Transcriptome Analysis in Idiopathic Nephrotic Syndrome: Steroid Responsiveness

Transcriptome Analysis in Idiopathic Nephrotic Syndrome: an Insight Into the Mechanisms of Steroid Responsiveness

Idiopathic nephrotic syndrome (INS) affects the glomerular barrier by damaging the podocytes with foot process effacement, leading to a pathological increase of permeability and protein loss. INS classification is based on the clinical response to glucocorticoid (GC) therapy. When GCs treatment fails to induce remission in a four-six weeks course, patients are defined as affected with steroid-resistant nephrotic syndrome (SRNS).

The whole transcriptome sequencing could consent the INS classification at onset, prior to glucocorticoids (GCs) treatment, allowing to reduction of unuseful GCs treatment. RNA sequencing technologies allow an extensive characterization of the transcriptomic profile and permit global changes in gene expression levels between different conditions such as active and remission of the disease.

Of great interest is the research of a molecular biomarker to predict steroid resistance, a predictor that is not yet available. Among the candidate biomarkers, pharmacogenomic determinants are promising, even if available studies are still limited. Among these, some epigenetic factors have been previously suggested. Data obtained in animal models suggests that nucleotide-binding oligomerization domain-like receptors (NOD-like receptor) pyrin domain containing 3 (NLRP3) inflammasome can be deregulated in a wide variety of glomerular diseases, including those causing INS. Another potential marker involved in steroid response is the long noncoding RNA GAS5. Data reported in the literature indicate that abnormal levels of GAS5 in peripheral blood mononuclear cells (PBMCs) may alter steroid effectiveness in autoimmune diseases, such as inflammatory bowel disease.

Preliminary findings show that the study of NLRP3 promoter methylation could be reduced in the blood of SRNS compared with steroid-sensitive nephrotic syndrome (SSNS) patients. Moreover, unpublished encouraging results on the association between Growth Arrest Specific 5 (GAS5) expression and steroid response in INS in PBMCs were obtained in a preliminary study conducted on 8 patients with the first episode of INS. PBMCs were obtained and GAS5 gene expression was evaluated using TaqMan technology. Patients affected with SRNS presented significantly higher levels of GAS5 in comparison with the SSNS group. In PBMCs from SRNS patients, the GAS5 expression could reduce the availability for binding to GCs target genes of the activated GCs receptor and suppresses GC transcriptional activity.

Study Overview

• Status: Recruiting
• Conditions: Nephrotic Syndrome
• Intervention / Treatment: Diagnostic test: Transcriptome analyses

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Marco Pennesi, MD; Phone Number: +39. 040-3785263; Email: marco.pennesi@burlo.trieste.it
• Study Contact Backup: Name: Barbara Bonifacio; Phone Number: +39.040.3785.422; Email: barbara.bonifacio@burlo.trieste.it

Study Locations

• Italy
  • Trieste, Italy, 34137
    • Recruiting
    • Institute for Maternal and Child Health - IRCCS "Burlo Garofolo"
    • Contact: Barbara Bonifacio; Phone Number: +39.040.3785.422; Email: barbara.bonifacio@burlo.trieste.it
    • Contact: Marco Pennesi, MD; Phone Number: +39.040-3785263; Email: marco.pennesi@burlo.trieste.it

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Children with nephrosic syndrome

Description

Inclusion Criteria:

• clinical diagnosis of INS
• age 1 - 12 years
• signed informed consent by parents or legal guardians
• For controls: aged-matched individuals with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

Exclusion Criteria:

• Patients aged <1 year or > 12 years
• Patients diagnosed with a secondary or genetic form of NS
• For controls: the presence of coexisting chronic kidney failure, autoimmune or autoinflammatory disease, or endocrinologic disorders.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with steroid-resistant nephrotic syndrome; Identification of a possible molecular signatures at t0 by whole transcriptome analysis from PBMCs	Diagnostic test: Transcriptome analyses; A sample of peripheral whole blood cells will be collected at the onset before the initiation of steroid treatment (time 0, t0) and after 6 weeks at the definition of steroid sensitivity/unresponsiveness (time 1, t1).
Patients with steroid sensitive nephrotic syndrome; Identification of a possible molecular signatures at t0 by whole transcriptome analysis from PBMCs	Diagnostic test: Transcriptome analyses; A sample of peripheral whole blood cells will be collected at the onset before the initiation of steroid treatment (time 0, t0) and after 6 weeks at the definition of steroid sensitivity/unresponsiveness (time 1, t1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between groups differences in molecular signature by whole transcriptome analysis	A sample of peripheral whole blood cells will be collected at the onset before the initiation of steroid treatment (time 0, t0)	At enrolment (T0)

Collaborators and Investigators

• Sponsor: IRCCS Burlo Garofolo

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2023
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: March 15, 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

• Keywords: Whole transcriptome sequencing; Idiopathic nephrotic syndrome pathogenesis; Steroid responsiveness prediction
• 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
• Other Study ID Numbers: RC 24/2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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