Set-up of a Platform for Personalized Diagnosis of Rare Kidney Diseases (NIKE)

NCT06325072 | Active Not Recruiting

• 1 other identifier: NIKE
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 4

Brief Summary

Chronic kidney disease (CKD) is a major health problem, with steadily increasing incidence and prevalence and the threat of a true "epidemic". Converging evidence suggests a high prevalence of genetic etiology in rare kidney diseases and the list of new disease-causing genes is constantly updated. Recent advances in next-generation sequencing (NGS) technologies have prompted a significant improvement in the diagnosis of rare kidney diseases. Notwithstanding this, NGS generates high numbers of information that need to be properly analysed by the joint efforts of geneticists, nephrologists and bioinformatics in order to integrate clinical and genetic information in a personalized manner. In addition, in selected cases, the contribution of researchers proves essential for the development of experimental models of the disease to study and understand the pathogenic features and propose a personalized therapeutic approach. Such an innovative, integrated diagnostic paradigm is currently available in few centers all over the world and cannot be easily translated in daily clinical practice. The aim of the study is to set-up an integrated diagnostic algorithm to extend the newest personalized diagnostic and treatment strategies for rare kidney diseases to all patients in the Tuscany region, under 40 years of age with kidney disease. This algorithm will be based on a constant cross-talk between participating centers and a dedicated multidisciplinary team. Diagnostic and therapeutic performances will be validated at European level.

Conditions

Chronic Kidney Diseases

Outcome Measures

Primary Outcomes (1)

• Validation of genetic diagnosis

  The investigators will assess the role of potentially pathogenic variants and variants of uncertain clinical significance (VUS) in determining a conclusive genetic diagnosis by patient reassessment (reverse phenotyping) or in vitro functional studies. In detail, after the results of ES, a multidisciplinary team will evaluate the results of sequencing and will eventually request additional investigations (e.g., laboratory or imaging tests, specific consultations, etc) to the patient and/or family member in order to look for previously undetected/overlooked signs of the genetic diseases suggested by ES (reverse phenotyping). In vitro functional studies on u-RPC will be requested in a subset of patients. The number of patients with a conclusive diagnosis obtained trough these strategies will contribute to the overall diagnostic rate of the workflow (number of conclusive genetic diagnosis/number of patients enrolled in the study).

  From enrollment (genetic testing) until the date of returning of genetic testing results (up to 6 months)

Secondary Outcomes (2)

• Identification of molecular pathways

  From enrollment (genetic testing) until the last patient last visit, estimated up to 12 months

• Explore the applicability of gene editing in rare kidney diseases

  From enrollment (genetic testing) until the last patient last visit, estimated up to 12 months

Study Arms (3)

Pathogenic variants

EXPERIMENTAL

Variants fitting bioinformatic prioritization criteria for pathogenicity according to ACMG guidelines and the clinical phenotype, and variants already reported in the literature will be defined as pathogenic variants

Diagnostic Test: Conclusive genetic testing

Potentially Pathogenic Variants

EXPERIMENTAL

Variants fitting bioinformatic prioritization criteria but apparently do not correlate with the clinical phenotype and have not been previously reported in the literature will be defined as potentially pathogenic variants

Diagnostic Test: Genotype-phenotype correlation for personalized diagnosis

Variants of Unknown Significance (VUS)

EXPERIMENTAL

Variants fitting the phenotype but not fitting bioinformatic prioritization criteria will be defined as variants of uncertain clinical significance (VUS)

Diagnostic Test: Personalized study of variants of uncertain clinical significance (VUS) through functional studies on 3D organ-on-a-chip

Interventions

Conclusive genetic testing DIAGNOSTIC_TEST

Patients will be referred for genetic counseling at the study coordinating center. This will lead to a conclusive genetic diagnosis.

Pathogenic variants

Genotype-phenotype correlation for personalized diagnosis DIAGNOSTIC_TEST

Patients and their family members will undergo a thorough clinical reassessment at the study coordinating center to identify diagnostic handles of the suspected disease based on the genetic test result (reverse phenotyping). The clinical reassessment could include the performance of additional clinical and instrumental tests, as well as other specialized consultations. This will lead to a conclusive genetic diagnosis in a substantial proportion of cases, cases, who will then be provided with genetic counselling.

Potentially Pathogenic Variants

Personalized study of variants of uncertain clinical significance (VUS) through functional studies on 3D organ-on-a-chip DIAGNOSTIC_TEST

The investigators will perform functional assessment trough urine derived Renal Progenitor Cells (u-RPC) to establish the role of variants in determining the clinical phenotype.

Variants of Unknown Significance (VUS)

Eligibility Criteria

• Age: Up to 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• family history of kidney disease and/or parental consanguinity;
• extra-renal involvement (e.g., sensorineural hearing loss);
• resistance to treatment (e.g., immunosuppressive);
• metabolic acidosis or metabolic alkalosis in the absence of renal failure;
• ultrasound detection of of at least 2 cystic lesions in each kidney or nephrocalcinosis;
• ultrasound detection of congenital abnormalities of the kidney and urinary tract (CAKUT) and CKD stage ≥ 2 according to KDIGO definition
• informed consent form.

You may not qualify if:

• age \> 40
• refuse to participate to the study

Sponsors & Collaborators

• Meyer Children's Hospital IRCCS: lead

Study Sites (4)

Azienda Ospedaliero Universitaria Careggi

Florence, Italy

Location

Meyer Children's Hospital IRCCS

Florence, Italy

Location

USL Toscana Centro

Florence, Italy

Location

Azienda Ospedaliero Universitaria Pisana

Pisa, Italy

Location

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Model Details: Patients selected based on the inclusion criteria will be evaluated by a multidisciplinary team of experts. All the selected patients will undergo genetic testing by clinical exome sequencing and in silico filtering for a panel of genes described as causing or in association with CKD. Identified variants will be classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Reverse phenotyping will be performed according to the results of genetic testing. The results of the diagnostic work-up will be evaluated by a multi-disciplinary team of experts in order to establish conclusive diagnosis.

Study Record Dates

• First Submitted: February 29, 2024
• First Posted: March 22, 2024
• Study Start: July 9, 2021
• Primary Completion: June 27, 2023
• Study Completion: June 30, 2024
• Last Updated: March 22, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4)