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Clinical course of proteinuria due to cubilin variants: a large multicenter pediatric cohort
Neslihan Cicek1, Ceren Alavanda2, Ayse Seda Pınarbası3
1Department of Pediatric Nephrology, Marmara University School of Medicine, Fevzi Çakmak Mahallesi Muhsin Yazıcıoğlu Caddesi No:10, Ust Kaynarca, Pendik, Istanbul, Türkiye. drneslihancicek@yahoo.com.
Insights
Children with persistent proteinuria due to CUBN variants showed a generally benign clinical course. Early genetic screening can guide conservative management, reducing unnecessary interventions.
Area of Science:
- Pediatric Nephrology
- Clinical Genetics
- Proteinuria Research
Background:
- Persistent proteinuria in children can have various causes.
- CUBN gene variants are increasingly recognized in kidney diseases.
- Understanding the clinical spectrum of CUBN-associated proteinuria is crucial.
Purpose of the Study:
- To evaluate the clinical and genetic characteristics of children with persistent proteinuria linked to CUBN variants.
- To describe the clinical course and outcomes in this pediatric cohort.
- To inform diagnostic and management strategies.
Main Methods:
- A multicenter study included 48 children with CUBN variants.
- Comprehensive clinical data, laboratory results, and genetic findings were collected.
- Analysis included urinalysis, kidney function tests, and treatment outcomes.
Main Results:
- Patients maintained normal serum albumin and creatinine with preserved eGFR.
- Proteinuria (uPCR) decreased over time.
- Most CUBN variants were missense, located in the C-terminal region.
- Kidney biopsies were largely normal, with one case of FSGS.
Conclusions:
- Proteinuria associated with CUBN variants typically follows a benign course in children.
- Targeted CUBN genetic testing can aid in early diagnosis and management.
- Conservative monitoring and potential discontinuation of ACEi/ARB therapy are supported.
- A stepwise care pathway involving genetic screening and monitoring is proposed.
Introduction:
We aimed to evaluate the clinical and genetic characteristics and clinical course of children with persistent proteinuria associated with CUBN variants.
Methods:
Forty-eight children with CUBN variants from 15 pediatric nephrology centers were included. Patients' characteristics, serum creatinine, albumin, hemoglobin, vitamin B12 levels, urinalysis, spot urine protein/creatinine (uPCR), microalbumin/creatinine (uACR), beta-2 microglobulin/creatinine (uBMCR) ratios, estimated glomerular filtration rates (eGFRs), treatments, kidney biopsies, and genetic findings were evaluated.
Results:
All patients had normal serum albumin and creatinine and preserved eGFR. There was no significant change in eGFR between the first and last visits (p = 0.15), whereas uPCR was lower at the last visit (p = 0.001). Kidney biopsy was performed in 13 (27%); light microscopy was normal in all except one patient with focal segmental glomerulosclerosis (FSGS). Thirty-five patients (72.9%) had ACEi/ARB therapy, which was discontinued in 21 patients without subsequent worsening of proteinuria. Overall, 26 distinct CUBN variants were identified, predominantly in the C-terminal region. The most frequent variant was c.10102A > G (p.Met3368Val). Variant types included 15 (57.7%) missense, 7 (27%) nonsense, 3 (11.5%) splicing, and 1 (3.8%) frameshift variants.
Conclusions:
In this multicenter, large pediatric cohort, proteinuria associated with CUBN variants generally followed a benign course over short to mid-term follow-up even without sustained ACEi/ARB therapy. Embedding targeted CUBN testing into the evaluation of children with asymptomatic proteinuria and normal kidney function may reduce unnecessary kidney biopsies and prolonged medication, while improving family counseling. We outline a stepwise care pathway → early genetic screening → conservative monitoring with periodic eGFR and proteinuria assessment → consideration of ACEi/ARB discontinuation and recommend prospective validation and cost-effectiveness studies.
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