Abstract: SA-PO583
Primary Genetic Mechanism with Secondary Focal Segmental Glomerulosclerosis Is the Prevalent Cause of Early-Onset Proteinuria Resistant to Treatment
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Becherucci, Francesca, Meyer Children's Hospital, Florence, Italy
- Mazzinghi, Benedetta, Meyer Children's Hospital, Florence, Italy
- Landini, Samuela, University of Florence, Florence, Italy
- Roperto, Rosa maria, Meyer Children's Hospital, Florence, Italy
- Ravaglia, Fiammetta, University of Florence, Florence, Italy
- Sansavini, Giulia, Meyer Children's Hospital, Florence, Italy
- Allinovi, Marco, University of Florence, Florence, Italy
- Giglio, Sabrina, University of Florence, Florence, Italy
- Romagnani, Paola, University of Florence, Florence, Italy
Background
Proteinuria is a hallmark of kidney diseases and represents an important determinant to the progression toward chronic kidney disease (CKD), especially in children and young adults. The importance of genetic causes is clearly emerging and has already been reported in about 30% of patients with steroid-resistant nephrotic syndrome (SRNS) and in 25% of patients with early-onset CKD.
Methods
To assess the role of genetic variants in the pathogenesis of proteinuria and CKD we applied whole-exome sequencing (WES) followed by bioinformatic filtering for 308 genes reported as even rare causes of CKD to 107 patients with different types of proteinuric diseases and an age at onset younger than 20 yeras, excluding immuno- and complement-mediated forms.
Results
This strategy allowed us to find a prevalence of potentially pathogenic genetic variants as high as 71.7% in patients presenting with SRNS and severe proteinuria, whereas no genetic defect was present in patients with steroid-sensitive nephrotic syndrome. These variants occurred in podocyte genes in 48.8% of cases and in COL4A genes associated with variants in modifier genes in 20.9% of cases.
Among patients with mutations, the most frequent pathologic finding was focal segmental glomerulosclerosis, irrespectively of the different genetic causes, whereas the clinical phenotype at onset mirrored the type of gene involved. In addition, the presence of pathogenic variants was associated with the lack of response to immunosuppressive treatments and complete remission of the disease could only be observed in the group of negative patients. Finally, progression toward CKD was significantly higher in patients with pathogenic variants than in negative patients, suggesting that the presence of genetic defects is highly predictive of the clinical outcome of these patients.
Conclusion
These results suggest that genetic abnormalities are key elements in the pathogenesis of proteinuric diseases and are predictive of specific phenotypic features, such as the response to therapies and the outcome of the disease, thus supporting the opportunity of including WES in the diagnostic flow-chart of these disorders, especially in patients with an early onset of the disease.