Primary Nephrotic Syndrome
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Landan Zand Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota

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Fernando C. Fervenza Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota

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  • 1

    Glassock RJ, Fervenza FC, Hebert L, Cameron JS: Nephrotic syndrome redux. Nephrol Dial Transplant 30: 1217, 2015 PubMed

  • 2

    van de Logt AE, Rijpma SR, Vink CH, Prudon-Rosmulder E, Wetzels JF, van Berkel M: The bias between different albumin assays may affect clinical decision-making. Kidney Int 95: 15141517, 2019 PubMed

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  • 3

    Meyrier A, Niaudet P: Acute kidney injury complicating nephrotic syndrome of minimal change disease. Kidney Int 94: 861869, 2018 PubMed

  • 4

    Glassock RJ: Secondary minimal change disease. Nephrol Dial Transplant 18[Suppl 6]: vi52vi58, 2003 PubMed

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  • 7

    Heslan JM, Branellec AI, Pilatte Y, Lang P, Lagrue G: Differentiation between vascular permeability factor and IL-2 in lymphocyte supernatants from patients with minimal-change nephrotic syndrome. Clin Exp Immunol 86: 157162, 1991 PubMed

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  • 8

    Cheung PK, Stulp B, Immenschuh S, Borghuis T, Baller JF, Bakker WW: Is 100KF an isoform of hemopexin? Immunochemical characterization of the vasoactive plasma factor 100KF. J Am Soc Nephrol 10: 17001708, 1999 PubMed

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  • 9

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  • 10

    Clement LC, Avila-Casado C, Macé C, Soria E, Bakker WW, Kersten S, et al.: Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 17: 117122, 2011 PubMed

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  • 11

    Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, et al.: Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol 18: 14761485, 2007 PubMed

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  • 12

    Chugh SS, Clement LC, Macé C: New insights into human minimal change disease: Lessons from animal models. Am J Kidney Dis 59: 284292, 2012 PubMed

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  • 14

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  • 15

    Clement LC, Macé C, Avila-Casado C, Joles JA, Kersten S, Chugh SS: Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med 20: 3746, 2014 PubMed

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    Kim AH, Chung JJ, Akilesh S, Koziell A, Jain S, Hodgin JB, et al.: B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight 2: e81836, 2017 PubMed

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  • 17

    Boumediene A, Vachin P, Sendeyo K, Oniszczuk J, Zhang SY, Henique C, et al.: NEPHRUTIX: A randomized, double-blind, placebo vs rituximab-controlled trial assessing T-cell subset changes in minimal change nephrotic syndrome. J Autoimmun 88: 91102, 2018 PubMed

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  • 18

    Watts AJB, Keller KH, Lerner G, Rosales I, Collins AB, Sekulic M, et al.: Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel autoimmune etiology. J Am Soc Nephrol 33: 238252, 2022 PubMed

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  • 19

    Yoshikawa N, Nakanishi K, Sako M, Oba MS, Mori R, Ota E, et al.; Japanese Study Group of Kidney Disease in Children: A multicenter randomized trial indicates initial prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-month treatment. Kidney Int 87: 225232, 2015 PubMed

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  • 20

    Sinha A, Saha A, Kumar M, Sharma S, Afzal K, Mehta A, et al.: Extending initial prednisolone treatment in a randomized control trial from 3 to 6 months did not significantly influence the course of illness in children with steroid-sensitive nephrotic syndrome. Kidney Int 87: 217224, 2015 PubMed

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  • 21

    Webb NJA, Woolley RL, Lambe T, Frew E, Brettell EA, Barsoum EN, et al.; PREDNOS Collaborative Group: Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: Phase III randomised controlled trial and economic evaluation. BMJ 365: l1800, 2019 PubMed

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  • 22

    Hahn D, Hodson EM, Willis NS, Craig JC: Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev (3): CD001533, 2015 PubMed

  • 23

    Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G, et al.: Adult minimal-change disease: Clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol 2: 445453, 2007 PubMed

