Open repair for thoracoabdominal aortic aneurysms precipitated by chronic aortic dissection

Chronic dissection of the thoracoabdominal aorta may require surgical repair for aneurysm, malperfusion, or rupture. Endovascular repair is made difficult by a noncompliant dissection septum, visceral vessels arising from different lumens, and the common use of diseased aortic landing zones. Thus, open repair remains the gold standard in terms of favorable outcomes and durability. During thoracoabdominal aortic repair, we use a multimodal strategy to prevent spinal cord and visceral or renal artery ischemia; key modalities include cerebrospinal fluid drainage, left heart bypass with and without visceral protection, cold renal protection, and aggressive reimplantation of intercostal or lumbar arteries. Patients with chronic dissection require lifelong surveillance, as there is a significant risk for subsequent intervention on unrepaired aortic segments.

Protective Effects of Eicosapentaenoic Acid on the Glomerular Endothelium via Inhibition of EndMT in Diabetes

Diabetes-induced endothelial pathologies are hypothesized to lead to the progression of diabetic kidney disease (DKD). The endothelial to mesenchymal transition (EndMT) possibly induces fibrosis, leading to glomerulosclerosis in the kidney. Furthermore, this could lead to albuminuria in diabetic nephropathy due to glomerular endothelial dysfunction. Eicosapentaenoic acid (EPA), purified from fish oil, decreases inflammatory cytokine levels in glomerulonephritis. Here, we aimed at finding whether ethyl eicosapentaenoate (EPA-E) exerts renal protective effects via EndMT inhibition. To find out whether EPA inhibits EndMT in vitro, the changes in CD31 expression were studied in cultured mouse endothelial cells. The addition of the conditioned medium from the adipocyte culture significantly decreased the protein levels of CD31, while the addition of EPA-E partially reversed this inhibition. Further, EndMT inhibition by EPA-E treatment might occur via the inhibition of the protein kinase Cβ (PKCβ)/transforming growth factor-β (TGF-β)/plasminogen activator inhibitor-1 (PAI-1) signaling and not via microRNAs. Streptozotocin-induced diabetic mice fed a high-fat diet (60% from fat) exhibited mesangial expansion and albuminuria. Induction of EPA-E ameliorated the mesangial expansion and decreased albuminuria without affecting blood pressure, triglyceride and free fatty acid levels, and intraperitoneal glucose. These findings suggest that EPA-E exerts renal protective effects on endothelial cells, by normalizing EndMT followed by the PKCβ/TGF-β/PAI-1 signaling. Thus, EPA-E has the potential for imparting renal protection by regulating EndMT in DKD.

Analysis of Risk Factors for Perioperative Acute Kidney Injury and Management Strategies

Acute kidney injury (AKI) is a serious clinical syndrome, and one of the common comorbidities in the perioperative period. AKI can lead to complications in surgical patients and is receiving increasing attention in clinical workup. In recent years, the analysis of perioperative risk factors has become more in-depth and detailed. In this review, the definition, diagnosis, and pathophysiological characteristics of perioperative AKI are reviewed, and the main risk factors for perioperative AKI are analyzed, including advanced age, gender, certain underlying diseases, impaired clinical status such as preoperative creatinine levels, and drugs that may impair renal function such as non-steroidal anti-inflammatory drugs (NASIDs), ACEI/ARB, and some antibiotics. Injectable contrast agents, some anesthetic drugs, specific surgical interventions, anemia, blood transfusions, hyperglycemia, and malnutrition are also highlighted. We also propose potential preventive and curative measures, including the inclusion of renal risk confirmation in the preoperative assessment, minimization of intraoperative renal toxin exposure, intraoperative management and hemodynamic optimization, remote ischemic preadaptation, glycemic control, and nutritional support. Among the management measures, we emphasize the need for careful perioperative clinical examination, timely detection and management of AKI complications, administration of dexmedetomidine for renal protection, and renal replacement therapy. We aim that this review can further increase clinicians' attention to perioperative AKI, early assessment and intervention to try to reduce the risk of AKI.

