RESUMO
Amino acids and SGLT2 inhibitors (SGLT2i) have recently been reported to attenuate the risk of hypoxic acute kidney injury (AKI), determined by changes in estimated glomerular filtration rate (GFR) following cardiac surgery and interventions with radiocontrast media, respectively. Yet, strategies to prevent or treat hypoxic AKI by the intensification of GFR, such as the administration of amino acids, in fact may predispose to intensified renal hypoxia and potential injury through enhanced tubular transport activity. Likewise, SGLT2i may intensify medullary hypoxia by translocating oxygen consumption for tubular transport from proximal to distal nephron segments. The outer medulla is particularly susceptible to hypoxic AKI, since intense regional oxygen consumption is barely met by a limited local blood supply, as reflected by low ambient oxygenation under normal conditions. In fact, declining GFR during AKI to large extent attenuates medullary hypoxia by the reduction of solute delivery for reabsorption in the distal nephron. Therefore, as outlined in this review, despite encouraging clinical outcomes, the safety, regarding renal parenchymal integrity, of enhancing GFR with amino acid infusion or by translocation of tubular transport to distal nephron segments by SGLT2i, administered to prevent AKI, should be assured, possibly by the determination of biomarkers of renal injury. Changes in renal oxygen expenditure, particularly within the hypoxic medulla should be considered in designing therapeutic interventions, conceivably with efforts aimed at reducing, rather than enhancing medullary tubular transport.
Assuntos
Injúria Renal Aguda , Aminoácidos , Túbulos Renais , Rim , Oxigênio , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Aminoácidos/administração & dosagem , Aminoácidos/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Túbulos Renais/metabolismo , Túbulos Renais/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Oxigênio/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Transporte BiológicoRESUMO
BACKGROUND: Hydroxyethyl starch (HES) is often used for maintaining vascular volume during major surgery. Long-term high-dose HES in septic patients promotes renal injury, whereas meta-analyses of current HES products in surgical patients do not show such effects. OBJECTIVE: We studied if the peri-operative use of HES is noninferior to crystalloids in terms of acute kidney injury. Secondary outcome was the noninferiority of HES on worsening of renal injury and/or the incidence of a composite endpoint of major complications and mortality until postoperative day 90. DESIGN: Randomised double-blind trial in patients undergoing elective abdominal surgery with expected blood loss at least 500âml. SETTING: Multicentre trial at 53 study sites in 10 European countries. PATIENTS: One thousand nine hundred and eighty-five (HES 977, crystalloid-only 981) patients aged 40 to 85âyears with ASA status II-III. INTERVENTION: Either 6% HES 130/0.4 or a crystalloid solution. Dosing was guided by mean arterial pressure and/or routine haemodynamic variables. MAIN OUTCOME MEASURE: Change from pre-operative to lowest cystatin C-based eGFR during the first 3 postoperative days. Key secondary outcome was a composite endpoint of mortality and major postoperative complications after 90âdays. RESULTS: Mean change in eGFR from baseline to minimum was -3.4â±â17.7âmlâmin -1 â1.73âm -2 in HES patients and -1.0â±â17.1âmlâmin -1 1.73âm -2 in crystalloid-only patients ( P â<â0.001 for noninferiority). The key secondary endpoint occurred in 35% of patients in each group. There were no clinically relevant differences in any safety endpoint including 90-day renal function. Any cause mortality-difference until the end of 1-year follow-up was not significantly different (8.6% in HES and 10.1% in crystalloid patients). CONCLUSION: Peri-operative use of HES was noninferior to crystalloids in short-term renal function or a composite of mortality and major complications at 90âdays. PHOENICS provides robust evidence that peri-operative in-label use of HES is well tolerated. TRIAL REGISTRATION AND FUNDING: EudraCT no. 2016-002162-30, clinicaltrials.gov ID NCT03278548.
Assuntos
Injúria Renal Aguda , Derivados de Hidroxietil Amido , Substitutos do Plasma , Humanos , Derivados de Hidroxietil Amido/efeitos adversos , Derivados de Hidroxietil Amido/administração & dosagem , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Método Duplo-Cego , Adulto , Idoso de 80 Anos ou mais , Soluções Cristaloides/administração & dosagem , Substitutos do Plasma/efeitos adversos , Substitutos do Plasma/administração & dosagem , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/prevenção & controle , Resultado do Tratamento , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Eletivos/efeitos adversosRESUMO
OBJECTIVES: The recently published PROTECTION trial (Intravenous Amino Acid Therapy for Kidney Protection in Cardiac Surgery) demonstrated that, in adult cardiac surgery patients, preoperative amino acid (AA) administration has a protective effect on renal function. However, large differences were observed within the participating centers. We aimed to investigate whether such center effects would remove the impact of AA on the prevention of cardiac surgery-associated acute kidney injury (CSA-AKI). DESIGN: A post hoc analysis of data from the PROTECTION trial was performed. SETTING: Multi-institutional data from centers that participated in the PROTECTION trial. PARTICIPANTS: Adult patients undergoing cardiac surgery enrolled in the PROTECTION trial. INTERVENTIONS: Two centers showed a significantly lower rate of CSA-AKI with respect to the pooled rate in all centers (low-rate centers) and 3 centers had a significantly higher rate (high-rate centers [HR-C]). These centers were compared for preoperative and intraoperative variables. RESULTS: Patients in the HR-C were significantly (p = 0.001) older, with lower left ventricular ejection fraction and hemoglobin values, a higher rate of class III and IV New York Heart Association functional class, arterial hypertension, previous myocardial infarction, diabetes, peripheral vascular disease, and more frequently received myocardial revascularization. During surgery, patients in the HR-C group had a longer aortic cross-clamp time, higher temperature on cardiopulmonary bypass, and received diuretics and hemofiltration at a lower rate. Additionally, a greater number of patients in the HR-C group required norepinephrine. However, once corrected for such a center effect, AA remained significantly independently associated with a reduction in CSA-AKI (relative risk, 0.79). CONCLUSIONS: HR-Cs treated patients with greater severity (unmodifiable risk factors) and received different operative and perioperative management. Taking into account such center effects, however, AA therapy remained independently associated with CSA-AKI prevention.
