent) or resistant to calcineurin-inhibitors (C-I) alone or combined with cellcept.

d) All patients had previously received three monthly doses of IV cytoxan (0.75 g/m 2 for normal creatinine clearance + adjusted for renal impairment) without benefit.

Study design

Four-weekly infusions of rituximab (mabthera) were given. Patients were pre-medicated with two 500 mg paracetamol and one piriton tablets followed by an infusion of 125 mg of solumedrol in 50 mL of D 5 W over 30 min before infusions. Then, 500 mg of rituximab was diluted in 450 mL of normal saline leading to a concentration of 1 mg/mL. The first infusion rate was 20 mL/h for the first 30 min, followed by 20 mL increments/h every 30 min till the total dose was achieved. The second infusion was a rate was started at 40 mL/h, the third at 80 mL/h and the fourth at 120 mL/h. Infusions were discontinued if allergic reactions developed.

Periodic assessment

Patients were seen weekly during the initial infusions, then every two months. After the 4 th week, the dose of C-I + cellcept were tapered off, and discontinued by eight weeks. In those visits, patients were assessed clinically for edema and side-effects of therapy. Laboratory investigations included complete blood count and serum estimates of sugar, renal, liver and lipid function tests, urine routine as well as 24-h urine collections for assessment of creatinine clearance and protein excretion were assessed at each visit. Moreover, flow cytometry was used to separate mononuclear cells and then immunophenotyping was done via staining with antibodies against cell markers. Depletion of B-cells was considered if CD20 was <0.5% of the total lymphocytes. [12]

Definition of response

Remission was considered complete (CR) if creatinine clearance remained normal and protein excretion decreased to < 200 mg/day in adults or (<40 mg/m 2 /h or protein:creatinine ratio <200 mg/μmol) in children. Partial response (PR) was defined as decrease in protein excretion to 50% of the initial value while creatinine clearance remains normal. Frequently relapsing (FR) INS was considered if the initial response was followed by ≥2 relapses per six months or ≥4 per 12 months while drug-dependence if relapses develop during dose-tapering or two weeks after drug discontinuation. Non-responders (NR) were defined as those who failed to achieve >50% decrement in protein excretion within 12 weeks of treatment.


   Results Top


A total of 83 patients were included in the study. However, five patients were excluded as they could not tolerate rituximab infusion for allergic reaction. Among the remaining 78 patients, 11 (14%) were from the pediatric age group (≤14 years old), nine of whom were in MCD and two in FSGS. Female patients were 30 (38%). All patients had NS for ≥34 months without evidence of spontaneous remission. The demographical data of the patients is summarized in [Table 1].
Table 1: The demogographical data of the patients with glomerulopathy who had received rituximab therapy.

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Lymphocyte subpopulation

As expected, none of the patients had a decline in the total circulating lymphocyte counts, yet all had achieved decline of their initially normal CD19 to <0.5% one month after infusion. The decline persisted for eight months later. Excluding those who had received a single infusion of rituximab and had to receive the remaining three infusions later, only four patients had low levels till the 10 th month, yet all recovered by the 12 th month.

Response to therapy

The response to treatment before and after rituximab in each subgroup in summarized in [Table 2]. The details are as follows:
Table 2: Response to rituximab in the patients with glomerulopathy.

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A. MCD

Twenty-four patients had CR with previous treatment, yet were C-I dependent on CyA 50 mg twice daily or prograf twice daily. Moreover, six patients had required cellcept also as a maintenance therapy and achieved PR. Two patients did not respond to the previous therapy. Eight months after rituximab treatment, 31 patients had CR and were off any immunosuppressive therapy, and one of the previous NR did not respond. By the 12 th month, 29 patients still enjoy a clinical remission while two had progressive rise in protein excretion and drop of serum albumin to <35 g/L. Those two patients received a second dose of rituximab and responded. Subsequent follow-up was available for the other 17 patients up to 28 months and six up to 36 months. The latter patients still enjoy CR.

B. FSGS

Ten patients had PR on previous drug therapy and were C-I dependent and seven required additional cellcept while eight did not respond at all and were kept only on ACEI, ARB, lasix and aldactone. Treatment with rituximab resulted in amelioration of the NS gradually over three months, with only one patient remaining as NR. Responders enjoyed a clinical remission without edema and C-I as well as cellcept were discontinued. The dose of diuretics, ACEI and ARB was reduced up to half the previous dosage. By eight to 12 months, proteinuria had increased to their baseline levels in all responders. However, retreatment with rituximab resulted in a similar response. Eight patients were available at 36 months of follow-up. They were clinically stable as described above and with their initial creatinine clearance levels.

