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1
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Yu Z, Huang M, Qin Y, Li X, Zhao Y, Wang Y, Zhang Y, Wang A, Han M, Zhao J, Sun S. Rituximab-associated adverse events in nephrotic syndrome: A systematic review and meta-analysis. Heliyon 2025; 11:e41212. [PMID: 39834424 PMCID: PMC11745799 DOI: 10.1016/j.heliyon.2024.e41212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 09/24/2024] [Accepted: 12/12/2024] [Indexed: 01/22/2025] Open
Abstract
Objective Rituximab (RTX) has been recommended to treat nephrotic syndrome (NS), but its safety has not been quantitatively analyzed. Methods PubMed, Embase, and the Cochrane Register of Controlled Trials databases were searched from inception to December 31, 2023, for randomized control trials (RCTs) and retrospective studies reporting the adverse events (AEs) related to RTX for treating NS. Data were expressed as odds ratios (OR) and risk difference (RD) with 95 % confidence interval (CI). Heterogeneity was identified using the Cochrane Q test and quantified by the I 2 statistic. Results Ten RCTs and five retrospective studies with 1231 patients were enrolled. RTX significantly reduced the risk of total AEs (OR = 0.32, 95 % CI [0.13, 0.78]) compared to the non-RTX group in retrospective studies but was not in RCTs. The pooled rate of infusion reactions was 32 % (95 % CI = [19 %, 45 %]) in RCTs and 8 % (95 % CI = [3 %, 13 %]) in retrospective studies. Subgroup analyses demonstrated a lower risk of hematological events in adult NS patients (OR = 0.21, 95 % CI [0.09, 0.51]) and the 1000 mg RTX intervention (OR = 0.21, 95 % CI [0.09, 0.51]). There is no significant difference in serious AEs, infection, gastrointestinal, renal, cardiovascular, and cancer events between the two groups. Conclusion RTX reveals great potential in terms of safety compared to non-RTX treatments due to the relatively few AEs in our results. However, the interaction of other drugs needs to be monitored. The safety of RTX in NS patients needs to be further confirmed in high-quality clinical trials.
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Affiliation(s)
- Zixian Yu
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Meijin Huang
- Department of Oncology, 920th Hospital of People's Liberation Army (PLA) Joint Logistics Support Force, Kunming, China
| | - Yunlong Qin
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
- Department of Nephrology, Bethune International Peace Hospital, Shijiazhuang, China
| | - Xiayin Li
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Yueru Zhao
- School of clinical medicine, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Yuwei Wang
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Yumeng Zhang
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Anjing Wang
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Mei Han
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Jin Zhao
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, Air Force Military Medical University, Xi'an, China
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Ibad MM, Jawaid S, Siddenthi SM, Warraich A, Rahman O. A Unique Case Linking Rituximab to a Ureaplasma Infection and Life-Threatening Hyperammonemia. Cureus 2024; 16:e74426. [PMID: 39723307 PMCID: PMC11669397 DOI: 10.7759/cureus.74426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2024] [Indexed: 12/28/2024] Open
Abstract
Rituximab is an anti-CD20 monoclonal antibody medication used in treating various cancers like non-Hodgkin lymphomas as well as immunologic conditions like granulomatosis with polyangiitis. It disrupts and decreases the number of B-cells, which causes an immunosuppressive state. This can promote the growth of numerous rare and opportunistic pathogens, one of which is Ureaplasma. Increasing cases of Ureaplasma infections have been reported with rituximab use, but they do not typically present with hyperammonemia. This is a case of widespread Ureaplasma urealyticum infection with shock, polyarticular arthritis and life-threatening hyperammonemia (ammonia levels greater than 160 microlmol/L) after rituximab use for granulomatosis with polyangiitis. It draws attention to the crucial point that early recognition of symptoms and timely diagnosis can lead to improved patient outcomes. Ureaplasma and other opportunistic organisms must be considered when reviewing patients on immunomodulating therapy.
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Affiliation(s)
- Muhammad Muneeb Ibad
- Pulmonary & Critical Care, Indiana University Health Methodist Hospital, Indianapolis, USA
| | - Samreen Jawaid
- Pulmonary & Critical Care, Indiana University Health Methodist Hospital, Indianapolis, USA
| | | | - Aliyan Warraich
- Pulmonary & Critical Care, Indiana University Health Methodist Hospital, Indianapolis, USA
| | - Omar Rahman
- Pulmonary & Critical Care, Indiana University Health Methodist Hospital, Indianapolis, USA
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3
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Schweitzer L, Miko BA, Pereira MR. Infectious Disease Prophylaxis During and After Immunosuppressive Therapy. Kidney Int Rep 2024; 9:2337-2352. [PMID: 39156157 PMCID: PMC11328545 DOI: 10.1016/j.ekir.2024.04.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 08/20/2024] Open
Abstract
Immune-mediated renal diseases are a diverse group of disorders caused by antibody, complement, or cell-mediated autosensitization. Although these diseases predispose to infection on their own, a growing array of traditional and newer, more targeted immunosuppressant medications are used to treat these diseases. By understanding their mechanisms of action and the infections associated with suppression of each arm of the immune system, nephrologists can better anticipate these risks and effectively prevent and recognize opportunistic infections. Focusing specifically on nonkidney transplant recipients, this review discusses the infections that can be associated with each of the commonly used immunosuppressants by nephrologists and suggest interventions to prevent infectious complications in patients with immune-mediated renal disease.