NanoGold Particles Suppresses 5-Flurouracil-Induced Renal Injury: An Insight into the Modulation of Nrf-2 and Its Downstream Targets, HO-1 and γ-GCS

The development of the field of nanotechnology has revolutionized various aspects in the fields of modern sciences. Nano-medicine is one of the primary fields for the application of nanotechnology techniques. The current study sheds light on the reno-protective impacts of gold nano-particles; nanoGold (AuNPs) against 5-flurouracil (5-FU)-induced renal toxicity. Indeed, the use of 5-FU has been associated with kidney injury which greatly curbs its therapeutic application. In the current study, 5-FU injection was associated with a significant escalation in the indices of renal injury, i.e., creatinine and urea. Alongside this, histopathological and ultra-histopathological changes confirmed the onset of renal injury. Both gene and/or protein expression of nuclear factor erythroid 2–related factor 2 (Nrf-2) and downstream antioxidant enzymes revealed consistent paralleled anomalies. AuNPs administration induced a significant renal protection on functional, biochemical, and structural levels. Renal expression of the major sensor of the cellular oxidative status Nrf-2 escalated with a paralleled reduction in the renal expression of the other contributor to this axis, known as Kelch-like ECH-associated protein 1 (Keap-1). On the level of the effector downstream targets, heme oxygenase 1 (HO-1) and gamma-glutamylcysteine synthetase (γ-GCS) AuNPs significantly restored their gene and protein expression. Additionally, combination of AuNPs with 5-FU showed better cytotoxic effect on MCF-7 cells compared to monotreatments. Thus, it can be inferred that AuNPs conferred reno-protective impact against 5-FU with an evident modulatory impact on Nrf-2/Keap-1 and its downstream effectors, HO-1 and γ-GCS, suggesting its potential use in 5-FU regimens to improve its therapeutic outcomes and minimize its underlying nephrotoxicity.

Therapeutic potential of resveratrol in diabetic nephropathy according to molecular signaling

Background: Diabetic nephropathy (DN) as a severe complication of diabetes mellitus (DM), is a crucial menace for human health and survival and remarkably elevates the healthcare systems’ costs. Therefore, it is worth noting to identify novel preventive and therapeutic strategies to alleviate the disease conditions. Resveratrol, as a well-defined anti-diabetic/ antioxidant agent has capabilities to counteract diabetic complications. It has been predicted that resveratrol will be a fantastic natural polyphenol for diabetes therapy in the next few years. Objective: Accordingly, the current review aims to depict the role of resveratrol in the regulation of different signaling pathways that are involved in the reactive oxygen species (ROS) production, inflammatory processes, autophagy, and mitochondrial dysfunction, as critical contributors to DN pathophysiology. Results: The pathogenesis of DN can be multifactorial; hyperglycemia is one of the prominent risk factors of DN development that is closely related to oxidative stress. Resveratrol, as a well-defined polyphenol, has various biological and medicinal properties, including anti-diabetic, anti-inflammatory, and anti-oxidative effects. Conclusion : Resveratrol prevents kidney damages that are caused by oxidative stress, enhances antioxidant capacity, and attenuates the inflammatory and fibrotic responses. For this reason, resveratrol is considered an interesting target in DN research due to its therapeutic possibilities during diabetic disorders and renal protection.

Non-classical Vitamin D Actions for Renal Protection

Chronic Kidney Disease (CKD), a disorder that affects 11% of the world's population, is characterized by an acceleration in skeletal, immune, renal, and cardiovascular aging that increases the risk of cardiovascular mortality by 10- to 20-fold, compared to that in individuals with normal renal function. For more than two decades, the progressive impairment in renal capacity to maintain normal circulating levels of the hormonal form of vitamin D (1,25-dihydroxyvitamin D or calcitriol) was considered the main contributor to the reduced survival of CKD patients. Accordingly, calcitriol administration was the treatment of choice to attenuate the progression of secondary hyperparathyroidism (SHPT) and its adverse impact on bone health and vascular calcification. The development of calcitriol analogs, designed to mitigate the resistance to calcitriol suppression of PTH associated with CKD progression, demonstrated survival benefits unrelated to the control of SHPT or skeletal health. The exhaustive search for the pathophysiology behind survival benefits associated with active vitamin D analogs has identified novel anti-inflammatory, anti-hypertensive, anti-aging actions of the vitamin D endocrine system. A major paradigm shift regarding the use of calcitriol or active vitamin D analogs to improve survival in CKD patients emerged upon demonstration of a high prevalence of vitamin D (not calcitriol) deficiency at all stages of CKD and, more significantly, that maintaining serum levels of the calcitriol precursor, 25(OH)vitamin D, above 23 ng/ml delayed CKD progression. The cause of vitamin D deficiency in CKD, however, is unclear since vitamin D bioactivation to 25(OH)D occurs mostly at the liver. Importantly, neither calcitriol nor its analogs can correct vitamin D deficiency. The goals of this chapter are to present our current understanding of the pathogenesis of vitamin D deficiency in CKD and of the causal link between defective vitamin D bioactivation to calcitriol and the onset of molecular pathways that promote CKD progression independently of the degree of SHPT. An understanding of these mechanisms will highlight the need for identification of novel sensitive biomarkers to assess the efficacy of interventions with vitamin D and/or calcitriol(analogs) to ameliorate CKD progression in a PTH-independent manner.

