Validation, Implementation, and Cost-analysis of a Strategy for Personalized Diagnosis of Rare Kidney Diseases

Chronic kidney disease (CKD) affects about 10% of the world population, with high morbidity and mortality. Genetic kidney diseases are increasingly recognized across all age groups and represent over 20% of all the causes of CKD. Accurate diagnosis allows necessary and unnecessary diagnostic procedures to be defined, avoids unnecessary treatments, improves prognosis prediction, identifies other family members for genetic counseling, and defines risks for living donor kidney transplantation. The research group coordinated by the Principal Investigator has recently developed an algorithm for the genetic diagnosis in pediatric and adult patients with CKD. The application of this personalized diagnostic algorithm on a local study led to a global diagnostic yield of 70%, suggesting that this strategy has the potential to substantially improve the diagnostic approach to patients with rare kidney disorders. The aim of this study is to validate and implement these results by extending its application in a multicentric study involving nephrology units that are referral centers for rare kidney diseases at national level.

Study Overview

• Status: Recruiting
• Conditions: Chronic Kidney Diseases
• Intervention / Treatment: Diagnostic test: Implementation of the diagnostic algorithm

• Study Type: Interventional
• Enrollment (Estimated): 300
• 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
  • Napoli, Italy
    • Recruiting
    • Azienda Ospedaliero Universitaria Vanvitelli
    • Contact: Miriam Zacchia
  • Palermo, Italy
    • Recruiting
    • Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone
    • Contact: Santina Cottone

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• proteinuria and/or hematuria in the absence of immune deposits on renal biopsy or immune-mediated glomerulopathy resistant to treatment (e.g., steroids, immunosuppressive drugs);
• family history of kidney diseases and/or consanguinity;
• extrarenal involvement;
• ultrasound evidence of at least two cysts in each kidney or hyperechogenic kidneys or nephrocalcinosis;
• persistent metabolic abnormalities (metabolic acidosis or alkalosis without kidney function impairment; calcium phosphate metabolism abnormalities) after exclusion of secondary causes;
• availability of clinical information.
• signed informed consent form

Exclusion Criteria:

• Refusal by the patient, parents, or legal guardian to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rare kidney diseases; Patients with rare kidney diseases

Diagnostic test: Implementation of the diagnostic algorithm; Patients will be selected based on specific clinical criteria and referred to the tertiary center for genetic testing. All selected patients will undergo genetic testing by whole-exome sequencing (WES), followed by in silico analysis for an extended panel of genes associated with kidney diseases. The results of genetic testing will be evaluated by a multidisciplinary team of experts to establish conclusive diagnosis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Implementation of a diagnostic algorithm for personalized diagnosis of rare kidney diseases	The previously established diagnostic algorithm for rare kidney diseases will be extended to out-of-region centers with a multicenter study design. This outcome will be assessed as diagnostic rate of the algorithm, i.e., number of conclusive genetic diagnosis/number of patients enrolled.	From enrollment of the first patient until the end of the study (up to 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of the functional role of variant of unknown clinical significance (VUS)	Analysis of the functional role of VUS identified by WES by in vitro functional studies and 3D-organ-on-a-chip models obtained by patients-specific urine-derived renal progenitor cells (u-RPC) cultures	Form enrollment until the last follow up visit (up to 12 months)
Identification of immunological and/or structural factors in genetic and nongenetic forms.	Identification of immunological and/or structural factors in genetic and nongenetic forms. In particular, the investigators will assess: - the presence of anti-nephrin antibodies on serum samples and/or kidney biopsy of patients (performed for diagnostic purposes)	Form enrollment until the last follow up visit (up to 12 months)
Cost-effectiveness of the diagnostic algorithm.	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 end of the study (up to 24 months)

Collaborators and Investigators

• Sponsor: Meyer Children's Hospital IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2023
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: March 1, 2024
• First Submitted That Met QC Criteria: March 15, 2024
• First Posted (Actual): March 21, 2024

Study Record Updates

• Last Update Posted (Actual): March 21, 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; Urologic Diseases; Disease Attributes; Renal Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: KIDNEY-PNRR

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