Set-up of a Platform for Personalized Diagnosis of Rare Kidney Diseases (NIKE)
- Conditions
- Chronic Kidney Diseases
- Registration Number
- NCT06325072
- Lead Sponsor
- Meyer Children's Hospital IRCCS
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 160
- 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.
- age > 40
- refuse to participate to the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Validation of genetic diagnosis From enrollment (genetic testing) until the date of returning of genetic testing results (up to 6 months) 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).
- Secondary Outcome Measures
Name Time Method Identification of molecular pathways From enrollment (genetic testing) until the last patient last visit, estimated up to 12 months 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.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 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.
Trial Locations
- Locations (4)
Azienda Ospedaliero Universitaria Careggi
🇮🇹Firenze, Italy
Meyer Children's Hospital IRCCS
🇮🇹Firenze, Italy
USL Toscana Centro
🇮🇹Firenze, Italy
Azienda Ospedaliero Universitaria Pisana
🇮🇹Pisa, Italy
Azienda Ospedaliero Universitaria Careggi🇮🇹Firenze, Italy