Actualización del tratamiento de la glomerulonefritis membranosa primaria
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Publicado:
Sep 27, 2023
Palabras clave:
Diagnóstico, Factores de Riesgo, Glomerulonefritis Membranosa, Terapéutica.
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Resumen
Introducción: la nefropatía membranosa (MN) representa un trastorno glomerular caracterizado por el engrosamiento de las paredes capilares debido a inmunocomplejos. Esta afección prevalece como la causa principal del síndrome nefrótico en adultos no diabéticos mayores de 40 años, aunque también afecta a niños con menor frecuencia. La incidencia estimada varía geográficamente, pero permanece limitada por la falta de estudios representativos. Aunque mayormente autoinmune y relacionada con anticuerpos anti-PLA2R, el tratamiento aborda nuevas terapias y descubrimientos de anticuerpos emergentes. Metodología: se realizará una revisión bibliográfica para recopilar y analizar estudios relevantes sobre el tratamiento de la glomerulonefritis membranosa primaria, utilizando criterios de inclusión específicos. Se excluyeron artículos no pertinentes y la búsqueda abarcó bases de datos como PubMed, Web of Science y ProQuest, empleando términos de búsqueda y operadores booleanos. Discusión: diversos estudios sobre el tratamiento de la glomerulonefritis membranosa primaria revelan enfoques variables. La ciclofosfamida aceleró la recuperación en un estudio, mientras que la prednisona y el rituximab tuvieron resultados limitados. La cantidad de proteinuria resultó clave para preservar la función renal. La terapia inmunosupresora fue más efectiva que la no inmunosupresora en general. La detección de altos niveles de anticuerpos anti-PLA2R indicó mala respuesta al tacrolimus. La disfunción tiroidea y el rituximab afectaron los resultados. La terapia guiada por anticuerpos mostró altas tasas de remisión. La aspirina o warfarina profilácticas pueden ser beneficiosas en pacientes con baja albúmina sérica. Conclusión: El tratamiento de la nefropatía membranosa idiopática es complejo. Rituximab y terapia guiada por anticuerpos son efectivos, pero la elección depende de factores como edad, anticuerpos, función tiroidea y otros. Se necesita un enfoque personalizado para mejorar la remisión y calidad de vida del paciente. Área de estudio general: Medicina. Área de estudio específica: Nefrología. Tipo de estudio: Revisión Bibliográfica.
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Pozo Guzmán, L. C., & Bueno Castro, A. S. (2023). Actualización del tratamiento de la glomerulonefritis membranosa primaria. ConcienciaDigital, 6(3.2), 146-170. https://doi.org/10.33262/concienciadigital.v6i3.2.2690
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Akiyama, S., Imai, E., & Maruyama, S. (2019). Immunology of membranous nephropathy [version 1; peer review: 3 approved]. F1000Research, 8(May), 1–9. https://doi.org/10.12688/f1000research.17589.1
Alsharhan, L., & Beck, L. H. (2021). Membranous Nephropathy: Core Curriculum 2021. American Journal of Kidney Diseases, 77(3), 440–453. https://doi.org/10.1053/j.ajkd.2020.10.009
Bose, B., Chung, E. Y. M., Hong, R., Strippoli, G. F. M., Johnson, D. W., Yang, W. ling, Badve, S. V., & Palmer, S. C. (2022). Immunosuppression therapy for idiopathic membranous nephropathy: systematic review with network meta-analysis. Journal of Nephrology, 35(4), 1159–1170. https://doi.org/10.1007/s40620-022-01268-2
Chen, S. Y., Chen, C. H., Huang, Y. C., Chan, C. J., Hsieh, Y. Y., Yu, M. C., Tsai, C. H., & Tsai, F. J. (2011). Association of STAT4 polymorphisms with susceptibility to primary membranous glomerulonephritis and renal failure. Clinica Chimica Acta, 412(21–22), 1899–1904. https://doi.org/10.1016/j.cca.2011.06.020