C. MG

Twelve patients were NR to the previous therapy and ten had PR while six were C-I and cellcept dependent. After rituximab infusion, 24 patients achieved CR in a gradual fashion over three months and were off all medications till the eight to 12 months. Two patients failed to respond and two had PR. By the 12 th month, proteinuria started to increase gradually and 12 additional patients had nephrotic range proteinuria. Repeat eight to 12 months dosing resulted in a similar effect for the same period of time. At 36 months, six patients were available for re-assessment and all had a similar response with normal creatinine clearance.

Course of response

Responders to rituximab in the MCD group had achieved CR by the first month, contrary to those with MG and FSGS, who reached their optimal response by the 3 rd month and in a gradual manner.

Effect of single infusion

Four patients with MCD received only one infusion dose. Two months later, the CD19 cells returned to normal and NS recurred. Subsequently, these patients received the remaining three infusions.

Adverse events

Immediate infusion-related symptoms included itching, mild hypotension and broncho-spasm during the first infusion. Five patients could not tolerate it despite pre-medication with corticosteroids, diphenhydramine and acetaminophen as well as slow infusion rate and hence were excluded from the study. No major reaction was noted except for bloody diarrhea occurring two months post-infusion in one patient. Two patients had transient increase of alkaline phosphatase to twice the upper limit of normal, but got normalized later.


   Discussion Top


Rituximab is a chimeric human/mouse monoclonal antibody that is approved in the USA since 1997 for treatment of non-Hodgkin lymphoma and recently for severe rheumatoid arthritis. [13] The drug binds avidly to the CD20 antigen expressed on normal differentiated B-lymphocytes and pre-B-cells, but not stem cells or plasma cells. Unlike murine monoclonal antibodies to CD20, rituximab persists in the circulation for long periods, interacts with human effector cells and rarely generates human anti-mouse antibody responses. It destroys the B-cell by multiple mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, induction of apoptosis and sensitization to other chemotherapeutic agents. [14] This potent chemotherapeutic effect was associated with good tolerability profile, with mild to moderate infusion-related reactions; hence, it has to be administered slowly over hours, especially the first time. [13]

The drug has shown potential in treatment of many autoimmune diseases, including systemic vasculitis and lupus erythematosis, [15] as well sporadic cases of MCD, FSGS and MG. [16],[17],[18] Our study is the first prospective study with an adequate number of patients from each group of INS. Over 2 years of follow-up, our results indicate that the drug is relatively safe, in both children and adults, provided that patients tolerate its initial allergic reactions and minor GI and cholestatic disorders. [13] The drug provided effective and long-term suppression of B-cells up to eight to ten months. Interestingly, the latter was achieved without significant decline in immunoglobulin levels, which indicate that its action may have been mediated via inhibition of antigen-presenting properties and interaction with T-lymphocyte subsets known to play pathogenic roles in the expression of INS. [19] Moreover, in some patients, the clinical remission induced by rituximab persisted beyond the effect of B-cell suppression induced by the drug as CD19 normalized after eight months post-therapy. The latter phenomenon may be related to alteration in the memory cells, which may persist up to six years. [20],[21]

Previous studies have reported successful suppression of CD20 in INS with a single dose of rituximab. [16] In our study, the effect was limited to two months only in the four patients with MCD. Hence, we do not recommend such practice. In fact, because of its human component, rituximab has a very low immunogenicity. Should recovery of CD20 cells occur, it would reflect a long-term reversibility of the CD20 cells rather than neutralization of the chimeric antibody, and allow successful retreatment. Overall, the beneficial effect of rituximab was excellent in patients with MCG. It produced fast response associated with high percentage of CR and long-term remission beyond its biological action on CD20. These encouraging results indicate the early use of rituximab in CI + cellcept dependent cases, especially in children, to avoid the long-term side-effects of conventional treatment. In patients with MG, remission was delayed up to three months and relapse was common after eight to 12 months. The beneficial effect of rituimab should not be underestimated, but such knowledge warns against early discontinuation of conventional therapy in patients with MG, and also indicates the need for retreatment in a high percentage of patients unless spontaneous remission emerges. Patients with idiopathic FSGS are unfortunate in therapy with rituximab. The response seen is only PR, and they relapse at eight to 12 months as a rule.

Fortunately, patients maintained adequate kidney function and were off CI ± cellcept without edema, which made their management easier, especially in children. Nephrologists should be aware and patients should be informed about the limitations and different beneficial responses to rituximab in the three different groups of INS and the possibility of need for further treatment in the future so that, when required, it can be easily initiated.

