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ORIGINAL ARTICLE JNEPHROL 2012; 25 ( 06 ) : 1060 -1066 DOI: 10.5301/jn.5000096 Efficacy and safety of rituximab treatment in children with primary glomerulonephritis Jacek Zachwieja, Magdalena Silska, Danuta Ostalska-Nowicka, Jolanta Soltysiak, Katarzyna Lipkowska, Andrzej Blumczynski, Anna Musielak Introduction Abstract Background: The aim of our study was to analyze the efficacy and safety of rituximab, a chimeric monoclonal antibody against CD20 lymphocytes, as a nonstandard immunosuppressive therapy in children with different types of primary glomerulonephritis who were not eligible for routine treatment. Methods: The study group was composed of 16 children with proteinuric glomerulopathies, not responding to standard immunosuppressive therapy. The indications included steroid-resistant nephrotic syndrome (n=14) and steroid-dependent nephrotic syndrome (n=2). The dose of rituximab was established as 375 mg/m2 of body surface area, administered by intravenous infusion once weekly for 1 to 4 weeks, depending on the CD19 lymphocyte count. We evaluated proteinuria and plasma concentration of CD19 lymphocytes at intervals of 1, 3 and 6 months, after which patients received a single repeat dose. Results: Remission, defined as proteinuria less than 150 mg per 24 hours, was observed in 7 of the 16 children. There were no statistically significant differences in leukocyte counts between single and multiple rituximab doses. We also did not observe any clinical or biochemical side effects. Conclusions: In conclusion, we postulate that alternative rituximab therapy should be taken into consideration in nephrotic patients not responding to standard therapy. Key words: Children, Nephrotic syndrome, Rituximab 1060 Department of Pediatric Nephrology, Poznan University of Medical Science, Poznan - Poland Glomerulonephritis, encompassing both the primary kidney disease and the consequent changes in the course of systemic disease, is characterized by an inflammatory process leading to damage of the glomeruli. According to the etiology as well as the clinical and microscopic picture, 8 main types of glomerulonephritis are distinguished. Secondary glomerulonephritis can be observed in systemic lupus erythematosus, Henoch-Schönlein purpura, small vessel disease, rheumatoid arthritis, in the course of infection, neoplastic changes or cirrhosis. The clinical manifestation of glomerulonephritis may be isolated proteinuria, isolated erythrocyturia, proteinuria with erythrocyturia, nephritic syndrome or nephrotic syndrome as well as acute or chronic kidney insufficiency. The most common variant occurring in children is idiopathic nephrotic syndrome with minimal changes in the kidney biopsy (1). Proteinuria, which is present in most cases of glomerulonephritis, is actually regarded as the crucial destructive factor for kidney structure. The inflammatory sequence within the nephrons and renal parenchyma progresses to end-stage renal disease with the necessity of renal replacement therapy (2). Among different types of secondary glomerulonephritis, the most hazardous cause in teenagers is systemic lupus erythematosus nephropathy, which may be associated with an unfavorable prognosis (3). The main treatment strategy is based on immunosuppressive therapy and usually starts with glucocorticosteroids (GCs). Although most children respond positively to GCs, © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 JNEPHROL 2012; 25 ( 06 ) : 1060 -1066 in many cases, due to steroid resistance or steroid dependence, it is necessary to prolong prednisolone therapy or introduce cyclophosphamide and/or calcineurin inhibitors to induce and maintain complete remission (4). The reported toxicity and inadequate clinical response to this therapy drive the search for more effective and safer treatments (57). Unfortunately, the clinical effectiveness of a still promising therapeutic alternative – mycophenolate mofetil – does not lead to achievement of complete remission in nearly half of patients (8). Rituximab, a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells, has been used for the last decade as an immunosuppressive agent in such diseases as lymphomas, leukemias, transplant rejection and some autoimmune disorders. Although the exact mechanism of its action is still unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and especially allowing activation of B cells. It primarily affects and entirely depletes peripheral B cells. Its cytotoxicity may occur through complement-mediated lysis