Publications by authors named "John A Kellum"

583 Publications

Association between Net Ultrafiltration Rate and Renal Recovery among Critically Ill Adults with Acute Kidney Injury Receiving Continuous Renal Replacement Therapy: An Observational Cohort Study.

Blood Purif 2021 Jul 21:1-13. Epub 2021 Jul 21.

Department of Intensive Care Medicine, Austin Hospital, The University of Melbourne, Parkville, Victoria, Australia.

Introduction: Higher net ultrafiltration (UFNET) rates are associated with mortality among critically ill patients with acute kidney injury (AKI) and treated with continuous renal replacement therapy (CRRT).

Objective: The aim of the study was to discover whether UFNET rates are associated with renal recovery and independence from renal replacement therapy (RRT).

Methods: Retrospective cohort study using data from the Randomized Evaluation of Normal versus Augmented Level of Renal Replacement Therapy trial that enrolled 1,433 critically ill patients with AKI and treated with CRRT between December 2005 and November 2008 across 35 intensive care units in Australia and New Zealand. We examined the association between UFNET rate and time to independence from RRT by day 90 using competing risk regression after accounting for mortality. The UFNET rate was defined as the volume of fluid removed per hour adjusted for patient body weight.

Results And Conclusions: Median age was 67.3 (interquartile range [IQR], 57-76.3) years, 64.4% were male, median Acute Physiology and Chronic Health Evaluation-III score was 100 (IQR, 84-118), and 634 (44.2%) died by day 90. Kidney recovery occurred in 755 patients (52.7%). Using tertiles of UFNET rates, 3 groups were defined: high, >1.75; middle, 1.01-1.75; and low, <1.01 mL/kg/h. Proportion of patients alive and independent of RRT among the groups were 47.8 versus 57.2 versus 53.0%; p = 0.01. Using competing risk regression, higher UFNET rate tertile compared with middle (cause-specific hazard ratio [csHR], 0.79, 95% CI, 0.66-0.95; subdistribution hazard ratio [sHR], 0.80, 95% CI, 0.67-0.97) and lower (csHR, 0.69, 95% CI, 0.56-0.85; sHR, 0.78, 95% CI 0.64-0.95) tertiles were associated with a longer time to independence from RRT. Every 1.0 mL/kg/h increase in rate was associated with a lower probability of kidney recovery (csHR, 0.81, 95% CI, 0.74-0.89; and sHR, 0.87, 95% CI, 0.80-0.95). Using the joint model, longitudinal increases in UFNET rates were also associated with a lower renal recovery (β = -0.29, p < 0.001). UFNET rates >1.75 mL/kg/h compared with rates 1.01-1.75 and <1.01 mL/kg/h were associated with a longer duration of dependence on RRT. Randomized clinical trials are required to confirm this UFNET rate-outcome relationship.
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http://dx.doi.org/10.1159/000517281DOI Listing
July 2021

Acute kidney injury.

Nat Rev Dis Primers 2021 07 15;7(1):52. Epub 2021 Jul 15.

Division of Nephrology, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany.

Acute kidney injury (AKI) is defined by a sudden loss of excretory kidney function. AKI is part of a range of conditions summarized as acute kidney diseases and disorders (AKD), in which slow deterioration of kidney function or persistent kidney dysfunction is associated with an irreversible loss of kidney cells and nephrons, which can lead to chronic kidney disease (CKD). New biomarkers to identify injury before function loss await clinical implementation. AKI and AKD are a global concern. In low-income and middle-income countries, infections and hypovolaemic shock are the predominant causes of AKI. In high-income countries, AKI mostly occurs in elderly patients who are in hospital, and is related to sepsis, drugs or invasive procedures. Infection and trauma-related AKI and AKD are frequent in all regions. The large spectrum of AKI implies diverse pathophysiological mechanisms. AKI management in critical care settings is challenging, including appropriate volume control, nephrotoxic drug management, and the timing and type of kidney support. Fluid and electrolyte management are essential. As AKI can be lethal, kidney replacement therapy is frequently required. AKI has a poor prognosis in critically ill patients. Long-term consequences of AKI and AKD include CKD and cardiovascular morbidity. Thus, prevention and early detection of AKI are essential.
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http://dx.doi.org/10.1038/s41572-021-00284-zDOI Listing
July 2021

Harmonizing acute and chronic kidney disease definition and classification: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference.

Kidney Int 2021 Jul 9. Epub 2021 Jul 9.

Kent Kidney Care Centre, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK. Electronic address:

Kidney disease is an important public health problem. Both acute kidney injury (AKI) and chronic kidney disease have been well defined and classified, leading to improved research efforts and subsequent management strategies and recommendations. For those patients with abnormalities in kidney function and/or structure who meet neither the definition of AKI nor chronic kidney disease, there remains a gap in research, care, and guidance. The term acute kidney diseases and disorders, abbreviated to acute kidney disease (AKD), has been introduced as an important construct to address this. To expand and harmonize existing definitions and to ultimately better inform research and clinical care, Kidney Disease: Improving Global Outcomes (KDIGO) organized a consensus workshop. Multiple invitees from around the globe, representing both acute and chronic kidney disease researchers and experts, met virtually to examine existing data, and discuss key concepts related to AKD. Despite some remaining unresolved questions, conference attendees reached general consensus on the definition and classification of AKD, management strategies, and research priorities. AKD is defined by abnormalities of kidney function and/or structure with implications for health and with a duration of ≤3 months. AKD may include AKI, but, more importantly, also includes abnormalities in kidney function that are not as severe as AKI or that develop over a period of >7 days. The cause(s) of AKD should be sought, and classification includes functional and structural parameters. Management of AKD is currently based on empirical considerations. A robust research agenda to enable refinement and validation of definitions and classification systems, and thus testing of interventions and strategies, is proposed.
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http://dx.doi.org/10.1016/j.kint.2021.06.028DOI Listing
July 2021

A translational study of Galectin-3 as an early biomarker and potential therapeutic target for ischemic-reperfusion induced acute kidney injury.