Assuntos
Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias , Humanos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/diagnóstico , Masculino , Feminino , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/tendências , Idoso , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/diagnósticoRESUMO
Background: Endovascular Aneurysm Repair (EVAR) is a proven, safe, and effective treatment; however, its application may be limited by the potential adverse effects of iodinated contrast medium (ICM), which can exacerbate renal function and may be contraindicated in patients with renal insufficiency. Purpose: This review aims to provide an overview of "zero-iodine contrast EVAR," which uses CO2 exclusively, as a strategy to mitigate the risk of acute kidney injury (AKI) associated with ICM. Research design: A systematic literature review was conducted in PubMed, Embase, and Cochrane databases following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to identify EVAR cases performed using carbon dioxide. The Medical Subject Headings (MeSH) terms used were "endovascular repair AND abdominal aortic aneurysm AND contrast medium" and "endovascular repair AND abdominal aortic aneurysm AND carbon dioxide," with inclusion criteria limited to articles in English published until December 2024. Results: The literature search yielded 1167 papers. After removing duplicates, titles and abstracts were screened, and 68 papers underwent full-text review. A total of 16 studies were included in the analysis, encompassing 1625 patients. Of these, 837 patients underwent EVAR with ICM, and 788 patients underwent EVAR with CO2. Of these, 510 patients were treated with EVAR using CO2 exclusively. Conclusions: Although this method still faces inherent limitations due to the physicochemical characteristics of CO2, its use, when combined with additional technical precautions, enables the achievement of zero-contrast results in standard EVAR procedures.
Assuntos
Injúria Renal Aguda , Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Dióxido de Carbono , Meios de Contraste , Procedimentos Endovasculares , Humanos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Implante de Prótese Vascular/efeitos adversos , Dióxido de Carbono/efeitos adversos , Dióxido de Carbono/administração & dosagem , Meios de Contraste/efeitos adversos , Meios de Contraste/administração & dosagem , Correção Endovascular de Aneurisma , Procedimentos Endovasculares/efeitos adversos , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
Diquat poisoning leads to acute kidney injury (AKI) with a high mortality rate. Sesamin possesses antioxidant, anti-inflammatory and anti-apoptotic properties. However, whether sesamin can protect against diquat-induced AKI remains unclear. This study aimed to investigate whether sesamin can exert protective effects against diquat-induced AKI and its potential molecular mechanisms. Diquat induced reactive oxygen species (ROS) generation, mitochondrial damage, apoptosis, and autophagy in human proximal tubular cells (HK-2 cells). SIRT5, a member of the sirtuin family of NAD + -dependent histone deacetylases, was slightly increased in diquat-exposed HK-2 cells. Additionally, diquat upregulated FOXO3a protein expression, accompanied by decreased acetyl-FOXO3a and enhanced nuclear translocation of FOXO3a in HK-2 cells. The toxic effects of diquat in HK-2 cells were further exacerbated by SIRT5 knockdown, but ameliorated by SIRT5 overexpression. Molecular docking and cellular thermal shift assay indicated that sesamin bound to SIRT5, with PHE70 likely serving as a key binding site. Sesamin attenuated diquat-induced ROS generation, mitochondrial damage, apoptosis, and autophagy in HK-2 cells by activating the SIRT5/FOXO3a pathway. Meanwhile, sesamin significantly attenuated diquat-induced AKI in mice by inhibiting oxidative stress, apoptosis and autophagy. Collectively, oxidative stress, apoptosis, and autophagy are involved in diquat-induced acute kidney injury. SIRT5/FOXO3a signaling pathway contributes to diquat-induced cytotoxicity in renal tubular epithelial cells. Sesamin exerts protective effects against diquat-induced acute kidney injury in mice.