Chung, E. Y. M., Wang, Y. M., Keung, K., Hu, M., McCarthy, H., Wong, G., Kairaitis, L., Bose, B., Harris, D. C. H., & Alexander, S. I. (2022). Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment. Frontiers in Immunology, 13(November), 1–20. https://doi.org/10.3389/fimmu.2022.1036249
Dai, P., Campbell, D., Culican, S., Brown, D. A., Byth, K., Hissaria, P., Ninnes, R., Nankivell, B., & Lin, M. W. (2020). Validation of phospholipase A2 receptor direct immunofluorescence staining in the diagnosis of primary membranous glomerulonephritis. Pathology, 52(5), 546–551. https://doi.org/10.1016/j.pathol.2020.04.003
Fervenza, F. C., Appel, G. B., Barbour, S. J., Rovin, B. H., Lafayette, R. A., Aslam, N., Jefferson, J. A., Gipson, P. E., Rizk, D. V., Sedor, J. R., Simon, J. F., McCarthy, E. T., Brenchley, P., Sethi, S., Avila-Casado, C., Beanlands, H., Lieske, J. C., Philibert, D., Li, T., … Cattran, D. C. (2019). Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. New England Journal of Medicine, 381(1), 36–46. https://doi.org/10.1056/nejmoa1814427
Gao, S., Cui, Z., Wang, X., Zhang, Y. M., Wang, F., Cheng, X. Y., Meng, L. Q., Zhou, F. De, Liu, G., & Zhao, M. H. (2021). Rituximab Therapy for Primary Membranous Nephropathy in a Chinese Cohort. Frontiers in Medicine, 8(May). https://doi.org/10.3389/fmed.2021.663680
Gao, S., Cui, Z., & Zhao, M. H. (2022). Complement C3a and C3a Receptor Activation Mediates Podocyte Injuries in the Mechanism of Primary Membranous Nephropathy. Journal of the American Society of Nephrology, 33(9), 1742–1756. https://doi.org/10.1681/ASN.2021101384
Gu, Q. hua, Cao, X., Mao, X. ming, Jia, J. ya, & Yan, T. kun. (2022). Significance of thyroid dysfunction in the patients with primary membranous nephropathy. BMC Nephrology, 23(1), 1–11. https://doi.org/10.1186/s12882-022-03023-y
Hemanth Kumar, M. K., Sandhu, J., & Sandhu, J. S. (2022). Profile and primary treatment outcomes in membranous nephropathy. Saudi Medical Journal, 43(9), 1051–1056. https://doi.org/10.15537/smj.2022.43.9.20220459
Keri, K. C., Blumenthal, S., Kulkarni, V., Beck, L., & Chongkrairatanakul, T. (2019). Primary membranous nephropathy: Comprehensive review and historical perspective. Postgraduate Medical Journal, 95(1119), 23–31. https://doi.org/10.1136/postgradmedj-2018-135729
Kim, Y., Yoon, H. E., Chung, B. H., Choi, B. S., Park, C. W., Yang, C. W., Kim, Y. S., Hong, Y. A., Kim, S. Y., Chang, Y. K., & Hwang, H. S. (2019). Clinical outcomes and effects of treatment in older patients with idiopathic membranous nephropathy. Korean Journal of Internal Medicine, 34(5), 1091–1099. https://doi.org/10.3904/kjim.2018.139
Lerner, G. B., Virmani, S., Henderson, J. M., Francis, J. M., & Beck, L. H. (2021). A conceptual framework linking immunology, pathology, and clinical features in primary membranous nephropathy. Kidney International, 100(2), 289–300. https://doi.org/10.1016/j.kint.2021.03.028
Maifata, S. M., Hod, R., Zakaria, F., & Ghani, F. A. (2020). Role of serum and urine biomarkers (PLA2R and THSD7A) in diagnosis, monitoring and prognostication of primary membranous glomerulonephritis. Biomolecules, 10(2). https://doi.org/10.3390/biom10020319
Matsuzaki, T., Watanabe, Y., Tanaka, A., Furuhashi, K., Saito, S., & Maruyama, S. (2023). Prognosis and incidence of infections in chronic kidney disease patients with membranous nephropathy enrolled in a large Japanese clinical claims database. BMC Nephrology, 24(1), 1–11. https://doi.org/10.1186/s12882-023-03190-6
Nafar, M., Dalili, N., & Samavat, S. (2020). Biomarkers in primary membranous nephropathy, a guide to precision medicine. Iranian Journal of Kidney Diseases, 14(5), 335–347.