with direct apoptosis induction or be based on antibody reaction (9). According to some preliminary reports, rituximab can be used not only in kidney transplantation but also as an alternative immunosuppressive therapy in primary and secondary glomerulonephritis (10). However, there are possible adverse events observed in patients during rituximab therapy, such as severe infusion reactions, cardiac arrest, infections, ), hepatitis B reactivation and immune or pulmonary toxicity, that can lead to disability or even death. Aim of the study In line with the above, the aim of our study was to analyze the efficacy and safety of rituximab as an alternative immunosuppressive therapy in children with different types of primary glomerulonephritis who were not eligible for the standard treatment routine or dependent on this treatment. Patients and methods The study group was composed of 16 children with proteinuric glomerulopathies, not responding to standard immunosuppressive therapy, hospitalized between 2010 and 2011 in the Department of Pediatric Nephrology, Poznan University of Medical Sciences in Poland. Five boys and 11 girls underwent a renal biopsy according to the recommendations of the International Study for Kidney Disease in Children. These indications included steroid-resistant nephrotic syndrome (SRNS, n=14) and steroid-dependent nephrotic syndrome (SDNS, n=2). According to the World Health Organization (WHO) definitions, histological evaluation of the study group revealed: minimal change disease (MCD, n=3), diffuse mesangial proliferation (DMP, n=6), membranoproliferative glomerulonephritis (MPGN, n=1), glomerulosclerosis (GS, n=2), focal segmental glomerulosclerosis (FSGS, n=3) and extracapillary proliferative glomerulonephritis (EPGN, n=1). Since rituximab is not yet approved for conventional therapy administered in different proteinuric glomerulonephropathies in Poland, we obtained the necessary approval from the Polish Health Department, which authorized the use of rituximab in this group of children. The study protocol was ratified by the local ethics committee of Poznan University of Medical Sciences, and all of the parents of all of the study participants gave written informed consent for the investigation. The study was in accordance with the Declaration of Helsinki (11). Treatment protocol The dose of rituximab was established as 375 mg/m2 of body surface area, administered by intravenous infusion once weekly for 1 to 4 weeks, depending on the CD19 lymphocyte concentration. The rate of supply of the drug initially was 50 ml/hour diluted in 500 mL of saline. In the group of patients in whom there occurred severe side effects during rituximab supply, the infusion rate was reduced to 20 ml/hour. At a rate of 20 ml/hour of rituximab supply further adverse events were not observed. During the procedure, basic vital signs such as heart rate, blood pressure and body temperature were monitored. The degree of proteinuria, number of leukocytes in the blood stream and plasma concentration of CD19 lymphocytes at intervals of 1, 3 and 6 months were evaluated, after which patients received a single repeat dose of rituximab. During treatment with rituximab the patients received co-trimoxazole prophylaxis for 3 months. To determine the number of CD19 lymphocytes, we used flow cytometry and monoclonal antibodies. The patients during the treatment were monitored for any side effects of the therapy. Therefore we assessed peripheral blood morphology and biochemical markers of potential renal or liver insufficiency. In case of respiratory tract infection a control chest X-ray was performed. The observation period ranged from 2 to 14 months, during which the patients continued to receive therapy with calcineurin inhibitors, prednisolone or both. Complete remission was defined as proteinuria less than 150 mg/24 hours, and partial remission as proteinuria less than 25 mg/kg per 24 hours. © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 1061 Zachwieja et al: Efficacy and safety of rituximab Control tests during treatment and assessment of therapy safety At the start of the treatment and after 1, 3 and 6 months, relative to the initial state, a detailed assessment of biochemical parameters and clinical status of the patients was conducted. We analyzed selected parameters including blood pressure, peripheral blood morphology with particular emphasis on leukocyturia, creatinine serum concentration, glomerular filtration rate, electrolytes, lipid profile, aminotransferases, glycemia and of course daily proteinuria. Every