To treat or not to treat: CUBN-associated persistent proteinuria

Abstract

Background: Persistent proteinuria is an important indicator of kidney damage and requires active evaluation and intervention. However, tubular proteinuria of genetic origin typically does not improve with immunosuppression or antiproteinuric treatment. Recently, defects in CUBN were found to cause isolated proteinuria (mainly albuminuria) due to defective tubular albumin reuptake. Unlike most other genetically caused persistent albuminuria, CUBN C-terminal variants have a benign course without progression to chronic kidney disease according to the literature. Here, we present Korean cases with persistent proteinuria associated with C-terminal variants of CUBN.

Methods: We identified Korean patients with CUBN variants among those with an identified genetic cause of proteinuria and evaluated their clinical features and clinical course. We also reviewed the literature on CUBN-associated isolated proteinuria published to date and compared it with Korean patients.

Results: All patients presented with incidentally found, asymptomatic isolated proteinuria at a median age of 5 years. The proteinuria was in the subnephrotic range and did not significantly change over time, regardless of renin- angiotensin system inhibition. Initial physical examination, laboratory findings, and kidney biopsy results, when available, were unremarkable other than significant proteinuria. All patients maintained kidney function throughout the follow-up duration. All patients had at least one splicing mutation, and most of the variants were located C-terminal side of the gene.

Conclusion: We report Korean experience of CUBN-related benign proteinuria, that aligns with previous reports, indicating that this condition should be considered in cases with incidentally found asymptomatic isolated proteinuria, especially in young children.

Keywords: CUBN variants; Chronic proteinuria; Cubilin; Genetic testing.

Figure 1.. Position of CUBN variants along the cubilin protein.

The cubilin protein structure consists of eight epidermal growth factor (EGF)-like (yellow) and 27 CUB domains (blue), consisting of complement C1r/C1s, EGF-related sea urchin protein and bone morphogenic protein 1. The red dots represent the theoretical Ca²⁺-binding sites. This figure includes previously reported data until 2022 [,,,–19]. Variants written in blue are associated with Imerslund-Gräsbeck syndrome in the Human Mutation Database, while variants written in black are previously identified variants causative of isolated proteinuria. Variants identified in this study are written in green and annotated with orange color. IF, intrinsic factor.

Figure 2.. Endocytic megalin and cubilin-amnionless complex in the apical membrane of the renal proximal tubule.

Figure 3.. Changes in proteinuria over the patient’s follow-up period.

Six patients were followed up for a period of 2 to 10 years. Among all patients, proteinuria remained similar during the follow-up period. However, Patient 6 had a follow-up duration of less than 1 year, and thus the patient’s data are excluded from this chart. uPCR, urine protein-to-creatinine ratio.