Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes
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Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes. / 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.
In: Diabetes Care, Vol. 45, No. 6, 2022, p. 1416-1427.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes
AU - Limonte, Christine P.
AU - Valo, Erkka
AU - Drel, Viktor
AU - Natarajan, Loki
AU - Darshi, Manjula
AU - Forsblom, Carol
AU - Henderson, Clark M.
AU - Hoofnagle, Andrew N.
AU - Ju, Wenjun
AU - Kretzler, Matthias
AU - Montemayor, Daniel
AU - Nair, Viji
AU - Nelson, Robert G.
AU - O’toole, John F.
AU - Toto, Robert D.
AU - Rosas, Sylvia E.
AU - Ruzinski, John
AU - Sandholm, Niina
AU - Schmidt, Insa M.
AU - Vaisar, Tomas
AU - Waikar, Sushrut S.
AU - Zhang, Jing
AU - Rossing, Peter
AU - Ahluwalia, Tarunveer S.
AU - Groop, Per Henrik
AU - Pennathur, Subramaniam
AU - Snell-Bergeon, Janet K.
AU - Costacou, Tina
AU - Orchard, Trevor J.
AU - Sharma, Kumar
AU - de Boer, Ian H.
AU - Kidney Precision Medicine Project
N1 - Publisher Copyright: © 2022 by the American Diabetes Association.
PY - 2022
Y1 - 2022
N2 - 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 spectrome-try to measure 38 peptides from 20 proteins implicated in diabetic kidney dis-ease. 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.
AB - 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 spectrome-try to measure 38 peptides from 20 proteins implicated in diabetic kidney dis-ease. 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.
U2 - 10.2337/dc21-2204
DO - 10.2337/dc21-2204
M3 - Journal article
C2 - 35377940
AN - SCOPUS:85131270263
VL - 45
SP - 1416
EP - 1427
JO - Diabetes Care
JF - Diabetes Care
SN - 1935-5548
IS - 6
ER -
ID: 313875709