Nicotinamide adenine dinucleotide (NAD + ) is a cosubstrate for several enzymes, including the sirtuin family of NAD + -dependent protein deacylases. Beneficial effects of increased NAD + levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits the proportion of ACMS able to undergo spontaneous cyclisation in the de novo NAD + synthesis pathway, controls cellular NAD + levels via an evolutionary conserved mechanism from C. elegans to the mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD + synthesis and SIRT1 activity, ultimately enhancing mitochondrial function. We furthermore characterized a series of potent and selective ACMSD inhibitors, which, given the restricted ACMSD expression in kidney and liver, are of high therapeutic interest to protect these tissues from injury. ACMSD hence is a key modulator of cellular NAD + levels, sirtuin activity, and mitochondrial homeostasis in kidney and liver.

Acute Kidney Injury (AKI) is strongly associated with adverse outcome and mortality independently of the cause of renal damage [1][2][3] . The mechanisms determining the deleterious systemic effects of AKI are poorly understood and specific interventions, including optimization of renal replacement therapy, had a marginal effect on AKI-associated mortality in clinical trials [4][5][6][7][8] . The kidney contributes to up to 40% of systemic glucose production by gluconeogenesis during fasting and stress conditions, mainly synthesized from lactate in the proximal tubule [9][10][11][12] , rendering this organ a major systemic lactate disposal 13 . Whether kidney gluconeogenesis is impaired during AKI and how this might influence systemic metabolism remains unknown. Here we demonstrate that glucose production and lactate clearance are impaired during human AKI using renal arteriovenous catheterization in patients. Using single cell transcriptomics in mice and RNA sequencing in human biopsies, we show that glycolytic and gluconeogenetic pathways are modified during AKI in the proximal tubule specifically, explaining the metabolic alterations. We further demonstrate that impaired renal gluconeogenesis and lactate clearance during AKI are major determinants of systemic glucose and lactate levels in critically ill patients. Most importantly, altered glucose metabolism in AKI emerged as a major determinant of AKIassociated mortality. Thiamine supplementation restored renal glucose metabolism and substantially reduced AKI-associated mortality in intensive care patients. This study highlights an unappreciated systemic role of renal glucose and lactate metabolism in stress conditions, delineates general mechanisms explaining AKI-associated mortality and introduces a potential therapeutic intervention for a highly prevalent clinical condition with limited therapeutic options.To study the impact of AKI on renal glucose and lactate metabolism, we performed renal vein catheterization in patients undergoing cardiac surgery with cardiopulmonary bypass and experiencing (n=18) or not (n=87) post-operative AKI (Supplementary Table 1). We found a switch from net renal lactate uptake to net renal lactate release in patients experiencing AKI (-0.01±0.03 mmol/min to 0.02±0.02 mmol/min, p<0.001). Moreover, AKI patients showed a decrease in the renal net glucose release (0.06±0.07 mmol/min to 0.01±0.04 mmol/min, p=0.016) compared to the control group (Fig. 1 a,b). This suggested a simultaneous reduction of gluconeogenesis and activation of glycolysis in the kidney in response to AKI. Glycosuria was unlikely to be involved since all patients had arterial glucose levels below the glycosuria threshold (5.4 ± 0.94 mmol/L). To further characterize this process, we compared kidney allograft biopsies obtained during transplantation shortly (49±16 minutes) after

Background Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI). Methods We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia–reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models. Results RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+  de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+  de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI. Conclusion Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models.

Glucose levels are tightly regulated at all times. Gluconeogenesis is the metabolic pathway dedicated to glucose synthesis from non-hexose precursors. Gluconeogenesis is critical for glucose homoeostasis, particularly during fasting or stress conditions. The renal contribution to systemic gluconeogenesis is increasingly recognized. During the post-absorptive phase, the kidney accounts for ∼40% of endogenous gluconeogenesis, occurring mainly in the kidney proximal tubule. The main substrate for renal gluconeogenesis is lactate and the process is regulated by insulin and cellular glucose levels, but also by acidosis and stress hormones. The kidney thus plays an important role in the maintenance of glucose and lactate homoeostasis during stress conditions. The impact of acute and chronic kidney disease and proximal tubular injury on gluconeogenesis is not well studied. Recent evidence shows that in both experimental and clinical acute kidney injury, impaired renal gluconeogenesis could significantly participate in systemic metabolic disturbance and thus alter the prognosis. This review summarizes the biochemistry of gluconeogenesis, the current knowledge of kidney gluconeogenesis, its modifications in kidney disease and the clinical relevance of this fundamental biological process in human biology.

Introduction Current knowledge on the use of extracorporeal membrane oxygenation (ECMO) in COVID‐19 remains limited to small series and registry data. In the present retrospective monocentric study, we report on our experience, our basic principles, and our results in establishing and managing ECMO in critically ill COVID‐19 patients. Methods A cohort study was conducted in patients with severe acute respiratory distress syndrome (ARDS) related to COVID‐19 pneumonia admitted to the ICU of the Geneva University Hospitals and supported by VV‐ECMO from March 14 to May 31. The VV‐ECMO implementation criteria were defined according to an institutional algorithm validated by the local crisis unit and the Swiss Society of Intensive Care Medicine. Results Out of 137 ARDS patients admitted to our ICU, 10 patients (age 57 ± 4 years, BMI 31.5 ± 5 kg/m2, and SAPS II score 56 ± 3) were put on VV‐ECMO. The mean duration of mechanical ventilation before ECMO and mean time under ECMO were 7 ± 3 days and 19 ± 11 days, respectively. The ICU and hospital length of stay were 26 ± 11 and 35 ± 10 days, respectively. The survival rate for patients on ECMO was 40%. The comparative analysis between survivors and non‐survivors highlighted that survivors had a significantly shorter mechanical ventilation duration before ECMO (4 ± 2 days vs. 9 ± 2 days, p = 0.01). All the patients who had more than 150 h of mechanical ventilation before the application of ECMO ultimately died. Conclusion The present results suggest that VV‐ECMO can be safely utilized in appropriately selected COVID‐19 patients with refractory hypoxemia. The main information for clinicians is that late VV‐ECMO therapy (i.e., beyond the seventh day of mechanical ventilation) seems futile.

