Maryam Afkarian1, Leila R Zelnick2, John Ruzinski3, Bryan Kestenbaum3, Jonathan Himmelfarb3, Ian H de Boer3, Rajnish Mehrotra3. 1. Kidney Research Institute and Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA. Electronic address: afkarian@u.washington.ed. 2. Kidney Research Institute and Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA; Department of Biostatistics, University of Washington. 3. Kidney Research Institute and Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA.
Abstract
AIMS: The renin-angiotensin-aldosterone system (RAAS), bone morphogenetic protein (BMP) and WNT pathways are dysregulated in diabetic kidney disease (DKD). Urine excretion of angiotensinogen, gremlin-1 and matrix metalloproteinase-7 (MMP-7), components of the RAAS, BMP and WNT pathways, respectively, is increased in DKD. We asked if this increase is associated with subsequent progression to end-stage renal disease (ESRD) or death. METHODS: Using time-to-event analyses, we examined the association of baseline urine concentration of these proteins with progression to ESRD or death in a predominantly Mexican-American cohort with type 2 diabetes and proteinuric DKD (n=141). RESULTS: Progression to ESRD occurred for 38 participants over a median follow-up of 3.0years; 39 participants died over a median follow-up of 3.6years. Urine MMP-7 and gremlin-1 were associated with increased risk of ESRD after adjustment for demographic and clinical covariates. Angiotensinogen showed a U-shaped relationship with ESRD, with the middle tertile associated with lowest risk of ESRD. After additional adjustment for glomerular filtration rate and albuminuria, all associations with ESRD lost significance. Only urine MMP-7 was associated with mortality, and this association remained robust in the fully adjusted model with a Hazard ratio of 3.59 (95% confidence interval 1.31 to 9.85) for highest vs. lowest tertile. Serum MMP-7 was not associated with mortality and did not attenuate the association of urine MMP-7 with mortality (HR 4.03 for highest vs. lowest urine MMP-7 tertile). CONCLUSIONS: Among people with type 2 diabetes and proteinuric DKD, urine MMP-7 concentration was strongly associated with subsequent mortality.
AIMS: The renin-angiotensin-aldosterone system (RAAS), bone morphogenetic protein (BMP) and WNT pathways are dysregulated in diabetic kidney disease (DKD). Urine excretion of angiotensinogen, gremlin-1 and matrix metalloproteinase-7 (MMP-7), components of the RAAS, BMP and WNT pathways, respectively, is increased in DKD. We asked if this increase is associated with subsequent progression to end-stage renal disease (ESRD) or death. METHODS: Using time-to-event analyses, we examined the association of baseline urine concentration of these proteins with progression to ESRD or death in a predominantly Mexican-American cohort with type 2 diabetes and proteinuric DKD (n=141). RESULTS: Progression to ESRD occurred for 38 participants over a median follow-up of 3.0years; 39 participants died over a median follow-up of 3.6years. Urine MMP-7 and gremlin-1 were associated with increased risk of ESRD after adjustment for demographic and clinical covariates. Angiotensinogen showed a U-shaped relationship with ESRD, with the middle tertile associated with lowest risk of ESRD. After additional adjustment for glomerular filtration rate and albuminuria, all associations with ESRD lost significance. Only urine MMP-7 was associated with mortality, and this association remained robust in the fully adjusted model with a Hazard ratio of 3.59 (95% confidence interval 1.31 to 9.85) for highest vs. lowest tertile. Serum MMP-7 was not associated with mortality and did not attenuate the association of urine MMP-7 with mortality (HR 4.03 for highest vs. lowest urine MMP-7 tertile). CONCLUSIONS: Among people with type 2 diabetes and proteinuric DKD, urine MMP-7 concentration was strongly associated with subsequent mortality.
Authors: T Zhou; X He; R Cheng; B Zhang; R R Zhang; Y Chen; Y Takahashi; A R Murray; K Lee; G Gao; J-X Ma Journal: Diabetologia Date: 2011-10-21 Impact factor: 10.122
Authors: Mohita J Mohan; Theresa Seaton; Justin Mitchell; Anne Howe; Kevin Blackburn; William Burkhart; Mary Moyer; Inder Patel; Gregory M Waitt; J David Becherer; Marcia L Moss; Marcos E Milla Journal: Biochemistry Date: 2002-07-30 Impact factor: 3.162
Authors: Rajiv Agarwal; Kevin L Duffin; Dennis A Laska; James R Voelker; Matthew D Breyer; Peter G Mitchell Journal: Nephrol Dial Transplant Date: 2014-08-01 Impact factor: 5.992
Authors: Maryam Afkarian; Michael C Sachs; Bryan Kestenbaum; Irl B Hirsch; Katherine R Tuttle; Jonathan Himmelfarb; Ian H de Boer Journal: J Am Soc Nephrol Date: 2013-01-29 Impact factor: 10.121
Authors: Muh Geot Wong; Vlado Perkovic; Mark Woodward; John Chalmers; Qiang Li; Graham S Hillis; Dania Yaghobian Azari; Min Jun; Neil Poulter; Pavel Hamet; Bryan Williams; Bruce Neal; Giuseppe Mancia; Mark Cooper; Carol A Pollock Journal: Kidney Int Date: 2012-12-12 Impact factor: 10.612
Authors: Kevin A Lidberg; Selvaraj Muthusamy; Mohamed Adil; Anish Mahadeo; Jade Yang; Ranita S Patel; Lu Wang; Theo K Bammler; Jonathan Reichel; Catherine K Yeung; Jonathan Himmelfarb; Edward J Kelly; Shreeram Akilesh Journal: J Am Soc Nephrol Date: 2022-02-23 Impact factor: 14.978