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Introduction <p>We aimed to evaluate the clinical and genetic characteristics and clinical course of children with persistent proteinuria associated with <i>CUBN</i> variants.</p> Methods <p>Forty-eight children with <i>CUBN</i> 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.</p> Results <p>All patients had normal serum albumin and creatinine and preserved eGFR. There was no significant change in eGFR between the first and last visits (<i>p</i> = 0.15), whereas uPCR was lower at the last visit (<i>p</i> = 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 <i>CUBN</i> variants were identified, predominantly in the C-terminal region. The most frequent variant was c.10102A &gt; G (p.Met3368Val). Variant types included 15 (57.7%) missense, 7 (27%) nonsense, 3 (11.5%) splicing, and 1 (3.8%) frameshift variants.</p> Conclusions <p>In this multicenter, large pediatric cohort, proteinuria associated with <i>CUBN</i> variants generally followed a benign course over short to mid-term follow-up even without sustained ACEi/ARB therapy. Embedding targeted <i>CUBN</i> 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.</p> Graphical abstract <p></p>

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Clinical course of proteinuria due to cubilin variants: a large multicenter pediatric cohort

  • 期刊论文

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  • 发表日期：

    2026年3月4日

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  • Neslihan Cicek,
  • Ceren Alavanda,
  • Ayse Seda Pınarbası,
  • Aylin Inal,
  • Bahriye Atmıs,
  • Secil Kezer,
  • Mehtap Akbalik Kara,
  • Okan Akaci,
  • Serim Pul,
  • Sevcan Hatipoglu,
  • Zeynep Nagehan Yuruk Yildirim,
  • Ayse Agbas,
  • Emre Leventoglu,
  • Ilknur Girisgen,
  • Mehtap Kaya,
  • Nimet Sasmaz Nurdag,
  • Sercin Guven,
  • Ozde Nisa Turkkan,
  • Nurdan Yildiz,
  • Pinar Ata,
  • Ismail Dursun,
  • Ibrahim Gokce

摘要

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.

Graphical abstract