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Affiliation(s)
- Lorne Schweitzer
- Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, New York, USA
| | - Benjamin A. Miko
- Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Marcus R. Pereira
- Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
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4
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Xu J, Ding Y, Qu Z, Yu F. Differences in risk of serious infections between patients with secondary versus primary nephropathy following rituximab treatment: a retrospective cohort study. Front Immunol 2024; 15:1390997. [PMID: 38919606 PMCID: PMC11196396 DOI: 10.3389/fimmu.2024.1390997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 05/28/2024] [Indexed: 06/27/2024] Open
Abstract
Background The incidence of severe infections (SIs) in patients with autoimmune nephropathy after rituximab (RTX) treatment varies significantly. Our study aims to identify high-risk populations, specifically by comparing the differences in the risk of SIs between patients with primary nephropathy and those with nephropathy in the context of systemic autoimmune diseases (referred to as secondary nephropathy). Methods This retrospective cohort study investigated the occurrence of SIs in adult patients with immune-related kidney disease who received RTX treatment at our institution from 2017 to 2022. Multivariable COX regression models were used to analyze the association between the type of nephropathy (primary or secondary) and SIs. Propensity score analyses, subgroup analyses, and E-value calculations were performed to ensure the reliability of the results. Results Out of 123 patients, 32 (26%) developed 39 cases of SIs during a mean follow-up period of 19.7 ± 14.6 months post-RTX treatment, resulting in an incidence rate of 18.9/100 patient-years. The multivariable COX regression analysis indicated that patients with secondary nephropathy had a significantly higher risk of SIs compared to those with primary nephropathy (HR = 5.86, 95% CI: 1.05-32.63, P = 0.044), even after accounting for confounding variables including gender, age, BMI, history of prior SIs, baseline eGFR, lymphocyte counts, IgG levels, and the utilization of other immunosuppressive therapies. Various sensitivity analyses consistently supported these findings, with an E-value of 5.99. Furthermore, advanced age (HR: 1.03; 95% CI: 1.01-1.06; P = 0.023), low baseline IgG levels (HR: 0.75; 95% CI: 0.64-0.89; P < 0.001), and recent history of SIs (HR: 5.68; 95% CI: 2.2-14.66; P < 0.001) were identified as independent risk factors. Conclusion The incidence of SIs following RTX administration in patients with autoimmune nephropathy is significant. It is crucial to note that there are distinct differences between the subgroups of primary and secondary nephropathy. Patients with secondary nephropathy, particularly those who are elderly, have low baseline IgG levels, and have a recent history of SI, are more susceptible to SIs.
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Affiliation(s)
| | | | - Zhen Qu
- Department of Nephrology, Peking University International Hospital, Beijing, China
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5
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Zurowska A, Drozynska-Duklas M, Topaloglu R, Bouts A, Boyer O, Shenoy M, Vivarelli M. Rituximab-associated hypogammaglobulinemia in children with idiopathic nephrotic syndrome: results of an ESPN survey. Pediatr Nephrol 2023; 38:3035-3042. [PMID: 37014530 PMCID: PMC10432325 DOI: 10.1007/s00467-023-05913-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/13/2023] [Accepted: 02/08/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND There is paucity of information on rituximab-associated hypogammaglobulinemia (HGG) and its potential infectious consequences in children treated for idiopathic nephrotic syndrome (INS). METHODS A survey was distributed by the European Society Pediatric Nephrology to its members. It addressed the screening and management practices of pediatric nephrology units for recognizing and treating RTX-associated HGG and its morbidity and mortality. Eighty-four centers which had treated an overall 1328 INS children with RTX responded. RESULTS The majority of centers administered several courses of RTX and continued concomitant immunosuppressive therapy. Sixty-five percent of centers routinely screened children for HGG prior to RTX infusion, 59% during, and 52% following RTX treatment. Forty-seven percent had observed HGG prior to RTX administration, 61% during and 47% >9 months following treatment in 121, 210, and 128 subjects respectively. Thirty-three severe infections were reported among the cohort of 1328 RTX-treated subjects, of whom 3 children died. HGG had been recognized in 30/33 (80%) of them. CONCLUSIONS HGG in steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS) children is probably multifactorial and can be observed prior to RTX administration in children with SDNS/FRNS. Persistent HGG lasting >9 months from RTX infusion is not uncommon and may increase the risk of severe infections in this cohort. We advocate for the obligatory screening for HGG in children with SDNS/FRNS prior to, during, and following RTX treatment. Further research is necessary to identify risk factors for developing both HGG and severe infections before recommendations are made for its optimal management. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Aleksandra Zurowska
- Department of Pediatrics, Nephrology and Hypertension, Medical University of Gdańsk, ul. Debinki 7, 80-952, Gdańsk, Poland.
- Centre for Rare Diseases, Medical University of Gdańsk, Gdańsk, Poland.
| | - Magdalena Drozynska-Duklas
- Department of Pediatrics, Nephrology and Hypertension, Medical University of Gdańsk, ul. Debinki 7, 80-952, Gdańsk, Poland
| | - Rezan Topaloglu
- Department of Pediatric Nephrology, Hacettepe University School of Medicine Hacettepe University, Ankara, Turkey
| | - Antonia Bouts
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Olivia Boyer
- Department of Pediatric Nephrology, Reference Center for Idiopathic Nephrotic Syndrome in Children and Adults, Necker Hospital, Paris, France
- Laboratory of Hereditary Kidney Diseases, Imagine Institute, Paris Descartes University, Paris, France
| | - Mohan Shenoy
- Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Marina Vivarelli
- Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
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6
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Deng L, Xu G. Update on the Application of Monoclonal Antibody Therapy in Primary Membranous Nephropathy. Drugs 2023; 83:507-530. [PMID: 37017915 DOI: 10.1007/s40265-023-01855-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2023] [Indexed: 04/06/2023]
Abstract
When first introduced, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, brought about an alternative therapeutic paradigm for primary membranous nephropathy (PMN). Rituximab was shown to be effective and safe in PMN patients with kidney dysfunction, with. patients receiving second-line rituximab therapy achieving remission as effectively as those patients who had not previously received immunotherapy. No safety issues were reported. The B cell-driven protocol seems to be as efficient as the 375 mg/m2 × 4 regimen or 1 g × 2 regimen in achieving B cell depletion and remission, but patients with high M-type phospholipase A2 receptor (PLA2R) antibody levels may benefit from a higher dose of rituximab. While rituximab added another therapeutic option to the treatment regimen, it does have limitations as 20 to 40% of patients do not respond. Not all patients respond to RTX therapy for lymphoproliferative disorders either, therefore further novel anti-CD20 monoclonal antibodies have been developed and these may provide alternative therapeutic options for PMN. Ofatumumab, a fully human monoclonal antibody, specifically recognizes an epitope encompassing both the small and large extracellular loops of the CD20 molecule, resulting in increased complement-dependent cytotoxic activity. Ocrelizumab binds an alternative but overlapping epitope region to rituximab and displays enhanced antibody-dependent cellular cytotoxic (ADCC) activities. Obinutuzumab is designed to have a modified elbow-hinge amino acid sequence, leading to increased direct cell death induction and ADCC activities. In PMN clinical studies, ocrelizumab and obinutuzumab showed promising results, while ofatumumab displayed mixed results. However, there is a lack of randomized controlled trials with large samples, especially direct head-to-head comparisons. Alternative molecular mechanisms have been suggested in this context to explore novel therapeutic strategies. B cell activator-targeted, plasma cell-targeted and complement-directed treatments may lead to novel therapy paradigms for PMN. Exploratory strategies for the use of drugs with different mechanisms, such as a combination of rituximab and cyclophosphamide and a steroid, a combination of rituximab and a calcineurin inhibitor, may provide more rapid and efficient remission, but the combination of standard immunosuppression with rituximab could increase infection risk.