J Crit Care 2021 Jul 2;65:192-199. Epub 2021 Jul 2.

Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China; Department of Critical Care Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. Electronic address:

Purpose: We evaluated Galectin-3 (Gal-3) as a potential early biomarker of acute kidney disease (AKI), and the effect of Gal-3 inhibition by modified citrus pectin (P-MCP) on renal ischemia/reperfusion (I/R) induced AKI.

Methods: Among fifty-two post-cardiac surgery patients, serum and urine Gal-3 levels were examined on intensive care unit (ICU) admission. In a rat renal I/R injury model, Gal-3 levels, renal function, and histopathology were evaluated in rats pretreated with P-MCP for one week (n = 16) compared to controls (n = 16).

Results: Among post-cardiac surgery patients, median serum and urine Gal-3 levels on ICU admission were higher in patients who developed AKI than those who did not (AKI vs non-AKI serum: 18.37 vs. 8.08 ng/ml, p < 0.001; AKI vs non-AKI urine:13.27 vs. 6.27 ng/ml, p < 0.001). Serum and urine Gal-3 levels were reliable biomarkers for detecting AKI (AUC: 0.88 and 0.87). In the rat renal I/R injury model, I/R caused an increase of Gal-3 at 0.5 h after reperfusion (p < 0.05). Gal-3 inhibition by P-MCP significantly decreased Gal-3 release and expression (p < 0.05), reduced interleukin (IL-6) release (p < 0.05), decreased renal dysfunction, and reduced renal tubular injury.

Conclusions: Gal-3 is a potential early biomarker in the diagnosis of AKI. Inhibition of Gal-3 may provide therapeutic utility in the treatment of I/R-induced AKI.
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http://dx.doi.org/10.1016/j.jcrc.2021.06.013DOI Listing
July 2021

KIM-1-mediated anti-inflammatory activity is preserved by MUC1 induction in the proximal tubule during ischemia-reperfusion injury.

Am J Physiol Renal Physiol 2021 Aug 21;321(2):F135-F148. Epub 2021 Jun 21.

Renal-Electrolyte Division, Department of Medicine, grid.21925.3dUniversity of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Cell-associated kidney injury molecule-1 (KIM-1) exerts an anti-inflammatory role following kidney injury by mediating efferocytosis and downregulating the NF-κB pathway. KIM-1 cleavage blunts its anti-inflammatory activities. We reported that mucin 1 (MUC1) is protective in a mouse model of ischemia-reperfusion injury (IRI). As both KIM-1 and MUC1 are induced in the proximal tubule (PT) during IRI and are a disintegrin and metalloprotease 17 (ADAM17) substrates, we tested the hypothesis that MUC1 protects KIM-1 activity. knockout (KO) mice and wild-type (WT) littermates were subjected to IRI. KIM-1, MUC1, and ADAM17 levels (and signaling pathways) were assessed by immunoblot analysis. PT localization was assessed by confocal microscopy and an in situ proximity ligation assay. Findings were extended using human kidneys and urine as well as KIM-1-mediated efferocytosis assays in mouse PT cultures. In response to tubular injury in mouse and human kidneys, we observed induction and coexpression of KIM-1 and MUC1 in the PT. Compared with WT mice, KO mice had higher urinary KIM-1 and lower kidney KIM-1. KIM-1 was apical in the PT of WT kidneys but predominately with luminal debris in KO mice. Efferocytosis was reduced in KO PT cultures compared with WT cultures, whereas inflammation was increased in KO kidneys compared with WT kidneys. MUC1 was cleaved by ADAM17 in PT cultures and blocked KIM-1 shedding in Madin-Darby canine kidney cells. We conclude that KIM-1-mediated efferocytosis and thus anti-inflammatory activity during IRI is preserved in the injured kidney by MUC1 inhibition of KIM-1 shedding. KIM-1 plays a key role in the recovery of the tubule epithelium during renal IRI by mediating efferocytosis and associated signaling that suppresses inflammation. Excessive cleavage of KIM-1 by ADAM17 provides a decoy receptor that aggravates efferocytosis and subsequent signaling. Our data from experiments in mice, patients, and cultured cells show that MUC1 is also induced during IRI and competes with KIM-1 for cleavage by ADAM17. Consequently, MUC1 protects KIM-1 anti-inflammatory activity in the damaged kidney.
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http://dx.doi.org/10.1152/ajprenal.00127.2021DOI Listing
August 2021

External validation of urinary C-C motif chemokine ligand 14 (CCL14) for prediction of persistent acute kidney injury.

Crit Care 2021 05 31;25(1):185. Epub 2021 May 31.

Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, 3550 Terrace St., Scaife Hall, Suite 600, Pittsburgh, PA, 15213, USA.

Background: Persistent acute kidney injury (AKI) portends worse clinical outcomes and remains a therapeutic challenge for clinicians. A recent study found that urinary C-C motif chemokine ligand 14 (CCL14) can predict the development of persistent AKI. We aimed to externally validate urinary CCL14 for the prediction of persistent AKI in critically ill patients.

Methods: This was a secondary analysis of the prospective multi-center SAPPHIRE study. We evaluated critically ill patients with cardiac and/or respiratory dysfunction who developed Kidney Disease: Improving Global Outcomes (KDIGO) stage 2-3 AKI within one week of enrollment. The main exposure was the urinary concentration of CCL14 measured at the onset of AKI stage 2-3. The primary endpoint was the development of persistent severe AKI, defined as  ≥ 72 h of KDIGO stage 3 AKI or death or renal-replacement therapy (RRT) prior to 72 h. The secondary endpoint was a composite of RRT and/or death by 90 days. We used receiver operating characteristic (ROC) curve analysis to assess discriminative ability of urinary CCL14 for the development of persistent severe AKI and multivariate analysis to compare tertiles of urinary CCL14 and outcomes.

Results: We included 195 patients who developed KDIGO stage 2-3 AKI. Of these, 28 (14%) developed persistent severe AKI, of whom 15 had AKI  ≥ 72 h, 12 received RRT and 1 died prior to  ≥ 72 h of KDIGO stage 3 AKI. Persistent severe AKI was associated with chronic kidney disease, diabetes mellitus, higher non-renal APACHE III score, greater fluid balance, vasopressor use, and greater change in baseline serum creatinine. The AUC for urinary CCL14 to predict persistent severe AKI was 0.81 (95% CI, 0.72-0.89). The risk of persistent severe AKI increased with higher values of urinary CCL14. RRT and/or death at 90 days increased within tertiles of urinary CCL14 concentration.

Conclusions: This secondary analysis externally validates urinary CCL14 to predict persistent severe AKI in critically ill patients.
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http://dx.doi.org/10.1186/s13054-021-03618-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166095PMC
May 2021

Optimising the timing of renal replacement therapy in acute kidney injury.

Crit Care 2021 05 31;25(1):184. Epub 2021 May 31.

Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, 606 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.

The optimal timing of renal replacement therapy (RRT) in critically ill patients with acute kidney injury (AKI) has been much debated. Over the past five years several studies have provided new guidance for evidence-based decision-making. High-quality evidence now supports an approach of expectant management in critically ill patients with AKI, where RRT may be deferred up to 72 h unless a life-threatening indication develops. Nevertheless, physicians' judgment still plays a central role in identifying appropriate patients for expectant management.
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http://dx.doi.org/10.1186/s13054-021-03614-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165519PMC
May 2021

Creating a High-Specificity Acute Kidney Injury Detection System for Clinical and Research Applications.

Am J Kidney Dis 2021 May 28. Epub 2021 May 28.

Center for Critical Care Nephrology, CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA. Electronic address:

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http://dx.doi.org/10.1053/j.ajkd.2021.03.024DOI Listing
May 2021

Postoperative acute kidney injury in adult non-cardiac surgery: joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative.

Nat Rev Nephrol 2021 May 11. Epub 2021 May 11.

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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http://dx.doi.org/10.1038/s41581-021-00418-2DOI Listing
May 2021

Urinary EGF and MCP-1 and risk of CKD after cardiac surgery.

JCI Insight 2021 Jun 8;6(11). Epub 2021 Jun 8.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

BACKGROUNDAssessment of chronic kidney disease (CKD) risk after acute kidney injury (AKI) is based on limited markers primarily reflecting glomerular function. We evaluated markers of cell integrity (EGF) and inflammation (monocyte chemoattractant protein-1, MCP-1) for predicting long-term kidney outcomes after cardiac surgery.METHODSWe measured EGF and MCP-1 in postoperative urine samples from 865 adults who underwent cardiac surgery at 2 sites in Canada and the United States and assessed EGF and MCP-1's associations with the composite outcome of CKD incidence or progression. We used single-cell RNA-Seq (scRNA-Seq) of AKI patient biopsies to perform transcriptomic analysis of programs corregulated with the associated genes.RESULTSOver a median (IQR) follow-up of 5.8 (4.2-7.1) years, 266 (30.8%) patients developed the composite CKD outcome. Postoperatively, higher levels of urinary EGF were protective and higher levels of MCP-1 were associated with the composite CKD outcome (adjusted HR 0.83, 95% CI 0.73-0.95 and 1.10, 95% CI 1.00-1.21, respectively). Intrarenal scRNA-Seq transcriptomes in patients with AKI-defined cell populations revealed concordant changes in EGF and MCP-1 levels and underlying molecular processes associated with loss of EGF expression and gain of CCL2 (encoding MCP-1) expression.CONCLUSIONUrinary EGF and MCP-1 were each independently associated with CKD after cardiac surgery. These markers may serve as noninvasive indicators of tubular damage, supported by tissue transcriptomes, and provide an opportunity for novel interventions in cardiac surgery.TRIAL REGISTRATIONClinicalTrials.gov NCT00774137.FUNDINGThe NIH funded the TRIBE-AKI Consortium and Kidney Precision Medicine Project. Yale O'Brien Kidney Center, American Heart Association, Patterson Trust Fund, Dr. Adam Linton Chair in Kidney Health Analytics, Canadian Institutes of Health Research, ICES, Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine & Dentistry, Western University, Lawson Health Research Institute, Chan Zuckerberg Initiative Human Cell Atlas Kidney Seed Network.
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http://dx.doi.org/10.1172/jci.insight.147464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262289PMC
June 2021

Limiting Acute Kidney Injury Progression In Sepsis: Study Protocol and Trial Simulation.

Crit Care Med 2021 Apr 30. Epub 2021 Apr 30.

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA. Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy. Global Medical Affairs, bioMérieux SA, Marcy l'Etoile, France. Excellence Center for Critical Care Nephrology, Division of Nephrology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Department of Medicine, University of Padova, Padova, Italy. Department of Nephrology Dialysis & Transplantation and International Renal Research Institute (IRRIV), San Bortolo Hospital, Vicenza, Italy. Florida Hospital, Orlando, FL. Novavax, Inc.,Gaithersburg, MD. Data Science, bioMérieux, Inc., Hazelwood. Astute Medical, Inc., San Diego. Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA.

Objectives: To describe study design considerations and to simulate a trial of biomarker-guided sepsis management aimed to reduce acute kidney injury (acute kidney injury). Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 , urinary biomarkers of cell-cycle arrest, and indicators of kidney stress can detect acute kidney injury before clinical manifestations. We sought to determine the event rates for acute kidney injury as a function of serial measurements of urinary (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) in patients at risk of sepsis-associated acute kidney injury, so that an escalating series of kidney-sparing sepsis bundles based on international guidelines could be applied.

Design: We described the study protocol of "Limiting acute kidney injury Progression In Sepsis," a phase 4, multicenter, adaptive, randomized controlled trial. We performed simulations to estimate the rates for the trial's primary endpoint using patient-level data from two previous studies (Sapphire and Protocolized Care for Early Septic Shock).

Setting: Academic and community ICUs.

Patients: Critically ill patients with sepsis or septic shock, without evidence of stage 2/3 acute kidney injury at enrollment.

Interventions: None.

Measurements And Main Results: Our primary endpoint is progression of two or more stages of acute kidney injury, death, or dialysis within 72 hours after enrollment. In the Sapphire simulation, 45 of 203 patients (22%) with sepsis met the endpoint. In Protocolized Care for Early Septic Shock, 144 of 607 patients (24%) with septic shock met the endpoint. In both simulations, (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) patterns, suggested by Limiting acute kidney injury Progression In Sepsis protocol, stratified the risk for the endpoint from 6% (three negative tests) to 41% (for patients eligible for the highest level of kidney-sparing sepsis bundle) in Sapphire, and 14% (two negative tests) to 46% (for the highest level of kidney-sparing sepsis bundle) in Protocolized Care for Early Septic Shock.

Conclusions: Findings of our Limiting acute kidney injury Progression In Sepsis trial simulation confirmed that (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) could identify patients with different rates of progression to moderate/severe acute kidney injury, death, or dialysis in 72 hours. The Limiting acute kidney injury Progression In Sepsis protocol algorithm is therefore feasible in terms of identifying suitably high-risk individuals for kidney-sparing sepsis bundle.
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http://dx.doi.org/10.1097/CCM.0000000000005061DOI Listing
April 2021

Effect of Cytokine Adsorption on Survival and Circulatory Stabilization in Patients Receiving Extracorporeal Cardiopulmonary Resuscitation.

ASAIO J 2021 Apr 19. Epub 2021 Apr 19.

From the Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, Germany Department of Cardiovascular Surgery, Heart Center Freiburg University, University of Freiburg, Freiburg, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA.

Even after the introduction of extracorporeal cardiopulmonary resuscitation (ECPR), survival after cardiac arrest remains poor. Excess release of vasoactive cytokines may be a reason for cardiovascular instability and death after ECPR. Recently, an extracorporeal cytokine adsorption device (CytoSorb) to reduce elevated levels of circulating cytokines has been introduced. So far, it remains unclear if this device may improve survival and cardiovascular stabilization after ECPR. We report data from our investigator-initiated, single-center ECPR registry. We compared 23 ECPR patients treated with cytokine adsorption with a propensity-matched cohort of ECPR patients without cytokine adsorption. We analyzed survival, lactate clearance, vasopressor need, and fluid demand in both groups and performed between-group comparisons. Survival to discharge from intensive care unit (ICU) was 17.4% (4/23) in the cytokine adsorption group and 21.7% in the control group (5/23, P > 0.99). In both groups, we observed a decrease of serum-lactate, need for vasopressors, and fluid demand during the first 72 hours after ECPR. However, in direct comparison, we did not find significant between-group differences. In this retrospective registry study employing propensity score matching, cytokine adsorption in severely ill patients after ECPR was not associated with improved ICU survival nor a decrease of lactate, fluid, or vasopressor levels. Due to small case numbers and the retrospective design of the study, our results neither disprove nor confirm a clinically relevant treatment effect of cytokine adsorption. Results from larger trials, preferably randomized-controlled trials are required to better understand the clinical benefit of cytokine adsorption after ECPR.
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http://dx.doi.org/10.1097/MAT.0000000000001441DOI Listing
April 2021

Endotoxin Adsorbent Therapy in Severe COVID-19 Pneumonia.

