Autoantibodies Against-nephrin in Idiopathic Nephrotic Syndrome
NCT ID: NCT06334692
Last Updated: 2025-09-04
Study Results
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Basic Information
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RECRUITING
100 participants
OBSERVATIONAL
2024-03-19
2028-03-31
Brief Summary
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Detailed Description
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Nephrotic-range proteinuria (\>3.5 g/day) is accompanied by a set of abnormalities collectively known as NS. It is characterized by systemic complications resulting from alterations in the composition of the body's protein pool, sodium retention, dyslipidemia, coagulation factor abnormalities and a variable degree of renal failure. When secondary causes cannot be identified, the clinical presentation is called idiopathic nephrotic syndrome (INS). INS is associated with disappearance of podocyte pedicels (visible under the electron microscope) and minimal changes (minimal change disease, MCD) or, at the more advanced stage, focal segmental glomerulosclerosis (FSGS) under the light microscope. INS can be treated with corticosteroids, which represent the first-line treatment, however, among the forms of NS, FSGS has the lowest rate of response to therapy. More importantly, in 30% of patients with FSGS, disease recurrence develops rapidly after transplantation, sometimes within minutes or hours, and leads to the immediate onset of proteinuria and graft dysfunction. For post-transplant FSGS recurrence, no prevention or treatment strategies are available and current therapeutic approaches are mostly based on clinical experience.
The recurrence of FSGS in the transplanted kidney presupposes the presence of one or more circulating factors of extrarenal origin which can selectively affect and damage the glomerular barrier, in particular the podocytes, resulting in massive proteinuria. However, the identity, nature and cellular source of factors circulating in the INS are not yet known.
Recent evidence of the therapeutic efficacy of anti-B cell antibodies in inducing and/or maintaining remission in patients with INS indicates the presence of possible B cell dysfunction.
In support of this, a recent study described the presence of anti-nephrin autoantibodies (a structural component of the podocyte slit diaphragm) in a subgroup of pediatric and adult patients with MCD. These autoantibodies were present during the active phase of the disease, and were associated with a punctate staining of IgG in renal biopsies in correspondence with the specific areas of presence of nephrin. Furthermore, the presence of autoantibodies against nephrin has been found in early post-transplant FSGS recurrence. This preliminary result was confirmed by a Japanese multicenter study conducted on 11 pediatric patients with post-transplant FSGS recurrence. In these patients, anti-nephrin autoantibodies were elevated both before transplantation and during disease relapse and were related to punctate deposition of immunoglobulins G (IgG) that colocalized with nephrin in the graft biopsy at the time of relapse. This recent evidence suggests that circulating anti-nephrin antibodies represent a possible circulating factor involved in the pathogenesis of INS, in particular post-transplant FSGS recurrence.
Conditions
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Study Design
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CASE_CONTROL
RETROSPECTIVE
Study Groups
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Cases
Sera from patients with biopsy-proven idiopathic MCD or FSGS who provided consent to store their samples in the certified biobank (Mario Negri Biological Resources Centre - Rare Diseases and Renal Diseases Biobank - CRB). Serum samples will be tested for the levels of anti-nephrin autoantibodies by in-house ELISA and results confirmed by commercial ELISA kits.
In-house ELISA, and ELISA kits from "DBA Italy" (Abbexa).
"Nunc MaxiSorp" ELISA plates will be coated with recombinant extracellular domain of human nephrin. Patient serum samples will be added in appropriate dilution. Plates will be then incubated with biotin-conjugated anti human IgG antibody followed by incubation with horseradish peroxidase (HRP)-avidin conjugate. Then tetramethylbenzidine substrate will be added, and absorbance read at 450 nm.
Controls
Sera from patients with biopsy-proven idiopathic membranous nephropathy who provided consent to store their samples in the certified biobank (Mario Negri Biological Resources Centre - Rare Diseases and Renal Diseases Biobank - CRB). Samples will be tested for the levels of anti-nephrin autoantibodies by in-house ELISA and results confirmed by commercial ELISA kits.
In-house ELISA, and ELISA kits from "DBA Italy" (Abbexa).