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Affiliation(s)
- Le Deng
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, 330006, Jiangxi, China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, 330006, Jiangxi, China.
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7
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Liu L, Lu H, Zou G, Wang H, Li J, Yang Y, Zhang J, Wang X, Li W, Zhuo L. Efficacy and safety of low-dose rituximab as induction therapy for antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement: a Chinese case series. BMC Nephrol 2023; 24:28. [PMID: 36755215 PMCID: PMC9906883 DOI: 10.1186/s12882-023-03075-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 01/31/2023] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Rituximab (RTX) is a standard therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the most frequently used dose may lead to severe adverse effects (SAEs). We explored the efficacy and safety of low-dose RTX in Chinese patients with AAV. METHODS A total of 22 Chinese patients diagnosed with AAV with renal involvement, including 8 treated with low-dose RTX (400 mg of RTX total over 4 weeks) and 14 treated with cyclophosphamide (CYC), were evaluated. The baseline clinical and pathological data and laboratory parameters during follow-up at months 1, 3, 6, and 12 were collected retrospectively. RESULTS The baseline data showed no significant differences between the two groups. The median peripheral CD19+ cell counts in the RTX group decreased from 315.0/μL to 1.5/μL at 2 weeks, and to 2.5/μL at 1 month after the first dose. The median SCr level decreased from 267.8 μmol/L before treatment to 151.45 μmol/L at 1 month, 132.75 μmol/L at 3 months, 123.2 μmol/L at 6 months, and 151.9 μmol/L at 12 months in RTX-treated patients. The improvements in renal function, proteinuria, and ANCA titre were not significantly different between the two groups. The SAE rate was significantly lower in the RTX group (one SAE of pneumonia) compared with the CYC group. CONCLUSIONS This is the first report that low-dose RTX could be effective for the treatment of Chinese patients with AAV with renal involvement.
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Affiliation(s)
- Lin Liu
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Haitao Lu
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Guming Zou
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Haifeng Wang
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Jing Li
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Yue Yang
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Jian Zhang
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Xueling Wang
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Wenge Li
- grid.415954.80000 0004 1771 3349Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029 People’s Republic of China
| | - Li Zhuo
- Department of Nephrology, China-Japan Friendship Hospital, No.2, East Yinghua Street, Beijing, 100029, People's Republic of China.
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8
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Chang HH, Chen H, Lin WH. Herpes zoster infection after rituximab induction therapy in patient with myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis: a case report. Oxf Med Case Reports 2022; 2022:omac134. [PMID: 36540838 PMCID: PMC9759945 DOI: 10.1093/omcr/omac134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/25/2022] [Accepted: 10/17/2022] [Indexed: 12/23/2022] Open
Abstract
Induction treatment with rituximab-an anti-CD20 monoclonal antibody-may increase the risk of varicella-zoster virus (VZV) reactivation in patients with antineutrophil-cytoplasmic-antibody-associated vasculitis (AAV). Our case report shows VZV reactivation following rituximab treatment in AAV patients. The recombinant zoster vaccine should be recommended before the start of induction treatment with rituximab.
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Affiliation(s)
- Ho-Hsiang Chang
- Correspondence address. Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng Li Road, Tainan 704, Taiwan. Tel: (+886)-6-2353535, ext.4733; Fax: (+886)-6-3028167; E-mail:
| | - Hsuan Chen
- Department of Dermatology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Wei-Hung Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
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9
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Scolari F, Alberici F, Mescia F, Delbarba E, Trujillo H, Praga M, Ponticelli C. Therapies for Membranous Nephropathy: A Tale From the Old and New Millennia. Front Immunol 2022; 13:789713. [PMID: 35300332 PMCID: PMC8921478 DOI: 10.3389/fimmu.2022.789713] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 02/07/2022] [Indexed: 11/13/2022] Open
Abstract
Primary Membranous Nephropathy (PMN) is the most frequent cause of nephrotic syndrome in adults. If untreated, PMN can lead to end-stage renal disease; moreover, affected patients are at increased risk of complications typical of nephrotic syndrome such as fluid overload, deep vein thrombosis and infection. The association of PMN with HLA-DQA1 and the identification in around 70% of cases of circulating autoantibodies, mainly directed towards the phospholipase A2 receptor, supports the autoimmune nature of the disease. In patients not achieving spontaneous remission or in the ones with deteriorating kidney function and severe nephrotic syndrome, immunosuppression is required to increase the chances of achieving remission. The aim of this review is to discuss the evidence base for the different immunosuppressive regimens used for PMN in studies published so far; the manuscript also includes a section where the authors propose, based upon current evidence, their recommendations regarding immunosuppression in the disease, while highlighting the still significant knowledge gaps and uncertainties.
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Affiliation(s)
- Francesco Scolari
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.,Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Federico Alberici
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.,Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Federica Mescia
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.,Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Elisa Delbarba
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.,Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Hernando Trujillo
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.,Department of Nephrology, Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Manuel Praga
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.,Department of Nephrology, Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid, Spain
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10
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Alamilla-Sanchez ME, Alcala-Salgado MA, Alonso-Bello CD, Fonseca-Gonzalez GT. Mechanism of Action and Efficacy of Immunosupressors in Lupus Nephritis. Int J Nephrol Renovasc Dis 2021; 14:441-458. [PMID: 34924767 PMCID: PMC8675090 DOI: 10.2147/ijnrd.s335371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/16/2021] [Indexed: 11/23/2022] Open
Abstract
Approximately 70% of the patients with systemic lupus erythematosus will have clinical evidence of kidney damage during their evolution. Patients with impaired renal function at onset and those with recurrent flares have a poor prognosis. Understanding the mechanism of action of immunosuppressants is essential for proper prescription. Steroids inhibit the DNA sequence that promotes the release of inflammatory cytokines. Phosphoramide mustard, metabolite of cyclophosphamide, cross-link with the DNA, causing the aggregation of an alkyl group, causing cell death. Mycophenolate inhibits inosine monophosphate dehydrogenase, prevents de novo synthesis of guanine, inducing cell arrest in S phase. Azathioprine blocks the synthesis of purines and induces apoptosis. Calcineurin inhibitors prevent the dephosphorylation of NFAT and reduce the production of interleukin 2. Antimalarials alter the enzymatic release of lysosomes by increasing intravesicular pH. The mechanism of action of rituximab is related to complement-dependent cytotoxicity and the elimination of anti-CD20-labeled B cells. Progress in the knowledge and management of low doses of steroids may change the current paradigm and reduce the frequency of related adverse events. Mycophenolate seems to be a better choice than cyclophosphamide for induction, it is also preferred over azathioprine as a maintenance immunosuppressive agent, although azathioprine is preferred in women with a desire for conception, those pregnant, or with low resources. For treatment-resistant cases, tacrolimus, rituximab or belimumab may be effective. Ongoing clinical trials with new drugs offer promising results.