Assuntos
Injúria Renal Aguda , Apoptose , Autofagia , Dioxóis , Diquat , Proteína Forkhead Box O3 , Lignanas , Estresse Oxidativo , Sirtuínas , Lignanas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Animais , Proteína Forkhead Box O3/metabolismo , Autofagia/efeitos dos fármacos , Sirtuínas/metabolismo , Sirtuínas/genética , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Humanos , Linhagem Celular , Camundongos , Diquat/toxicidade , Dioxóis/farmacologia , Masculino , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Herbicidas/toxicidadeRESUMO
Sepsis-associated acute kidney injury (SA-AKI) is a major contributor to death in intensive care units (ICU). The proviral integration site for Moloney murine leukemia virus-1 (PIM1), possesses multiple cellular functions, its function and mechanism in SA-AKI remain unclear. PIM1 was found abnormally upregulated in kidney tissues of SA-AKI mice and LPS-triggered HK-2 cells. Our findings demonstrated that PIM1 protected sepsis-induced kidney injury via restraining reactive oxygen species (ROS) and ferroptosis. In vivo, upregulation of PIM1 effectively relieved sepsis-induced kidney dysfunction, kidney damage, mitochondrial damage, and redox imbalance. In vitro, PIM1 preserved mitochondrial function by restoring the level of mitochondrial membrane potential. Furthermore, PIM1 reduced iron accumulation and mitochondria ROS, inhibited acyl-CoA synthetase long chain family member 4 (ACSL4), ferritin heavy chain 1 (FTH1), prostaglandin synthase 2 (PTGS2) expression, restored glutathione (GSH) level and glutathione peroxidase 4 (GPx4) expression, and regulated lipid metabolism to inhibit sepsis-related ferroptosis. Our findings imply that PIM1 protects SA-AKI via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for PIM1 as a promising target for kidney protection during sepsis.
Assuntos
Injúria Renal Aguda , Ferroptose , Proteínas Proto-Oncogênicas c-pim-1 , Sepse , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Animais , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/genética , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/biossíntese , Sepse/metabolismo , Sepse/complicações , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Humanos , Espécies Reativas de Oxigênio/metabolismo , Linhagem CelularRESUMO
PURPOSE OF REVIEW: Postoperative acute kidney injury (PO-AKI) is a common complication associated with increased morbidity and mortality. Despite its frequency, guidelines for the prevention of PO-AKI are relatively recent and still based on weak or contradictory evidence. This review aims to summarize large recent studies published in the past 2 years that have attempted to address these gaps. RECENT FINDINGS: While the POST-CABGDM and Stop-or-Not trials have provided additional evidence on the preoperative prescription of RAAS and SGLT2 inhibitors in selected surgical settings, future research must integrate preoperative risk profiling to personalize therapy. Likewise, although the POISE-3 trial seems to suggest that maintaining a mean arterial pressure of at least 60âmmHg is crucial in noncardiac surgery, it does not explore how targets might be personalized. In cardiac surgery, both the SIRAKI02 trial (i.e., extracorporeal blood purification membrane connected to the cardiopulmonary bypass) and the PROTECTION trial (i.e., intraoperative amino-acid infusion) demonstrated benefit only for mild AKI, raising questions about their mechanistic basis and clinical significance. SUMMARY: "Prevention is better than cure," a principle that holds particularly true for PO-AKI, a common complication that still lacks effective curative treatments. Although the recent abovementioned trials have yielded important findings, they concurrently underscore the significant obstacles in conducting clinical trials on PO-AKI and in formulating robust recommendations based on their outcomes.
Assuntos
Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias , Humanos , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/diagnóstico , Complicações Pós-Operatórias/prevenção & controle , Fatores de Risco , Ensaios Clínicos como Assunto , Resultado do Tratamento , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
BACKGROUND: Acute kidney injury (AKI) is a frequent complication following cardiac surgery involving cardiopulmonary bypass (CPB). This is partly attributable to crystalloid-based priming solutions causing both hemolysis and loss of oncotic pressure with tissue edema. While colloids like albumin and starches have not shown clear benefits, pilot studies using dextran-based priming reported improved oncotic pressure, reduced hemolysis, and lower levels of a renal injury marker, suggesting potential renal protective effects. OBJECTIVE: We hypothesized that a dextran-based priming solution can reduce the incidence of postoperative AKI in high-risk patients undergoing cardiac surgery with CPB. METHODS: In this randomized, controlled, double-blinded, multicenter trial, adult patients with a calculated postoperative AKI risk of ≥ 50% were assigned to receive either a dextran or a crystalloid-based CPB priming solution. The primary outcome was the incidence of AKI within 96 h postoperatively. Secondary outcomes included perioperative hemolysis, net fluid balance, and the need for postoperative renal replacement therapy. RESULTS: The trial was terminated early due to slow enrolment, with 101 of the planned 366 patients recruited. A total of 92 patients were included in the final analysis (43 in the dextran group, 49 in the control group). Postoperative AKI occurred in 81% and 53% of patients in the dextran and control groups, respectively (risk ratio 1.53, 95% confidence interval 1.15-2.06, p = 0.004). The dextran group demonstrated lower intraoperative hemolysis and a more favorable net fluid balance. Postoperative renal replacement therapy was required in 7% of the dextran group and 4% of the control group (p = 0.66). No significant differences in adverse events were observed between the groups. CONCLUSION: In high-risk patients undergoing cardiac surgery with CPB, the use of a dextran-based priming solution was associated with a significantly increased risk of postoperative AKI. EDITORIAL COMMENT: This randomized multicenter trial compared dextran to a crystalloid-based priming solution during cardiopulmonary bypass in participants with elevated risk of acute kidney injury. While the trial had to be terminated due to slow enrolment after about a third of planned cases were included, acute kidney injury was significantly more common in the dextran group, contrary to the primary hypothesis of the study. The study highlights the complexity and logistical challenges of conducting randomized treatment protocols for cardiopulmonary bypass, but at the same time highlights the importance of conducting such studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04293744.