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  • 24

    Li H, Shi X, Shen H, Li X, Wang H, Li H, et al.: Tacrolimus versus intravenous pulse cyclophosphamide therapy in Chinese adults with steroid-resistant idiopathic minimal change nephropathy: A multicenter, open-label, nonrandomized cohort trial. Clin Ther 34: 11121120, 2012 PubMed

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  • 25

    Ponticelli C, Edefonti A, Ghio L, Rizzoni G, Rinaldi S, Gusmano R, et al.: Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: A multicentre randomized controlled trial. Nephrol Dial Transplant 8: 13261332, 1993 PubMed

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  • 26

    Li X, Li H, Chen J, He Q, Lv R, Lin W, et al.: Tacrolimus as a steroid-sparing agent for adults with steroid-dependent minimal change nephrotic syndrome. Nephrol Dial Transplant 23: 19191925, 2008 PubMed

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  • 27

    Meyrier A, Condamin MC, Broneer D; Collaborative Group of the French Society of Nephrology: Treatment of adult idiopathic nephrotic syndrome with cyclosporin A: Minimal-change disease and focal-segmental glomerulosclerosis. Clin Nephrol 35[Suppl 1]: S37S42, 1991 PubMed

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  • 28

    Li X, Liu Z, Wang L, Wang R, Ding G, Shi W, et al.: Tacrolimus monotherapy after intravenous methylprednisolone in adults with minimal change nephrotic syndrome. J Am Soc Nephrol 28: 12861295, 2017 PubMed

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  • 29

    Medjeral-Thomas NR, Lawrence C, Condon M, Sood B, Warwicker P, Brown H, et al.: Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with de novo minimal change disease: A multicenter, randomized, controlled trial. Clin J Am Soc Nephrol 15: 209218, 2020 PubMed

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  • 30

    Gellermann J, Weber L, Pape L, Tönshoff B, Hoyer P, Querfeld U; Gesellschaft für Pädiatrische Nephrologie (GPN): Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome. J Am Soc Nephrol 24: 16891697, 2013 PubMed

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  • 31

    Geng HY, Ji LN, Chen CY, Tu J, Li HR, Bao R, et al.: [Mycophenolate mofetil versus cyclosporine A in children with primary refractory nephrotic syndrome]. Zhonghua Er Ke Za Zhi 56: 651656, 2018 PubMed

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  • 32

    Sinha A, Puraswani M, Kalaivani M, Goyal P, Hari P, Bagga A: Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome: An open-label randomized controlled trial. Kidney Int 95: 210218, 2019 PubMed

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  • 33

    Rémy P, Audard V, Natella PA, Pelle G, Dussol B, Leray-Moragues H, et al.; MSN Trial Investigators: An open-label randomized controlled trial of low-dose corticosteroid plus enteric-coated mycophenolate sodium versus standard corticosteroid treatment for minimal change nephrotic syndrome in adults (MSN study). Kidney Int 94: 12171226, 2018 PubMed

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  • 34

    Benz K, Dötsch J, Rascher W, Stachel D: Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol 19: 794797, 2004 PubMed

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  • 35

    Ravani P, Rossi R, Bonanni A, Quinn RR, Sica F, Bodria M, et al.: Rituximab in children with steroid-dependent nephrotic syndrome: A multicenter, open-label, noninferiority, randomized controlled trial. J Am Soc Nephrol 26: 22592266, 2015 PubMed

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  • 36

    Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, et al.; Rituximab for Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study Group: Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: A multicentre, double-blind, randomised, placebo-controlled trial. Lancet 384: 12731281, 2014 PubMed

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  • 37

    Ruggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, Marasà M, et al.; Rituximab in Nephrotic Syndrome of Steroid-Dependent or Frequently Relapsing Minimal Change Disease Or Focal Segmental Glomerulosclerosis (NEMO) Study Group: Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J Am Soc Nephrol 25: 850863, 2014 PubMed

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  • 38

    Webb H, Jaureguiberry G, Dufek S, Tullus K, Bockenhauer D: Cyclophosphamide and rituximab in frequently relapsing/steroid-dependent nephrotic syndrome. Pediatr Nephrol 31: 589594, 2016 PubMed