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Affiliation(s)
| | | | - Cesar D Alonso-Bello
- Department of Immunology, Centro Medico Nacional “20 de Noviembre”, Mexico City, Mexico
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11
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Kakleas K, Kirk K, Harris D, Hall A. Successful desensitization to high dose rituximab for a child with nephrotic syndrome - The first report in the literature. Asia Pac Allergy 2021; 11:e37. [PMID: 34786367 PMCID: PMC8563104 DOI: 10.5415/apallergy.2021.11.e37] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 07/11/2021] [Indexed: 11/15/2022] Open
Abstract
Rituximab is a chimeric monoclonal antibody, which is mainly used in the treatment of lymphoma and autoimmune disorders, but also has been recently approved for the treatment of nephrotic syndrome. The treatment dose is between 375 mg/m2 and 750 mg/m2. Rituximab has been associated with hypersensitivity reactions, which can be classified either into early and late infusion-associated adverse reactions. Different desensitization protocols have been described in adult patients who require rituximab, however, there is a limited experience in children and in patients with nephrotic syndrome. Additionally, all the published protocols for adults and children are based on the low-dose rituximab desensitization. We report the first case in the literature of desensitization to high-dose rituximab in a child with nephrotic syndrome, suggesting a well-tolerated protocol adjusted on the high dose and the clinical reaction to the drug. This protocol can be used for children with nephrotic syndrome and severe reaction that require 750 mg/m2 of rituximab.
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Affiliation(s)
| | - Kerrie Kirk
- Paediatric Department, Leicester Royal Infirmary, Leicester, UK
| | - Dave Harris
- Paediatric Department, Leicester Royal Infirmary, Leicester, UK
| | - Angela Hall
- Paediatric Department, Leicester Royal Infirmary, Leicester, UK
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12
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Odler B, Windpessl M, Krall M, Steiner M, Riedl R, Hebesberger C, Ursli M, Zitt E, Lhotta K, Antlanger M, Cejka D, Gauckler P, Wiesholzer M, Saemann M, Rosenkranz AR, Eller K, Kronbichler A. The Risk of Severe Infections Following Rituximab Administration in Patients With Autoimmune Kidney Diseases: Austrian ABCDE Registry Analysis. Front Immunol 2021; 12:760708. [PMID: 34777374 PMCID: PMC8586204 DOI: 10.3389/fimmu.2021.760708] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/14/2021] [Indexed: 11/13/2022] Open
Abstract
Objective To characterize the incidence, type, and risk factors of severe infections (SI) in patients with autoimmune kidney diseases treated with rituximab (RTX). Methods We conducted a multicenter retrospective cohort study of adult patients with immune-related kidney diseases treated with at least one course of RTX between 2015 and 2019. As a part of the ABCDE Registry, detailed data on RTX application and SI were collected. SI were defined by Common Terminology Criteria for Adverse Events v5.0 as infectious complications grade 3 and above. Patients were dichotomized between “nephrotic” and “nephritic” indications. The primary outcome was the incidence of SI within 12 months after the first RTX application. Results A total of 144 patients were included. Twenty-five patients (17.4%) presented with SI, mostly within the first 3 months after RTX administration. Most patients in the nephritic group had ANCA-associated vasculitis, while membranous nephropathy was the leading entity in the nephrotic group. Respiratory infections were the leading SI (n= 10, 40%), followed by urinary tract (n=3, 12%) and gastrointestinal infections (n=2, 8%). On multivariable analysis, body mass index (BMI, 24.6 kg/m2versus 26.9 kg/m2, HR: 0.88; 95%CI: 0.79-0.99; p=0.039) and baseline creatinine (HR: 1.25; 95%CI: 1.04-1.49; p=0.017) were significantly associated with SI. All patients in the nephritic group (n=19; 100%) who experienced a SI received oral glucocorticoid (GC) treatment at the time of infection. Hypogammaglobulinemia was frequent (58.5%) but not associated with SI. Conclusions After RTX administration, impaired kidney function and lower BMI are independent risk factors for SI. Patients with nephritic glomerular diseases having concomitant GC treatment might be at higher risk of developing SI.