Blood Purif 2021 Apr 15:1-8. Epub 2021 Apr 15.

Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Introduction: Uncontrolled systemic inflammation may occur in severe coronavirus disease 19 (COVID-19). We have previously shown that endotoxemia, presumably from the gut, may complicate COVID-19. However, the role of endotoxin adsorbent (EA) therapy to mitigate organ dysfunction in COVID-19 has not been explored.

Methods: We conducted a retrospective observational study in COVID-19 patients who received EA therapy at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between March 13 and April 17, 2020. Relevant clinical and laboratory data were collected by inpatient chart review.

Results: Among 147 hospitalized COVID-19 patients, 6 patients received EA therapy. All of the 6 patients had severe COVID-19 infection with acute respiratory distress syndrome (ARDS). Among these, 5 of them were mechanically ventilated and 4 had complications of secondary bacterial infection. The endotoxin activity assay (EAA) results of pre-EA therapy ranged from 0.47 to 2.79. The choices of EA therapy were at the discretion of attending physicians. One patient was treated with oXiris® along with continuous renal replacement therapy, and the others received polymyxin B hemoperfusion sessions. All patients have survived and were finally free from the mechanical ventilation as well as had improvement in PaO2/FiO2 ratio and decreased EAA level after EA therapy.

Conclusions: We demonstrated the clinical improvement of severe COVID-19 patients with elevated EAA level upon receiving EA therapy. However, the benefit of EA therapy in COVID-19 ARDS is still unclear and needs to be elucidated with randomized controlled study.
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http://dx.doi.org/10.1159/000515628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089445PMC
April 2021

Development of a Theory-Informed Behavior Change Intervention to Reduce Inappropriate Prescribing of Nephrotoxins and Renally Eliminated Drugs.

Ann Pharmacother 2021 Apr 15:10600280211009567. Epub 2021 Apr 15.

University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background: Goals of managing patients with acute kidney injury (AKI) are mitigating disease progression and ensuring safety while providing supportive care because no effective treatment exists. One strategy recommended in guidelines to meet these goals is optimizing medication management. Unfortunately, guideline implementation appears to be lacking as observed by the frequent occurrence of medication errors and adverse drug events.

Objective: To address this performance gap in the care of hospitalized patients receiving nephrotoxins and renally eliminated drugs, we sought to provide a potential intervention based on theory-informed behavior change.

Methods: Formative research with a qualitative analysis identifying what needs to change in patient care was completed by obtaining clinician opinion and expert opinion and reviewing the published literature. Frontline providers, including 8 physicians, 4 pharmacists, and a multiprofessional group of authors, provided insight into possible barriers to appropriate prescribing. Capability, Opportunity, Motivation and Behavior model and Theoretical Domain Framework were applied to characterize behavior change interventions and inform a potential implementation intervention for changing inappropriate prescribing behaviors.

Results: Lack of knowledge about appropriate drug management in patients at risk for adverse outcomes was provided as a major barrier. Other reported barriers included a lack of: (1) tools to assist with drug management, (2) motivation to make changes, (3) routinization, and (4) an accountable clinician.

Conclusions And Relevance: Assigning a designated clinician to execute a stepwise, routine care process following the checklist provided is a recommended intervention to overcome barriers. The intended impact is behavior change that reduces inappropriate prescribing.
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http://dx.doi.org/10.1177/10600280211009567DOI Listing
April 2021

Comparison of C-C motif chemokine ligand 14 with other biomarkers for adverse kidney events after cardiac surgery.

J Thorac Cardiovasc Surg 2021 Mar 10. Epub 2021 Mar 10.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany. Electronic address:

Objective: Outcomes after acute kidney injury are affected by both the severity and the duration of the insult. Patients with persistent acute kidney injury have higher major adverse kidney events, including 90-day mortality, renal replacement therapy, and persistent kidney dysfunction. Methods to identify these patients are urgently needed to improve outcomes. The purpose of this study was to evaluate whether biomarkers, including C-C motif chemokine ligand 14, were able to predict persistent acute kidney injury and major adverse kidney events after cardiac surgery.

Methods: This study was a single-center, prospective, observational study. Patients who developed moderate or severe acute kidney injury (Kidney Disease Improving Global Outcomes 2 or 3) within 72 hours after cardiac surgery were enrolled with a primary end point of persistent severe acute kidney injury (Kidney Disease Improving Global Outcomes 3) lasting 72 hours or more.

Results: A total of 100 patients were available for the primary analysis, and 37 met the primary end point. C-C motif chemokine ligand 14 was the most predictive biomarker for the primary end point with an area under the curve of 0.930 (95% confidence interval, 0.881-0.979). The area under the curve of C-C motif chemokine ligand 14 was significantly higher than the area under the curve for the other biomarkers analyzed. C-C motif chemokine ligand 14 was significantly higher in end point positive patients at enrollment (4.47 ng/mL [2.35-11.5] vs 0.67 ng/mL [0.38-1.07]; P = .001). Sensitivity and specificity were 78% and 95% at a cutoff value of 2.21 ng/mL, respectively. C-C motif chemokine ligand 14 was also highly accurate for predicting renal replacement therapy within 7 days (area under the curve, 0.915; 95% confidence interval, 0.858-0.972; P < .001).

