ADAMTS13 Predicts Renal and Cardiovascular Events in Type 2 Diabetic Patients and Response to Therapy
- Erica Rurali1,
- Marina Noris1⇑,
- Antonietta Chianca1,
- Roberta Donadelli1,
- Federica Banterla1,
- Miriam Galbusera1,
- Giulia Gherardi1,
- Sara Gastoldi1,
- Aneliya Parvanova1,
- Ilian Iliev1,
- Antonio Bossi2,
- Carolina Haefliger3,
- Roberto Trevisan4,
- Giuseppe Remuzzi1,5,
- Piero Ruggenenti1,5,
- for the BENEDICT Study Group*
- 1IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri,” Bergamo, Italy
- 2Unit of Diabetology, Treviglio Hospital, Bergamo, Italy
- 3F. Hoffmann-La Roche Ltd., Basel, Switzerland
- 4Unit of Diabetology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
- 5Unit of Nephrology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
- Corresponding author: Marina Noris, .
E.R. and M.N. contributed equally as first author, and G.R. and P.R. contributed equally as last author of this work.
In patients with diabetes, impaired ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) proteolysis of highly thrombogenic von Willebrand factor (VWF) multimers may accelerate renal and cardiovascular complications. Restoring physiological VWF handling might contribute to ACE inhibitors’ (ACEi) reno- and cardioprotective effects. To assess how Pro618Ala ADAMTS13 variants and related proteolytic activity interact with ACEi therapy in predicting renal and cardiovascular complications, we genotyped 1,163 normoalbuminuric type 2 diabetic patients from BErgamo NEphrologic DIabetes Complications Trial (BENEDICT). Interaction between Pro618Ala and ACEi was significant in predicting both renal and combined renal and cardiovascular events. The risk for renal or combined events versus reference Ala carriers on ACEi progressively increased from Pro/Pro homozygotes on ACEi (hazard ratio 2.80 [95% CI 0.849–9.216] and 1.58 [0.737–3.379], respectively) to Pro/Pro homozygotes on non-ACEi (4.77 [1.484–15.357] and 1.99 [0.944–4.187]) to Ala carriers on non-ACEi (8.50 [2.416–29.962] and 4.00 [1.739–9.207]). In a substudy, serum ADAMTS13 activity was significantly lower in Ala carriers than in Pro/Pro homozygotes and in case subjects with renal, cardiovascular, or combined events than in diabetic control subjects without events. ADAMTS13 activity significantly and negatively correlated with all outcomes. In patients with diabetes, ADAMTS13 618Ala variant associated with less proteolytic activity, higher risk of chronic complications, and better response to ACEi therapy. Screening for Pro618Ala polymorphism may help identify patients with diabetes at highest risk who may benefit the most from early reno- and cardioprotective therapy.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0530/-/DC1.
* A complete list of members of the BENEDICT Study Group can be found in the Supplementary Data.
See accompanying commentary, p. 3331.
- Received April 8, 2013.
- Accepted May 29, 2013.
- © 2013 by the American Diabetes Association.
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