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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Kidney Diseases
• Intervention / Treatment: Diagnostic test: Conclusive genetic testing; Diagnostic test: Genotype-phenotype correlation for personalized diagnosis; Diagnostic test: Personalized study of variants of uncertain clinical significance (VUS) through functional studies on 3D organ-on-a-chip

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Firenze, Italy
    • Azienda Ospedaliero Universitaria Careggi
  • Firenze, Italy
    • Meyer Children's Hospital IRCCS
  • Firenze, Italy
    • USL Toscana Centro
  • Pisa, Italy
    • Azienda Ospedaliero Universitaria Pisana

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• age > 40
• refuse to participate to the study

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pathogenic variants; 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; Patients will be referred for genetic counseling at the study coordinating center. This will lead to a conclusive genetic diagnosis.
Experimental: Potentially Pathogenic Variants; 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; 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.
Experimental: Variants of Unknown Significance (VUS); 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of molecular pathways	The investigators aim to o identify molecular pathways that could represent potential therapeutic targets in a selection of patients carrying potentially pathogenic variants. To this goal, the investigators will perform single-cell RNA sequencing on kidney biopsy fragments of patients who have undergone a diagnostic kidney biopsy. After obtaining intracellular transcriptome of individual cells carrying the potentially pathogenic variants, the investigators will compare their RNA expression profile to the same type of cells obtained from non-mutated patients.	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	The investigators will explore the applicability of CRISPR/Cas9 gene editing in rare kidney diseases through u-RPCs obtained from patients carrying pathogenic mutations. In order to achieve the rescue of disease causative variants, the investigators will perform a stable correction of genetic variants identified through CRISPR/Cas9 gene editing approach, in u-RPC isolated from patients carrying pathogenic variants.	From enrollment (genetic testing) until the last patient last visit, estimated up to 12 months

Collaborators and Investigators

• Sponsor: Meyer Children's Hospital IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2021
• Primary Completion (Actual): June 27, 2023
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: February 29, 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; 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: NIKE

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