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      The Efficacy of Cyclophosphamide Combined with Prednisone in Membranous Nephropathy Patients with Different Cytochrome P450 2B6 Gene Polymorphisms and Analysis of Factors Influencing the Efficacy


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          To investigate the efficacy of cyclophosphamide combined with prednisone in membranous nephropathy (MN) patients with different cytochrome P450 (CYP) 2B6 gene polymorphisms and explore the factors influencing the efficacy.


          We performed a prospective and interventional study including 153 outpatients diagnosed with membranous nephropathy from April 2020 to June 2020 in the Bayannur Hospital. Based on the results of CYP2B6 gene polymorphisms, patients were divided into CYP2B6*4 group (785A>G) with 93 cases and CYP2B6*5 group (1459C>T) with 60 cases, and all patients were treated with cyclophosphamide and prednisone. The efficacy of the two groups was compared, and the serum levels of antibody against thrombospondin type-1 domain-containing 7A (THSD7A-Ab), 8-hydroxy-2’-deoxyguanosine (8-OHdG) and antibody against the M-type phospholipase A2 receptor (PLA2R-Ab) determined by the enzyme-linked immunosorbent method were analyzed in the two groups before and after treatment.


          After the treatment with cyclophosphamide and prednisone, serum levels of THSD7A-Ab, 8-OHdG, and PLA2R-Ab were higher in the CYP2B6*4 group than those in the CYP2B6*5 group (All three P<0.001). The univariate Logistic regression analysis showed that CYP2B6*4 (OR = 1.727, 95% CI: 1.028–2.654. P=0.012), CYP2B6*5 (OR = 1.802, 95% CI: 1.179–2.752. P=0.031), THSD7A-Ab (OR = 1.832, 95% CI: 0.871–2.348. P=0.023), 8-OHdG (OR = 1.661, 95% CI: 1.123–2.231. P=0.009), PLA2R-Ab (OR = 1.649, 95% CI: 1.083–2.761. P=0.017) were independent influencing factors on the efficacy of MN. The multivariate Logistic regression analysis showed that CYP2B6*4 (OR = 2.009, 95% CI: 1.327–2.703. P<0.001), CYP2B6*5 (OR = 3.009, 95% CI: 1.467–5.231. P=0.005), THSD7A-Ab (OR = 1.396, 95% CI: 1.002–1.897. P=0.019), 8-OHdG (OR = 0.704, 95% CI: 0.591–0.742. P<0.001), PLA2R-Ab (OR = 2.761, 95% CI: 1.231–3.918. P=0.017) were independent factors influencing the efficacy of cyclophosphamide and prednisone on MN.


          Cyclophosphamide combined with prednisone was effective in treating MN with different CYP2B6 gene polymorphisms. CYP2B6*4, CYP2B6*5, and serum levels of THSD7A-Ab, 8-OHdG, and PLA2R-Ab were independent influencing factors on the outcome of MN.

          Most cited references26

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          KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

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            An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain–Containing 7A–Specific Antibodies in Membranous Nephropathy

            Thrombospondin type 1 domain-containing 7A (THSD7A) is a target antigen identified in adult membranous nephropathy (MN) along with the major antigen phospholipase A2 receptor 1 (PLA2R1). The prevalence of THSD7A-Ab-positive patients is unknown, and it is unclear whether the clinical presentation differs between patients positive for PLA2R1-Ab or THSD7A-Ab. We screened serum samples of 1276 patients with MN from three different cohorts for the presence of THSD7A-Ab by Western blot analysis and a newly developed indirect immunofluorescence test (IFT). Compared with Western blot analysis, the IFT had a 92% sensitivity and a 100% specificity. The prevalence of THSD7A-associated MN in a prospective cohort of 345 patients with MN was 2.6%, and most were women. In this cohort, the percentage of patients with THSD7A-associated MN and malignant disease significantly exceeded that of patients with PLA2R1-associated MN and malignant disease. In all cohorts, we identified 40 patients with THSD7A-associated MN, eight of whom developed a malignancy within a median time of 3 months from diagnosis of MN. In one patient with THSD7A-associated MN and metastases of an endometrial carcinoma, immunohistochemistry showed THSD7A expression on the metastatic cells and within follicular dendritic cells of the metastasis-infiltrated lymph node. We conclude that the IFT allows sensitive and specific measurement of circulating THSD7A-Ab in patients with MN. Patients with THSD7A-associated MN differ in their clinical characteristics from patients with PLA2R1-associated MN, and more intensive screening for the presence of malignancies may be warranted in those with THSD7A-associated MN.
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              Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy.

              Phospholipase A2 receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location of a major epitope in the N-terminal cysteine-rich ricin domain of PLA2R that is recognized by 90% of human anti-PLA2R autoantibodies. The epitope was sensitive to reduction and SDS denaturation in the isolated ricin domain and the larger fragment containing the ricin, fibronectin type II, first and second C-type lectin domains (CTLD). However, in nondenaturing conditions the epitope was protected against reduction in larger fragments, including the full-length extracellular region of PLA2R. To determine the composition of the epitope, we isolated immunoreactive tryptic fragments by Western blotting and analyzed them by mass spectrometry. The identified peptides were tested as inhibitors of autoantibody binding to PLA2R by surface plasmon resonance. Two peptides from the ricin domain showed strong inhibition, with a longer sequence covering both peptides (31-mer) producing 85% inhibition of autoantibody binding to PLA2R. Anti-PLA2R antibody directly bound this 31-mer peptide under nondenaturing conditions and binding was sensitive to reduction. Analysis of PLA2R and the PLA2R-anti-PLA2R complex using electron microscopy and homology-based representations allowed us to generate a structural model of this major epitope and its antibody binding site, which is independent of pH-induced conformational change in PLA2R. Identification of this major PLA2R epitope will enable further therapeutic advances for patients with idiopathic membranous nephropathy, including antibody inhibition therapy and immunoadsorption of circulating autoantibodies.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                20 October 2022
                : 16
                : 3655-3662
                [1 ]Department of Nephrology, Bayannur Hospital , Bayannur, Inner Mongolia, People’s Republic of China
                [2 ]Department of Orthopedics, the Second Affiliated Hospital of Shandong First Medical University , Taian, Shandong, People’s Republic of China
                [3 ]Department of Traumatic Orthopedics, Bayannur Hospital , Bayannur, Inner Mongolia, People’s Republic of China
                Author notes
                Correspondence: Haokui Liu, Department of Traumatic Orthopedics, Bayannur Hospital , No. 98 Wulan Buhe Road, Linhe District, Bayannur City, Inner Mongolia, 015000, People’s Republic of China, Tel +86-15047899415, Email liuhaokui123@163.com
                © 2022 Zhang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 05 May 2022
                : 21 September 2022
                Page count
                Figures: 0, Tables: 5, References: 26, Pages: 8
                There is no funding to report.
                Original Research

                Pharmacology & Pharmaceutical medicine
                cyclophosphamide,prednisone,gene polymorphisms,membranous nephropathy,influencing factor


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