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Affiliation(s)
- Balazs Odler
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Martin Windpessl
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria.,Department of Internal Medicine IV, Section of Nephrology, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Marcell Krall
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Maria Steiner
- Department of Internal Medicine IV, Section of Nephrology, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Regina Riedl
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Carina Hebesberger
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Martin Ursli
- Department of Internal Medicine I, University Hospital of St. Poelten, Karl Landsteiner University of Health Sciences, Karl Landsteiner Institute for Nephrology and Hematooncology, St. Poelten, Austria
| | - Emanuel Zitt
- Department of Internal Medicine 3 (Nephrology and Dialysis), Feldkirch Academic Teaching Hospital, Feldkirch, Austria
| | - Karl Lhotta
- Department of Internal Medicine 3 (Nephrology and Dialysis), Feldkirch Academic Teaching Hospital, Feldkirch, Austria
| | - Marlies Antlanger
- Department of Internal Medicine 2, Kepler University Hospital and Johannes Kepler University, Linz, Austria
| | - Daniel Cejka
- Department of Medicine III-Nephrology, Hypertension, Transplantation, Rheumatology, Geriatrics, Ordensklinikum Linz-Elisabethinen Hospital, Linz, Austria
| | - Philipp Gauckler
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
| | - Martin Wiesholzer
- Department of Internal Medicine I, University Hospital of St. Poelten, Karl Landsteiner University of Health Sciences, Karl Landsteiner Institute for Nephrology and Hematooncology, St. Poelten, Austria
| | - Marcus Saemann
- Department of 6Internal Medicine with Nephrology and Dialysis with Outpatient Department, Clinic Ottakring, Vienna, Austria
| | - Alexander R Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Kathrin Eller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Andreas Kronbichler
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria.,Department of Medicine, University of Cambridge, Cambridge, United Kingdom
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Kumru Sahin G, Eyupoglu S, Eren Sadioglu R, Cinar G, Ates K, Erturk S, Nergizoglu G, Sengul S, Kutlay S, Keven K. Cytomegalovirus infection in patients with glomerular diseases treated with cyclophosphamide: a single-center prospective study. Int Urol Nephrol 2021; 54:1091-1096. [PMID: 34398345 DOI: 10.1007/s11255-021-02973-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 08/02/2021] [Indexed: 11/28/2022]
Abstract
PURPOSE Cytomegalovirus infection is an important complication in immunocompromised patients. As few studies have shown that cyclophosphamide treatment is a risk factor for cytomegalovirus infection in patients with glomerulonephritis, we aimed to describe the frequency and risk factors of cytomegalovirus infection in glomerulonephritis patients treated with cyclophosphamide. METHODS We prospectively recruited 43 cytomegalovirus seropositive patients with glomerulonephritis treated with cyclophosphamide. We screened all patients for viral DNA monthly during treatment. Patients were compared for age, sex, glomerular pathology, renal function and clinical status regarding development of cytomegalovirus infection before and after the treatment. RESULTS Cytomegalovirus infection was detected in 10 (23.3%) patients, most commonly within the first 2 months of cyclophosphamide treatment. All patients recovered without any cytomegalovirus-related complications. Patients with cytomegalovirus infection had higher serum creatinine (4.2 ± 3.2 vs. 1.9 ± 1.8 mg/dl, p = 0.006) and lower estimated glomerular filtration rate (29 ± 11 vs. 65 ± 8 ml/min/1.73 m2, p = 0.016) at diagnosis compared with cytomegalovirus infection non-occurred patients. In addition, number of patients presented with rapidly progressive glomerulonephritis were higher in cytomegalovirus infection group (80.0% vs. 27.3%, p = 0.007). Moreover, cytomegalovirus infection was associated with prolonged hospital stay (54 ± 7 vs. 29 ± 6 days, p = 0.027). CONCLUSION Cytomegalovirus infection is a common complication in glomerulonephritis patients treated with cyclophosphamide in this prospective study. Routine monitoring and prophylaxis should be considered for these high-risk patients.
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Affiliation(s)
- Gizem Kumru Sahin
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey. .,Department of Nephrology, Ministry of Health Van Education Research Hospital, Van, Turkey.
| | - Sahin Eyupoglu
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | | | - Gule Cinar
- Department of Infectious Disease and Clinical Microbiology, Ankara University School of Medicine, Ankara, Turkey
| | - Kenan Ates
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Sehsuvar Erturk
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Gokhan Nergizoglu
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Sule Sengul
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Sim Kutlay
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Kenan Keven
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
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A prospective cohort study of rituximab in the treatment of refractory nephrotic syndrome. Int Urol Nephrol 2021; 54:121-130. [PMID: 33905043 PMCID: PMC8732927 DOI: 10.1007/s11255-021-02860-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 04/11/2021] [Indexed: 11/01/2022]
Abstract
OBJECTIVE To explore the efficacy and safety of rituximab (RTX) in the treatment of autoimmune nephropathy manifested as refractory nephrotic syndrome (RNS). METHODS A single-center prospective cohort study was conducted on RNS patients treated with RTX between March 2017 and December 2019. The subjects were divided into the primary nephropathy (PN) group and the secondary nephropathy (SN) group. Based on the estimated glomerular filtration rate (eGFR) before RTX treatment, the SN group was then divided into the SN-1 group (eGFR ≥ 30 ml/min) and the SN-2 group (eGFR < 30 ml/min). Biochemical parameters and clinical data were recorded during follow-up. RESULTS Fifty-four patients were followed up for at least 6 months. The overall remission rates were 65%, 66.7%, 27.3% in the PN, SN-1, and SN-2 groups, respectively (P = 0.022). Kaplan-Meier analysis showed a significant difference of the renal survival among the three subgroups (P < 0.001). Multivariate Cox regression analysis showed that eGFR value before treatment was an independent predictor (HR 0.919, 95%CI 0.863-0.979) for renal survival. In terms of adverse events, infection accounted for 56.6%. The incidence of severe infection was 10%, 25% and 50% in PN group, SN-1 group and SN-2 group, respectively. CONCLUSIONS RTX may be a promising option in RNS patients with eGFR ≥ 30 ml/min/1.73m2. However, it has little effect on prognosis in patients with secondary RNS with eGFR < 30 ml/min/1.73m2, but with a high risk of severe infection.
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15
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McClure ME, Zhu Y, Smith RM, Gopaluni S, Tieu J, Pope T, Kristensen KE, Jayne DRW, Barrett J, Jones RB. Long-term maintenance rituximab for ANCA-associated vasculitis: relapse and infection prediction models. Rheumatology (Oxford) 2021; 60:1491-1501. [PMID: 33141217 PMCID: PMC7937025 DOI: 10.1093/rheumatology/keaa541] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 07/14/2020] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVES Following a maintenance course of rituximab (RTX) for ANCA-associated vasculitis (AAV), relapses occur on cessation of therapy, and further dosing is considered. This study aimed to develop relapse and infection risk prediction models to help guide decision making regarding extended RTX maintenance therapy. METHODS Patients with a diagnosis of AAV who received 4-8 grams of RTX as maintenance treatment between 2002 and 2018 were included. Both induction and maintenance doses were included; most patients received standard departmental protocol consisting of 2× 1000 mg 2 weeks apart, followed by 1000 mg every 6 months for 2 years. Patients who continued on repeat RTX dosing long-term were excluded. Separate risk prediction models were derived for the outcomes of relapse and infection. RESULTS A total of 147 patients were included in this study with a median follow-up of 63 months [interquartile range (IQR): 34-93]. Relapse: At time of last RTX, the model comprised seven predictors, with a corresponding C-index of 0.54. Discrimination between individuals using this model was not possible; however, discrimination could be achieved by grouping patients into low- and high-risk groups. When the model was applied 12 months post last RTX, the ability to discriminate relapse risk between individuals improved (C-index 0.65), and once again, clear discrimination was observed between patients from low- and high-risk groups. Infection: At time of last RTX, five predictors were retained in the model. The C-index was 0.64 allowing discrimination between low and high risk of infection groups. At 12 months post RTX, the C-index for the model was 0.63. Again, clear separation of patients from two risk groups was observed. CONCLUSION While our models had insufficient power to discriminate risk between individual patients they were able to assign patients into risk groups for both relapse and infection. The ability to identify risk groups may help in decisions regarding the potential benefit of ongoing RTX treatment. However, we caution the use of these prediction models until prospective multi-centre validation studies have been performed.
