Genetic testing in steroid-resistant nephrotic syndrome: when and how?
Steroid-resistant nephrotic syndrome (SRNS) represents the second most frequent cause of chronic kidney disease in the first three decades of life. It manifests histologically as focal segmental glomerulosclerosis (FSGS) and carries a 33% risk of relapse in a renal transplant. No efficient treatment exists. Identification of single-gene (monogenic) causes of SRNS has moved the glomerular epithelial cell (podocyte) to the center of its pathogenesis. Recently, mutations in >30 recessive or dominant genes were identified as causing monogenic forms of SRNS, thereby revealing the encoded proteins as essential for glomerular function. These findings helped define protein interaction complexes and functional pathways that could be targeted for treatment of SRNS. Very recently, it was discovered that in the surprisingly high fraction of ∼30% of all individuals who manifest with SRNS before 25 years of age, a causative mutation can be detected in one of the ∼30 different SRNS-causing genes. These findings revealed that SRNS and FSGS are not single disease entities but rather are part of a spectrum of distinct diseases with an identifiable genetic etiology. Mutation analysis should be offered to all individuals who manifest with SRNS before the age of 25 years, because (i) it will provide the patient and families with an unequivocal cause-based diagnosis, (ii) it may uncover a form of SRNS that is amenable to treatment (e.g. coenzyme Q10), (iii) it may allow avoidance of a renal biopsy procedure, (iv) it will further unravel the puzzle of pathogenic pathways of SRNS and (v) it will permit personalized treatment options for SRNS, based on genetic causation in way of 'precision medicine'.
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Svjetlana
S
Lovric
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Shazia
S
Ashraf
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Weizhen
W
Tan
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Friedhelm
F
Hildebrandt
D004252:DNA Mutational Analysis; D005819:Genetic Markers / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics
D005819:Genetic Markers
clinical genetic testing; molecular genetics; monogenic disease; pathogenesis of nephrotic syndrome; steroid-resistant nephrotic syndrome (SRNS)