"Nunc MaxiSorp" ELISA plates will be coated with recombinant extracellular domain of human nephrin. Patient serum samples will be added in appropriate dilution. Plates will be then incubated with biotin-conjugated anti human IgG antibody followed by incubation with horseradish peroxidase (HRP)-avidin conjugate. Then tetramethylbenzidine substrate will be added, and absorbance read at 450 nm.
Interventions
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In-house ELISA, and ELISA kits from "DBA Italy" (Abbexa).
"Nunc MaxiSorp" ELISA plates will be coated with recombinant extracellular domain of human nephrin. Patient serum samples will be added in appropriate dilution. Plates will be then incubated with biotin-conjugated anti human IgG antibody followed by incubation with horseradish peroxidase (HRP)-avidin conjugate. Then tetramethylbenzidine substrate will be added, and absorbance read at 450 nm.
Eligibility Criteria
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Inclusion Criteria
* Patients with biopsy-proven idiopathic MCD or FSGS (cases)
* Patients with biopsy-proven idiopathic membranous nephropathy (controls)
* Patients who provided consent to store their samples in the certified CRB biobank
Exclusion Criteria
* Active viral or bacterial infections at time of blood collections
18 Years
ALL
No
Sponsors
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Mario Negri Institute for Pharmacological Research
OTHER
Responsible Party
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Principal Investigators
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Giuseppe Remuzzi, MD
Role: STUDY_DIRECTOR
Istituto Di Ricerche Farmacologiche Mario Negri
Locations
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Clinical Research Center for Rare Disease Aldo e Cele Daccò
Ranica, BG, Italy
Countries
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Central Contacts
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Facility Contacts
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References
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McCarthy ET, Sharma M, Savin VJ. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010 Nov;5(11):2115-21. doi: 10.2215/CJN.03800609. Epub 2010 Oct 21.
D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011 Dec 22;365(25):2398-411. doi: 10.1056/NEJMra1106556. No abstract available.
Gallon L, Leventhal J, Skaro A, Kanwar Y, Alvarado A. Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N Engl J Med. 2012 Apr 26;366(17):1648-9. doi: 10.1056/NEJMc1202500. No abstract available.
Ruggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, Marasa M, Chianca A, Rubis N, Ene-Iordache B, Rudnicki M, Pollastro RM, Capasso G, Pisani A, Pennesi M, Emma F, Remuzzi G; 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. 2014 Apr;25(4):850-63. doi: 10.1681/ASN.2013030251. Epub 2014 Jan 30.
Maas RJ, Deegens JK, Smeets B, Moeller MJ, Wetzels JF. Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat Rev Nephrol. 2016 Dec;12(12):768-776. doi: 10.1038/nrneph.2016.147. Epub 2016 Oct 17.
Watts AJB, Keller KH, Lerner G, Rosales I, Collins AB, Sekulic M, Waikar SS, Chandraker A, Riella LV, Alexander MP, Troost JP, Chen J, Fermin D, Yee JL, Sampson MG, Beck LH Jr, Henderson JM, Greka A, Rennke HG, Weins A. Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology. J Am Soc Nephrol. 2022 Jan;33(1):238-252. doi: 10.1681/ASN.2021060794. Epub 2021 Nov 3.
Casiraghi F, Todeschini M, Podesta MA, Mister M, Ruggiero B, Trillini M, Carrara C, Diadei O, Villa A, Benigni A, Remuzzi G. Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome. Int J Mol Sci. 2023 Apr 22;24(9):7687. doi: 10.3390/ijms24097687.
Salfi G, Casiraghi F, Remuzzi G. Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis. Front Immunol. 2023 Sep 19;14:1247606. doi: 10.3389/fimmu.2023.1247606. eCollection 2023.
Shirai Y, Miura K, Ishizuka K, Ando T, Kanda S, Hashimoto J, Hamasaki Y, Hotta K, Ito N, Honda K, Tanabe K, Takano T, Hattori M. A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence. Kidney Int. 2024 Mar;105(3):608-617. doi: 10.1016/j.kint.2023.11.022. Epub 2023 Dec 16.
Other Identifiers
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BLINDER
Identifier Type: -
Identifier Source: org_study_id
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