Assuntos
Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Soluções Cristaloides , Dextranos , Complicações Pós-Operatórias , Humanos , Dextranos/uso terapêutico , Dextranos/efeitos adversos , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/epidemiologia , Masculino , Feminino , Idoso , Método Duplo-Cego , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Cardíacos/métodos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Ponte Cardiopulmonar , Soluções Isotônicas/uso terapêutico , Hemólise/efeitos dos fármacos , Substitutos do PlasmaRESUMO
BACKGROUND: Postoperative acute kidney injury (AKI) worsens surgical outcomes. Previous studies have observed an age- and sex-dependent effect on postoperative AKI rates. The objective of our study was to determine whether preoperative exposure to male or female sex hormone therapies modified AKI risk after both noncardiac and cardiac surgery. We hypothesized that women older than 55 years on estrogen/progesterone replacement therapy and men on antiandrogen therapy would have lower odds of postoperative AKI compared to counterparts not receiving sex hormone therapies. METHODS: We conducted a retrospective cohort study, using data from Duke University Medical Center from 2013 to 2023. The study included women older than 55 years and men older than 18 years undergoing surgery. Exclusions included patients with missing creatinine values, patients with chronic kidney disease stage 5 (CKD5), transplant cases, and minor cases. The primary exposure was preoperative utilization of exogenous sex hormones, and the primary outcome was the development of postoperative AKI, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria. Multivariable logistic regression was used to examine the association of preoperative sex hormones with postoperative AKI. RESULTS: There were 82,557 patients in the cohort, with 68,471 undergoing noncardiac surgery and 14,086 undergoing cardiac surgery. Among men undergoing noncardiac surgery, exposure to antiandrogens was associated with lower odds of postoperative AKI (0.83, 95% confidence interval [CI], 0.72-0.96, P < .01). Among women undergoing noncardiac surgery, preoperative exposure to vaginal estrogen was associated with lower odds of postoperative AKI (adjusted odds ratio [OR], 0.61, 95% CI, 0.47-0.79, P < .001). Neither male nor female sex hormone exposures were associated with AKI risk after cardiac surgery. CONCLUSIONS: Preoperative antiandrogen therapy in men and vaginal estrogen therapy in women older than 55 years were associated with reduced odds of postoperative AKI after noncardiac surgery. Our findings provide correlative evidence that sex hormones might modify postoperative AKI outcomes, while revealing complexity in drug and patient selection.
Assuntos
Injúria Renal Aguda , Antagonistas de Androgênios , Hormônios Esteroides Gonadais , Complicações Pós-Operatórias , Cuidados Pré-Operatórios , Humanos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/etiologia , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/diagnóstico , Medição de Risco , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/administração & dosagem , Cuidados Pré-Operatórios/métodos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Fatores Sexuais , Estrogênios/administração & dosagem , Hormônios Esteroides Gonadais/administração & dosagem , Hormônios Esteroides Gonadais/efeitos adversosRESUMO
BACKGROUND: Acute kidney injury (AKI) is a common complication after coronary artery bypass grafting (CABG), associated with adverse short- and long-term outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce occurrence of AKI in several populations, yet their perioperative effects in patients undergoing CABG are unknown. METHODS: We conducted a retrospective study at the Department of Cardiac Surgery, Medical University of Graz (2020-2024) to evaluate the impact of preoperative SGLT2i use on cardiac surgery-associated AKI in adults undergoing urgent or emergent isolated coronary artery bypass grafting in patients with an indication for SGLT2i therapy (type 2 diabetes mellitus, heart failure with reduced ejection fraction, or chronic kidney disease). Patients with preoperative dialysis, sepsis, reoperation, mechanical circulatory support or missing laboratory data were excluded. Exposure was defined as SGLT2i use within two weeks before surgery, and the primary outcome was cardiac surgery-associated AKI (CSA-AKI) according to KDIGO criteria. Secondary outcomes included kidney replacement therapy, ICU length of stay, 30-day mortality and postoperative diabetic ketoacidosis. Causal effects were estimated using entropy balancing. Results were reported as weighted risk differences, risk ratios, and adjusted mean differences, with time-to-event outcomes analyzed via weighted Cox models and Kaplan-Meier estimates. RESULTS: Among 484 patients, 135 were on SGLT2i. CSA-AKI occurred in 23.0 % of SGLT2i users vs. 28.1 % of non-users (risk ratio of 0.63 [95 % CI 0.44-0.91; p = 0.014]). The association was pronounced in patients with heart failure with reduced ejection fraction and those with high EuroSCORE II. No differences were observed in other secondary endpoints and no cases of postoperative diabetic ketoacidosis occurred. CONCLUSION: Preoperative SGLT2i use was associated with a significantly lower risk of CSA-AKI in patients undergoing urgent or emergent CABG. These findings need to be confirmed in prospective multicenter trials but underline the favorable safety profile of this medication.