Conclusions: Elevated C-C motif chemokine ligand 14 levels predict persistent acute kidney injury in cardiac surgery patients with moderate or severe acute kidney injury. This new biomarker may help stratify patients destined to receive renal replacement therapy and identify patients who may benefit from novel therapeutic approaches to acute kidney injury.
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http://dx.doi.org/10.1016/j.jtcvs.2021.03.016DOI Listing
March 2021

Author Correction: Conceptual advances and evolving terminology in acute kidney disease.

Nat Rev Nephrol 2021 Jul;17(7):503

Department of Critical Care, Austin Hospital, Melbourne, Australia.

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http://dx.doi.org/10.1038/s41581-021-00426-2DOI Listing
July 2021

Acute Kidney Injury in the Intensive Care Unit: Advances in the Identification, Classification, and Treatment of a Multifactorial Syndrome.

Crit Care Clin 2021 04 13;37(2):xiii-xv. Epub 2021 Feb 13.

Department of Critical Care Medicine, The Center for Critical Care Nephrology, 3347 Forbes Avenue, Suite 220, Pittsburgh, PA 15213, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ccc.2021.01.001DOI Listing
April 2021

Biomarkers in Acute Kidney Injury.

Crit Care Clin 2021 Apr;37(2):385-398

Division of Nephrology, Faculty of Medicine, Chulalongkorn University, 10th Floor, Bhumisiri mangkhalanusorn Building, Ratchadamri Road, Pathum Wan, Bangkok 10330, Thailand; Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, 1873 Rama IV Road, Pathum Wan, Bangkok 10330, Thailand; Department of Critical Care Medicine, Center for Critical Care Nephrology, The CRISMA Center, University of Pittsburgh School of Medicine, 3347 Forbes Avenue, Suite 220, Pittsburgh, PA 15213, USA; Critical Care Nephrology Research Unit, Chulalongkorn University, Bangkok, Thailand; Academy of Science, Royal Society of Thailand, Bangkok, Thailand; Tropical Medicine Cluster, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Critical Care Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Electronic address:

Biomarkers have become a pillar of precision medicine in acute kidney injury (AKI). Traditional markers for diagnosis of AKI are insensitive and insufficient to provide comprehensive information for prognostication. Several emerging biomarkers have shown promising results in large-scale clinical studies. These novel markers likely will be beneficial for personalized AKI prevention and treatment.
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http://dx.doi.org/10.1016/j.ccc.2020.11.012DOI Listing
April 2021

Defining Acute Kidney Injury.

Crit Care Clin 2021 Apr;37(2):251-266

Center for Critical Care Nephrology, University of Pittsburgh Medical Center, 3550 Terrace Street, Pittsburgh, PA 15213, USA; Department of Critical Care Medicine, University of Pittsburgh Medical Center, Center for Critical Care Nephrology, 3347 Forbes Avenue, Suite 220, Pittsburgh, PA 15213, USA. Electronic address:

Acute kidney injury (AKI) is a syndrome of impaired kidney function associated with reduced survival and increased morbidity. International consensus criteria were developed based on changes in serum creatinine and urine output. Based on these definitions, epidemiologic studies have shown strong associations with clinical outcomes including death and dialysis. However, numerous limitations exist for creatinine and urine volume as markers of AKI and novel biomarkers have been developed to detect cellular stress or damage. Persistent AKI and acute kidney disease are relatively new concepts that explore the idea of AKI as a continuum with chronic kidney disease.
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http://dx.doi.org/10.1016/j.ccc.2020.11.001DOI Listing
April 2021

Galectin-3 in septic acute kidney injury: a translational study.

Crit Care 2021 03 18;25(1):109. Epub 2021 Mar 18.

Amitabha Medical Center, Santa Rosa, CA, USA.

Background: Galectin-3 (Gal-3) is a pleiotropic glycan-binding protein shown to be involved in sepsis and acute kidney injury (AKI). However, its role has never been elucidated in sepsis-associated AKI (S-AKI). We aimed to explore Gal-3's role and its potential utility as a therapeutic target in S-AKI.

Methods: In 57 patients admitted to the intensive care unit (ICU) with sepsis, serum Gal-3 was examined as a predictor of ICU mortality and development of AKI. In a rat model of S-AKI induced by cecal ligation and puncture (CLP), 7-day mortality and serum Gal-3, Interleukin-6 (IL-6), and creatinine were examined at 2, 8, and 24 hours (h) post-CLP. Two experimental groups received the Gal-3 inhibitor modified citrus pectin (P-MCP) at 400 mg/kg/day and 1200 mg/kg/day, while the control group received water only (n = 18 in each group).