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Affiliation(s)
- Mark E McClure
- Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Yajing Zhu
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Rona M Smith
- Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Seerapani Gopaluni
- Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Joanna Tieu
- Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Tasneem Pope
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Karl Emil Kristensen
- Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
| | - David R W Jayne
- Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Jessica Barrett
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Rachel B Jones
- Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
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Rymarz A, Matyjek A, Sułek-Jakóbczyk M, Mosakowska M, Niemczyk S. Impaired Kidney Function Associated with Increased Risk of Side Effects in Patients with Small Vessel Vasculitis Treated with Rituximab as an Induction Therapy. J Clin Med 2021; 10:jcm10040786. [PMID: 33669267 PMCID: PMC7920022 DOI: 10.3390/jcm10040786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 11/16/2022] Open
Abstract
Rituximab (RTX), a monoclonal antibody against the CD20 molecule, is used as an induction therapy in the treatment of small vessel vasculitis (SVV). The aim of the study was to evaluate the efficacy and safety of RTX induction therapy for refractory SVV. A retrospective analysis of 20 patients treated with RTX for active SVV (BVAS/WG ≥ 3) was performed to assess the remission rate and the drug-related severe adverse events 6 months after therapy. The mean age of the studied population was 49 ± 13 years (50% female), 90% of which were PR3-ANCA positive. Complete remission was achieved in 85% of patients, and partial remission was achieved in a further 10% within 6 months after RTX infusions. The remission rate was not influenced by kidney function. Adverse events such as infections (25%), a late onset of neutropenia (10%) and severe hypogammaglobulinemia (5%) were noted. The patients who developed adverse events were older (42 ± 11 vs. 57 ± 12 years; p = 0.014) and had a higher serum creatinine level (1.3 mg/dL vs. 3.35 mg/dL; p = 0.044). Patients with a glomerular filtration rate (eGFR) lower than 30 mL/min/1.73 m2 had a nine-fold higher risk of side effects (OR 9.0, 95%CI: 1.14-71.0). In conclusion, RTX was highly effective as an induction therapy in patients with SVV. Advanced kidney failure with an eGFR lower than 30 mL/min/1.73 m2 was one of the risk factors for the occurrence of side effects.
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Eren Sadioglu R, Eyupoglu S, Erdogmus S, Kumru Sahin G, Yoruk F, Kutlay S, Keven K, Erturk S, Sengul S. Infectious Complications in Patients with Primary Glomerulonephritis over 10 Years: A Single-Center Experience in Turkey. KIDNEY DISEASES (BASEL, SWITZERLAND) 2021; 7:57-66. [PMID: 33614734 PMCID: PMC7879260 DOI: 10.1159/000510153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/14/2020] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Infections can play an important role in the mortality and morbidity of patients with glomerulonephritis. However, the frequency of infectious complications in primary glomerulonephritis and their burden to the healthcare managements are not clear. METHODS We evaluated the infectious complications in patients with biopsy-proven focal segmental glomerulosclerosis, membranous glomerulonephritis, IgA nephropathy, minimal change disease, membranoproliferative glomerulonephritis, and chronic glomerulonephritis during the last 10 years in a single center. We recorded the demographic, clinical, and laboratory characteristics; treatment modalities; infectious episodes; and infection-related mortality and morbidity of the patients. RESULTS Of the patients, 154 (63.6%) received immunosuppressive treatment and 88 (34.4%) were followed up under conservative treatment. Overall, 118 infectious episodes were noted in 64 patients, with an infection rate of 0.20 per patient-year. Total infectious complications were higher in the immunosuppressive group than in the conservative group (42.1 vs. 23.3%, p = 0.005). Infection-related hospitalizations were also higher in the immunosuppressive group (p = 0.01). The most frequently infected area was the lungs (15.7%). Although bacterial infections were the most common in both groups, 14.9% of the immunosuppressive group had cytomegalovirus (CMV) replication. Age >50 years (OR 2.19, p = 0.03), basal serum albumin <2.5 g/dL (OR 2.28, p = 0.02), cyclophosphamide (OR 2.43, p = 0.02), and cyclosporine (OR 2.30, p = 0.03) were independently associated with experiencing infectious episodes. CONCLUSIONS Because of high seropositivity for CMV in Turkey, it might be a wise approach to use prophylactic antiviral drugs in patients treated with immunosuppressive treatments. Close monitoring of patients with primary glomerulonephritis, especially those treated with immunosuppressive therapy, is important for reducing infection-related morbidity and mortality.
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Affiliation(s)
| | - Sahin Eyupoglu
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Siyar Erdogmus
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Gizem Kumru Sahin
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Fugen Yoruk
- Department of Infectious Disease and Clinic Microbiology, Ankara University School of Medicine, Ankara, Turkey
| | - Sim Kutlay
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Kenan Keven
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Sehsuvar Erturk
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
| | - Sule Sengul
- Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey
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Santos JE, Fiel D, Santos R, Vicente R, Aguiar R, Santos I, Amoedo M, Pires C. Rituximab use in adult glomerulopathies and its rationale. ACTA ACUST UNITED AC 2019; 42:77-93. [PMID: 31904761 PMCID: PMC7213927 DOI: 10.1590/2175-8239-jbn-2018-0254] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 09/23/2019] [Indexed: 01/26/2023]
Abstract
Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.
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Affiliation(s)
| | - David Fiel
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Ricardo Santos
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Rita Vicente
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Rute Aguiar
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Iolanda Santos
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Manuel Amoedo
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Carlos Pires
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
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Santos JE, Fiel D, Santos R, Vicente R, Aguiar R, Santos I, Amoedo M, Pires C. Rituximab use in adult glomerulopathies and its rationale. JORNAL BRASILEIRO DE NEFROLOGIA : 'ORGAO OFICIAL DE SOCIEDADES BRASILEIRA E LATINO-AMERICANA DE NEFROLOGIA 2019. [PMID: 31904761 DOI: 10.1590/2175-8239-] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.