Assuntos
Injúria Renal Aguda , Ponte de Artéria Coronária , Complicações Pós-Operatórias , Cuidados Pré-Operatórios , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Masculino , Estudos Retrospectivos , Feminino , Idoso , Pessoa de Meia-Idade , Ponte de Artéria Coronária/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Cuidados Pré-Operatórios/métodos , Tempo de Internação/estatística & dados numéricos , Insuficiência Cardíaca/complicações , Fatores de Risco , Cetoacidose Diabética/epidemiologia , Terapia de Substituição Renal/estatística & dados numéricosRESUMO
BACKGROUND: Acute kidney injury (AKI) is a common and serious complication of cisplatin chemotherapy in cancer patients, with no effective treatment currently available. Oxidative stress and renal tubular damage are key contributors to its pathogenesis. This study aimed to investigate the antioxidant and renoprotective effects of black garlic water extract in a cisplatin-induced AKI mouse model. METHODS: Mice were randomly divided into six groups: Control, Cisplatin only (20 mg/kg), black garlic extract pretreatment at 50 or 100 mg/kg followed by cisplatin (Cis + B50, Cis + B100), amifostine pretreatment (200 mg/kg) as positive control (Cis + A200), and black garlic extract only (100 mg/kg). Black garlic extract was characterized for its sulfur compound content and antioxidant potential. RESULTS: Black garlic contained significantly higher levels of S-allyl-L-cysteine (191.2 ± 32.87 µg/g) than raw garlic (20.7 ± 0.8 µg/g) and effectively delayed low-density lipoprotein oxidation. Pretreatment with black garlic extract reduced cisplatin-induced weight loss, renal index elevation, and tubular damage. Antioxidant enzyme activities, including superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, were significantly increased in the Cis + B100 and Cis + B50 groups. CONCLUSIONS: Black garlic extract confers protection against cisplatin-induced AKI by enhancing renal antioxidant defenses and mitigating oxidative stress-related damage. These findings support its potential as a complementary approach for preventing nephrotoxicity during cisplatin therapy.
Assuntos
Injúria Renal Aguda , Antioxidantes , Cisplatino , Alho , Extratos Vegetais , Animais , Cisplatino/efeitos adversos , Alho/química , Extratos Vegetais/farmacologia , Camundongos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Antioxidantes/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Substâncias Protetoras/farmacologiaRESUMO
BACKGROUND: Contrast-induced nephropathy (CIN) is a serious complication in patients undergoing cardiac interventions, especially in patients with chronic kidney disease. This study aims to assess the efficacy of Nicorandil in CIN reduction and its impact on renal function outcomes. METHODS: A comprehensive search was conducted from inception to September, 2024 across four databases. Randomized controlled trials (RCTs) assessing the efficacy of Nicorandil for patients undergoing coronary procedures were included. RESULTS: Based on analysis of 11 clinical trials involving 2837 patients, Nicorandil significantly reduced the incidence of CIN compared to control group (RR = 0.37, 95%CI [0.27 to 0.49], P < 0.001) without heterogeneity. Nicorandil group was superior to control group in reducing the rise in serum creatinine level at 24, 48 and 72 h (MD= -4.45 umol/L, 95%CI [-7.94 to -0.97], P = 0.01), (MD= -5.57 umol/L, 95%CI [-8.95 to -2.20], P < 0.001) and (MD= -5.70 umol/L, 95%CI [-9.57 to -1.82], P = 0.004) respectively. However, there was no statistically significant difference between Nicorandil group and control group regarding estimated glomerular filtration rate (eGFR) measured at 24, 48 and 72 h (MD = 2.17, 95%CI [-2.03 to 6.37], P = 0.31), (MD = 1.89, 95%CI [-0.15 to 3.93], P = 0.17) and (MD = 2.26, 95%CI [-0.37 to 4.89], P = 0.09) respectively. Nicorandil showed no statistically significant difference between both groups regarding any major adverse event, including stroke, myocardial infarction, conversion to emergency Percutaneous Coronary Intervention (PCI), or urgent need for dialysis. CONCLUSION: Nicorandil had an effective role in reducing the incidence of CIN, lower rise in creatinine, and a good safety profile in patients undergoing coronary interventions. CLINICAL TRIAL NUMBER: Not applicable.
