Rituximab in Membranous Nephropathy

Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification phospholipase A2 receptor (PLA2R) as target antigen in patients changed management MN dramatically, and provided a rationale for B-cell depleting agents such rituximab. efficacy rituximab inducing remission has been investigated several studies, including 3 randomized controlled trials, which complete partial proteinuria was achieved approximately two-thirds treated patients. Due to its favorable safety profile, now considered first-line treatment option MN, especially at moderate high risk deterioration kidney function. However, questions remain about how best use rituximab, optimal dosing regimen, potential need maintenance therapy, assessment long-term outcomes. In this review, we provide an overview current literature discuss both strengths limitations “the new standard.” (NS) adults worldwide with predominance Caucasian male individuals. Secondary causes like underlying malignancies, infections, or autoimmune disorders account 20% all cases.1Couser W.G. Primary membranous nephropathy.Clin J Am Soc Nephrol. 2017; 12: 983-997Crossref PubMed Scopus (203) Google Scholar remaining 80% cases are referred focus review. natural course heterogeneous, implying that uniform not appropriate. Without treatment, half attain spontaneous over period 5 10 years, other sustain progressive loss function.2van den Brand J.A. van Dijk P.R. Hofstra J.M. Wetzels J.F. Long-term outcomes idiopathic using restrictive strategy.J 2014; 25: 150-158Crossref (58) Besides outcomes, complications, venous thromboembolism cardiovascular events, have significant impact on morbidity mortality therefore be their disease management.3Barbour S.J. Greenwald A. Djurdjev O. et al.Disease-specific thromboembolic events increased glomerulonephritis.Kidney Int. 2012; 81: 190-195Abstract Full Text PDF (114) Scholar, 4Lee T. Derebail V.K. Kshirsagar A.V. al.Patients events.Kidney 2016; 89: 1111-1118Abstract (36) 5Plaisier E. Ronco P. Screening cancer glomerular diseases.Clin 2020; 15: 886-888Crossref (10) Major progress pathogenetic understanding during past decade when M-type PLA2R autoantibody identified 70% patients.6Beck Jr., L.H. Bonegio R.G. Lambeau G. al.M-type nephropathy.N Engl Med. 2009; 361: 11-21Crossref (1351) another 3% 5% patients, autoantibodies directed against thrombospondin type-1 domain-containing 7A can identified.7Tomas N.M. Beck Meyer-Schwesinger C. al.Thrombospondin 371: 2277-2287Crossref (455) Recently, neural epidermal growth factor-like 1 protein semaphorin 3b were also autoantigens associated MN.8Sethi S. Debiec H. Madden B. al.Neural (NELL-1) nephropathy.Kidney 97: 163-174Abstract (83) Scholar,9Sethi al.Semaphorin 3B-associated distinct type predominantly present pediatric patients.Kidney 98: 1253-1264Abstract (39) Although biopsy samples usually show IgG4 antibody deposition, IgG1 major IgG subtype 1- 3b-associated possibly indicating secondary these cases.10Ohtani Wakui Komatsuda al.Distribution subclass deposits malignancy-associated nephropathy.Nephrol Dial Transplant. 2004; 19: 574-579Crossref (145) fact, detection recently concurrent malignancy.11Caza T, Hassen S, Dvanajscak Z, al. NELL1 [e-pub ahead print]. Kidney https://doi.org/10.1016/j.kint.2020.07.039, Accessed March 12, 2021.Google may either caused by yet unidentified antigens reflect misclassified MN. A group shows association diseases related accumulation exostosin basement membrane should rather classified MN.12Sethi B.J. al.Exostosin 1/Exostosin 2-associated nephropathy.J 2019; 30: 1123-1136Crossref (86) Emerging evidence (Ab) titer correlates activity.13De Vriese A.S. Glassock R.J. Nath K.A. al.A proposal serology-based approach 28: 421-430Crossref (150) As result, novel algorithms proposed facilitate diagnosis monitor treatment.13De Under certain conditions, even established without histologic verification.14Floege J. Barbour Cattran D.C. al.Management (part 1): conclusions from Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney 95: 268-280Abstract (123) PLA2R-positive low Ab levels predict higher likelihood changes titers precede months.14Floege 15Radice Trezzi Maggiore U. al.Clinical usefulness monitoring activity (IMN).Autoimmun Rev. 146-154Crossref (49) 16Ruggenenti Ruggiero al.Anti-phospholipase predicts post-rituximab outcome 2015; 26: 2545-2558Crossref (180) This latency between immediate treatment-induced immunologic delayed clinical explained gradual resolution subepithelial immune observed repeated after treatment.17Ruggenenti Cravedi Sghirlanzoni M.C. al.Effects morphofunctional abnormalities glomerulopathy.Clin 2008; 3: 1652-1659Crossref (57) addition, recurrence therapeutic response relapse. Hence, immunosuppressive therapy guide adaption regimen individual patient.13De Scholar,16Ruggenenti Of note, PLA2R-associated diagnosed do (initially) positive serologic testing. saturation tissue auto-Abs, seroconversion detected serial serological testing follow-up. explain why missed relapsing they first rise proteinuria. enhanced staining strongly (and goes along testing), further diagnostic evaluation exclude performed those negative only faintly and/or non-IgG4 deposits.18Hoxha Kneissler Stege al.Enhanced expression glomeruli serum antibodies 82: 797-804Abstract (204) There debate whether ability Abs multiple epitopes (epitope spreading) could poor prognostic marker,19Seitz-Polski Dahan K. al.High-dose early PLA2R1-related 14: 1179-1182Crossref (34) but recent data call into question. prospective cohort 150 epitope spreading highly dependent total levels, although clearly predicted epitope-recognition patterns alone showed no impact.20Reinhard L. Zahner Menzel relevance domain-specific 31: 197-207Crossref (16) advances it autoantibody-driven disease. Given pivotal role B cells producing pathogenic autoantibodies, there clear modalities. Supportive antihypertensive, antiproteinuric, dietary measures proteinuric diseases.21Floege Amann glomerulonephritides.Lancet. 387: 2036-2048Abstract (105) Additional anticoagulant recommended severe hypoalbuminemia NS assessment. variable proportion receiving supportive will outcome, benefits harms immunosuppressants must carefully weighed.2van Thus, initial stratification crucial assess Such criteria, presented Table 1. low-risk presenting signs preserved function, “watch wait” strategy appropriate up 6 months under maximal antiproteinuric treatment. contrast, immunomodulating initiated immediately unresponsive deteriorating function.22KDIGOKDIGO Clinical Practice Guideline Glomerular Diseases.Public Review Draft (June. 2020). (Available at:)https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GN-GL-Public-Review-Draft_1-June-2020.pdfDate accessed: 2021Google ScholarTable 1Criteria functionLow riskModerate riskHigh riskVery riskeGFRNormalNormal<60 ml/min per 1.73 m2Rapid deteriorationProteinuria<3.5 g/d albumin >30 g/l>4 decrease >50% mo therapy>8 >6 monthsLife-threatening syndromePLA2R AbaSerial measurement every performed, signs. Dynamics additional value estimation.<50 RU/ml>150 RU/mlLow molecular weight proteinuriaMildHighHigh (in 2 urine collected interval 6–12 mo)Urinary IgG<250 mg/d>250 mg/dSelectivity indexbRatio clearance molecules (IgG, IgM, ?2-macroglobulin) albumin.78<0.15>0.20eGFR, estimated filtration rate; Ab, antibody.Modified according provisional guidelines (public review draft).22KDIGOKDIGO Scholara Serial estimation.b Ratio albumin.78Tencer Torffvit Thysell al.Proteinuria selectivity index based upon alpha 2-macroglobulin IgM superior differentiating diseases.Technical note. 1998; 54: 2098-2105Abstract (40) Open table tab eGFR, antibody. Modified detrimental effects prolonged glucocorticoids, steroid-sparing used since 1970s some success.23Ponticelli C, Patrizia P, Del Vecchio L, Locatelli F. evolution Nephrol https://doi.org/10.1093/ndt/gfaa014, To date, alkylating cyclophosphamide chlorambucil drugs proven prevent end-stage death.14Floege Therefore, cyclical corticosteroids (from here abbreviated “a therapy”) recognized choice decades (“Ponticelli regimen”), consisting daily intravenous application g methylprednisolone days, followed oral dose (0.5 mg/kg/d) 27 days month (0.15–0.2 mg/kg day) (2.0 30 second continued alternating cycles months.24KDIGOChapter 7: Idiopathic Int Suppl. 2: 186-197Abstract (63) Other tested trials reduction surrogate endpoint. Calcineurin inhibitors (CNIs) similar induction better short-term safety, relapse rates discontinuation (40%–50%) both, cyclosporin tacrolimus.25Qiu T.T. Zhang Zhao H.W. Zhou J.W. versus nephropathy: systematic meta-analysis 21 trials.Autoimmun 16: 136-145Crossref (26) 26Ramachandran R. Yadav A.K. Kumar V. al.Two-year follow-up study tacrolimus cyclophosphamide.Kidney Rep. 610-616Abstract (1) 27Alfaadhel D. Management Western countries.Kidney Dis (Basel). 