Background:Following the short-term outbreak of coronavirus disease 2019(COVID-19)in December 2022 in China,clinical data on kidney transplant recipients(KTRs)with COVID-19 are lacking.Methods:We conducted a single-ce...Background:Following the short-term outbreak of coronavirus disease 2019(COVID-19)in December 2022 in China,clinical data on kidney transplant recipients(KTRs)with COVID-19 are lacking.Methods:We conducted a single-center retrospective study to describe the clinical features,complications,and mortality rates of hospitalized KTRs infected with COVID-19 between Dec.16,2022 and Jan.31,2023.The patients were followed up until Mar.31,2023.Results:A total of 324 KTRs with COVID-19 were included.The median age was 49 years.The median time between the onset of symptoms and admission was 13 d.Molnupiravir,azvudine,and nirmatrelvir/ritonavir were administered to 67(20.7%),11(3.4%),and 148(45.7%)patients,respectively.Twenty-nine(9.0%)patients were treated with more than one antiviral agent.Forty-eight(14.8%)patients were treated with tocilizumab and 53(16.4%)patients received baricitinib therapy.The acute kidney injury(AKI)occurred in 81(25.0%)patients and 39(12.0%)patients were admitted to intensive care units.Fungal infections were observed in 55(17.0%)patients.Fifty(15.4%)patients lost their graft.The 28-d mortality rate of patients was 9.0%and 42(13.0%)patients died by the end of follow-up.Multivariate Cox regression analysis identified that cerebrovascular disease,AKI incidence,interleukin(IL)-6 level of>6.8 pg/mL,daily dose of corticosteroids of>50 mg,and fungal infection were all associated with an increased risk of death for hospitalized patients.Conclusions:Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality.The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival,while higher doses of corticosteroids may increase the death risk.展开更多
Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Here...Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Herein,we demonstrated that dexrazoxane(DXZ),a U.S.Food and Drug Administration(FDA)-approved cardioprotective drug,can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically.This effect is characterized by decreasing lipid peroxidation,shown by the biomarker of oxidative stress 4-hydroxynonenal(HNE)and prostaglandinendoperoxide synthase 2(Ptgs2),while reversing the downregulation of glutathione peroxidase 4(GPX4)and ferritin 1(FTH-1).Mechanistically,the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressingα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase(ACMSD).Furthermore,the conjugation of dexrazoxane and polysialic acid(DXZ-PSA)is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney,especially retention and targeting in the renal tubules.This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZPSA with the enhanced renal distribution.展开更多
Ferroptosis plays a critical pathophysiological role in several types of acute kidney injury(AKI).The development of nanomaterials targeting iron metabolism and ferroptosis is a promising approach for AKI treatment.He...Ferroptosis plays a critical pathophysiological role in several types of acute kidney injury(AKI).The development of nanomaterials targeting iron metabolism and ferroptosis is a promising approach for AKI treatment.Herein,we synthesized gallic acid-gallium polyvinyl pyrrolidone nanoparticles(GGP NPs)as a potential iron-scavenging agent because of their nearly ionic radius and chemical similarity with iron.The results indicated that GGP NPs accumulated in tubular epithelial cells and showed good biocompatibility.GGP NPs significantly inhibited cisplatin(CP)-induced ferroptosis in HK-2 cells by reducing the accumulation of intracellular free iron and mitochondrial dysfunction,and suppressing the perturbations of ferroptosis processes,including lipid peroxidation,nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH)levels,glutathione peroxidase 4(GPX4)activity,and ferritinophagy.An in vivo study demonstrated that treatment with GGP NPs significantly ameliorated the renal tubular injury and mitochondrial damage induced by CP treatment or ischemia-reperfusion injury.Our study suggests that GGP NPs may be an effective and promising candidate for AKI treatment and enable potential clinical translation.展开更多
基金supported by the National Natural Science Foundation of China(No.2022YFC82200842)the Zhejiang Provincial Natural Science Foundation of China(No.LQ22H050004).
文摘Background:Following the short-term outbreak of coronavirus disease 2019(COVID-19)in December 2022 in China,clinical data on kidney transplant recipients(KTRs)with COVID-19 are lacking.Methods:We conducted a single-center retrospective study to describe the clinical features,complications,and mortality rates of hospitalized KTRs infected with COVID-19 between Dec.16,2022 and Jan.31,2023.The patients were followed up until Mar.31,2023.Results:A total of 324 KTRs with COVID-19 were included.The median age was 49 years.The median time between the onset of symptoms and admission was 13 d.Molnupiravir,azvudine,and nirmatrelvir/ritonavir were administered to 67(20.7%),11(3.4%),and 148(45.7%)patients,respectively.Twenty-nine(9.0%)patients were treated with more than one antiviral agent.Forty-eight(14.8%)patients were treated with tocilizumab and 53(16.4%)patients received baricitinib therapy.The acute kidney injury(AKI)occurred in 81(25.0%)patients and 39(12.0%)patients were admitted to intensive care units.Fungal infections were observed in 55(17.0%)patients.Fifty(15.4%)patients lost their graft.The 28-d mortality rate of patients was 9.0%and 42(13.0%)patients died by the end of follow-up.Multivariate Cox regression analysis identified that cerebrovascular disease,AKI incidence,interleukin(IL)-6 level of>6.8 pg/mL,daily dose of corticosteroids of>50 mg,and fungal infection were all associated with an increased risk of death for hospitalized patients.Conclusions:Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality.The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival,while higher doses of corticosteroids may increase the death risk.
基金This work was supported by grants from Zhejiang Provincial Natural Science Foundation of China(No.LZ22H050001)the National Natural Science Foundation of China(Nos.81970573,81670651,81900683,82000637,and 82173662)+1 种基金Zhejiang provincial program for the Cultivation of High-level Innovative Health talents,Natural Science Foundation of Shanghai(No.20ZR1410400)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(No.2020KY538).
文摘Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Herein,we demonstrated that dexrazoxane(DXZ),a U.S.Food and Drug Administration(FDA)-approved cardioprotective drug,can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically.This effect is characterized by decreasing lipid peroxidation,shown by the biomarker of oxidative stress 4-hydroxynonenal(HNE)and prostaglandinendoperoxide synthase 2(Ptgs2),while reversing the downregulation of glutathione peroxidase 4(GPX4)and ferritin 1(FTH-1).Mechanistically,the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressingα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase(ACMSD).Furthermore,the conjugation of dexrazoxane and polysialic acid(DXZ-PSA)is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney,especially retention and targeting in the renal tubules.This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZPSA with the enhanced renal distribution.
基金supported by grants from the National Key R&D Program of China(No.2018YFC2000400)Zhejiang Provincial Natural Science Foundation of China(No.LZ22H050001)+1 种基金the National Natural Science Foundation of China(Nos.81970573,81670651,and 82000637)Zhejiang provincial program for the Cultivation of High-level Innovative Health talents,and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(No.2020KY538).
文摘Ferroptosis plays a critical pathophysiological role in several types of acute kidney injury(AKI).The development of nanomaterials targeting iron metabolism and ferroptosis is a promising approach for AKI treatment.Herein,we synthesized gallic acid-gallium polyvinyl pyrrolidone nanoparticles(GGP NPs)as a potential iron-scavenging agent because of their nearly ionic radius and chemical similarity with iron.The results indicated that GGP NPs accumulated in tubular epithelial cells and showed good biocompatibility.GGP NPs significantly inhibited cisplatin(CP)-induced ferroptosis in HK-2 cells by reducing the accumulation of intracellular free iron and mitochondrial dysfunction,and suppressing the perturbations of ferroptosis processes,including lipid peroxidation,nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH)levels,glutathione peroxidase 4(GPX4)activity,and ferritinophagy.An in vivo study demonstrated that treatment with GGP NPs significantly ameliorated the renal tubular injury and mitochondrial damage induced by CP treatment or ischemia-reperfusion injury.Our study suggests that GGP NPs may be an effective and promising candidate for AKI treatment and enable potential clinical translation.