Background There is recent evidence to show that patients suffering from acute kidney injury (AKI) are at increased risk of developing chronic kidney disease (CKD), despite the fact that surviving tubular epithelial cells have the capacity to fully regenerate renal tubules and restore renal function within days or weeks. The aim of the study was to investigate the impact of AKI on de novo CKD. Methods We conducted a retrospective population-based cohort study of patients initially free from CKD, who were scheduled for elective cardiac surgery with cardiopulmonary bypass, and who developed an episode of AKI from which they recovered. The study was conducted at two French university hospitals between 2005 and 2015. These individuals were matched with patients without AKI according to a propensity score for developing AKI. Results Among the 4791 patients meeting our inclusion criteria, 1375 (29%) developed AKI, and 685 fully recovered. Propensity score matching was used to balance the distribution of covariates between AKI and non-AKI control patients. Matching was possible for 597 cases. During follow-up, 34(5.7%) had reached a diagnosis of CKD, as opposed to 17 (2.8%) in the control population (HR=2.3; bootstrapping 95%CI= [1.9-2.6]). Conclusions Our data consolidate the recent paradigm shift, reporting AKI as a strong risk factor for the rapid development of CKD.

Objectives: To compare estimated glomerular filtration rate using classical static and kinetic equations with measured glomerular filtration rate assessed by plasma iohexol clearance in a mixed population of critical care patients. Patients: Unselected patients older than 18 and admitted to a general ICU. Design: Interventional prospective single center study. Intervention: Measurement of glomerular filtration rate by the plasma clearance of an IV single dose of iohexol and estimation of glomerular filtration rate with creatinine or cystatin C–based standard and kinetic equations as well as urinary creatinine clearance. Measurements and Main Results: Sixty-three patients were included with a median age of 66 years old. The median measured glomerular filtration rate was 51 mL/min/1.73 m2 (interquartile range, 19–85 mL/min/1.73 m2). All used equations displayed significant biases, high errors, and poor accuracy when compared with measured glomerular filtration rate, overestimating renal function. The highest accuracy and lowest error were observed with cystatin C–based chronic kidney disease epidemiology collaboration equations. Both modification of diet in renal disease and Cockcroft-Gault equations displayed the lowest performance. Kinetic models did not improve performances, except in patients with unstable creatinine levels. Creatinine- but not cystatin C–based estimations largely derived over ICU stay, which appeared more related to sarcopenia than fluid balance. Finally, estimated glomerular filtration rate misclassified patients according to classical glomerular filtration rate categories in approximately half of the studied cases. Conclusions: All known estimated glomerular filtration rate equations displayed high biases and unacceptable errors when compared with measured glomerular filtration rate in a mixed ICU population, with the lowest performance related to creatinine-based equations compared with cystatin C. In the ICU, we advocate for caution when using creatinine based estimated glomerular filtration rate equations. Drifting of serum creatinine levels over time should also be taken into consideration when assessing renal function in the ICU.

OBJECTIVES: Sepsis is a common condition in the ICU. Despite much research, its prognosis remains poor. In 2017, a retrospective before/after study reported promising results using a combination of thiamine, ascorbic acid, and hydrocortisone called “metabolic resuscitation cocktail” and several randomized controlled trials assessing its effectiveness were performed. DESIGN: We conducted a systematic review and meta-analysis of randomized controlled trials in septic ICU patients to assess the effects of this combination therapy. SETTING: PubMed, Embase, and the Cochrane library databases were searched from inception to March of 2021. Data were extracted independently by two authors. The main outcome was the change in Sequential Organ Failure Assessment score within 72 hours. Secondary outcomes included renal composite endpoints (acute kidney injury) Kidney Disease - Improving Global Outcome organization stage 3 or need for renal replacement therapy, vasopressor duration, and 28-day mortality. SUBJECTS: We included randomized controlled trials with patients admitted to the ICU with sepsis or septic shock. INTERVENTION: The trials compared a combination of thiamine, ascorbic acid, and hydrocortisone to standard care or placebo in patients admitted to ICU with sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: We included eight randomized controlled trials (n = 1,335 patients). Within 72 hours, the median of mean improvement was –1.8 and –3.2 in the control and intervention groups, respectively (eight randomized controlled trials, n = 1,253 patients); weighted mean difference –0.82 (95% CI, –1.15 to –0.48). Data were homogeneous and the funnel plot did not suggest any publication bias. Duration of vasopressor requirement was significantly reduced in the intervention group (six randomized controlled trials). There was no evidence of a difference regarding the ICU mortality and the renal composite outcome (acute kidney injury KDIGO 3 or need for renal replacement therapy, seven randomized controlled trials). CONCLUSIONS: Metabolic resuscitation cocktail administrated in ICU septic patients improves change in Sequential Organ Failure Assessment score within 72 hours. However, this improvement is modest and its clinical relevance is questionable. The impact on renal failure and mortality remains unclear.