ADAMTS13 predicts renal and cardiovascular events in type 2 diabetic patients and response to therapy

Erica Rurali, Marina Noris, Antonietta Chianca, Roberta Donadelli, Federica Banterla, Miriam Galbusera, Giulia Gherardi, Sara Gastoldi, Aneliya Parvanova, Ilian Iliev, Antonio Bossi, Carolina Haefliger, Roberto Trevisan, Giuseppe Remuzzi, Piero Ruggenenti

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3599-3609
Number of pages11
JournalDiabetes
Volume62
Issue number10
DOIs
Publication statusPublished - Oct 2013

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Angiotensin-Converting Enzyme Inhibitors
Kidney
Homozygote
von Willebrand Factor
Therapeutics
Thrombospondin 1
Disintegrins
Metalloproteases
Diabetes Complications
Proteolysis
Serum

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

ADAMTS13 predicts renal and cardiovascular events in type 2 diabetic patients and response to therapy. / Rurali, Erica; Noris, Marina; Chianca, Antonietta; Donadelli, Roberta; Banterla, Federica; Galbusera, Miriam; Gherardi, Giulia; Gastoldi, Sara; Parvanova, Aneliya; Iliev, Ilian; Bossi, Antonio; Haefliger, Carolina; Trevisan, Roberto; Remuzzi, Giuseppe; Ruggenenti, Piero.

In: Diabetes, Vol. 62, No. 10, 10.2013, p. 3599-3609.

Research output: Contribution to journalArticle

Rurali, E, Noris, M, Chianca, A, Donadelli, R, Banterla, F, Galbusera, M, Gherardi, G, Gastoldi, S, Parvanova, A, Iliev, I, Bossi, A, Haefliger, C, Trevisan, R, Remuzzi, G & Ruggenenti, P 2013, 'ADAMTS13 predicts renal and cardiovascular events in type 2 diabetic patients and response to therapy', Diabetes, vol. 62, no. 10, pp. 3599-3609. https://doi.org/10.2337/db13-0530
Rurali, Erica ; Noris, Marina ; Chianca, Antonietta ; Donadelli, Roberta ; Banterla, Federica ; Galbusera, Miriam ; Gherardi, Giulia ; Gastoldi, Sara ; Parvanova, Aneliya ; Iliev, Ilian ; Bossi, Antonio ; Haefliger, Carolina ; Trevisan, Roberto ; Remuzzi, Giuseppe ; Ruggenenti, Piero. / ADAMTS13 predicts renal and cardiovascular events in type 2 diabetic patients and response to therapy. In: Diabetes. 2013 ; Vol. 62, No. 10. pp. 3599-3609.
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abstract = "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.",
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AU - Rurali, Erica

AU - Noris, Marina

AU - Chianca, Antonietta

AU - Donadelli, Roberta

AU - Banterla, Federica

AU - Galbusera, Miriam

AU - Gherardi, Giulia

AU - Gastoldi, Sara

AU - Parvanova, Aneliya

AU - Iliev, Ilian

AU - Bossi, Antonio

AU - Haefliger, Carolina

AU - Trevisan, Roberto

AU - Remuzzi, Giuseppe

AU - Ruggenenti, Piero

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