1266. Melatonin for Renal Protection of Patients Treated with Polymyxin B: A Double Blind Randomized Clinical Trial

Background Polymyxins are one of the last resort treatments for carbapenem resistant gram-negative infections. Nephrotoxicity is its main adverse effect and has been related to oxidative stress mechanisms. Melatonin was associated to reduction in polymyxins nephrotoxicity in animal studies. Our objective is to evaluate the effect of melatonin on renal protection of patients receiving polymyxin B. Methods We did a single center, double blind, randomized clinical trial (NCT03725267) of melatonin 30mg versus placebo for patients treated with polymyxin B from October 2018 to April 2021, in Porto Alegre, Brazil. Patients ≥18 years old, receiving polymyxin B for ≤48 hours, who accepted informed consent terms were included and excluded if intensive care unit (ICU) admission at enrollment, estimated glomerular rate estimated glomerular rate < 10ml/min, dialysis or previous melatonin use. Treatment with melatonin or placebo was randomized in blocks of 4 and maintained until the end of polymyxin B treatment of for a maximum of 14 days. Our main outcome was any level of nephrotoxicity by RIFLE score. Secondary outcomes were renal failure and need for dialysis. We estimated a sample size of 100 patients, however the study had to be stopped earlier due to recruitment restrictions imposed by the COVID-19 pandemic. Results Eighty-eight patients were randomized, 44 received melatonin and 44 received identical placebo pills. Patients had a mean age of 63.6±17.3 years, 60.2% were male, and had a median Charlson index of 5 (3-8.3). Most infections (79.5%) were microbiologically confirmed, having 68.6% Klebsiella sp isolated. Urinary tract accounted for47.7% of infection sites. Median time of polymyxin B therapy was 9.1±6.6 days. Combination therapy was prescribed for 89.8% of patients and 38.6% received at least another nephrotoxic drug. All variables were equally distributed among groups. Nephrotoxicity rates occurred in 23 of 44 (52.3%) in both groups, P=0.99. Patients who developed renal failure were 8(18.2%) vs 9(20.5%) and dialysis occurred in 4(9.1%) vs 5 (11.4%) of melatonin and placebo groups respectively. Conclusion Melatonin did not show a clinically significant renal protective effect in patients treated with polymyxin B. Disclosures Maria Helena Rigatto, MD, PhD, CNPq (Grant/Research Support) Diego Rodrigues Falci, MD, MSc, PhD, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)GSK (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)MSD (Speaker’s Bureau)Pfizer (Speaker’s Bureau)United Medical (Speaker’s Bureau, Other Financial or Material Support) Alexandre Zavascki, MD, PhD, Pfizer (Grant/Research Support)

Fisetin attenuates Renal Ischemia/Reperfusion Injury by improving mitochondrial quality, reducing apoptosis and oxidative stress

Purpose Renal ischemic reperfusion (IR) injury is one of the major source of mortality and morbidity associated with acute kidney injury (AKI). Several flavonoids have shown to be renal protective against many nephrotoxic agents causing AKI. Fisetin, a promising flavonoid, is effective in the management of septic AKI, expected to ameliorate renal IR injury. Present study aim to generate evidence for fisetin mediated renal protection against IR injury Methodology: Male wistar rats of 200-250 g subjected to IR protocol by performing bilateral clamping for 45 minutes and reperfusion for 24 hours. Fisetin administrated 30 minutes ( 20 mg/kg b.wt, ip) before the surgery. Renal injury was evaluated by measuring the biomarkers in plasma, examining the ultrastructure of kidney and analyzing the apoptotic changes. Oxidative stress, antioxidant levels and mitochondrial function were analysed in the renal tissue. Results Fisetin administration significantly reduced the renal damages associated with IR, by improving estimated glomerular filtration rate (eGFR: IR-0.35 ml/min, F_IR-9.03 ml/min), reducing plasma creatinine level (IR-2.2 mg/dl, F_IR-0.92 mg/dl) and lowering urinary albumin/creatinine ratio (IR- 6.09 F_IR-2.16), caspase activity, decreased DNA fragmentation and reduced tubular injury score (IR- 11 F_IR-6.5). At cellular level, fisetin significantly reduced renal oxidative stress and augmented the antioxidant levels. Fisetin found to preserve mitochondrial electron transport chain activities and improved the ATP producing capacity in the renal tissue upon IR injury. Conclusion fisetin pre-treatment attenuate renal IR injury by improving the renal function, reducing the renal injury mediated by apoptosis, reducing free radical release, and augmenting mitochondrial function.