Implementation of a Diagnostic Workflow for Personalized Diagnosis of Nephrotic Syndrome

Nephrotic syndrome (NS) is a clinical picture common to several diseases resulting from damage to podocytes and glomerular filtration barrier. Currently, there is limited consensus regarding the diagnostic pathway and management of the specific etiology. Some patients show complete response to first-line steroid therapy (steroid-sensitive nephrotic syndrome, SSNS), especially in children and young adults. The prognosis of this group is generally favorable. In contrast, patients unresponsive to steroids (steroid-resistant NS, SRNS) frequently undergo immunosuppressive therapies, which are burdened with numerous side effects. Resistance to treatment is associated with a high likelihood of progression to chronic renal disease (CKD) and kidney failure (ESKD). Recent evidence suggests that immunological mechanisms (including permeabilizing factors) are involved in the pathogenesis of post-transplant NS recurrence and SSNS.

Providing patients with NS with a correct diagnosis is the cornerstone of personalized medicine, reducing morbidity and side effects of therapies, ensuring their appropriate prescription, and slowing or preventing progression to ESKD.

Study Overview

• Status: Recruiting
• Conditions: Nephrotic Syndrome
• Intervention / Treatment: Diagnostic test: Anti-nephrin antibodies; Diagnostic test: u-RPC cultures

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Paola Romagnani, Prof, MD, PhD; Phone Number: 055 5662562; Email: paola.romagnani@meyer.it

Study Locations

• Italy
  • Firenze, Italy
    • Recruiting
    • Meyer Children's Hospital IRCCS
    • Contact: Paola Romagnani

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinical diagnosis of NS (SSNS, SRNS, or NS relapsed after transplantation regardless of initial response to steroid therapy)
• Age below 40 years at disease onset
• Availability of clinical information
• Signed informed consent form

Exclusion Criteria:

• Age at onset above 40 years
• Kidney biopsy proving lesions other than FSGS and MCD

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with SSNS; Patients with SSNS and patients undergoing renal transplantation for NS with post-transplant disease recurrence will be enrolled for serum sampling for the study of immunological and/or permeabilizing factors (including anti-nephrin antibodies).	Diagnostic test: Anti-nephrin antibodies; Assessment of anti-nephrin antibodies on serum samples and in vitro study of permeabilizing effect on 3D organ-on-a-chip models and STED microscopy on healthy human kidneys.
Experimental: Patients with SRNS undergoing genetic testing by WES; Patients with SRNS undergoing genetic testing by WES and variant prioritization will undergo serum sampling for the study of immunologic and/or permeabilizing factors (including the anti-nephrin antibodies), and urine sampling for u-RPC cultures.	Diagnostic test: Anti-nephrin antibodies; Assessment of anti-nephrin antibodies on serum samples and in vitro study of permeabilizing effect on 3D organ-on-a-chip models and STED microscopy on healthy human kidneys.; Diagnostic test: u-RPC cultures; Urine sample collection for u-RPC cultures

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Role of anti-nephrin antibodies in the pathogenesis of NS	The presence of circulating permeabilizing factors, including anti-nephrin antibodies, will be evaluated in serum samples of patients with NS and/or kidney transplant recipients with NS recurrence. The results will be correlated with the clinical history of disease in order to understand the disease pathomechanisms and the risk of recurrence.	From enrollment until the last patient visit (up to 12 months from enrollment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional role of VUS in the pathogenesis of SRNS	The functional role of VUS identified by WES will be assessed by in vitro studies on u-RPCs and 3D organ-on-a-chip models. The results will be expressed as diagnostic rate, i.e., number of conclusive diagnosis allowed by functional studies of VUS/number of patients enrolled in the study.	From enrollment until the last patient last visit (up to 12 months from enrollment)
Identification of potential predictive biomarkers of renal outcome.	The identification of potential biomarkers of disease progression and kidney failure will be performed by gene expression by scRNA-seq of u-RPCs. The results will be correlated to clinical data.	From enrollment until the last patient visit (up to 12 months from enrollment)
Cost-effectiveness analysis	A modeled cost-effectiveness analysis (including direct and indirect medical costs) will be performed to compare the proposed diagnostic algorithm with the current standard-of-care.	From enrollment of the last patient until the last visit (up to 12 months from enrollment)

Collaborators and Investigators

• Sponsor: Meyer Children's Hospital IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2022
• Primary Completion (Estimated): January 31, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: March 1, 2024
• First Submitted That Met QC Criteria: March 15, 2024
• First Posted (Actual): March 22, 2024

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Syndrome; Nephrotic Syndrome; Nephrosis; Physiological Effects of Drugs; Immunologic Factors; Antibodies
• Other Study ID Numbers: PER-NEPH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No