Assuntos
Injúria Renal Aguda , Meios de Contraste , Nefropatias , Nicorandil , Intervenção Coronária Percutânea , Humanos , Nicorandil/uso terapêutico , Nicorandil/farmacologia , Meios de Contraste/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Taxa de Filtração Glomerular/efeitos dos fármacos , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/induzido quimicamente , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controleRESUMO
OBJECTIVES: This study aimed to assess whether continuous furosemide administration during cardiopulmonary bypass (CPB) in minimally invasive cardiac surgery (MICS) reduces the incidence of cardiac surgery-associated acute kidney injury (AKI). METHODS: A total of 100 patients undergoing MICS with CPB were randomly assigned to receive either continuous furosemide infusion or no continuous furosemide during CPB. The primary endpoint was the incidence of AKI. Secondary endpoints included the cardiac surgery-associated neutrophil gelatinase-associated lipocalin (CSA-NGAL) score, urine output within 12 h postoperatively, postoperative furosemide dose requirements, red blood cell transfusion volume, PaO2/FiO2 ratio, duration of mechanical ventilation, length of stay in the intensive care unit (ICU) and hospital, and in-hospital mortality. RESULTS: AKI occurred in 8 patients (16%) in the continuous furosemide group and in 6 patients (12%) in the non-continuous group (relative risk, 0.72; 95% CI, 0.23-2.23). Among the secondary endpoints, urine output within the first 3 h postoperatively and the PaO2/FiO2 ratio were significantly higher in the continuous furosemide group. However, subgroup analyses revealed no significant differences between the two groups. CONCLUSIONS: Continuous furosemide administration during CPB did not effectively reduce the incidence of AKI. However, it was associated with a significant increase in postoperative urine output and an improvement in the PaO2/FiO2 ratio.
Assuntos
Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Ponte Cardiopulmonar , Furosemida , Procedimentos Cirúrgicos Minimamente Invasivos , Complicações Pós-Operatórias , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/epidemiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ponte Cardiopulmonar/efeitos adversos , Diuréticos/administração & dosagem , Furosemida/administração & dosagem , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Resultado do TratamentoRESUMO
Drug-induced nephrotoxicity poses a significant clinical challenge that limits the therapeutic application of various critical medications, such as antibiotics, chemotherapeutic agents, and nonsteroidal anti-inflammatory drugs. It accounts for 19%-26% of Acute Kidney Injury cases and may advance to chronic kidney disease if not promptly addressed. The kidneys are particularly vulnerable to injury caused by xenobiotics due to their role in drug metabolism and excretion. The mechanisms of nephrotoxicity include oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, crystal nephropathy, and vascular injury, all of which impair renal structure and function. Contemporary therapeutic approaches are primarily confined to supportive care and depend on traditional renal biomarkers, including serum creatinine and blood urea nitrogen, which exhibit insufficient sensitivity for early detection. Thus, there is an increasing demand for efficacious nephroprotective measures and dependable diagnostic indicators. Phytochemicals have garnered considerable interest due to their renoprotective capabilities, which are attributed to their antioxidant, anti-inflammatory, and anti-apoptotic properties. Compounds like quercetin, silymarin, resveratrol, and curcumin have shown encouraging results in experimental models of nephrotoxicity. Furthermore, innovative biomarkers such as NGAL, KIM-1, IL-18, and cystatin C enhance diagnostic accuracy for early renal injury. This narrative review examines nephroprotective phytochemicals, novel biomarkers, and nanotechnology-based delivery methods to improve therapeutic efficacy.
Assuntos
Injúria Renal Aguda , Produtos Biológicos , Substâncias Protetoras , Humanos , Animais , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Produtos Biológicos/uso terapêutico , Produtos Biológicos/farmacologia , Substâncias Protetoras/uso terapêutico , Substâncias Protetoras/farmacologia , Biomarcadores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/uso terapêuticoRESUMO
BACKGROUND: High-dose methotrexate (HD-MTX) is used to treat various malignancies in adults and children. However, HD-MTX can lead to severe toxicity, which can require the use of glucarpidase, a recombinant enzyme that rapidly reduces MTX concentrations. Current guidelines, approximated from both adult and pediatric studies and established prescribing indications, do not provide detailed recommendations tailored to children to guide glucarpidase use in clinical practice. METHODS: The current study used modified Delphi methodology to develop expert consensus recommendations for the safe administration of HD-MTX, and management of delayed MTX elimination (DME) and/or HD-MTX-induced acute kidney injury (AKI) in children with cancer. Consensus statements were developed by a multidisciplinary Scientific Board of eight Italian physicians, then circulated to an expert panel of 20 pediatric hemato-oncologists for voting. Expert panel members rated their level of agreement using a 5-point Likert scale; consensus was reached if ≥66.6 % of respondents indicated that they "agreed" or "strongly agreed" with each statement. RESULTS: Of the 46 statements, 40 achieved consensus. Clinicians agreed that harmonized glucarpidase treatment guidelines are needed. Careful risk assessment performed by a multidisciplinary team should be established to ensure correct management of pediatric patients on relevant factors such as concomitant medications, monitoring of plasma MTX levels for DME, collection and processing of blood samples, monitoring of renal function for AKI prevention or management, and prompt availability of glucarpidase. CONCLUSIONS: These expert consensus recommendations will help pediatric hemato-oncologists to better deal with the various aspects associated with managing HD-MTX in general and with DME or AKI in particular.
