Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes
Christine P. Limonte, Erkka Valo, Viktor R. 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, Tomáš 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, for the Kidney Precision Medicine Project
Abstract
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. Case and control subjects were categorized based on eGFR decline ≥3 and <1 mL/min/1.73 m2/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 1,270 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 with combination of 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-BSA increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA. CONCLUSIONS: Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury.