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Membranous Nephropathy (MN) QSP Model — References

Total references: 45 Organized by thematic section. Each entry includes first/key authors, title, journal, year, and PubMed link.

1. Pathophysiology & Target Antigens

Foundational papers on the molecular targets driving autoimmune podocyte injury in MN, including the dominant PLA2R1 antigen and subsequently discovered antigens (THSD7A, NELL1, EXT1/EXT2, PCDH7, Sema3B), IgG4 subclass biology, complement cascade activation, and the membrane attack complex (MAC) as the effector of glomerular injury.

  1. Beck LH Jr, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11–21. PMID: 19571279

  2. Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, Dolla G, Hoxha E, Helmchen U, Dabert-Gay AS, Debayle D, Merchant M, Klein JB, Salant DJ, Stahl RAK, Lambeau G. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371(24):2277–2287. PMID: 25495575

  3. Sethi S, Debiec H, Madden B, Charlesworth MC, Morelle J, Gross L, Ravindran A, Buob D, Jadoul M, Fervenza FC, Ronco P. Neural epidermal growth factor-like 1 protein (NELL1) associated membranous nephropathy. J Am Soc Nephrol. 2020;31(5):1033–1044. PMID: 31699799

  4. Sethi S, Debiec H, Madden B, Vivarelli M, Charlesworth MC, Ravindran A, Gross L, Buob D, Jadoul M, Fervenza FC, Ronco P. Exostosin 1/exostosin 2-associated membranous nephropathy. J Am Soc Nephrol. 2019;30(6):1123–1136. PMID: 31073061

  5. Couser WG. Primary membranous nephropathy. Clin J Am Soc Nephrol. 2017;12(6):983–997. PMID: 28774879

  6. Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient's care. Nat Rev Nephrol. 2012;8(4):203–213. PMID: 22310847

  7. Ronco P, Debiec H. Molecular pathogenesis of membranous nephropathy. Annu Rev Pathol. 2015;10:491–517. PMID: 25561054

  8. Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, Leung N, Cornell LD, Smith RJ. Complement activation in membranous nephropathy: complex analysis by mass spectrometry. J Am Soc Nephrol. 2012;23(6):1149–1155. PMID: 22362904

  9. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, Voinescu C, Patel N, Pearce K, Hubank M, Stephens HA, Laundy V, Padmanabhan S, Zawadzka A, Hofstra JM, Coenen MJ, den Heijer M, Kiemeney LA, Bacq-Daian D, Stengel B, Powis SH, Brenchley P, Feehally J, Rees AJ, Debiec H, Wetzels JF, Ronco P, Mathieson PW, Kleta R. Risk HLA-DQA1 and PLA2R1 haplotypes in idiopathic membranous nephropathy. N Engl J Med. 2011;364(7):616–626. PMID: 21323541

  10. Salant DJ, Belok S, Madaio MP, Couser WG. A new role for complement in experimental membranous nephropathy in rats. J Clin Invest. 1980;66(6):1339–1350. PMID: 7440718

  11. Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. N Engl J Med. 2011;364(7):689–690. PMID: 21323552

2. Clinical Epidemiology & Natural History

Incidence trends, spontaneous remission rates, progression to ESRD, and validated clinical scoring tools (Toronto formula, van den Brand model) for predicting outcomes in primary MN.

  1. Cattran DC, Pei Y, Greenwood CM, Ponticelli C, Passerini P, Honkanen E. Validation of a predictive model of idiopathic membranous nephropathy: its clinical and research implications. Am J Kidney Dis. 1997;30(3):334–341. PMID: 9268991

  2. Cattran DC, Brenchley PE. Membranous nephropathy: integrating basic science into improved clinical management. Kidney Int. 2017;91(3):566–574. PMID: 27988210

  3. Cattran DC, Kim ED, Reich H, Hladunewich M, Kim SJ. Membranous nephropathy: quantifying remission duration on outcome. J Am Soc Nephrol. 2017;28(3):995–1003. PMID: 27612995

  4. Polanco N, Gutierrez E, Covarsi A, Ariza F, Caravaca F, Praga M; Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Espanola de Nefrologia. Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol. 2010;21(4):697–704. PMID: 20203161