case of infection was monitored. Adverse reactions occurring during rituximab infusion or in direct temporal association with it were subject to a special investigation. The severity of side effects such as fever, chills, nausea and abdominal pain were transient and did not result in the need to withdraw treatment. Results Table I summarizes the characteristics of the 16 studied patients, 5 boys and 11 girls aged 9-16, receiving rituximab therapy. All underwent a renal biopsy. The indications included SRNS (n=14) and SDNS (n=2). According to the regimen, most of the patients received medicaments such as prednisolone, methylprednisolone, cyclophosphamide, cyclosporin A or mycophenolate mofetil prior to rituximab therapy. Complete remission was observed in 7 of the 16 children after 6 months of observation. In patients who did not respond to therapy, 7 children maintained partial remission with nonnephrotic proteinuria. Both of them had SRNS. On kidney biopsy both presented diffuse mesangial proliferation. In one case of a girl with SDNS and steroid-induced diabetes mellitus, recurrence of nephrotic syndrome 7 months after TABLE I PROTEINURIA IN THE VARIOUS STAGES OF TREATMENT Patient no., indication for treatment Number of rituximab pulses Output proteinuria (mg/kg per 24 hours) at start of treatment Proteinuria 1 month after rituximab infusion (mg/kg per 24 hours) Proteinuria 3 months after rituximab infusion (mg/kg per 24 hours) Proteinuria 6 months after rituximab infusion (mg/kg per 24 hours) 1. SRNS 4 0 0 0 11 2. SRNS 4 75 37 4 0 3. SDNS 4 0 0 0 0 4. SRNS 1 0 0 0 0 5. SRNS 1 15 5 15 19 6. SDNS 1 0 0 0 0 7. SRNS 1 5 0 0 249 8. SRNS 4 27 20 9.4 8 9. SRNS 1 5 0 5 8.4 10. SRNS 1 0 0 5 0 11. SRNS 1 10 0 15.8 13.2 13. SRNS 1 5 0 0 10 14. SRNS 1 15 0 4.3 7.1 15. SRNS 1 0 0 0 0 16. SRNS 1 30 20 15 15 SDNS = steroid-dependent nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome. 1062 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 JNEPHROL 2012; 25 ( 06 ) : 1060 -1066 the first rituximab infusion was observed. Histopathological examination also showed DMP. In another case of a girl with steroid-resistant and cyclosporine-dependent nephrotic syndrome and DMP, acute renal failure developed which required renal replacement therapy for 2 weeks, plasmapheresis and GC therapy. Currently the patient continues treatment with cyclosporin A and remains in remission. Her glomerular filtration rate stabilized at a level corresponding to the second stage of chronic renal disease. At the start of treatment, 6 patients were without proteinuria. Five of them maintained remission in the 6-month observation period. In 1 patient with SRNS non-nephrotic proteinuria was observed 6 months after the date of the primary rituximab dose. In the remaining 10 patients, non-nephrotic proteinuria was observed at baseline. In this group steroid-resistant patients dominated. Most of them did not manage to achieve permanent remission. Treatment failures were independent of age and sex of patients. Most of them were children with SRNS. Table II shows that under the influence of rituximab treatment, there were no changes in the average total leukocyte count, which varied from 4.1345x10³ to 15.45x10³ after 1 month. There were also no statistically significant differences in leukocyte count when comparing single and multiple rituximab doses. In 14 patients after a single dose of rituximab, the number of CD19 lymphocytes on flow cytometry was of the order of 0.0 (Tab. III). In the whole study group, the number was 0.0 after 1 month of observation, and in accordance with what is known about rituximab metabolism, it increased again after 6 months, when the repeat dose was administered. With the exception of flu-like reactions in half of the patients who were administered the drug, we did not observe any important clinical or biochemical side effects requiring termination of further drug administration, as monitored by blood morphology as well as plasma renal and liver markers. TABLE II TOTAL NUMBER OF LEUKOCYTES IN THE VARIOUS STAGES OF TREATMENT Patient no., indication for treatment Rituximab number of infusions Leukocytes at start of treatment 1 month 3 months 6 months 1. SRNS 4 9.28 11.58 8.14 8.43 2. SRNS 4 6.7 10.39 6.6 6.24 3. SDNS 4 12.6 6.47 5.5 8.48 4. SRNS 1 9.3 5.6 4.77 5.52 5. SRNS 1 5.81 6.43 7.06 7.00 6. SDNS 1 6.82 4.5 4.3 5.88 7. SRNS 1 5.32 4.6 3.42 5.1 8. SRNS 4 9.13 8.2 5.09 7.09 9. SRNS 1 15 9.5 5.5 6.2 10. SRNS 1 6.15 4.85 6.37 5.58 11. SRNS 1 3.79 9.6 8.6 9.14 12. SRNS 1 7.03 6.08 5.3 5.98 13. SRNS 1 8.73 8.66 9.96 