 
   References Top

1.Kaysen GA. Nephrotic syndrome. In: Glassock RJ (ed). Current therapy in nephrology and hypertension. St. Louis: Mosby-year book; 1998. p. 223-30.  Back to cited text no. 1
    
2.El-Reshaid W, El-Reshaid K, Kapoor M, Hakim A. Chronic renal failure in Kuwaiti nationals: a prospective study during the past 4 years. Ren Fail 2005;27:227-33.  Back to cited text no. 2
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3.El-Reshaid W, El-Reshaid K, Kapoor MM, Madda JP. Glomerulopathy in Kuwait: the spectrum over the past 7 years. Ren Fail 2003; 25:619-30.  Back to cited text no. 3
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4.U.S. Renal Data System, USRDS 1998 Annual Data Report. National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Bethesda, MD, April 1998. p. 23-35.  Back to cited text no. 4
    
5.Meyrier A. Minimal change disease and focal segmental glomerulosclerosis. In: Pusey CD (ed). The treatment of glomerulnephritis. Berlin, Heidelberg: Kluwer Academic Publishers; 1999. p. 39-54.  Back to cited text no. 5
    
6.El-Reshaid K, Amer E, Madda JP, Kapoor M. Long-term cyclosporin A treatment in adults with refractory nephrotic syndrome. Ren Fail 1995;17:695-703.  Back to cited text no. 6
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7.Loeffler K, Gowrishankar M, Tiu V. Tacrolimus therapy in pediatric patients with treatment-resistant nephritic syndrome. Pediatr Nephrol 2004;19:281-7.  Back to cited text no. 7
    
8.Niaudet P, Broyer M, Habib R. Serial renal biopsies in children with idiopathic nephrosis receiving cyclosporine. In: Tejani A, ed. Cyclosporin in the Therapy of Renal Disease. Basel: Karger; 1995. p. 78-83.  Back to cited text no. 8
    
9.Melcoton TL, Kamil ES, Cohen AH, Fine RN. Long-term cyclosporine a treatment of steroid-resistant and steroid-dependant nephrotic syndrome. Am J Kidney Dis 1991;18:583-8.  Back to cited text no. 9
    
10.Niaudet P, Habib R. Cyclosporine in treatment of idiopathic nephrosis. J Am Soc Nephrol 1994;5:1049-56  Back to cited text no. 10
    
11.El-Reshaid K, El-Reshaid W, Madda JP. Combination of immunosuppressive agents in treatment of steroid-resistant minimal change disease and primary focal segmental glomerulosclerosis". Ren Fail 2005;27:523-30.  Back to cited text no. 11
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12.Samarghitean C, Valiaho J, Vihiaho J, Vihinen M. Online registry of genetic and clinical immunodeficiency diagnostic laboratories, ID diagnostics. J Clin Immunol 2004;24:53-61.  Back to cited text no. 12
    
13.Kimby E. Tolerability and safety of retuximab (MabThera). Cancer Treat Rev 2005;31:456-73.  Back to cited text no. 13
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14.Johnson P, Glennie M. The mechanism of action of rituximab in the elimination of tumor cells. Semin Oncol 2003;30(Supp.2):2-8.  Back to cited text no. 14
    
15.El-Halak M, Binstadt BA, Leichtener AM, et al. Clinical effects and safety of rituximab for treatment of refractory pediatric autoimmune diseases. J Pediatr 2007;150:376-82.  Back to cited text no. 15
    
16.Smith GC. Is there a role for rituximab in the treatment of idiopathic childhood nephritic syndrome ? Pediatr Nephrol 2007;22:893-8.  Back to cited text no. 16
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17.Kumar N, Faguer S, Esposito L, et al. Treatment of focal segmental glomerular sclerosis with rituximab: 2 case reports. Clin Nephrol 2007;67:250-4.  Back to cited text no. 17
    
18.Ruggenenti P, Chiurchiu C, Brusegan V, et al. Rituximab in idiopathic membranous glomerulopathy: a one-year prospective study. J Am Soc Nephrol 2003;14:1851-7.  Back to cited text no. 18
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19.Takemura S, Klmiuk PA, Braun A, Goronzy JJ, Weyand CM. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-8.  Back to cited text no. 19
    
20.Muhammad K, Roll P, Einsele H, Dorner T, Tony HP. Delayed acquisition of somatic hypermutations in repopulated IgD+CD27+ memory B cell receptors after rituximab treatment. Arthritis Rheum 2009;60:2284-93.  Back to cited text no. 20
    
21.Snider RA, Book BK, Agarwal A, Bearden CM, Vieira CA, Pescovitz MD. In vivo human B-cell subset recovery after in vivo depletion with rituximab, anti-human CD20 monoclonal antibody. Hum Antibodies 2004;55:55-62.  Back to cited text no. 21
    

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Correspondence Address:
Kamel El-Reshaid
Professor, Department of Medicine, Faculty of Medicine, Kuwait University, P. O. Box 24923, 13110 Safat
Kuwait
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DOI: 10.4103/1319-2442.100878

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    Tables

  [Table 1], [Table 2]

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