Rojas-Rivera, J. E., & Ortiz Arduán, A. (2021). Nefropatía membranosa primaria en la era de los autoanticuerpos y de las terapias biológicas. Medicina Clínica, 157(3), 121–129. https://doi.org/10.1016/j.medcli.2021.02.010
Rojas-Rivera, J., Fervenza, F. C., & Ortiz, A. (2022). Recent Clinical Trials Insights into the Treatment of Primary Membranous Nephropathy. Drugs, 82(2), 109–132. https://doi.org/10.1007/s40265-021-01656-1
Ronco, P., Beck, L., Debiec, H., Fervenza, F. C., Hou, F. F., Jha, V., Sethi, S., Tong, A., Vivarelli, M., & Wetzels, J. (2021). Membranous nephropathy. Nature Reviews Disease Primers, 7(1). https://doi.org/10.1038/s41572-021-00303-z
Ronco, P., & Debiec, H. (2021). Membranous nephropathy: Current understanding of various causes in light of new target antigens. Current Opinion in Nephrology and Hypertension, 30(3), 287–293. https://doi.org/10.1097/MNH.0000000000000697
Safar-Boueri, L., Piya, A., Beck, L. H., & Ayalon, R. (2021). Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era. Pediatric Nephrology, 36(1), 19–30. https://doi.org/10.1007/s00467-019-04425-1
Salant, D. J. (2018). Unmet Challenges in Membranous Nephropathy. Physiology & Behavior, 176(5), 139–148. https://doi.org/10.4049/jimmunol.1801473.The
Scolari, F., Alberici, F., Mescia, F., Delbarba, E., Trujillo, H., Praga, M., & Ponticelli, C. (2022). Therapies for Membranous Nephropathy: A Tale From the Old and New Millennia. Frontiers in Immunology, 13(March). https://doi.org/10.3389/fimmu.2022.789713
Scolari, F., Delbarba, E., Santoro, D., Gesualdo, L., Pani, A., Dallera, N., Mani, L. Y., Santostefano, M., Feriozzi, S., Quaglia, M., Boscutti, G., Ferrantelli, A., Marcantoni, C., Passerini, P., Magistroni, R., Alberici, F., Ghiggeri, G. M., Ponticelli, C., & Ravani, P. (2021). Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial. Journal of the American Society of Nephrology, 32(4), 972–982. https://doi.org/10.1681/ASN.2020071091
Stahl, R. A. K., Reinhard, L., & Hoxha, E. (2019). Characterization of autoantibodies in primary membranous nephropathy and their clinical significance. Expert Review of Clinical Immunology, 15(2), 165–175. https://doi.org/10.1080/1744666X.2019.1548934
Starzyńska-Kubicka, A., Perkowska-Ptasińska, A., & Górnicka, B. (2018). Membranous glomerulonephritis – A common,unspecific pattern of glomerular injury. Polish Journal of Pathology, 69(3), 209–218. https://doi.org/10.5114/pjp.2018.79540
Tesar, V., & Hruskova, Z. (2021). Autoantibodies in the Diagnosis, Monitoring, and Treatment of Membranous Nephropathy. Frontiers in Immunology, 12(March), 1–10. https://doi.org/10.3389/fimmu.2021.593288
van de Logt, A. E., Fresquet, M., Wetzels, J. F., & Brenchley, P. (2019). The anti-PLA2R antibody in membranous nephropathy: what we know and what remains a decade after its discovery. Kidney International, 96(6), 1292–1302. https://doi.org/10.1016/j.kint.2019.07.014
Vink, C. H., Logt, A. E. van de, van der Molen, R. G., Hofstra, J. M., & Wetzels, J. F. M. (2023). Antibody-Guided Therapy in Phospholipase A2 Receptor-Associated Membranous Nephropathy. Kidney International Reports, 8(3), 432–441. https://doi.org/10.1016/j.ekir.2022.12.003
Wang, B., Zhu, Z., Huang, F., Huang, H., Tu, L., Wang, Y., Zheng, L., Zhou, J., & Wei, X. (2022). Anti-phospholipase A2 receptor antibody levels at diagnosis predicts outcome of TAC-based treatment for idiopathic membranous nephropathy patients. BMC Nephrology, 23(1), 1–10. https://doi.org/10.1186/s12882-022-02914-4
Westermann, L., Rottmann, F. A., Hug, M. J., Staudacher, D. L., Wobser, R., Arnold, F., & Welte, T. (2023). Clinical covariates influencing clinical outcomes in primary membranous nephropathy. BMC Nephrology, 24(1), 235. https://doi.org/10.1186/s12882-023-03288-x
Yamaguchi, M., Ando, M., Katsuno, T., Tsuboi, N., & Maruyama, S. (2018). Urinary protein and renal prognosis in idiopathic membranous nephropathy: a multicenter retrospective cohort study in Japan. Renal Failure, 40(1), 435–441. https://doi.org/10.1080/0886022X.2018.1487864
Zhang, J., Bian, L., Ma, F. Z., Jia, Y., & Lin, P. (2018). Efficacy and safety of rituximab therapy for membranous nephropathy: A meta-analysis. European Review for Medical and Pharmacological Sciences, 22(22), 8021–8029. https://doi.org/10.26355/eurrev-201811-16431
Zou, H., Li, Y., & Xu, G. (2019). Management of anticoagulation and antiplatelet therapy in patients with primary membranous nephropathy. BMC Nephrology, 20(1), 1–12. https://doi.org/10.1186/s12882-019-1637-y
Alsharhan, L., & Beck, L. H. (2021). Membranous Nephropathy: Core Curriculum 2021. American Journal of Kidney Diseases, 77(3), 440–453. https://doi.org/10.1053/j.ajkd.2020.10.009
Bose, B., Chung, E. Y. M., Hong, R., Strippoli, G. F. M., Johnson, D. W., Yang, W. ling, Badve, S. V., & Palmer, S. C. (2022). Immunosuppression therapy for idiopathic membranous nephropathy: systematic review with network meta-analysis. Journal of Nephrology, 35(4), 1159–1170. https://doi.org/10.1007/s40620-022-01268-2
Chen, S. Y., Chen, C. H., Huang, Y. C., Chan, C. J., Hsieh, Y. Y., Yu, M. C., Tsai, C. H., & Tsai, F. J. (2011). Association of STAT4 polymorphisms with susceptibility to primary membranous glomerulonephritis and renal failure. Clinica Chimica Acta, 412(21–22), 1899–1904. https://doi.org/10.1016/j.cca.2011.06.020
Chung, E. Y. M., Wang, Y. M., Keung, K., Hu, M., McCarthy, H., Wong, G., Kairaitis, L., Bose, B., Harris, D. C. H., & Alexander, S. I. (2022). Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment. Frontiers in Immunology, 13(November), 1–20. https://doi.org/10.3389/fimmu.2022.1036249
Dai, P., Campbell, D., Culican, S., Brown, D. A., Byth, K., Hissaria, P., Ninnes, R., Nankivell, B., & Lin, M. W. (2020). Validation of phospholipase A2 receptor direct immunofluorescence staining in the diagnosis of primary membranous glomerulonephritis. Pathology, 52(5), 546–551. https://doi.org/10.1016/j.pathol.2020.04.003
Fervenza, F. C., Appel, G. B., Barbour, S. J., Rovin, B. H., Lafayette, R. A., Aslam, N., Jefferson, J. A., Gipson, P. E., Rizk, D. V., Sedor, J. R., Simon, J. F., McCarthy, E. T., Brenchley, P., Sethi, S., Avila-Casado, C., Beanlands, H., Lieske, J. C., Philibert, D., Li, T., … Cattran, D. C. (2019). Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. New England Journal of Medicine, 381(1), 36–46. https://doi.org/10.1056/nejmoa1814427
Gao, S., Cui, Z., Wang, X., Zhang, Y. M., Wang, F., Cheng, X. Y., Meng, L. Q., Zhou, F. De, Liu, G., & Zhao, M. H. (2021). Rituximab Therapy for Primary Membranous Nephropathy in a Chinese Cohort. Frontiers in Medicine, 8(May). https://doi.org/10.3389/fmed.2021.663680