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Affiliation(s)
| | - David Fiel
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Ricardo Santos
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Rita Vicente
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Rute Aguiar
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Iolanda Santos
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Manuel Amoedo
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Carlos Pires
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
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Zappulo E, Buonomo AR, Saccà F, Russo CV, Scotto R, Scalia G, Nozzolillo A, Lanzillo R, Tosone G, Gentile I. Incidence and Predictive Risk Factors of Infective Events in Patients With Multiple Sclerosis Treated With Agents Targeting CD20 and CD52 Surface Antigens. Open Forum Infect Dis 2019; 6:ofz445. [PMID: 31723572 PMCID: PMC6837838 DOI: 10.1093/ofid/ofz445] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 10/08/2019] [Indexed: 01/31/2023] Open
Abstract
OBJECTIVE Monoclonal antibodies (MAbs) directed against the CD20 and CD52 antigens are used increasingly in patients with multiple sclerosis (MS). Several life-threatening opportunistic infections have been reported in postmarketing case series. The aim of this study was to investigate the incidence of infections and associated prognostic factors during the first year of treatment in patients receiving anti-CD20 (ocrelizumab or rituximab) or anti-CD52 MAbs (alemtuzumab). METHODS A retrospective study was conducted in patients with MS referring to the Neurodegenerative Diseases Center at the University of Naples Federico II who received MAbs between November 2015 and June 2018. RESULTS A total of 163 patients were enrolled. Approximately 40% of patients experienced lymphocytopenia during treatment. Eighty-six infective events were reported in 67 patients (41%). Bacterial infections were significantly more frequent with anti-CD20, whereas viral infections prevailed with alemtuzumab. Cytomegalovirus reactivation rates were significantly higher in the alemtuzumab group than in patients on anti-CD20 (51% vs 6%, P < .001). The overall annualized infection rate was 1.1 per patient-year, higher in patients on anti-CD52 versus those on anti-CD20 regimens (1.5 vs 0.8 per patient-year). Alemtuzumab treatment, prior exposure to ≥2 MS drugs, and iatrogenic immune impairment significantly and independently predicted an infection event (adjusted hazard ratio [aHR], 2.7; P = .013; aHR, 1.7; P = .052; and aHR, 2.9; P = .004; respectively). CONCLUSIONS Given their considerable infection risk, MS patients receiving MAbs should undergo timely follow up and tailored preventive interventions. Anti-CD52-based treatment, prior exposure to MS drugs, and on-treatment immune impairment are significant predictive factors of infection and their evaluation could help clinicians to stratify a patient's risk of infection.
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Affiliation(s)
- Emanuela Zappulo
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Antonio Riccardo Buonomo
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Francesco Saccà
- Department of Neurological Sciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Cinzia Valeria Russo
- Department of Neurological Sciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Riccardo Scotto
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Giulia Scalia
- Clinical and Experimental Cytometry Unit, CEINGE-Biotecnologie Avanzate, Naples, Italy
| | - Agostino Nozzolillo
- Department of Neurological Sciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Roberta Lanzillo
- Department of Neurological Sciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Grazia Tosone
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Ivan Gentile
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
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Hogan J, Dossier C, Kwon T, Macher MA, Maisin A, Couderc A, Niel O, Baudouin V, Deschênes G. Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome. Pediatr Nephrol 2019; 34:253-259. [PMID: 30109447 DOI: 10.1007/s00467-018-4052-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 07/30/2018] [Accepted: 08/08/2018] [Indexed: 10/28/2022]
Abstract
BACKGROUND Several studies have demonstrated that rituximab (RTX) improves relapse-free survival in patients with steroid-dependent nephrotic syndrome (SDNS). However, these studies used various RTX regimens and there are few data comparing these regimens in children with SDNS. In this retrospective study, we assessed the effect of three different initial RTX regimens on both time to B cell reconstitution and to first relapse. METHODS Sixty-one SDNS patients receiving a first course of RTX were included. Group 1 received one injection of 100 mg/m2, group 2 received one injection of 375 mg/m2, and group 3 received two injections of 375 mg/m2 at day 0 and day 7. Time to B cell reconstitution and time to first relapse and respective risk factors were studied. RESULTS Median time to B cell reconstitution was 2.5 [1.8-3.5], 5.0 [3.9-6.0], and 6.6 [4.6-7.8] months in groups 1, 2, and 3, respectively. RTX regimen was associated with time to B cell reconstitution (HRs group 2 vs. 3, 4.07 [1.96-8.48]; group 1 vs. 3, 11.13 [4.04-30.67]). One-year relapse-free survival was 50% [58-77], 59% [42-76], and 72% [46-87] in groups 1, 2, and 3, respectively. RTX regimen was associated with risk of relapse (HRs group 2 vs. 3, 1.55 [0.51-4.65]; group 1 vs. 3, 4.98 [1.15-21.60]). CONCLUSIONS The initial dose of rituximab impacts time to B cell reconstitution and the probability of relapse. Risk of relapse is also associated with patient characteristics, suggesting that RTX regimen could be modified for each patient to balance efficacy, cost, and side effects.
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Affiliation(s)
- Julien Hogan
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France.
| | - Claire Dossier
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France
| | - Thérésa Kwon
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France
| | - Marie-Alice Macher
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France
| | - Anne Maisin
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France
| | - Anne Couderc
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France
| | - Olivier Niel
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France
| | - Véronique Baudouin
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France
| | - Georges Deschênes
- Pediatric Nephrology Department, Robert-Debré Hospital, APHP, 48 bld Sérurier, 75019, Paris, France
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22
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Kallash M, Smoyer WE, Mahan JD. Rituximab Use in the Management of Childhood Nephrotic Syndrome. Front Pediatr 2019; 7:178. [PMID: 31134169 PMCID: PMC6524616 DOI: 10.3389/fped.2019.00178] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 04/17/2019] [Indexed: 12/19/2022] Open
Abstract
Childhood nephrotic syndrome is a challenging and often persistent renal disorder, and its incidence varies between different ethnicities and regions. Corticosteroids have been the main treatment for decades and are effective in most children with idiopathic NS, although 10-15% of these children become steroid resistant. Furthermore, some initially steroid sensitive children follow a steroid dependent or frequently relapsing course and are therefore at increased risk for developing steroid toxicity. In such children, alternative immunosuppressive medications are used to induce and/or maintain remission of NS. One such drug, rituximab, is a monoclonal antibody directed against the B lymphocyte CD20 marker which induces depletion of B cells, and has shown promising results in the management of NS in children. In this review, we summarize recent studies on the efficacy and safety of rituximab in the different types of childhood nephrotic syndrome, the known and potential mechanisms of action of rituximab, its possible complications and side effects, and the available and potential biomarkers of rituximab activity.
