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Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes

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posted on 04.04.2022, 19:26 authored by Christine P. Limonte, Erkka Valo, Viktor Drel, Loki Natarajan, Manjula Darshi, Carol Forsblom, Clark M. Henderson, Andrew N. Hoofnagle, Wenjun Ju, Matthias Kretzler, Daniel Montemayor, Viji Nair, Robert G. Nelson, John F. O’Toole, Robert D. Toto, Sylvia E. Rosas, John Ruzinski, Niina Sandholm, Insa M. Schmidt, Tomas Vaisar, Sushrut S. Waikar, Jing Zhang, Peter Rossing, Tarunveer S. Ahluwalia, Per-Henrik Groop, Subramaniam Pennathur, Janet K. Snell-Bergeon, Tina Costacou, Trevor J. Orchard, Kumar Sharma, Ian H. de Boer, the Kidney Precision Medicine Project
Objective: Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D).

Research Design and Methods: We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Cases and controls were defined by eGFR decline >3 and <1 ml/min/1.73m2/year, respectively. We used targeted liquid chromatography-tandem mass spectrometry to measure 38 peptides from 20 proteins implicated in diabetic kidney disease. Significant proteins were investigated in complementary human cohorts and in mouse proximal tubular epithelial cell cultures.

Results: The cohort study included 1270 participants followed a median 8 years. In the discovery set, only cathepsin D peptide and protein were significant on full adjustment for clinical and laboratory variables. In the validation set, associations of cathepsin D with eGFR decline were replicated in minimally-adjusted models but lost significance with adjustment for albuminuria. In a meta-analysis combining discovery and validation sets, the odds ratio for the association of cathepsin D with rapid eGFR decline was 1.29 per SD (95%CI 1.07-1.55). In complementary human cohorts, urine cathepsin D was associated with tubulointerstitial injury, and tubulointerstitial cathepsin D expression was associated with increased cortical interstitial fractional volume. In mouse proximal tubular epithelial cell cultures, advanced glycation end product-bovine serum albumin increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA.

Conclusion: Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury.

Funding

JDRF Network grant 3-SRA-2016-104 (PI:KS) provided major support for this study. The FinnDiane study was funded by the Folkhälsan Research Foundation, the Wilhelm and Else Stockmann Foundation, the Liv och Hälsa Society, the Novo Nordisk Foundation (NNF OC0013659), the Helsinki University Hospital Research Funds, and the Academy of Finland (299200, 275614, 316664). The EDC study was funded by NIH grant DK34818 and the Rossi Memorial Fund. The CACTI study was funded by NIH grants R01HL113029, R01HL079611, RC1DK086958, and R01DE026480. CPL was funded by NIDDK grants T32DK007467 and R01DK088762, and Northwest Kidney Centers. RGN was supported by the Intramural Research Program of NIDDK and the imaging of kidney tissue specimens was also supported in part by the American Diabetes Association (Clinical Science Award 1-08-42). LN and JZ were partially supported by NIDDK grant 1R01DK110541-01A1. The development of the urine proteomics assay was partially supported by the University of Washington Nutrition Obesity Research Center (P30 DK035816) and Diabetes Research Center (P30 DK017047). This study was also supported, in part, by the George M. O’Brien Michigan Kidney Translational Core Center, funded by NIH/NIDDK grant 2P30-DK-081943. The KPMP is funded by the following grants from the NIDDK: U2C DK114886, UH3DK114861, UH3DK114866, UH3DK114870, UH3DK114908, UH3DK114915, UH3DK114926, UH3DK114907, UH3DK114920, UH3DK114923, UH3DK114933, and UH3DK114937.

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