Kidney Week

Abstract: SA-OR18

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

Session Information

• Diabetic Kidney Disease: From Mechanisms to Treatment
  October 24, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Limonte, Christine P., University of Washington, Seattle, Washington, United States

Christine P. Limonte, MD



Christine Limonte is a Nephrology Clinical Research Fellow at the University of Washington. Her research interests include diabetic kidney disease pathophysiology and the mechanisms underlying various phenotypes of diabetic kidney disease.

• Natarajan, Loki, University of California San Diego, La Jolla, California, United States

Loki Natarajan,

• Valo, Erkka A., Folkhälsan Research Center, Helsinki, Finland

Erkka A. Valo,

• Darshi, Manjula, UT Health Science Center San Antonio, San Antonio, Texas, United States

Manjula Darshi,

• Drel, Viktor, UT Health Science Center San Antonio, San Antonio, Texas, United States

Viktor Drel,

• Hoofnagle, Andrew N., University of Washington, Seattle, Washington, United States

Andrew N. Hoofnagle,

• Montemayor, Daniel, UT Health Science Center San Antonio, San Antonio, Texas, United States

Daniel Montemayor,

• Sandholm, Niina, Folkhälsan Research Center, Helsinki, Finland

Niina Sandholm,

• Vaisar, Tomas, University of Washington, Seattle, Washington, United States

Tomas Vaisar,

• Zhang, Jing, University of California San Diego, La Jolla, California, United States

Jing Zhang,

• Rossing, Peter, Steno Diabetes Center Copenhagen, Copenhagen, Denmark

Peter Rossing,

• Groop, Per-Henrik, Folkhälsan Research Center, Helsinki, Finland

Per-Henrik Groop,

• Snell-Bergeon, Janet, University of Colorado Denver Barbara Davis Center for Childhood Diabetes, Denver, Colorado, United States

Janet Snell-Bergeon,

• Orchard, Trevor J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Trevor J. Orchard,

• de Boer, Ian H., University of Washington, Seattle, Washington, United States

Ian H. de Boer,

• Sharma, Kumar, UT Health Science Center San Antonio, San Antonio, Texas, United States

Kumar Sharma,

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