Diabetes care · 2022
Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes.
СтатьяМетаанализПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод пока не подготовлен
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Limonte Christine P, Valo Erkka, Drel Viktor, Natarajan Loki, Darshi Manjula, Forsblom Carol, Henderson Clark M, Hoofnagle Andrew N, Ju Wenjun, Kretzler Matthias, Montemayor Daniel, Nair Viji, Nelson Robert G, O'Toole John F, Toto Robert D, Rosas Sylvia E, Ruzinski John, Sandholm Niina, Schmidt Insa M, Vaisar Tomas, Waikar Sushrut S, Zhang Jing, Rossing Peter, Ahluwalia Tarunveer S, Groop Per-Henrik, Pennathur Subramaniam, Snell-Bergeon Janet K, Costacou Tina, Orchard Trevor J, Sharma Kumar, de Boer Ian H, Kidney Precision Medicine Project
Аннотация
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.
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.