Gao, S., Cui, Z., & Zhao, M. H. (2022). Complement C3a and C3a Receptor Activation Mediates Podocyte Injuries in the Mechanism of Primary Membranous Nephropathy. Journal of the American Society of Nephrology, 33(9), 1742–1756. https://doi.org/10.1681/ASN.2021101384
Gu, Q. hua, Cao, X., Mao, X. ming, Jia, J. ya, & Yan, T. kun. (2022). Significance of thyroid dysfunction in the patients with primary membranous nephropathy. BMC Nephrology, 23(1), 1–11. https://doi.org/10.1186/s12882-022-03023-y
Hemanth Kumar, M. K., Sandhu, J., & Sandhu, J. S. (2022). Profile and primary treatment outcomes in membranous nephropathy. Saudi Medical Journal, 43(9), 1051–1056. https://doi.org/10.15537/smj.2022.43.9.20220459
Keri, K. C., Blumenthal, S., Kulkarni, V., Beck, L., & Chongkrairatanakul, T. (2019). Primary membranous nephropathy: Comprehensive review and historical perspective. Postgraduate Medical Journal, 95(1119), 23–31. https://doi.org/10.1136/postgradmedj-2018-135729
Kim, Y., Yoon, H. E., Chung, B. H., Choi, B. S., Park, C. W., Yang, C. W., Kim, Y. S., Hong, Y. A., Kim, S. Y., Chang, Y. K., & Hwang, H. S. (2019). Clinical outcomes and effects of treatment in older patients with idiopathic membranous nephropathy. Korean Journal of Internal Medicine, 34(5), 1091–1099. https://doi.org/10.3904/kjim.2018.139
Lerner, G. B., Virmani, S., Henderson, J. M., Francis, J. M., & Beck, L. H. (2021). A conceptual framework linking immunology, pathology, and clinical features in primary membranous nephropathy. Kidney International, 100(2), 289–300. https://doi.org/10.1016/j.kint.2021.03.028
Maifata, S. M., Hod, R., Zakaria, F., & Ghani, F. A. (2020). Role of serum and urine biomarkers (PLA2R and THSD7A) in diagnosis, monitoring and prognostication of primary membranous glomerulonephritis. Biomolecules, 10(2). https://doi.org/10.3390/biom10020319
Matsuzaki, T., Watanabe, Y., Tanaka, A., Furuhashi, K., Saito, S., & Maruyama, S. (2023). Prognosis and incidence of infections in chronic kidney disease patients with membranous nephropathy enrolled in a large Japanese clinical claims database. BMC Nephrology, 24(1), 1–11. https://doi.org/10.1186/s12882-023-03190-6
Nafar, M., Dalili, N., & Samavat, S. (2020). Biomarkers in primary membranous nephropathy, a guide to precision medicine. Iranian Journal of Kidney Diseases, 14(5), 335–347.
Rojas-Rivera, J. E., & Ortiz Arduán, A. (2021). Nefropatía membranosa primaria en la era de los autoanticuerpos y de las terapias biológicas. Medicina Clínica, 157(3), 121–129. https://doi.org/10.1016/j.medcli.2021.02.010
Rojas-Rivera, J., Fervenza, F. C., & Ortiz, A. (2022). Recent Clinical Trials Insights into the Treatment of Primary Membranous Nephropathy. Drugs, 82(2), 109–132. https://doi.org/10.1007/s40265-021-01656-1
Ronco, P., Beck, L., Debiec, H., Fervenza, F. C., Hou, F. F., Jha, V., Sethi, S., Tong, A., Vivarelli, M., & Wetzels, J. (2021). Membranous nephropathy. Nature Reviews Disease Primers, 7(1). https://doi.org/10.1038/s41572-021-00303-z
Ronco, P., & Debiec, H. (2021). Membranous nephropathy: Current understanding of various causes in light of new target antigens. Current Opinion in Nephrology and Hypertension, 30(3), 287–293. https://doi.org/10.1097/MNH.0000000000000697
Safar-Boueri, L., Piya, A., Beck, L. H., & Ayalon, R. (2021). Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era. Pediatric Nephrology, 36(1), 19–30. https://doi.org/10.1007/s00467-019-04425-1
