CLINICAL AND GENETIC CHARACTERISTICS CHILDREN WITH PROTEINURIA ASSOCIATED WITH CUBN VARIANTS

Introduction:

Persistent glomerular proteinuria is independent predictor for progression to chronic kidney disease. Mutations in the CUBN gene commonly cause Imerslund-Gräsbeck syndrome, while isolated proteinuria as a result of CUBN variants is rarely reported. The aim of the study was to investigate clinical and genetic characteristics in children with persistent proteinuria, associated with CUBN variants.

Methods:

Kidney biopsy with light and electron microscopy and immunofluorescence was done in 2 children with isolated glomerular proteinuria. Genetic testing was performed in five (2M/3F) patients, including two siblings by next-generation sequencing of a custom-designed kidney disease gene panel (n=4) and whole exome sequencing (n=1). All patients were treated with angiotensin-converting enzyme inhibitors (ACEi) at a dose of 0.18 (IQR: 0.15; 0.23) mg/kg/day. The median follow-up was 52.0 (IQR: 9.0; 109.0) months. The median age of patients at the last follow up was 9.5 (IQR: 2.9; 15.3) years.

Results:

All five children presented with isolated glomerular proteinuria in the absence of nephrotic syndrome, hypertension and any extrarenal features. The median age at diagnosis of proteinuria was 2.0 (IQR: 0.7; 4.5) years. Kidney biopsy revealed MCD (n=1) and FSGS (n=1) with negative immunofluorescence and diffuse effacement of podocytes in electron microscopy in both of patients. We identified six different variants in the CUBN gene, three of which were novel, located in highly conserved sites after the vitamin B12-binding domain of Cubilin (Table 1). Patients showed lack of response to ACEi: the median proteinuria was 0.69 (IQR: 1.0; 1.5) g/l before start of ACEi and 0.86 (IQR: 0.35; 1.0) g/l on the treatment with ACEi at the last follow-up (p=0.25). The median GFR (CKiDU25) at diagnosis and at the last follow-up was not different significantly: 90.0 (IQR: 73.0; 93.0) vs. 94.0 (IQR: 76.0; 103.0) ml/min/1.73 m2 (p=0.063).

Conclusions:

Children with proteinuria associated with CUBN variants showed MSD and FSGS, lack of response to ACEi in most of them and preservation of normal kidney function over time. Identification of CUBN variants in patients with glomerular proteinuria will allow to avoid unnecessary kidney biopsy and immunosuppressive treatment. Long-term follow-up from further large-scale studies are required to validate the benign nature of the disease.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.