Assuntos
Injúria Renal Aguda , Antimetabólitos Antineoplásicos , Metotrexato , Neoplasias , gama-Glutamil Hidrolase , Humanos , Metotrexato/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , gama-Glutamil Hidrolase/uso terapêutico , gama-Glutamil Hidrolase/administração & dosagem , Criança , Consenso , Neoplasias/tratamento farmacológico , Técnica Delphi , Itália , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Guias de Prática Clínica como Assunto , Proteínas RecombinantesRESUMO
INTRODUCTION: Peripheral arterial disease (PAD) commonly coexists with chronic kidney disease (CKD). Patients with symptomatic PAD often require endovascular revascularisation to relieve pain or salvage limbs. However, the iodinated intra-arterial contrast routinely used in these procedures is nephrotoxic, placing patients with CKD at increased risk of acute kidney injury (AKI) and long-term renal decline. Carbon dioxide (CO2) delivered via automated injection is a potential alternative imaging contrast medium. This trial will evaluate whether using CO2 instead of iodinated contrast reduces the risk of AKI and short-term renal function decline in this high-risk group. METHODS AND ANALYSIS: This is a multicentre, open-label, prospective randomised controlled trial across six secondary-care National Health Service (NHS) vascular surgery centres. A total of 174 patients with PAD and CKD undergoing endovascular intervention will be randomised 1:1 to receive iodinated contrast (standard of care) or CO2 via automated injector (Angiodroid). All perioperative care will follow local NHS protocols.The primary outcome is log serum creatinine at 2, 30 and 90 days postprocedure. Key secondary outcomes include: incidence and severity of AKI within 48 hours postprocedure, major adverse kidney events (death, dialysis or >25% estimated glomerular filtration rate decline) by 90 days, inpatient length of stay, procedural pain, quality of life, procedural success, reinterventions, acceptability and feasibility (patient/practitioner questionnaires) of using CO2, and cost-effectiveness (healthcare resource use analysis). A mixed-methods process evaluation will be undertaken with patients and clinicians. ETHICS AND DISSEMINATION: The trial has been approved by an NHS ethical review committee (24/WA/0332) and patients have been involved in trial design. Findings will be disseminated to participants, clinicians and the wider public through patient groups, lay summaries, social media, conferences, peer-reviewed journals and NHS policy channels. TRIAL REGISTRATION NUMBER: ISRCTN23564393.
Assuntos
Injúria Renal Aguda , Dióxido de Carbono , Meios de Contraste , Procedimentos Endovasculares , Doença Arterial Periférica , Insuficiência Renal Crônica , Humanos , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/induzido quimicamente , Dióxido de Carbono/administração & dosagem , Dióxido de Carbono/uso terapêutico , Meios de Contraste/efeitos adversos , Meios de Contraste/administração & dosagem , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , Doença Arterial Periférica/complicações , Doença Arterial Periférica/cirurgia , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Procedimentos Endovasculares/efeitos adversosRESUMO
BACKGROUND: Acute kidney injury (AKI) is a common and important complication of major surgery, yet recommended preventive care is rarely administered. We used urinary biomarkers to identify patients at high risk of AKI and implemented a preventive care strategy to reduce AKI within 72 h after major surgery. METHODS: BigpAK-2 was a multicentre randomised clinical trial done in 34 hospitals in Europe. Patients (aged ≥18 years) undergoing major surgery at high risk for AKI identified by predefined clinical risk factors and tubular stress biomarkers were randomly assigned to usual care or a preventive care strategy as per recommendations by the Kidney Disease Improving Global Outcome guidelines: advanced hemodynamic monitoring, optimisation of volume status and haemodynamics, avoidance of nephrotoxic drugs and radiocontrast agents, and prevention of hyperglycaemia. The primary outcome was the occurrence of moderate or severe AKI within 72 h after surgery, assessed in the intention-to-treat population. Safety was assessed by comparing rates of adverse events between groups. This trial is registered with ClinicalTrials.gov, NCT04647396. FINDINGS: From Nov 25, 2020, to June 21, 2024, 7873 patients were screened and 1180 (15·0%) were randomly assigned (589 [49·9%] to the intervention group and 591 [50·1%] to the control group). Among the 1176 patients available for the primary endpoint analysis, moderate or severe AKI occurred in 84 (14·4%) patients in the intervention group and in 131 (22·3%) patients in the control group (odds ratio 0·57 [95% CI 0·40-0·79; p=0·0002; number needed to treat 12 [7-33]). There were no differences in adverse events. The most common adverse events were atrial fibrillation (50 [8·8%] in the intervention group vs 56 (9·7%) in the control group), hemodynamically relevant arrhythmias (41 [7·2%] in the intervention group vs 50 [8·6%] in the control group), significant bleeding or haemorrhage (34 [6·0%] in the intervention group vs 31 [5·3%] in the control group), and unplanned return to the operating room (29 [5·1%] in the intervention vs 38 [6·5%] in the control group). INTERPRETATION: Among adults at high risk for AKI undergoing major surgery, a preventive care strategy consisting of supportive measures and avoidance of nephrotoxins significantly reduced the occurrence of moderate or severe AKI without increasing adverse events. FUNDING: BioMérieux.