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  • 39

    Basu B, Sander A, Roy B, Preussler S, Barua S, Mahapatra TKS, et al.: Efficacy of rituximab vs tacrolimus in pediatric corticosteroid-dependent nephrotic syndrome: A randomized clinical trial. JAMA Pediatr 172: 757764, 2018 PubMed

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  • 40

    Hogan J, Dossier C, Kwon T, Macher MA, Maisin A, Couderc A, et al.: Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome. Pediatr Nephrol 34: 253259, 2019 PubMed

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  • 41

    Chan EY, Webb H, Yu E, Ghiggeri GM, Kemper MJ, Ma AL, et al.: Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes. Kidney Int 97: 393401, 2020 PubMed

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  • 42

    Ravani P, Magnasco A, Edefonti A, Murer L, Rossi R, Ghio L, et al.: Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: A randomized controlled trial. Clin J Am Soc Nephrol 6: 13081315, 2011 PubMed

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  • 43

    Ravani P, Ponticelli A, Siciliano C, Fornoni A, Magnasco A, Sica F, et al.: Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome. Kidney Int 84: 10251033, 2013 PubMed

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  • 44

    Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, et al.: Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 23: 11171124, 2012 PubMed

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  • 45

    Ravani P, Bonanni A, Ghiggeri GM: Randomised controlled trial comparing ofatumumab to rituximab in children with steroid-dependent and calcineurin inhibitor-dependent idiopathic nephrotic syndrome: Study protocol. BMJ Open 7: e013319, 2017 PubMed

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  • 46

    Iwabuchi Y, Miyabe Y, Makabe S, Nakano M, Manabe S, Karasawa K, et al.: Comparison of the response of frequently relapsing steroid-dependent minimal change nephrotic syndrome to rituximab therapy between childhood-onset and adult-onset disease. Medicine (Baltimore) 97: e12704, 2018 PubMed

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  • 47

    Fenoglio R, Sciascia S, Beltrame G, Mesiano P, Ferro M, Quattrocchio G, et al.: Rituximab as a front-line therapy for adult-onset minimal change disease with nephrotic syndrome. Oncotarget 9: 2879928804, 2018 PubMed

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  • 48

    Kronbichler A, Kerschbaum J, Fernandez-Fresnedo G, Hoxha E, Kurschat CE, Busch M, et al.: Rituximab treatment for relapsing minimal change disease and focal segmental glomerulosclerosis: A systematic review. Am J Nephrol 39: 322330, 2014 PubMed

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  • 49

    Kittanamongkolchai W, Cheungpasitporn W, Zand L: Efficacy and safety of adrenocorticotropic hormone treatment in glomerular diseases: A systematic review and meta-analysis. Clin Kidney J 9: 387396, 2016 PubMed

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  • 50

    Madan A, Mijovic-Das S, Stankovic A, Teehan G, Milward AS, Khastgir A: Acthar gel in the treatment of nephrotic syndrome: A multicenter retrospective case series. BMC Nephrol 17: 37, 2016 PubMed

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  • 51

    Wang CS, Travers C, McCracken C, Leong T, Gbadegesin R, Quiroga A, et al.: Adrenocorticotropic hormone for childhood nephrotic syndrome: The ATLANTIS randomized trial. Clin J Am Soc Nephrol 13: 18591865, 2018 PubMed

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  • 52

    Szeto CC, Lai FM, Chow KM, Kwan BC, Kwong VW, Leung CB, et al.: Long-term outcome of biopsy-proven minimal change nephropathy in Chinese adults. Am J Kidney Dis 65: 710718, 2015 PubMed

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  • 53

    Sethi S, Glassock RJ, Fervenza FC: Focal segmental glomerulosclerosis: Towards a better understanding for the practicing nephrologist. Nephrol Dial Transplant 30: 375384, 2015 PubMed

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  • 54

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    Kriz W, Lemley KV: A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol 26: 258269, 2015 PubMed

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  • 58

    Kriz W, Lemley KV: Potential relevance of shear stress for slit diaphragm and podocyte function. Kidney Int 91: 12831286, 2017 PubMed

