Thomas M Kitzler1, Nadezda Kachurina2, Martin M Bitzan3, Elena Torban2, Paul R Goodyer4. 1. Department of Medical Genetics, The Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada. 2. Department of Medicine, McGill University and McGill University Health Center, Montreal, Quebec, Canada. 3. Division of Nephrology, The Montreal Children's Hospital, McGill University Health Center, 1001 Boulevard Décarie, Room EM1.2232, Montreal, Quebec, H4A 3J1, Canada. 4. Division of Nephrology, The Montreal Children's Hospital, McGill University Health Center, 1001 Boulevard Décarie, Room EM1.2232, Montreal, Quebec, H4A 3J1, Canada. paul.goodyer@mcgill.ca.
Abstract
BACKGROUND: Children with genetic causes of steroid-resistant nephrotic syndrome (SRNS) usually do well after renal transplantation, while some with idiopathic SRNS show recurrence due to a putative podocyte-toxic factor. Distinguishing different forms of SRNS based on clinical criteria has been difficult. The aim of our study was to test a novel approach that allows categorization of patients into clinically useful subgroups. METHODS: Seventeen patients with clinically confirmed SRNS were analyzed by next-generation sequencing (NGS) of 37 known SRNS genes and a functional assay of cultured human podocytes, which indirectly tests for toxicity of patients' sera by evidenced loss of podocyte focal adhesion complex (FAC) number. RESULTS: We identified a pathogenic mutation in seven patients (41%). Sera from patients with monogenic SRNS caused mild loss of FAC number down to 73% compared to untreated controls, while sera from seven of the remaining ten patients with idiopathic SRNS caused significant FAC number loss to 43% (non-overlapping difference 30%, 95% CI 26-36%, P < 0.001). All patients with recurrent SRNS (n = 4) in the graft showed absence of podocyte gene mutations but significant FAC loss. Three patients had no mutation nor serum podocyte toxicity. CONCLUSIONS: Our approach allowed categorization of patients into three subgroups: (1) patients with monogenic SRNS; (2) patients with idiopathic SRNS and marked serum podocyte toxicity; and (3) patients without identifiable genetic cause nor evidence of serum podocyte toxicity. Post-transplant SRNS recurrence risk appears to be low in groups 1 and 3, but high in group 2.
BACKGROUND:Children with genetic causes of steroid-resistant nephrotic syndrome (SRNS) usually do well after renal transplantation, while some with idiopathic SRNS show recurrence due to a putative podocyte-toxic factor. Distinguishing different forms of SRNS based on clinical criteria has been difficult. The aim of our study was to test a novel approach that allows categorization of patients into clinically useful subgroups. METHODS: Seventeen patients with clinically confirmed SRNS were analyzed by next-generation sequencing (NGS) of 37 known SRNS genes and a functional assay of cultured human podocytes, which indirectly tests for toxicity of patients' sera by evidenced loss of podocyte focal adhesion complex (FAC) number. RESULTS: We identified a pathogenic mutation in seven patients (41%). Sera from patients with monogenic SRNS caused mild loss of FAC number down to 73% compared to untreated controls, while sera from seven of the remaining ten patients with idiopathic SRNS caused significant FAC number loss to 43% (non-overlapping difference 30%, 95% CI 26-36%, P < 0.001). All patients with recurrent SRNS (n = 4) in the graft showed absence of podocyte gene mutations but significant FAC loss. Three patients had no mutation nor serum podocyte toxicity. CONCLUSIONS: Our approach allowed categorization of patients into three subgroups: (1) patients with monogenic SRNS; (2) patients with idiopathic SRNS and marked serum podocyte toxicity; and (3) patients without identifiable genetic cause nor evidence of serum podocyte toxicity. Post-transplant SRNS recurrence risk appears to be low in groups 1 and 3, but high in group 2.
Authors: Aaron McKenna; Matthew Hanna; Eric Banks; Andrey Sivachenko; Kristian Cibulskis; Andrew Kernytsky; Kiran Garimella; David Altshuler; Stacey Gabriel; Mark Daly; Mark A DePristo Journal: Genome Res Date: 2010-07-19 Impact factor: 9.043
Authors: Stephen J Tonna; Alexander Needham; Krishna Polu; Andrea Uscinski; Gerald B Appel; Ronald J Falk; Avi Katz; Salah Al-Waheeb; Bernard S Kaplan; George Jerums; Judy Savige; Jennifer Harmon; Kang Zhang; Gary C Curhan; Martin R Pollak Journal: BMC Nephrol Date: 2008-09-29 Impact factor: 2.388
Authors: Aleksandra Musiała; Piotr Donizy; Hanna Augustyniak-Bartosik; Katarzyna Jakuszko; Mirosław Banasik; Katarzyna Kościelska-Kasprzak; Magdalena Krajewska; Dorota Kamińska Journal: J Clin Med Date: 2022-06-08 Impact factor: 4.964
Authors: Susan Veissi; Bart Smeets; Lambertus P van den Heuvel; Michiel F Schreuder; Jitske Jansen Journal: Pediatr Nephrol Date: 2019-02-28 Impact factor: 3.714
Authors: Chen-Fang Chung; Thomas Kitzler; Nadezda Kachurina; Katarina Pessina; Sima Babayeva; Martin Bitzan; Frederic Kaskel; Ines Colmegna; Nada Alachkar; Paul Goodyer; Andrey V Cybulsky; Elena Torban Journal: PLoS One Date: 2019-05-16 Impact factor: 3.240