Salant, D. J. (2018). Unmet Challenges in Membranous Nephropathy. Physiology & Behavior, 176(5), 139–148. https://doi.org/10.4049/jimmunol.1801473.The
Scolari, F., Alberici, F., Mescia, F., Delbarba, E., Trujillo, H., Praga, M., & Ponticelli, C. (2022). Therapies for Membranous Nephropathy: A Tale From the Old and New Millennia. Frontiers in Immunology, 13(March). https://doi.org/10.3389/fimmu.2022.789713
Scolari, F., Delbarba, E., Santoro, D., Gesualdo, L., Pani, A., Dallera, N., Mani, L. Y., Santostefano, M., Feriozzi, S., Quaglia, M., Boscutti, G., Ferrantelli, A., Marcantoni, C., Passerini, P., Magistroni, R., Alberici, F., Ghiggeri, G. M., Ponticelli, C., & Ravani, P. (2021). Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial. Journal of the American Society of Nephrology, 32(4), 972–982. https://doi.org/10.1681/ASN.2020071091
Stahl, R. A. K., Reinhard, L., & Hoxha, E. (2019). Characterization of autoantibodies in primary membranous nephropathy and their clinical significance. Expert Review of Clinical Immunology, 15(2), 165–175. https://doi.org/10.1080/1744666X.2019.1548934
Starzyńska-Kubicka, A., Perkowska-Ptasińska, A., & Górnicka, B. (2018). Membranous glomerulonephritis – A common,unspecific pattern of glomerular injury. Polish Journal of Pathology, 69(3), 209–218. https://doi.org/10.5114/pjp.2018.79540
Tesar, V., & Hruskova, Z. (2021). Autoantibodies in the Diagnosis, Monitoring, and Treatment of Membranous Nephropathy. Frontiers in Immunology, 12(March), 1–10. https://doi.org/10.3389/fimmu.2021.593288
van de Logt, A. E., Fresquet, M., Wetzels, J. F., & Brenchley, P. (2019). The anti-PLA2R antibody in membranous nephropathy: what we know and what remains a decade after its discovery. Kidney International, 96(6), 1292–1302. https://doi.org/10.1016/j.kint.2019.07.014
Vink, C. H., Logt, A. E. van de, van der Molen, R. G., Hofstra, J. M., & Wetzels, J. F. M. (2023). Antibody-Guided Therapy in Phospholipase A2 Receptor-Associated Membranous Nephropathy. Kidney International Reports, 8(3), 432–441. https://doi.org/10.1016/j.ekir.2022.12.003
Wang, B., Zhu, Z., Huang, F., Huang, H., Tu, L., Wang, Y., Zheng, L., Zhou, J., & Wei, X. (2022). Anti-phospholipase A2 receptor antibody levels at diagnosis predicts outcome of TAC-based treatment for idiopathic membranous nephropathy patients. BMC Nephrology, 23(1), 1–10. https://doi.org/10.1186/s12882-022-02914-4
Westermann, L., Rottmann, F. A., Hug, M. J., Staudacher, D. L., Wobser, R., Arnold, F., & Welte, T. (2023). Clinical covariates influencing clinical outcomes in primary membranous nephropathy. BMC Nephrology, 24(1), 235. https://doi.org/10.1186/s12882-023-03288-x
Yamaguchi, M., Ando, M., Katsuno, T., Tsuboi, N., & Maruyama, S. (2018). Urinary protein and renal prognosis in idiopathic membranous nephropathy: a multicenter retrospective cohort study in Japan. Renal Failure, 40(1), 435–441. https://doi.org/10.1080/0886022X.2018.1487864
Zhang, J., Bian, L., Ma, F. Z., Jia, Y., & Lin, P. (2018). Efficacy and safety of rituximab therapy for membranous nephropathy: A meta-analysis. European Review for Medical and Pharmacological Sciences, 22(22), 8021–8029. https://doi.org/10.26355/eurrev-201811-16431
Zou, H., Li, Y., & Xu, G. (2019). Management of anticoagulation and antiplatelet therapy in patients with primary membranous nephropathy. BMC Nephrology, 20(1), 1–12. https://doi.org/10.1186/s12882-019-1637-y