1: 126-137Crossref 28Cattran Appel G.B. Hebert L.A. al.Cyclosporine steroid-resistant trial.Kidney 2001; 59: 1484-1490Abstract (286) High cyclosporine confirmed MENTOR trial, trial (RCT) comparing MN.29Fervenza F.C. al.Rituximab 381: 36-46Crossref (137) published STARMEN single-dose 6-month reduced rate relapses 12%, overall combined tacrolimus-rituximab lower compared cyclophosphamide.30Fernández-Juárez G, Rojas-Rivera J, Logt A-Evd, indicates sequential https://doi.org/10.1016/j.kint.2020.10.014, These direct action CNI actin cytoskeleton podocytes, effect reduce levels.31Hoxha Thiele I. al.Phospholipase 1357-1366Crossref (209) Scholar,32Faul Donnelly M. Merscher-Gomez al.The podocytes A.Nat 931-938Crossref (703) particularly useful addition standard very so achieve remission. Data supporting mycophenolate mofetil conflicting. monotherapy appears ineffective,33Dussol Morange Burtey al.Mycophenolate 1-year trial.Am Dis. 52: 699-705Abstract (82) low-quality small cohorts Asian Indian supports combination steroids alternative therapy.34Chan T.M. Lin A.W. Tang S.C. al.Prospective prednisolone syndrome.Nephrology (Carlton). 2007; 576-581Crossref Scholar,35Senthil Nayagam Ganguli Rathi focal segmental glomerulosclerosis: pilot study.Nephrol 23: 1926-1930Crossref (72) Adrenocorticotrophic hormone appeared promising results RCT 2006.36Ponticelli Passerini Salvadori plus cytotoxic agent synthetic adrenocorticotropic nephropathy.Am 2006; 47: 233-240Abstract (140) Following that, open-label prove any benefit adrenocorticotrophic therapy.37van de A.E. Beerenhout C.H. Brink H.S. al.Synthetic prospective, open label study.PLoS One. 10e0142033Crossref lack evidence, adverse (e.g., hyperglycemia, edema, mood disorders), costs preclude widespread use.38Kittanamongkolchai W. Cheungpasitporn Zand Efficacy diseases: meta-analysis.Clin 9: 387-396Crossref (18) Scholar,39Duarte-Garcia Matteson E.L. Shah N.D. Older limited evidence: worth expense? case repository corticotropin marketed H.P. Acthar Gel.Ann Intern 171: 602Crossref (2) effective options established, preceding disadvantages, limiting elevated infection risk, potentially fatal toxic side effects, oncogenicity, urotoxicity, myelotoxicity, infertility.40Ponticelli Treatment renal insufficiency: what choose?.J 2013; 427-429Crossref (3) Scholar,41van Ruggenenti Chianca al.Safety 2729-2737Crossref (68) mainly gastrointestinal CNIs exhibit broad spectrum arterial hypertension, dyslipidemia, glucose intolerance, hirsutism) CNI-related nephrotoxicity relevant treatment-limiting factor.42Jefferson Complications immunosuppression disease.Clin 2018; 13: 1264-1275Crossref (22) concomitant glucocorticoids originally designated mentioned regimens, leading myriad bone density, infections. Rituximab chimeric, monoclonal exerts via binding CD20. approved U.S. Food Drug Administration European Medicines Agency non-Hodgkin lymphoma, rheumatoid arthritis, anti-neutrophil cytoplasmic autoantibody–associated vasculitis, off-label increasing diseases.43MacIsaac Siddiqui Jamula al.Systematic globulin.Transfusion. 58: 2729-2735Crossref (25) Since experience 8 reported 2002 Remuzzi al.,44Remuzzi Chiurchiu Abbate nephropathy.Lancet. 2002; 360: 923-924Abstract (265) RCTs retrospective studies published.29Fervenza Scholar,45Dahan Plaisier extended follow-up.J 348-358Crossref (161) Strengths summarized 2.Table 2Strengths nephropathyProConEfficacyRemission patientsPossibly CR therapyLow ratesApplicationSimple dosingFrequent IRRLong intervals (?6 mo) Ab-positive treatmentDelicate scheduling due persistent depletion COVID-19 pandemic)Side effectsOverall beneficial profile; SAENo experience, late-onset neutropeniaLong-term sequelaeNo malignancy increase mortalityTreatment-associated long-lasting hypogammaglobulinemiaCOVID-19, coronavirus CR, remission; IRR; infusion-related reactions; antibody; SAE, events. COVID-19, An currently available given 3. Several methodological differences limit comparability, eligibility criteria heterogeneous groups manifestation vs. prior courses), different protocols, inconsistent define Despite marked differences, (complete partial) 12 consistently 60% 70%, ranging 44%46Moroni Depetri al.Low-dose poorly 32: 1691-1696PubMed 85%.47Waldman Braun al.Membranous combining rituximab.Kidney 73-84Abstract (19) portion who respond (PR). Complete (CR) vary tend longer periods. Consequently, 30% 40% might additional/other treatments.Table 3Overview nephropathyFirst author, (study)YearDesignnRTX / ImmunosuppressionMean FU, moComplete + ratesaVarying definitions listed cutoff <3 [e.g., Fervenza al.79] 3.5 Refs.29,45,46,81,82] creatinine 24 h) comparability.Complete rates% SAE [% infections]Fervenza79Fervenza Cosio F.G. Erickson S.B. 73: 117-125Abstract (187) Scholar2008Uncontrolled, trial15RTX (1 day & 15; 2nd if recovery)1212 mo: 57%12 14%No SAESegarra80Segarra Praga Ramos N. al.Successful glomerulonephritis calcineurin inhibitor-dependent patients.Clin 4: 1083-1088Crossref (78) Scholar2009Uncontro