9.54 14. SRNS 1 3.85 4.13 4.35 4.45 15. SRNS 1 18.9 15.45 8.64 12.29 16. SRNS 1 4.31 9.21 7.93 8.76 SDNS = steroid-dependent nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome. © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 1063 Zachwieja et al: Efficacy and safety of rituximab Discussion Referring to the research of recent years, which suggests the possibility of safe and effective use of rituximab treatment as an alternative therapy in children with primary and secondary chronic glomerulonephritis, we attempted to summarize our own experience in this matter. Rituximab, a chimeric monoclonal antibody against the lymphocyte B CD20 protein, was brought into use in 1986 for the first time (12). The exact mode of action of rituximab is presumably connected with the Ca²+ ion influx across plasma membranes, complement-mediated cell lysis with direct or antibody-mediated apoptosis, and as a final result lymphocyte B down-regulation. Depletion of malignant B cells caused by rituximab is reflected in treatment of hematological neoplastic diseases (13). Currently due to its antiinflammatory effect, it is also widely used in such disorders as rheumatoid arthritis, autoimmune hemolytic anemia, multiple sclerosis and systemic lupus erythematosus (14). Rituximab is also increasingly used in nephrology in kidney transplant recipients and as an alternative immunosuppressive therapy in patients with glomerulonephritis not responding to standard treatment. The growing interest shown by nephrologists in rituximab’s therapeutic opportunities is associated with the hypothesis concerning B lymphocytes’ crucial role in the pathogenesis of the nephrotic syndrome (15, 16). In our studies the dose of rituximab established as 375 mg/m2 was administered by intravenous infusion once weekly for 1 to 4 weeks, depending on the CD19 lymphocyte concentration. Smith et al reported a single dose of rituximab as effective for patients with SDNS. Regarding SDNS patients a similar observation was made by Westphal et al (17, 18). Refer- TABLE III CD19 LYMPHOCYTE CONCENTRATIONS IN THE VARIOUS STAGES OF TREATMENT Patient no., indication for treatment Number of rituximab pulses Output CD19 lymphocytes (%) at start of treatment CD19 lymphocytes CD19 lymphocytes CD19 lymphocytes (%) 1 month after (%) 3 months after (%) 6 months after rituximab infusion rituximab infusion rituximab infusion 1. SRNS 4 24 0 0 0 2. SRNS 4 6 0 0 1 3. SDNS 4 17 0.1 0 5 4. SRNS 1 27 0 0 17 5. SRNS 1 5 0 0 1.6 6. SDNS 1 15 0 0 2 7. SRNS 1 1 1 0 15 8. SRNS 4 7 0 0 2 9. SRNS 1 14 0 0 0 10. SRNS 1 16 0 8 19 11. SRNS 1 2 0 0 0 12. SRNS 1 9 0 0 8 13. SRNS 1 18 0 0 15 14. SRNS 1 10 0 0.1 0 15. SRNS 1 10 0 0 1.7 16. SRNS 1 11 0 0 0 SDNS = steroid-dependent nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome. 1064 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 JNEPHROL 2012; 25 ( 06 ) : 1060 -1066 ring to the concept of 4 rituximab doses proposed by Bagga et al, in our study group, including in SRNS patients, remission was received after a single intravenous drug infusion (19). In the group of 16 patients, 14 steroidresistant and 2 steroid-dependent, complete clinical and biochemical remission 1 month after drug administration was observed in 11 of them. Nakayama et al reported that a single rituximab dose was associated with a delayed therapeutic response, but this was not confirmed in our study (20). There was no correlation between number of doses and time of remission. After 6 months of observation 1 steroid-dependent and 6 steroid-resistant patients responded to the therapy. Seven steroid-resistant patients with DMP did not achieve complete remission, which was different from the report of Bagga et al, who reported that rituximab was efficacious in inducing remission in patients with SRNS resistant to standard treatment with corticosteroids and calcineurin inhibitors (19). In our study group, all of the patients who at baseline had negative proteinuria remained in remission in the first 6 months of treatment. In the remaining 10 patients with initial non-nephrotic proteinuria, only 3 maintained long-lasting remission. In all patients responding to the treatment, its therapeutic result was visible within the first month after a single intravenous infusion. There were no statistically significant differences in response to the treatment depending on the kidney biopsy result. In 3 of the 7 patients who did not achieve remission, diffuse mesangial proliferation was found. Across all types of MPGN, the efficacy of various forms of treatment including