Results: Among 57 patients, 27 developed AKI and 8 died in the ICU. Serum Gal-3 was an independent predictor of AKI (OR = 1.2 [95% CI 1.1-1.4], p = 0.01) and ICU mortality (OR = 1.4 [95% CI 1.1-2.2], p = 0.04) before and after controlling for age, AKI, and acute physiology and chronic health evaluation (APACHE II) score. In the CLP rat experiment, serum Gal-3 peaked earlier than IL-6. Serum Gal-3 was significantly lower in both P-MCP groups compared to control at 2 h post-CLP (400 mg: p = 0.003; 1200 mg: p = 0.002), and IL-6 was significantly lower in both P-MCP groups at all time points with a maximum difference at 24 h post-CLP (400 mg: p = 0.015; 1200 mg: p = 0.02). In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced from 61% in the control group to 28% (400 mg P-MCP: p = 0.03) and 22% (1200 mg P-MCP: p = 0.001). Rates of AKI per RIFLE criteria were significantly reduced from 89% in the control group to 44% in both P-MCP groups (400 mg: p = 0.007; 1200 mg: p = 0.007).

Conclusions: This translational study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target.
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http://dx.doi.org/10.1186/s13054-021-03538-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977587PMC
March 2021

The authors reply.

Crit Care Med 2021 Apr;49(4):e476-e477

Department of Critical Care, Center for Critical Care Nephrology, Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh Medical Center, Pittsburgh, PA.

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http://dx.doi.org/10.1097/CCM.0000000000004903DOI Listing
April 2021

Conceptual advances and evolving terminology in acute kidney disease.

Nat Rev Nephrol 2021 Jul 12;17(7):493-502. Epub 2021 Mar 12.

Department of Critical Care, Austin Hospital, Melbourne, Australia.

Over the past decade, new insights into epidemiology, pathophysiology and biomarkers have modified our understanding of acute kidney dysfunction and damage, and their association with subsequent chronic kidney disease. The concept of acute kidney injury (AKI), which has relied on established but nonetheless flawed biomarkers of solute clearance (serum creatinine levels and urinary output), has been challenged by the identification of novel biomarkers of tubular stress and/or damage. The expression of some of these novel biomarkers precedes changes in conventional biomarkers or can increase their predictive power, and might therefore enhance the clinical accuracy of the definition of AKI. In addition, the need to consider AKI recurrence, duration and progression to chronic kidney disease within the clinical and epidemiological framework of AKI led to the emergence of the concept of acute kidney disease. New definitions of acute syndromes of kidney impairment and injury are needed.
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http://dx.doi.org/10.1038/s41581-021-00410-wDOI Listing
July 2021

Prevention of Cardiac Surgery-Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.

Anesth Analg 2021 Aug;133(2):292-302

From the Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, University Hospital Münster, Münster, Germany.

Background: Prospective, single-center trials have shown that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations in high-risk patients significantly reduced the development of acute kidney injury (AKI) after surgery. We sought to evaluate the feasibility of implementing a bundle of supportive measures based on the KDIGO guideline in high-risk patients undergoing cardiac surgery in a multicenter setting in preparation for a large definitive trial.

Methods: In this multicenter, multinational, randomized controlled trial, we examined the adherence to the KDIGO bundle consisting of optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia in high-risk patients identified by the urinary biomarkers tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin growth factor-binding protein 7 [IGFBP7] after cardiac surgery. The primary end point was the adherence to the bundle protocol and was evaluated by the percentage of compliant patients with a 95% confidence interval (CI) according to Clopper-Pearson. Secondary end points included the development and severity of AKI.

Results: In total, 278 patients were included in the final analysis. In the intervention group, 65.4% of patients received the complete bundle as compared to 4.2% in the control group (absolute risk reduction [ARR] 61.2 [95% CI, 52.6-69.9]; P < .001). AKI rates were statistically not different in both groups (46.3% intervention versus 41.5% control group; ARR -4.8% [95% CI, -16.4 to 6.9]; P = .423). However, the occurrence of moderate and severe AKI was significantly lower in the intervention group as compared to the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; P = .034). There were no significant effects on other specified secondary outcomes.

Conclusions: Implementation of a KDIGO-derived treatment bundle is feasible in a multinational setting. Furthermore, moderate to severe AKI was significantly reduced in the intervention group.
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http://dx.doi.org/10.1213/ANE.0000000000005458DOI Listing
August 2021

Rationale and design of the Kidney Precision Medicine Project.

Kidney Int 2021 03;99(3):498-510

Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Renal Section, Veterans Administration Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.
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http://dx.doi.org/10.1016/j.kint.2020.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330551PMC
March 2021

Use of Biomarkers to Identify Acute Kidney Injury to Help Detect Sepsis in Patients With Infection.

Crit Care Med 2021 04;49(4):e360-e368

Department of Medicine, Veterans Affairs Medical Center, San Diego, CA.

Objectives: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care.

Design: Retrospective, international, Sapphire study.

Setting: Academic Medical Center.

Patients: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment.

Interventions: None.

Measurements And Main Results: We stratified patients enrolled in the Sapphire study into three groups-those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2-3 acute kidney injury within the first 3 days compared with 14% without stage 2-3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53-11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2-3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8-34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury.

Conclusions: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria.
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http://dx.doi.org/10.1097/CCM.0000000000004845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963439PMC
April 2021

ICU-Based Renal Replacement Therapy.

Crit Care Med 2021 03;49(3):406-418

Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA.

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http://dx.doi.org/10.1097/CCM.0000000000004831DOI Listing
March 2021

A systematic review of cost-effectiveness analyses across the acute kidney injury landscape.

Expert Rev Pharmacoecon Outcomes Res 2021 Feb 7:1-8. Epub 2021 Feb 7.