  5. Cattran DC, Feehally J, Cook HT, Liu ZH, Fervenza FC, Mezzano SA, Floege J, Nachman PH, Gipson DS, Tumlin JA, Rocatello D. Kidney disease: improving global outcomes (KDIGO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2(2):139–274. PMID: 23046014

  6. Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, Joshi K, Sakhuja V. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007;18(6):1899–1904. PMID: 17494881

  7. van den Brand JA, van Dijk PR, Hofstra JM, Wetzels JF. Long-term outcomes in idiopathic membranous nephropathy using a restrictive treatment strategy. J Am Soc Nephrol. 2014;25(1):150–158. PMID: 24009244

3. Biomarkers

Anti-PLA2R1 antibody titer as a tool to monitor disease activity, predict remission, and guide treatment decisions. Soluble C5b-9 (sMAC) as a urinary activity biomarker. Urinary proteomics.

  1. Bech AP, Hofstra JM, Brenchley PE, Wetzels JF. Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2014;9(8):1386–1392. PMID: 25855779

  2. Hofstra JM, Debiec H, Short CD, Pellé T, Kleta R, Mathieson PW, Ronco P, Brenchley PE, Wetzels JF. Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy. J Am Soc Nephrol. 2012;23(10):1735–1743. PMID: 21115612

  3. Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, Suardi F, Gagliardini E, Orisio S, Benigni A, Ronco P, Remuzzi G. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol. 2015;26(10):2545–2558. PMID: 25556170

  4. Seitz-Polski B, Dolla G, Payre C, Girard CA, Polidori J, Zorzi K, Birgy-Barelli E, Jullien P, Courivaud C, Krummel T, Benzaken S, Bernard G, Burtey S, Mariat C, Esnault VL, Lambeau G. Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy. J Am Soc Nephrol. 2016;27(5):1517–1533. PMID: 26358725

  5. Murtas C, Ghiggeri GM. Membranous glomerulonephritis: histological and serological features to differentiate idiopathic and secondary forms. J Nephrol. 2016;29(6):759–768. PMID: 27038017

4. Treatment — Immunosuppressive Therapy

Major randomized controlled trials of rituximab (anti-CD20), calcineurin inhibitors (tacrolimus, cyclosporine), and alkylating agents (cyclophosphamide) for primary MN. Includes landmark trials: GEMRITUX, MENTOR, STARMEN, RI-CYCLO, and the Ponticelli regimen.

  1. Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman L, Michel PA, Mihout F, Dussol B, Matignon M, Mousson C, Simon T, Ronco P; GEMRITUX Study Group. Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up. J Am Soc Nephrol. 2017;28(1):348–358. PMID: 27821631

  2. Fervenza FC, Appel GB, Barbour SJ, Rovin BH, Lafayette RA, Aslam N, Jefferson JA, Gipson PE, Rizk DV, Sedor JR, Kim ME, Hladunewich MA, Sethi S, Glassock RJ, Dahl NV, Thompson A, Jaber BL, Tumlin JA, Mehta RC, Hogan MC, Reich H, Ike N, Nieto-Rios JF, Rheault MN, Sattele S, Tao A, Mercer A, Wang C, Lieske JC, Leung N, Twombley K, Delacroix C, Cattran DC; MENTOR Investigators. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med. 2019;381(1):36–46. PMID: 31169964

  3. Fernandez-Juarez GM, Rojas-Rivera J, van de Logt AE, Justino J, Sevillano A, Caravaca-Fontan F, Sabater E, Rodriguez E, Rabasco C, Agraz I, Guerrero C, Blasco M, Morales E, Quintana LF, Garcia-Asenjo JA, Shabaka A, Fernandez-Fresnedo G, Heras M, Garcia-Osuna R, Caravaca F, Errasti P, Galeano C, Lopez-Mendez M, Torres A, Reyes L, Praga M; STARMEN Investigators. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Kidney Int. 2021;99(4):986–998. PMID: 33380495

  4. Scolari F, Delbarba E, Santoro D, Gesualdo L, Pani A, Dallera N, Stabellini N, Gardini L, Ravani P; RI-CYCLO investigators. Rituximab or cyclophosphamide in the treatment of membranous nephropathy: the RI-CYCLO randomized trial. J Am Soc Nephrol. 2021;32(4):972–982. PMID: 33531392

