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      Timing of Renal Replacement Therapy for Severe Acute Kidney Injury in Critically Ill Patients

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          PGC1α-dependent NAD biosynthesis links oxidative metabolism to renal protection

          The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischemia. Indeed, acute kidney injury (AKI) affects 3% of all hospitalized patients. 1,2 Here we show that the mitochondrial biogenesis regulator, PGC1α, 3,4 is a pivotal determinant of renal recovery from injury by regulating NAD biosynthesis. Following renal ischemia, PGC1α−/− mice developed local deficiency of the NAD precursor niacinamide (Nam), marked fat accumulation, and failure to re-establish normal function. Remarkably, exogenous Nam improved local NAD levels, fat accumulation, and renal function in post-ischemic PGC1α−/− mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulated the effects of Nam supplementation, including more local NAD and less fat accumulation with better renal function after ischemia. PGC1α coordinately upregulated the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuated the de novo pathway. Nam enhanced NAD via the enzyme NAMPT and augmented production of the fat breakdown product beta-hydroxybutyrate (β-OHB), leading to increased prostaglandin PGE2, a secreted autocoid that maintains renal function. 5 Nam treatment reversed established ischemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of β-OHB signaling or prostaglandins similarly abolished PGC1α-dependent renoprotection. Given the importance of mitochondrial health in aging and the function of metabolically active organs, the results implicate Nam and NAD as key effectors for achieving PGC1α-dependent stress resistance.
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            Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study.

            We aimed to determine the incidence, risk factors and outcome of acute kidney injury (AKI) in Finnish ICUs. This prospective, observational, multi-centre study comprised adult emergency admissions and elective patients whose stay exceeded 24 h during a 5-month period in 17 Finnish ICUs. We defined AKI first by the Acute Kidney Injury Network (AKIN) criteria supplemented with a baseline creatinine and second with the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We screened the patients' AKI status and risk factors for up to 5 days. We included 2,901 patients. The incidence (95 % confidence interval) of AKI was 39.3 % (37.5-41.1 %). The incidence was 17.2 % (15.8-18.6 %) for stage 1, 8.0 % (7.0-9.0 %) for stage 2 and 14.1 % (12.8-15.4 %) for stage 3 AKI. Of the 2,901 patients 296 [10.2 % (9.1-11.3 %)] received renal replacement therapy. We received an identical classification with the new KDIGO criteria. The population-based incidence (95 % CI) of ICU-treated AKI was 746 (717-774) per million population per year (reference population: 3,671,143, i.e. 85 % of the Finnish adult population). In logistic regression, pre-ICU hypovolaemia, diuretics, colloids and chronic kidney disease were independent risk factors for AKI. Hospital mortality (95 % CI) for AKI patients was 25.6 % (23.0-28.2 %) and the 90-day mortality for AKI patients was 33.7 % (30.9-36.5 %). All AKIN stages were independently associated with 90-day mortality. The incidence of AKI in the critically ill in Finland was comparable to previous large multi-centre ICU studies. Hospital mortality (26 %) in AKI patients appeared comparable to or lower than in other studies.
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              Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial.

              Whether continuous renal replacement therapy is better than intermittent haemodialysis for the treatment of acute renal failure in critically ill patients is controversial. In this study, we compare the effect of intermittent haemodialysis and continuous venovenous haemodiafiltration on survival rates in critically ill patients with acute renal failure as part of multiple-organ dysfunction syndrome. Our prospective, randomised, multicentre study took place between Oct 1, 1999, and March 3, 2003, in 21 medical or multidisciplinary intensive-care units from university or community hospitals in France. Guidelines were provided to achieve optimum haemodynamic tolerance and effectiveness of solute removal in both groups. The two groups were treated with the same polymer membrane and bicarbonate-based buffer. 360 patients were randomised, and the primary endpoint was 60-day survival based on an intention-to-treat analysis. Rate of survival at 60-days did not differ between the groups (32% in the intermittent haemodialysis group versus 33% in the continuous renal replacement therapy group [95 % CI -8.8 to 11.1,]), or at any other time. These data suggest that, provided strict guidelines to improve tolerance and metabolic control are used, almost all patients with acute renal failure as part of multiple-organ dysfunction syndrome can be treated with intermittent haemodialysis.
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                Author and article information

                Journal
                American Journal of Respiratory and Critical Care Medicine
                Am J Respir Crit Care Med
                American Thoracic Society
                1073-449X
                1535-4970
                May 2019
                May 2019
                : 199
                : 9
                : 1066-1075
                Affiliations
                [1 ]AP-HP, Hôpital Avicenne, Service de Réanimation Médico-Chirurgicale, Bobigny, France
                [2 ]INSERM UMR S 1155 “Common and Rare Kidney Diseases: from Molecular Events to Precision Medicine,” and
                [3 ]Health Care Simulation Center, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France
                [4 ]Department of Intensive Care, François Mitterrand University Hospital, Dijon, France
                [5 ]Lipness Team, INSERM Research Center, LNC-UMR1231 and LabEx LipSTIC, and
                [6 ]INSERM CIC 1432, Clinical Epidemiology, University of Burgundy, Dijon, France
                [7 ]Renal ICU and Transplantation, Sorbonne Universités, Hôpital Tenon, AP-HP, Paris, France
                [8 ]Unité de Réanimation Médicale, CHU de Nîmes - Hôpital Carémeau, Nîmes, France
                [9 ]Département Biostatistique Santé Publique et Information Médicale, Centre de Pharmacoépidémiologie (Cephepi), Sorbonne Université, CIC-1421, AP-HP, Hôpital Pitié Salpêtrière, Paris, France
                [10 ]INSERM, UMR 1123, ECEVE, Paris, France
                [11 ]AP-HP, Hôpital Louis Mourier, Service de Réanimation Médico-Chirurgicale, Colombes, France
                [12 ]IAME, UMRS 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France
                [13 ]INSERM, IAME, U1137, Paris, France; and
                [14 ]University Paris Diderot, Sorbonne Paris Cité, Paris, France
                Article
                10.1164/rccm.201810-1906CP
                30785784
                f21d56d4-bc57-4758-aaf7-54bb12a0455e
                © 2019
                History

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