University of Pittsburgh, Pittsburgh, PA, USA.

: Acute kidney injury (AKI) is a complex and common condition associated with increased morbidity, mortality, and costs. Evidence from cost-effectiveness analysis (CEA) have targeted various aspects of AKI including detection with biomarkers, treatment with renal replacement therapy, and prevention when using contrast media. However, there has not been a systematic review of these studies across the entirety of AKI.: PubMed, Embase, and Cochrane library were used to identify CEA studies that involved AKI from 2004 onwards. These studies compared AKI treatment through renal replacement therapies ( = 6), prevention of contrast-induced-AKI (CI-AKI) using different media ( = 3), and diagnosis with novel biomarkers ( = 2). Treatment strategies for AKI focused on continuous versus intermittent renal replacement therapy. While there was no consensus, the majority of studies favored the continuous form. For contrast media, both studies found iodixanol to be cost-effective compared to iohexol for preventing CI-AKI. Additionally, novel biomarkers showed potential to be cost-effective in risk assessment and detection of AKI.: Consistent criteria such as a lifetime time horizon would allow for better model comparisons. Further research on clinical parameters to capture transition probabilities between stages within AKI and progression to downstream kidney disease is needed.
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http://dx.doi.org/10.1080/14737167.2021.1882307DOI Listing
February 2021

Outcomes of end-stage renal disease patients in the PROCESS trial.

J Am Coll Emerg Physicians Open 2021 Feb 18;2(1):e12358. Epub 2021 Jan 18.

Department of Emergency Medicine McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth) Houston Texas USA.

Objective: Intravenous fluid administration is a main component of sepsis therapy, but physicians are cautious about giving fluids to end-stage renal disease (ESRD) patients out of concern for causing volume overload. We compared the outcomes of septic shock patients with and without ESRD and evaluated the association between early intravenous fluid administration and outcomes.

Methods: We analyzed patients enrolled in the Protocolized Care for Early Septic Shock (PROCESS) trial, which studied different resuscitation strategies for early septic shock. Stratifying for ESRD, we compared patient characteristics, course of care, and outcomes between ESRD and non-ESRD. Using multivariable logistic regression, we determined the association between 6-hour total fluid volume (> = 30 mL/kg vs < 30 mL/kg) from preenrollment and outcomes.

Results: There were 84 ESRD and 1257 non-ESRD patients. ESRD patients had a higher median Charlson Comorbidity score (5 vs 2,  < .001), higher median acute physiology and chronic health evaluation (APACHE) II score (26.5 vs 20.0,  < .001), and lower 6-hour intravenous fluid administration (54.7 vs 68.3 mL/kg,  < .001). Ninety-day mortality (33.3% vs 29.3%,  = .43) and intubation rate (31.0% vs 33.4%,  = .64) did not differ between groups. Fewer ESRD received > = 30 mL/kg (66.6% vs 86.7%  < .001). For ESRD, receipt of > = 30 mL/kg intravenous fluid did not alter any outcome. For non-ESRD patients, receiving   ≥30 mL/kg of intravenous fluid was associated with increased 90-day mortality (adjusted odds ratio = 1.64; 95% confidence interval, 1.03-2.61).

Conclusions: In the PROCESS trial, ESRD patients had similar outcomes to non-ESRD patients. Although ESRD patients received less intravenous fluid administration, most received over 30 mL/kg in the first 6 hours. In contrast to non-ESRD patients, receiving  ≥30 mL/kg of intravenous fluid was not associated with worse outcomes in ESRD.
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http://dx.doi.org/10.1002/emp2.12358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813517PMC
February 2021

Innovations and Emerging Therapies to Combat Renal Cell Damage: NAD As a Drug Target.

Antioxid Redox Signal 2021 Mar 17:1-18. Epub 2021 Mar 17.

TES Pharma, Perugia, Italy.

Acute kidney injury (AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is defined by an abrupt deterioration in renal function, clinically manifested by increased serum creatinine levels, decreased urine output, or both. To execute all its functions, namely excretion of waste products, fluid/electrolyte balance, and hormone synthesis, the kidney requires incredible amounts of energy in the form of adenosine triphosphate. Adequate mitochondrial functioning and nicotinamide adenine dinucleotide (NAD) homeostasis are essential to meet these high energetic demands. NAD is a ubiquitous essential coenzyme to many cellular functions. NAD as an electron acceptor mediates metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis, serves as a cosubstrate of aging molecules (, sirtuins), participates in DNA repair mechanisms, and mediates mitochondrial biogenesis. In many forms of AKI and chronic kidney disease, renal function deterioration has been associated with mitochondrial dysfunction and NAD depletion. Based on this, therapies aiming to restore mitochondrial function and increase NAD availability have gained special attention in the last two decades. Experimental and clinical studies have shown that by restoring mitochondrial homeostasis and increasing renal tubulo-epithelial cells, NAD availability, AKI incidence, and chronic long-term complications are significantly decreased. This review covers some general epidemiological and pathophysiological concepts; describes the role of mitochondrial homeostasis and NAD metabolism; and analyzes the underlying rationale and role of NAD aiming therapies as promising preventive and therapeutic strategies for AKI.
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http://dx.doi.org/10.1089/ars.2020.8066DOI Listing
March 2021
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