  • 59

    De Vriese AS, Wetzels JF, Glassock RJ, Sethi S, Fervenza FC: Therapeutic trials in adult FSGS: Lessons learned and the road forward. Nat Rev Nephrol 17: 619630, 2021 PubMed

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  • 60

    Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, et al.: Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases. Kidney Int 100: 753779, 2021 PubMed

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  • 61

    Campbell KN, Tumlin JA: Protecting podocytes: A key target for therapy of focal segmental glomerulosclerosis. Am J Nephrol 47[Suppl 1]: 1429, 2018 PubMed

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    Campbell KN, Wong JS, Gupta R, Asanuma K, Sudol M, He JC, et al.: Yes-associated protein (YAP) promotes cell survival by inhibiting proapoptotic dendrin signaling. J Biol Chem 288: 1705717062, 2013 PubMed

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  • 63

    Schwartzman M, Reginensi A, Wong JS, Basgen JM, Meliambro K, Nicholas SB, et al.: Podocyte-specific deletion of Yes-associated protein causes FSGS and progressive renal failure. J Am Soc Nephrol 27: 216226, 2016 PubMed

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  • 64

    Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, et al.: Podocyte depletion causes glomerulosclerosis: Diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 16: 29412952, 2005 PubMed

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  • 65

    Eng DG, Sunseri MW, Kaverina NV, Roeder SS, Pippin JW, Shankland SJ: Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental glomerulosclerosis. Kidney Int 88: 9991012, 2015 PubMed

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  • 66

    Kretzler M: Role of podocytes in focal sclerosis: Defining the point of no return. J Am Soc Nephrol 16: 28302832, 2005 PubMed

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    Savin VJ, Sharma M, Zhou J, Gennochi D, Fields T, Sharma R, et al.: Renal and hematological effects of CLCF-1, a B-cell-stimulating cytokine of the IL-6 family. J Immunol Res 2015: 714964, 2015 PubMed

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  • 68

    Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, et al.: Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17: 952960, 2011 PubMed

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  • 69

    Delville M, Sigdel TK, Wei C, Li J, Hsieh SC, Fornoni A, et al.: A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 6: 256ra136, 2014 PubMed

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  • 70

    Wada T, Nangaku M: A circulating permeability factor in focal segmental glomerulosclerosis: The hunt continues. Clin Kidney J 8: 708715, 2015 PubMed

  • 71

    Lepori N, Zand L, Sethi S, Fernandez-Juarez G, Fervenza FC: Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults. Clin Kidney J 11: 179190, 2018 PubMed

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  • 72

    De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC: Differentiating primary, genetic, and secondary FSGS in adults: A clinicopathologic approach. J Am Soc Nephrol 29: 759774, 2018 PubMed

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  • 73

    Buxeda A, Said S, Nasr SH, Soler MJ, Howard MT, Maguire LJ, et al.: Crystal-induced podocytopathy producing collapsing focal segmental glomerulosclerosis in monoclonal gammopathy of renal significance: A case report. Kidney Med 3: 659664, 2021 PubMed

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  • 74

    Sethi S, Zand L, Nasr SH, Glassock RJ, Fervenza FC: Focal and segmental glomerulosclerosis: Clinical and kidney biopsy correlations. Clin Kidney J 7: 531537, 2014 PubMed

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  • 75

    Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al.; CREDENCE Trial Investigators: Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380: 22952306, 2019 PubMed

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    van den Berg JG, van den Bergh Weerman MA, Assmann KJ, Weening JJ, Florquin S: Podocyte foot process effacement is not correlated with the level of proteinuria in human glomerulopathies. Kidney Int 66: 19011906, 2004 PubMed

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    Deegens JK, Dijkman HB, Borm GF, Steenbergen EJ, van den Berg JG, Weening JJ, et al.: Podocyte foot process effacement as a diagnostic tool in focal segmental glomerulosclerosis. Kidney Int 74: 15681576, 2008 PubMed

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  • 78

    Maas RJ, Deegens JK, Smeets B, Moeller MJ, Wetzels JF: Minimal change disease and idiopathic FSGS: Manifestations of the same disease. Nat Rev Nephrol 12: 768776, 2016 PubMed