Assuntos
Injúria Renal Aguda , Complicações Pós-Operatórias , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/urina , Biomarcadores/urina , Europa (Continente) , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: Cisplatin causes nephrotoxicity in approximately 30% of patients. Mannitol has been proposed as a nephroprotective agent, yet the clinical evidence remains inconclusive. METHODS: We systematically searched PubMed, EMBASE, and the Cochrane Library through December 2024 for randomized controlled trials (RCTs) evaluating mannitol versus control interventions for prevention of cisplatin-induced nephrotoxicity. The primary outcome was acute kidney injury (AKI), standardized across CTCAE, AKIN, and RIFLE systems. Given heterogeneous comparators, analyses were stratified by control type without cross-comparator pooling. Odds ratios (ORs) were used for AKI; risk differences (RDs) were used for adverse events. Pooled estimates were generated only when ≥ 5 trials were available per stratum. RESULTS: Nine RCTs (357 participants) were included. For severe AKI (grade ≥ 2), three small trials (n = 164) were available. Two placebo-controlled studies showed lower AKI risk with mannitol (absolute reductions ~ 15-20%), while one furosemide-controlled study showed no clear difference. These preliminary observations require confirmation in larger trials. For overall AKI (grade ≥ 1; six trials, n = 297), results were inconsistent across studies. Renal function outcomes were heterogeneous: one placebo-controlled trial favored mannitol, one hydration-controlled trial favored control, and a furosemide-controlled trial showed minimal difference. Adverse events were sparsely reported: no consistent differences were seen for electrolyte or hematological toxicities, while several studies suggested modest reductions in nausea/vomiting and a possible increase in diarrhea. CONCLUSIONS: Based on only three small trials (n = 164), preliminary trends suggest mannitol might reduce severe AKI in cisplatin-treated patients, particularly versus placebo. However, this evidence is insufficient to support clinical implementation. The observed protective trend should be considered hypothesis-generating rather than definitive. Effects on overall AKI, renal function, and toxicities remain inconclusive. Larger, well-designed RCTs with adequate statistical power are urgently needed before mannitol can be recommended for routine nephroprotection in clinical practice.
Assuntos
Injúria Renal Aguda , Antineoplásicos , Cisplatino , Manitol , Humanos , Manitol/uso terapêutico , Manitol/administração & dosagem , Manitol/farmacologia , Cisplatino/efeitos adversos , Cisplatino/administração & dosagem , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagemRESUMO
Acute kidney injury (AKI) is a serious complication following on-pump cardiac surgery. Choosing the cardioplegic solution with the most appropriate myocardial protection and lowest grade of AKI could improve patient outcome. We compared the crystalloid histidine-tryptophan-ketoglutarate (HTK) solution and a Jonosteril®-based DelNido blood cardioplegic solution regarding AKI in a porcine model. Therefore, German landrace pigs (50-60kg) underwent median sternotomy, cardiopulmonary bypass at 34 °C and 90 min of cardiac arrest. Animals were randomized to single-shot cardioplegia of HTK (n = 9) or DelNido (n = 9) cardioplegic solution followed by 120 min of reperfusion. This study demonstrated that DelNido cardioplegia induced less hemoglobin (p < 0.01) and electrolyte imbalances of blood sodium, chloride, and calcium levels (all p < 0.01) after aortic cross-clamp than HTK cardioplegia. Renal biopsy analysis after 120 min of reperfusion revealed that histomorphological changes, oxidative and nitrosative stress as well as the cytosolic release of pro-apoptotic molecules in different nephron structures were comparable in HTK and DelNido cardioplegia. The comparability of both cardioplegic solutions was supported by measurements of the urine AKI biomarkers of L-type fatty acid-binding protein 1 (p = 0.38), neutrophil gelatinase-associated lipocalin (p = 0.34), and cystatin C (p = 0.46), which could not detect any differences between the groups. This large animal study demonstrated superiority of the DelNido solution regarding hemoglobin and blood electrolyte concentrations, but comparability of the HTK and DelNido blood cardioplegic solution regarding AKI for surgical interventions requiring cardiac arrest of 90 min. Patients with a higher risk for adverse events, due to either complex, prolonged surgery or a multitude of comorbidities, could especially benefit from the more physiological arrest conditions with DelNido cardioplegia.
Assuntos
Injúria Renal Aguda , Soluções Cardioplégicas , Parada Cardíaca Induzida , Parada Cardíaca , Animais , Soluções Cardioplégicas/efeitos adversos , Soluções Cardioplégicas/farmacologia , Suínos , Parada Cardíaca/terapia , Parada Cardíaca Induzida/métodos , Parada Cardíaca Induzida/efeitos adversos , Procaína , Manitol/farmacologia , Cloreto de Potássio , Modelos Animais de Doenças , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/patologia , Ponte Cardiopulmonar/efeitos adversos , Glucose/farmacologia , Rim/patologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Bicarbonato de Sódio , Lidocaína , Sulfato de Magnésio , Eletrólitos , SoluçõesRESUMO
Receptor-interacting protein 1 (RIP1) is a critical regulator of inflammatory cell death induced by diverse stimuli including TNF family ligands and ischemic injury. As such, the inhibition of RIP1 with small molecule kinase inhibitors is predicted to ameliorate tissue damage and associated inflammation. A novel ketone class of RIP1 inhibitors was identified via a high-throughput screen followed by structure-based scaffold hopping. Subsequent optimization yielded clinical molecule GDC-8264 (compound 19), which has excellent target selectivity and druglike attributes for once-daily oral dosing. GDC-8264 is currently being tested in a Phase 2 trial for the prevention of cardiac surgery-associated acute kidney injury (CSA-AKI) in hopes of providing benefit for patients requiring cardio-pulmonary bypass at medium to high risk of developing CSA-AKI.