rituximab therapy remains controversial. Some authors recommend long-term steroids as effective in children with nephrotic-range proteinuria (21). However, it should be noted that in a group of 6 DMP patients, exactly half of them achieved remission. This justifies an attempt of rituximab treatment in any patient with primary or secondary glomerulonephritis and an unsatisfactory result with standard therapy. The efficacy of rituximab is insufficient especially in some steroid-resistant patients. This phenomenon might be explained by the presence of antibodies against the human-mouse chimeric protein or gene polymorphism for receptor required for RTX binding to phagocytes (22, 23). In our study group, the decisive factor for the success of treatment was the initial occurrence of proteinuria at the time of its inception. The presence of proteinuria at baseline was a negative prognostic factor. We did not observe differences in terms of either efficacy or occurrence of any adverse effects between single and multiple starting rituximab doses. After 6 months, consistent with the pharmacokinetics of rituximab, restoration of CD20 cell number, regardless of sustained remission, had a decisive influence on the decision of a single repeat dose. We did not observe changes in average total leukocyte count, which was stable throughout the time of observation. These facts in our opinion support single intravenous rituximab pulse administration at a dose of 375 mg/m2 every 6 months. We are aware of the need to continue current therapy in the study group, but are currently unable to determine the probable time of its duration and safety. We are considering the possibility of adding mycophenolate mofetil to maintain the remission without a rituximab repeat dose, according to the suggestion of Filler et al (24). Nearly all treated children receiving the drug experienced flu-like symptoms. Predominant side effects were abdominal pain, headache, increased body temperature, fever and nausea lasting up to several hours. We did not observe any major potential complications of rituximab therapy (25, 26). Conclusions In conclusion, we postulate that alternative rituximab therapy should be taken into consideration in nephrotic patients not responding to standard therapy. In this group, the potential benefits of the therapy may outweigh the expected side effects. Financial support: No grants and funds were received to perform this study. Conflict of interest statement: None of authors has conflict of interest. Address for correspondence: Prof. Jacek Zachwieja, MD, PhD Department of Pediatric Nephrology Poznan University of Medical Sciences Szpitalna 27/33 Street PL-60-572 Poznan, Poland [email protected] © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 1065 Zachwieja et al: Efficacy and safety of rituximab References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 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Is there a role for rituximab in the treatment of idiopathic childhood nephrotic syndrome? Pediatr Nephrol. 2007;22(6):893-898. 18. Westphal S, Hansson S, Mjörnstedt L, Mölne J, Swerkersson S, Friman S. Early recurrence of nephrotic syndrome (immunoglobulin m nephropathy) after renal transplantation successfully treated with combinations of plasma exchanges, immunoglobulin, and rituximab. Transplant Proc. 2006;38(8):2659-2660. 19. Bagga A, Sinha A, Moudgil A. Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med. 2007;356 (26):2751-2752. 20. Nakayama M, Kamei K, Nozu K, et al. Rituximab for refractory focal segmental glomerulosclerosis. Pediatr Nephrol. 2008;23(3):481-485. 21. Alchi B, Jayne D. Membranoproliferative glomerulonephritis. Pediatr Nephrol. 2010;25(8):1409-1418. 22. Sfikakis PP, Boletis JN, Tsokos GC. Rituximab anti-B-cell therapy in systemic lupus erythematosus: pointing to the future. Curr Opin Rheumatol. 2005;17(5):550-557. 23. Anolik JH, Campbell D, Felgar RE, et al. The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 2003;48(2):455-459. 24. Filler G, Huang SH, Sharma AP. Should we consider MMF therapy after rituximab for nephritic syndrome? Pediatr Nephrol. 2011;26(10):1759-1762. 25. Nwobi O, Abitbol CL, Chandar J, Seeherunvong W, Zilleruelo G. Rituximab therapy for juvenile-onset systemic lupus erythematosus. Pediatr Nephrol. 2008;23(3):413-419. 26. Calabrese LH, Molloy ES, Huang D, Ransohoff RM. Progressive multifocal leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis Rheum. 2007;56(7):2116-2128. Accepted: December 09, 2011 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428