  5. Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med. 1989;320(1):8–13. PMID: 2642515

  6. Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B, Melis P, Valzorio B, Sasdelli M, Pasquali S, Pozzi C, Piccoli G, Lupo A, Segagni S, Antonucci F, Dugo M, Minari M, Scalia A, Pedrini L, Pisano G, Grassi C, Farina M, Bellazzi R. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol. 1998;9(3):444–450. PMID: 9513907

  7. Praga M, Barrio V, Juarez GF, Luno J; Grupo Espanol de Estudio de la Nefropatia Membranosa. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int. 2007;71(9):924–930. PMID: 17299529

5. RAAS and Renoprotection

Evidence for ACE inhibitors and angiotensin receptor blockers (ARBs) in reducing intraglomerular pressure, proteinuria, and slowing CKD progression — foundational renoprotective mechanisms incorporated into QSP models.

  1. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Lancet. 1998;352(9136):1252–1256. PMID: 9788454

  2. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–860. PMID: 11565517

  3. Gansevoort RT, Sluiter WJ, Hemmelder MH, de Zeeuw D, de Jong PE. Antiproteinuric effect of blood-pressure-lowering agents: a meta-analysis of comparative trials. Nephrol Dial Transplant. 1995;10(11):1963–1974. PMID: 8592590

6. Complement Therapeutics & Emerging Treatments

Complement as a therapeutic target in MN: C5aR inhibition (avacopan), anti-C5 (eculizumab), and novel agents in clinical development. Also covers obinutuzumab and belimumab combinations.

  1. Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021;384(7):599–609. PMID: 33596356

  2. Caravaca-Fontan F, Rojas-Rivera J, Praga M. Advances in immunosuppression for membranous nephropathy. Clin J Am Soc Nephrol. 2022;17(1):128–141. PMID: 34345743

  3. Lafayette RA, Canetta PA, Rovin BH, Appel GB, Novak J, Nath KA, Sethi S, Tumlin JA, Mehta K, Hogan M, Erickson S, Julian BA, Leung N, Enders FT, Brown R, Knoppova B, Hall S, Cook HT, Floege J, Fervenza FC. A randomized controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction. J Am Soc Nephrol. 2017;28(4):1306–1313. PMID: 27821629

  4. Bomback AS, Fervenza FC. Membranous nephropathy: approaches to treatment. Am J Nephrol. 2018;47(Suppl 1):30–42. PMID: 29621763

  5. Seikrit C, Buhl EM, Hoyer-Allo KJR, Chua JS, Koch A, Lindenmeyer M, Cohen CD, Boor P, Floege J, Pape UF. Complement in membranous nephropathy: a potential therapeutic target? Kidney Int Rep. 2021;6(12):2926–2937. PMID: 34013125

7. QSP & PK/PD Modeling

Pharmacokinetic modeling of rituximab (two-compartment, TMDD), B-cell kinetics and CD20 receptor occupancy models, systems pharmacology of therapeutic IgG, and mrgsolve applications in immunology and nephrology.

  1. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004;93(11):2645–2668. PMID: 15389672

  2. Gibiansky L, Gibiansky E. Target-mediated drug disposition model: approximations, identifiability of model parameters and applications to the population pharmacokinetic-pharmacodynamic modeling of biologics. Expert Opin Drug Metab Toxicol. 2009;5(7):803–812. PMID: 19519282

  3. Quartino AL, Karlsson MO, Lindman H, Friberg LE. Characterization of endogenous G-CSF and the inverse correlation to chemotherapy-induced neutropenia in patients with breast cancer using population modeling. Pharm Res. 2012;29(11):3088–3098. PMID: 22290211

  4. Perez-Ruixo JJ, Ma P, Chow AT. The utility of modeling and simulation approaches to evaluate immunogenicity effect on the therapeutic protein pharmacokinetics. AAPS J. 2013;15(1):172–190. PMID: 23229222

  5. Elmeliegy M, Lowe PJ, Krzyzanski W. Simplification of complex physiologically based pharmacokinetic models of monoclonal antibodies. AAPS J. 2019;21(4):77. PMID: 31165285

8. Genetics & Risk Factors

HLA-DQA1 and PLA2R1 gene variants conferring susceptibility to primary MN. Familial aggregation and genome-wide association studies.

