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Abstract: SA-OR18

Urinary Proteomics Identifies Proteins Associated with Rapid eGFR Decline in Type 1 Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Limonte, Christine P., University of Washington, Seattle, Washington, United States
  • Natarajan, Loki, University of California San Diego, La Jolla, California, United States
  • Valo, Erkka A., Folkhälsan Research Center, Helsinki, Finland
  • Darshi, Manjula, UT Health Science Center San Antonio, San Antonio, Texas, United States
  • Drel, Viktor, UT Health Science Center San Antonio, San Antonio, Texas, United States
  • Hoofnagle, Andrew N., University of Washington, Seattle, Washington, United States
  • Montemayor, Daniel, UT Health Science Center San Antonio, San Antonio, Texas, United States
  • Sandholm, Niina, Folkhälsan Research Center, Helsinki, Finland
  • Vaisar, Tomas, University of Washington, Seattle, Washington, United States
  • Zhang, Jing, University of California San Diego, La Jolla, California, United States
  • Rossing, Peter, Steno Diabetes Center Copenhagen, Copenhagen, Denmark
  • Groop, Per-Henrik, Folkhälsan Research Center, Helsinki, Finland
  • Snell-Bergeon, Janet, University of Colorado Denver Barbara Davis Center for Childhood Diabetes, Denver, Colorado, United States
  • Orchard, Trevor J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • de Boer, Ian H., University of Washington, Seattle, Washington, United States
  • Sharma, Kumar, UT Health Science Center San Antonio, San Antonio, Texas, United States
Background

Varying rates of eGFR decline have been observed in patients with type 1 diabetes (T1D), the pathophysiologic mechanisms of which remain poorly understood.

Methods

We performed a case-control study nested within four T1D cohorts (EDC, CACTI, STENO, FinnDiane) to identify urinary proteins associated with rapid eGFR loss. Cases and controls were defined by annual eGFR decline >3ml/min/1.73m2 and <1ml/min/1.73m2, respectively. We developed a targeted liquid chromatography-tandem mass spectrometry assay to measure 38 peptides of 20 proteins implicated in diabetic kidney disease. Peptide associations with rapid eGFR loss in discovery and validation sets were compared using logistic regression. Associations of significant peptides with diabetic kidney disease were investigated in the Nephroseq transcriptomic database.

Results

1271 participants (508 cases, 763 controls) with baseline median eGFR 95ml/min/1.73m2 and ACR >30mg/gCr in 36% were included. Over 8 years median follow-up, mean eGFR slope was -5.65 and 0.57ml/min/1.73m2 per year for cases and controls, respectively. Out of 38 urine peptides, 2 cathepsin D (CatD) peptides were associated with rapid eGFR loss adjusting for demographic and clinical variables with a false discovery rate of <5% in the discovery set (fully-adjusted OR per SD 1.52, 95%CI 1.22-1.88; 1.41, 95%CI 1.14-1.74). In the validation set, CatD peptides were associated with rapid eGFR decline adjusting for demographic but not clinical variables (1.26, 95%CI 0.99-1.60; 1.15, 95%CI 0.91-1.46). When stratified by baseline urine albumin creatinine ratio (UACR), CatD peptides were associated with rapid eGFR loss among those with UACR 30-300mg/g in both discovery (2.36, 95%CI 1.39-4.03; 2.28, 95%CI 1.32-3.92) and validation (1.93, 95%CI 1.10-1.39; 1.84, 95%CI 1.08-3.13) sets. Across several Nephroseq cohorts, CatD transcription was increased in tubulointerstitial but not glomerular specimens in diabetic kidney disease compared to healthy living donors.

Conclusion

Among patients with T1D and largely normal kidney function, differences in renal lysosomal function as suggested by increased urine CatD may represent a mechanism of rapid eGFR loss early in the course of T1D.

Funding

  • Private Foundation Support