Effect of Deferoxamine on Renal Fibrosis

Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22phox expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses

Current status of a helicopter transportation system on remote islands for patients undergoing mechanical thrombectomy

Background: Mechanical thrombectomy (MT) is standard treatment for acute ischemic stroke (AIS) with large-vessel occlusion within 6 h of symptom onset to treatment initiation (OTP). Recent trials have extended the therapeutic time window for MT to within 24 h. However, MT treatment remains low in remote areas. Nagasaki Prefecture, Japan has many inhabited islands with no neurointerventionalists. Our hospital on the mainland is a regional hub for eight island hospitals. We evaluated clinical outcomes of MT for patients with AIS on these islands versus on the mainland. Methods: During 2014–2019, we reviewed consecutive patients with AIS who received MT at our hospital. Patients comprised the Islands group and Mainland group. Patient characteristics and clinical outcomes were compared between groups. Results: We included 91 patients (Islands group: 15 patients, Mainland group: 76 patients). Seven patients (46.7%) in the Islands group versus 43 (56.6%) in the Mainland group achieved favorable outcomes. Successful recanalization was obtained in 11 patients (73.3%) on the islands and 67 (88.2%) on the mainland. The median OTP time in the Islands was 365 min. In both the Islands and Mainland groups, the OTP time and successful recanalization were associated with functional outcome. The modified Rankin Scale (mRS) score at 90 days ≤2 was obtained in two patients and mRS = 3 in four patients among eight patients with OTP time >6 h. Conclusions: Few patients with AIS on remote islands have received MT. Although patients who underwent MT on the islands had longer OTP, the clinical outcomes were acceptable. OTP time on remote islands must be shortened, as this is related to functional outcome. In some cases with successful recanalization, a favorable outcome can still be obtained even after 6 h. Even if OTP exceeds 6 h, it is desirable to appropriately select patients and actively perform MT

Efficacy of the Drip and Ship Method in 24-h Helicopter Transportation and Teleradiology for Isolated Islands

Our hospital, located on the mainland, serves as a hub center for nine hospitals on the remote islands of Nagasaki Prefecture, Japan. There are no stroke specialists on these islands. We can transfer emergency patients from these islands to our hospital at any time, using a teleradiology system and three types of helicopter transport. We examined the efficacy of the drip and ship (DS) method for treating patients with acute ischemic stroke (AIS) on these islands, in comparison with patients on the mainland. From 2010 to 2017, we reviewed 98 consecutive patients with AIS who received intravenous recombinant tissue plasminogen activator (IV rt-PA) in our hospital or were transported to our hospital after IV rt-PA. Patients were divided into the Islands group (received IV rt-PA on the islands, DS; 31 cases) and the Mainland group (67 cases). The median transport distance from the islands was 112 km. The rate of patients achieving favorable outcomes was 54.8% in the Islands group and 64.2% in the Mainland group, with no significant differences. Multivariate analysis revealed that patients living on isolated islands did not have increased risks of unfavorable outcomes. Endovascular therapy (EVT), as part of the drip, ship, and retrieve method, was performed in 22.6% of patients in the Islands group and EVT in 38.8% of those in the Mainland group. The DS method seems feasible and safe for patients living on isolated islands with the use of 24-h helicopter transportation and teleradiology

Efficacy of the Drip and Ship Method in 24-h Helicopter Transportation and Teleradiology for Isolated Islands

Our hospital, located on the mainland, serves as a hub center for nine hospitals on the remote islands of Nagasaki Prefecture, Japan. There are no stroke specialists on these islands. We can transfer emergency patients from these islands to our hospital at any time, using a teleradiology system and three types of helicopter transport. We examined the efficacy of the drip and ship (DS) method for treating patients with acute ischemic stroke (AIS) on these islands, in comparison with patients on the mainland. From 2010 to 2017, we reviewed 98 consecutive patients with AIS who received intravenous recombinant tissue plasminogen activator (IV rt-PA) in our hospital or were transported to our hospital after IV rt-PA. Patients were divided into the Islands group (received IV rt-PA on the islands, DS; 31 cases) and the Mainland group (67 cases). The median transport distance from the islands was 112 km. The rate of patients achieving favorable outcomes was 54.8% in the Islands group and 64.2% in the Mainland group, with no significant differences. Multivariate analysis revealed that patients living on isolated islands did not have increased risks of unfavorable outcomes. Endovascular therapy (EVT), as part of the drip, ship, and retrieve method, was performed in 22.6% of patients in the Islands group and EVT in 38.8% of those in the Mainland group. The DS method seems feasible and safe for patients living on isolated islands with the use of 24-h helicopter transportation and teleradiology

Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.

Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22(phox) expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses

Effect of DFO on the UUO-induced acceleration of TGF-β-Smad pathway.

<p>(A) Upper panels: representative immunoblotting for TGF-β1 expression. Lower panels: quantitative evaluation of TGF-β1 protein expression at day 7. Results are expressed as the mean ± SEM. *<i>P</i><0.05, **<i>P</i><0.01. <i>n = </i>12 in each group. (B) Upper panel: representative western blots of phopsho-Smad3, total-Smad3, and tubulin. Lower panel: quantification of western blots. Results are expressed as the mean ± SEM. *<i>P</i><0.05, **<i>P</i><0.01. <i>n = </i>12 per group.</p

Effect of iron chelation on protein expression related to inflammation and the extracellular matrix.

<p>(A) Analysis of the renal expression of MCP-1 and IL-1β. Upper panels: representative immunoblotting for MCP-1 and IL-1β. Lower panels: quantitative analysis of MCP-1 and IL-1β expression normalized to tubulin. Results are expressed as the mean ± SEM. *<i>P</i><0.05, **<i>P</i><0.01. <i>n = </i>12 per group. (B) Quantitative analysis of αSMA expression. Results are expressed as the mean ± SEM. *<i>P</i><0.05, **<i>P</i><0.01. <i>n = </i>12 per group. (C) Representative immunochemistry results for αSMA expression in kidney sections. (D) Quantitative analysis of fibronectin expression normalized to tubulin. Results are expressed as the mean ± SEM. *<i>P</i><0.05, **<i>P</i><0.01. <i>n = </i>12 per group. (e) Representative immunochemistry results for fibronectin expression in kidney sections.</p

Body weight, kidney weight, hemoglobin content, and kidney iron content in mice, 7 days after surgery.

<p>Data are the mean ± SEM, <i>n</i> = 14–18, as indicated.</p><p>*<i>P</i><0.05,</p><p>**<i>P</i><0.01 vs. sham with vehicle;</p>†<p><i>P</i><0.05,</p>††<p><i>P</i><0.01 vs. sham with DFO;</p>#<p><i>P</i><0.05,</p>##<p><i>P</i><0.01 vs. UUO with vehicle.</p