Set-up of a Platform for Personalized Diagnosis of Rare Kidney Diseases (NIKE)
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 160
- 试验地点
- 4
- 主要终点
- Validation of genetic diagnosis
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- — 至 40 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •age > 40
- •refuse to participate to the study
研究组 & 干预措施
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
干预措施: Conclusive genetic testing (Diagnostic Test)
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
干预措施: Genotype-phenotype correlation for personalized diagnosis (Diagnostic Test)
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)
干预措施: Personalized study of variants of uncertain clinical significance (VUS) through functional studies on 3D organ-on-a-chip (Diagnostic Test)
结局指标
主要结局
Validation of genetic diagnosis
时间窗: 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).
次要结局
- 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)
研究者
Paola Romagnani
MD
Meyer Children's Hospital IRCCS