Antioxidant Roles of SGLT2 Inhibitors in the Kidney

Diabetic kidney disease; Mitochondrial dysfunction; Oxidative stressMalaltia renal diabètica; Disfunció mitocondrial; Estrès oxidatiuEnfermedad renal diabética; Disfunción mitocondrial; Estrés oxidativoThe reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated thanks to serial reduction-oxidation enzymatic reactions. These reactions happen in every cell and produce radical oxidants that can be mainly classified into reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS modulate cell-signaling pathways and cellular processes fundamental to normal cell function. However, overproduction of oxidative species can lead to oxidative stress (OS) that is pathological. Oxidative stress is a main contributor to diabetic kidney disease (DKD) onset. In the kidney, the proximal tubular cells require a high energy supply to reabsorb proteins, metabolites, ions, and water. In a diabetic milieu, glucose-induced toxicity promotes oxidative stress and mitochondrial dysfunction, impairing tubular function. Increased glucose level in urine and ROS enhance the activity of sodium/glucose co-transporter type 2 (SGLT2), which in turn exacerbates OS. SGLT2 inhibitors have demonstrated clear cardiovascular benefits in DKD which may be in part ascribed to the generation of a beneficial equilibrium between oxidant and antioxidant mechanisms.The authors are current recipients of grants from FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII (PI17/00257 and RICORS RD21/0005/0016), and Fundació la Marató de TV3 (421/C/2020, 759/U/2020 and 215/C/2021)

The Impact of Age on Mortality in Chronic Haemodialysis Population with COVID-19

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hemodiàlisi; MortalitatCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hemodiálisis; MortalidadCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Haemodialysis; MortalityAge and chronic kidney disease have been described as mortality risk factors for coronavirus disease 2019 (COVID-19). Currently, an important percentage of patients in haemodialysis are elderly. Herein, we investigated the impact of age on mortality among haemodialysis patients with COVID-19. Data was obtained from the Spanish COVID-19 chronic kidney disease (CKD) Working Group Registry. From 18 March 2020 to 27 August 2020, 930 patients on haemodialysis affected by COVID-19 were included in the Registry. A total of 254 patients were under 65 years old and 676 were 65 years or older (elderly group). Mortality was 25.1% higher (95% CI: 22.2–28.0%) in the elderly as compared to the non-elderly group. Death from COVID-19 was increased 6.2-fold in haemodialysis patients as compared to the mortality in the general population in a similar time frame. In the multivariate Cox regression analysis, age (hazard ratio (HR) 1.59, 95% CI: 1.31–1.93), dyspnea at presentation (HR 1.51, 95% CI: 1.11–2.04), pneumonia (HR 1.74, 95% CI: 1.10–2.73) and admission to hospital (HR 4.00, 95% CI: 1.83–8.70) were identified as independent mortality risk factors in the elderly haemodialysis population. Treatment with glucocorticoids reduced the risk of death (HR 0.68, 95% CI: 0.48–0.96). In conclusion, mortality is dramatically increased in elderly haemodialysis patients with COVID-19. Our results suggest that this high risk population should be prioritized in terms of protection and vaccination.The authors are current recipients of FONDOS DE INVESTIGACIÓN SANITARIA—FEDER (ISCIII) PI17/00257, REDINREN RD16/0009/0030, RD/16/0009/0026, and EIN2020-112338

Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice

Chronic kidney disease; Diabetic nephropathy; Endothelin receptor antagonistsEnfermedad renal crónica; Nefropatía diabética; Antagonistas de los receptores de endotelinaMalaltia renal crònica; Nefropatia diabètica; Antagonistes dels receptors d'endotelinaTreatments with sodium–glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin–angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.The following study was funded with Spanish government grants (FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII (PI17/00257 and RICORS RD21/0005/0016)) and with financial support from Boehringer Ingelheim Pharma GmbH. The funders had no role in study design, analyses, interpretation of the data, drafting of the manuscript, or decision to submit the manuscript for publication. The funders were allowed to comment on the manuscript prior to publication; however, the final wording was at the full discretion of the investigators

Asymptomatic Hyperuricemia Promotes Recovery from Ischemic Organ Injury by Modulating the Phenotype of Macrophages

Acute organ injury, such as acute kidney injury (AKI) and disease (AKD), are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function but the impact of asymptomatic HU on the different phases of AKI/AKD is incompletely understood. We hypothesized that asymptomatic HU would attenuate AKD because soluble, in contrast to crystalline, uric acid (sUA) can attenuate sterile inflammation. In vitro, 10 mg/dL sUA decreased reactive oxygen species and interleukin-6 production in macrophages, while enhancing fatty acid oxidation as compared with a physiological concentration of 5 mg/dL sUA or medium. In transgenic mice, asymptomatic HU of 7–10 mg/dL did not affect post-ischemic AKI/AKD but accelerated the recovery of kidney excretory function on day 14. Improved functional outcome was associated with better tubular integrity, less peritubular inflammation, and interstitial fibrosis. Mechanistic studies suggested that HU shifted macrophage polarization towards an anti-inflammatory M2-like phenotype characterized by expression of anti-oxidative and metabolic genes as compared with post-ischemic AKI-chronic kidney disease transition in mice without HU. Our data imply that asymptomatic HU acts as anti-oxidant on macrophages and tubular epithelial cells, which endorses the recovery of kidney function and structure upon AKI

The Impact of Age on Mortality in Chronic Haemodialysis Popu-Lation with COVID-19.

Age and chronic kidney disease have been described as mortality risk factors for coronavirus disease 2019 (COVID-19). Currently, an important percentage of patients in haemodialysis are elderly. Herein, we investigated the impact of age on mortality among haemodialysis patients with COVID-19. Data was obtained from the Spanish COVID-19 chronic kidney disease (CKD) Working Group Registry. From 18 March 2020 to 27 August 2020, 930 patients on haemodialysis affected by COVID-19 were included in the Registry. A total of 254 patients were under 65 years old and 676 were 65 years or older (elderly group). Mortality was 25.1% higher (95% CI: 22.2-28.0%) in the elderly as compared to the non-elderly group. Death from COVID-19 was increased 6.2-fold in haemodialysis patients as compared to the mortality in the general population in a similar time frame. In the multivariate Cox regression analysis, age (hazard ratio (HR) 1.59, 95% CI: 1.31-1.93), dyspnea at presentation (HR 1.51, 95% CI: 1.11-2.04), pneumonia (HR 1.74, 95% CI: 1.10-2.73) and admission to hospital (HR 4.00, 95% CI: 1.83-8.70) were identified as independent mortality risk factors in the elderly haemodialysis population. Treatment with glucocorticoids reduced the risk of death (HR 0.68, 95% CI: 0.48-0.96). In conclusion, mortality is dramatically increased in elderly haemodialysis patients with COVID-19. Our results suggest that this high risk population should be prioritized in terms of protection and vaccination

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field