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, BENEDICT Study Group, G Remuzzi, P Ruggenenti, Villa Camozzi, R Trevisan, A R Dodesini, G Lepore, I Nosari, A Fassi, A Belviso, M Trillini, P Cravedi, C Chiurchiu, S Rota, S Prandini, A Bossi, A Parvanova, I P Iliev, V Lecchi, S Yakymchuk, R Mangili, M Filipponi, I P Iliev, S Tadini, N Rubis, G Gherardi, W Calini, O Diadei, M Lesti, D Rossoni, D Villa, G Gaspari, S Gelmi, A Remuzzi, B Ene-Iordache, S Carminati, A Perna, N Motterlini, A Chianca, F Gaspari, F Carrara, S Ferrari, N Stucchi, A Cannata, M Galbusera, S Gastoldi, C Tentori, M Noris, R Donadelli, E Rurali, S Nosari, E Valoti, G Gherardi, D Cugini, P Boccardo, L Minetti, G Remuzzi, U F Legler, B Kalsch, D Nehrdich, A Nicolucci, A Perna, P Ruggenenti, R Kay, G C Viberti, 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, BENEDICT Study Group, G Remuzzi, P Ruggenenti, Villa Camozzi, R Trevisan, A R Dodesini, G Lepore, I Nosari, A Fassi, A Belviso, M Trillini, P Cravedi, C Chiurchiu, S Rota, S Prandini, A Bossi, A Parvanova, I P Iliev, V Lecchi, S Yakymchuk, R Mangili, M Filipponi, I P Iliev, S Tadini, N Rubis, G Gherardi, W Calini, O Diadei, M Lesti, D Rossoni, D Villa, G Gaspari, S Gelmi, A Remuzzi, B Ene-Iordache, S Carminati, A Perna, N Motterlini, A Chianca, F Gaspari, F Carrara, S Ferrari, N Stucchi, A Cannata, M Galbusera, S Gastoldi, C Tentori, M Noris, R Donadelli, E Rurali, S Nosari, E Valoti, G Gherardi, D Cugini, P Boccardo, L Minetti, G Remuzzi, U F Legler, B Kalsch, D Nehrdich, A Nicolucci, A Perna, P Ruggenenti, R Kay, G C Viberti

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.

Trial registration: ClinicalTrials.gov NCT00235014.

Figures

FIG. 1.
FIG. 1.
Schematic diagram of BENEDICT phase A type 2 diabetic patients screened for the Pro618Ala ADAMTS13. ACEi allocation: Ala carriers vs. Pro/Pro homozygotes, χ2 = 0.715, P = 0.398. Renal event development: Ala carriers, ACEi vs. non-ACEi, χ2 = 8.907, P = 0.003; Pro/Pro homozygotes, ACEi vs. non-ACEi, χ2 = 5.032, P = 0.025; ACEi, Ala carriers vs. Pro/Pro homozygotes, χ2 = 1.961, P = 0.161; non-ACEi, Ala carriers vs. Pro/Pro homozygotes, χ2 = 1.436, P = 0.231. Cardiovascular event development: Ala carriers, ACEi vs. non-ACEi, χ2 = 1.057, P = 0.304; Pro/Pro homozygotes, ACEi vs. non-ACEi, χ2 = 0.218, P = 0.641; ACEi, Ala carriers vs. Pro/Pro homozygotes, χ2 = 0.114, P = 0.736; non-ACEi, Ala carriers vs. Pro/Pro homozygotes, χ2 = 4.673, P = 0.031. Combined event development: Ala carriers, ACEi vs. non-ACEi, χ2=8.255, P = 0.004; Pro/Pro homozygotes, ACEi vs. non-ACEi, χ2 = 2.109, P = 0.146; ACEi, Ala carriers vs. Pro/Pro homozygotes, χ2 = 0.747, P = 0.388; non-ACEi, Ala carriers vs. Pro/Pro homozygotes, χ2 = 4.523, P = 0.033.
FIG. 2.
FIG. 2.
Impact of Pro618Ala polymorphism and ACEi therapy on considered events. Kaplan-Meyer curves show the percentages of Ala carriers or Pro/Pro homozygotes with or without ACEi therapy progressing to renal (A) or combined renal and/or cardiovascular (B) events throughout the study period. P values of unadjusted Cox analyses are shown. Boldface P values indicate statistical significance.
FIG. 3.
FIG. 3.
HR for considered events according to Pro618Ala genotype and ACEi treatment. HRs (95% CI) for renal and combined renal and/or cardiovascular events according to Pro618Ala polymorphism and ACEi therapy compared with Ala carriers on ACEi taken as the reference group are shown.
FIG. 4.
FIG. 4.
UAE rate, BP, and HbA1c according to Pro618Ala polymorphism and ACEi therapy. A: UAE rate (geometric mean and 95% CI) at basal and final visit. B: Mean SBP and DBP. C: HbA1c throughout the whole observation period. Differences in UAE rate between treatment groups are adjusted for baseline values by ANCOVA. Differences in BP and HbA1c between different groups are not significant.
FIG. 5.
FIG. 5.
Serum ADAMTS13 activity in case and control subjects. Diabetic case subjects with renal or cardiovascular events were compared with matched diabetic control subjects without events (A). B: Diabetic case subjects with renal and/or cardiovascular combined events were compared with matched diabetic control subjects without events and nondiabetic healthy control subjects. Data are expressed as means (SD). Boldface P values indicate statistical significance.

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