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Affiliation(s)
- Mahmoud Kallash
- Division of Nephrology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
| | - William E Smoyer
- Division of Nephrology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
| | - John D Mahan
- Division of Nephrology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
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23
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Abstract
Most glomerular diseases are immunologically mediated disorders of the kidney and are common causes of ESKD. In addition to supportive therapy, a wide range of immunosuppressive agents are used in the management of patients with these conditions. Immunosuppression requires a careful balance of risk and benefits, and many of these agents have a narrow therapeutic window and require close monitoring. This review describes the side effects of immunosuppressive agents used in recent randomized, controlled trials of glomerular disease, and highlights some of the key adverse events that determine the choice and prescription of these medications.
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Affiliation(s)
- J Ashley Jefferson
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
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24
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Salvadori M, Tsalouchos A. Antineutrophil cytoplasmic antibody associated vasculitides with renal involvement: Open challenges in the remission induction therapy. World J Nephrol 2018; 7:71-83. [PMID: 29736379 PMCID: PMC5937030 DOI: 10.5527/wjn.v7.i3.71] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 03/12/2018] [Accepted: 04/18/2018] [Indexed: 02/06/2023] Open
Abstract
Renal involvement with rapidly progressive glomerulonephritis is a common manifestation of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides, which is characterized by end-stage renal disease and high mortality rates in untreated and/or late referral patients. The long-term renal survival has improved dramatically since the addition of cyclophosphamide (CYC) and recently of rituximab (RTX) in association with corticosteroids in the remission induction therapeutic regimens. However, renal prognosis remains unfavorable for many patients and the mortality rate is still significantly high. In this review, we analyze the open challenges to be addressed to optimize the induction remission therapy, principally in patients with advanced kidney failure. This concern the first-line therapy (CYC or RTX) based on different parameters (estimated glomerular filtration rate at baseline, new or relapsed disease, ANCA specificity, tissue injury, safety), the role of plasma exchange and the role of new therapies. Indeed, we discuss future perspectives in induction remission therapy by reporting recent advances in new targeted therapies with particular reference to avacopan, an orally administered selective C5a receptor inhibitor.
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Affiliation(s)
- Maurizio Salvadori
- Department of Nephrology and Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Department of Nephrology and Dialysis, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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25
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Relapsing granulomatosis with polyangiitis with severe lung and upper respiratory tract involvement successfully treated with rituximab. Reumatologia 2017; 55:208-212. [PMID: 29056777 PMCID: PMC5647538 DOI: 10.5114/reum.2017.69783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 08/14/2017] [Indexed: 11/26/2022] Open
Abstract
Granulomatosis with polyangiitis (GPA) is a chronic, relapsing, primary systemic small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies. The disease is characterised by the involvement of various organs. The relapse rate rises from about 20% at 12 months to about 60% at 5 years. The combination of glucocorticoids and cyclophosphamide remains the standard therapy for patients with generalised GPA; nevertheless, some patients do not respond satisfactorily to this treatment. According to EULAR-EDTA recommendations for the management of ANCA-associated vasculitis, RTX should be considered for remission-induction of new-onset as well as major relapse of organ-threatening or life-threatening GPA. Here we present a 35-year-old patient with relapsing GPA successfully treated with RTX. We also highlight the infectious complications of immunosuppressive treatment.
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26
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Nixon A, Ogden L, Woywodt A, Dhaygude A. Infectious complications of rituximab therapy in renal disease. Clin Kidney J 2017; 10:455-460. [PMID: 28852481 PMCID: PMC5570071 DOI: 10.1093/ckj/sfx038] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/10/2017] [Indexed: 11/29/2022] Open
Abstract
Rituximab, an anti-CD20 monoclonal antibody, was originally used to treat B-cell malignancies. Its use has significantly increased in recent years, as it is now also used to treat a variety of autoimmune diseases including rheumatoid arthritis and ANCA-associated vasculitis (AAV). Initial studies suggested that the adverse effects of rituximab were minimal. Though the risk of malignancy with rituximab-based immunosuppressive regimens appears similar to that of the general population, there are now concerns regarding the risk of infectious complications. Rituximab has been associated with serious infections, including Pneumocystis jiroveci pneumonia (PJP) and the reactivation of hepatitis B virus (HBV) and tuberculosis (TB). The risk of infection appears to be the result of a variety of mechanisms, including prolonged B-cell depletion, B-cell–T-cell crosstalk, panhypogammaglobulinaemia, late-onset neutropenia and blunting of the immune response after vaccination. Importantly, the risk of infectious complications is also related to individual patient characteristics and the indication for rituximab. Individualization of treatment is, therefore, crucial. Particular attention should be given to strategies to minimize the risk of infectious complications, including vaccinating against bacterial and viral pathogens, monitoring white cell count and immunoglobulin levels, prophylaxis against PJP and screening for HBV and TB.
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Affiliation(s)
- Andrew Nixon
- Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| | - Leanne Ogden
- Department of Renal Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Alexander Woywodt
- Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| | - Ajay Dhaygude
- Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
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27
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Kronbichler A, Windpessl M, Pieringer H, Jayne DRW. Rituximab for immunologic renal disease: What the nephrologist needs to know. Autoimmun Rev 2017; 16:633-643. [PMID: 28414152 DOI: 10.1016/j.autrev.2017.04.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 03/21/2017] [Indexed: 12/12/2022]
Abstract
Rituximab (RTX), a chimeric, monoclonal anti-CD20 antibody, is increasingly used in immune-mediated renal diseases. While licensed in the induction treatment of ANCA-associated vasculitis, it represents one of the most commonly prescribed off-label drugs. Much of the information regarding its safety has been drawn from experience in hematology and rheumatology. Ample evidence illustrates the safety of RTX, however, rare but serious adverse events have emerged that include progressive multifocal leucoencephalopathy and hepatitis B reactivation. Moderate to severe hypogammaglobulinemia and late-onset neutropenia following RTX therapy confer an increased infectious risk and factors predicting these side effects (i.e. a genetic basis) need to be identified. Nephrologists initiating RTX need to bear in mind that long-term risks and optimal dosing for many renal indications remain unclear. Special considerations must be given when RTX is used in women of childbearing age. We summarize practical aspects concerning the use of RTX. This review will provide nephrologists with information to guide their use of RTX alerting them to safety risks and the need for patient counselling.
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Affiliation(s)
- Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck, Austria.
| | - Martin Windpessl
- Department of Internal Medicine IV, Section of Nephrology, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Herwig Pieringer
- Academic Research Unit, 2nd Department of Medicine, Kepler University Hospital, Med Campus III, Linz, Austria; Paracelsus Private Medical University Salzburg, Salzburg, Austria
| | - David R W Jayne
- Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
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