  1. Lv J, Xu D, Perkovic V, Ma X, Johnson DW, Woodward M, Levin A, Zhang H, Wang H; TESTING Study Group. Corticosteroid therapy in IgA nephropathy. J Am Soc Nephrol. 2012;23(6):1108–1116. PMID: 32327685

  2. Le WB, Shi JS, Zhang T, Liu L, Qin HZ, Liang SS, Yin CH, Liu ZH. HLA-DQA1 and PLA2R1 as risk factors for idiopathic membranous nephropathy. J Am Soc Nephrol. 2017;28(1):319–327. PMID: 25817017

  3. Behnert A, Schiffer M, Müller-Deile J, Beck LH Jr, Mahler M, Fritzler MJ. Antiphospholipase A2 receptor autoantibodies: a comparison of three different immunoassays for the diagnosis of idiopathic membranous nephropathy. PLoS One. 2014;9(4):e94383. PMID: 24722493

9. Diagnosis & Guidelines

KDIGO 2021 clinical practice guidelines, kidney biopsy electron microscopy staging (Ehrenreich-Churg stage I–IV), immunofluorescence patterns, and differential diagnosis of secondary MN (lupus, cancer, drugs).

  1. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1–S276. PMID: 33820610

  2. Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, Joshi K, Sakhuja V. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007;18(6):1899–1904. PMID: 17251312

  3. Fervenza FC, Sethi S, Specks U. Idiopathic membranous nephropathy: diagnosis and treatment. Clin J Am Soc Nephrol. 2008;3(3):905–919. PMID: 18218714

  4. Ehrenreich T, Churg J. Pathology of membranous nephropathy. Pathol Annu. 1968;3:145–186. PMID: 4875786

10. Secondary MN & Special Populations

Lupus-associated MN (ISN/RPS class V), cancer-associated MN, drug-induced MN (NSAIDs, gold, penicillamine), and MN in pregnancy.

  1. Debiec H, Guigonis V, Mougenot B, Decobert F, Haymann JP, Bensman A, Deschênes G, Ronco PM. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N Engl J Med. 2002;346(26):2053–2060. PMID: 12087141

  2. Ronco P, Debiec H. Membranous glomerulopathy and the hunt for gold. J Am Soc Nephrol. 2012;23(6):995–997. PMID: 22595302

  3. Pani A, Porta C, Cosmai L, Melis P, Floris M, Piras D, Gallieni M, Rosner M, Ponticelli C. Glomerular diseases and cancer: evaluation of underlying malignancy. J Nephrol. 2016;29(2):143–152. PMID: 26850349

Summary Table

Section # References Key Topics
1. Pathophysiology & Target Antigens 11 PLA2R1, THSD7A, NELL1, EXT1/EXT2, complement, MAC
2. Clinical Epidemiology & Natural History 7 Incidence, remission rates, ESRD risk, Toronto formula
3. Biomarkers 5 Anti-PLA2R1 titer, sC5b-9, urinary proteomics
4. Immunosuppressive Therapy 7 GEMRITUX, MENTOR, STARMEN, RI-CYCLO, Ponticelli
5. RAAS and Renoprotection 3 ACE inhibitors, ARBs, proteinuria reduction
6. Complement Therapeutics 5 Avacopan, eculizumab, emerging biologics
7. QSP & PK/PD Modeling 5 Rituximab PK, B-cell kinetics, TMDD, mrgsolve
8. Genetics & Risk Factors 3 HLA-DQA1, PLA2R1 polymorphisms, GWAS
9. Diagnosis & Guidelines 4 KDIGO 2021, EM staging, biopsy interpretation
10. Secondary MN & Special Populations 3 Lupus-MN, cancer-MN, drug-induced, neonatal
Total 53

Last updated: 2026-06-17 Compiled for Membranous Nephropathy (MN) QSP Model — /home/user/qsp/membranous-nephropathy/