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  • 79

    Hommos MS, De Vriese AS, Alexander MP, Sethi S, Vaughan L, Zand L, et al.: The incidence of primary vs secondary focal segmental glomerulosclerosis: A clinicopathologic study. Mayo Clin Proc 92: 17721781, 2017 PubMed

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  • 80

    Zand L, Glassock RJ, De Vriese AS, Sethi S, Fervenza FC: What are we missing in the clinical trials of focal segmental glomerulosclerosis? Nephrol Dial Transplant 32[Suppl 1]: i14i21, 2017 PubMed

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  • 81

    Hogan J, Mohan P, Appel GB: Diagnostic tests and treatment options in glomerular disease: 2014 update. Am J Kidney Dis 63: 656666, 2014 PubMed

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    Rood IM, Bavinck A, Lipska-Ziętkiewicz BS, Lugtenberg D, Schaefer F, Deegens JKJ, et al.: Later response to corticosteroids in adults with primary focal segmental glomerular sclerosis is associated with favorable outcomes. Kidney Int Rep 7: 8798, 2021 PubMed

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  • 83

    Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, et al.; North America Nephrotic Syndrome Study Group: A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. Kidney Int 56: 22202226, 1999 PubMed

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  • 84

    Ramachandran R, Kumar V, Rathi M, Nada R, Jha V, Gupta KL, et al.: Tacrolimus therapy in adult-onset steroid-resistant nephrotic syndrome due to a focal segmental glomerulosclerosis single-center experience. Nephrol Dial Transplant 29: 19181924, 2014 PubMed

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  • 85

    Laurin LP, Gasim AM, Poulton CJ, Hogan SL, Jennette JC, Falk RJ, et al.: Treatment with glucocorticoids or calcineurin inhibitors in primary FSGS. Clin J Am Soc Nephrol 11: 386394, 2016 PubMed

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  • 86

    Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al.: The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14: 931938, 2008 PubMed

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  • 87

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  • 88

    DaSilva I, Huerta A, Quintana L, Redondo B, Iglesias E, Draibe J, et al.; Spanish Group for the Study of Glomerular Diseases (GLOSEN): Rituximab for steroid-dependent or frequently relapsing idiopathic nephrotic syndrome in adults: A retrospective, multicenter study in Spain. BioDrugs 31: 239249, 2017 PubMed

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  • 89

    Tedesco M, Mescia F, Pisani I, Allinovi M, Casazza G, Del Vecchio L, et al.; Italian Society of Nephrology Immunopathology Working Group: The role of rituximab in primary focal segmental glomerular sclerosis of the adult. Kidney Int Rep 7: 18781886, 2022 PubMed

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  • 90

    Kronbichler A, Gauckler P, Bruchfeld A: Rituximab in minimal change disease and focal segmental glomerulosclerosis. Nephrol Dial Transplant 36: 983985, 2021 PubMed

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  • 91

    Roccatello D, Sciascia S, Rossi D, Alpa M, Naretto C, Radin M, et al.: High-dose rituximab ineffective for focal segmental glomerulosclerosis: A long-term observation study. Am J Nephrol 46: 108113, 2017 PubMed

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  • 92

    Furie RA, Aroca G, Cascino MD, Garg JP, Rovin BH, Alvarez A, et al.: B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: A randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 81: 100107, 2022 PubMed

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  • 93

    Klomjit N, Fervenza FC, Zand L: Successful treatment of patients with refractory PLA2R-associated membranous nephropathy with obinutuzumab: A report of 3 cases. Am J Kidney Dis 76: 883888, 2020 PubMed

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  • 94

    Gipson DS, Trachtman H, Kaskel FJ, Greene TH, Radeva MK, Gassman JJ, et al.: Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int 80: 868878, 2011 PubMed

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  • 95

    Hogan J, Bomback AS, Mehta K, Canetta PA, Rao MK, Appel GB, et al.: Treatment of idiopathic FSGS with adrenocorticotropic hormone gel. Clin J Am Soc Nephrol 8: 20722081, 2013 PubMed

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