CCL14 Predicts Oliguria and Dialysis Requirement in Patients with Moderate to Severe Acute Kidney Injury.

INTRUDUCTION: AKI is a frequent complication in critical illness and portends poor outcome. CCL14 has been validated to predict persistent severe AKI in critically ill patients. We examined the association of CCL14 with urine output within 48 hours. METHODS: In pooled data from 2 studies of critically ill patients with KDIGO stage 2-3 AKI, CCL14 was measured by NEPHROCLEAR™CCL14 Test on the Astute 140® Meter, and divided to low, intermediate and high categories (1.3 and 13 ng/mL). Average hourly urine output over 48 hours, stage 3 AKI per urine output criterion on day 2, and composite of dialysis or death within 7 days were examined using multivariable mixed, and logistic regression models. RESULTS: Of the 497 subjects with median age of 65 [56-74] years, 49% (242/497) were on diuretics. CCL14 concentration was low in 219 (44%), intermediate in 217 (44%), and high in 61 (12%) patients. In mixed regression analysis, urine output trajectory over time was different within each CCL14 risk category based on diuretic use due to significant three-way interaction (p < 0.001). In logistic regression analysis CCL14 risk category was independently associated with low urine output on day 2 (KDIGO stage 3) adjusted for diuretic use and baseline clinical variables and composite of dialysis or death within 7 days (adjusted for urine output within 48 hours of CCL14 measurement). CONCLUSIONS: CCL14 measured in patients with moderate to severe AKI is associated with urine output trajectory within 48 hours, oliguria on day 2, and dialysis within 7 days.

CCL14 testing to guide clinical practice in patients with AKI: Results from an international expert panel.

PURPOSE: Urinary C-C motif chemokine ligand 14 (CCL14) is a strong predictor of persistent stage 3 acute kidney injury (AKI). Multiple clinical actions are recommended for AKI but how these are applied in individual patients and how the CCL14 test results may impact their application is unknown. METHODS: We assembled an international panel of 12 experts and conducted a modified Delphi process to evaluate patients at risk for persistent stage 3 AKI (lasting 72 hours or longer). Using a Likert scale, we rated 11 clinical actions based on international guidelines applied to each case before and after CCL14 testing and analyzed the association between the strength and direction of recommendations and CCL14 results. RESULTS: The strength and direction of clinical recommendations were strongly influenced by CCL14 results (P < 0.001 for the interaction). Nine (82%) recommendations for clinical actions were significantly impacted by CCL14 results (P < 0.001 comparing low to highest CCL14 risk category). CONCLUSIONS: Most recommendations for care of patients with stage 2-3 by an international panel of experts were strongly modified by CCL14 test results. This work should set the stage for clinical practice protocols and studies to determine the effects of recommended actions informed by CCL14.

"Renal": the first forbidden word in the medical lexicon.

In October 2023 a letter appeared in The Lancet summarizing the view, of more than 200 physicians from 25 countries, that attempts to censor physician communication by forbidding the word Renal are both misguided and harmful [1]. Since letters are necessarily constrained by length, we now present a more comprehensive report on this issue.

Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials.

Acute kidney injury (AKI) often complicates sepsis and is associated with high morbidity and mortality. In recent years, several important clinical trials have improved our understanding of sepsis-associated AKI (SA-AKI) and impacted clinical care. Advances in sub-phenotyping of sepsis and AKI and clinical trial design offer unprecedented opportunities to fill gaps in knowledge and generate better evidence for improving the outcome of critically ill patients with SA-AKI. In this manuscript, we review the recent literature of clinical trials in sepsis with focus on studies that explore SA-AKI as a primary or secondary outcome. We discuss lessons learned and potential opportunities to improve the design of clinical trials and generate actionable evidence in future research. We specifically discuss the role of enrichment strategies to target populations that are most likely to derive benefit and the importance of patient-centered clinical trial endpoints and appropriate trial designs with the aim to provide guidance in designing future trials.

Distribution of Acute and Chronic Kidney Disease Across Clinical Phenotypes for Sepsis.

BACKGROUND: Sepsis is the most common cause of acute kidney injury (AKI) in critically ill patients. Four phenotypes (α, ß, γ, δ) for sepsis, which have different outcomes and responses to treatment, were described using routine clinical data in the electronic health record. RESEARCH QUESTION: Do the frequencies of AKI, acute kidney disease (AKD), chronic kidney disease (CKD), and AKI on CKD differ by sepsis phenotype? STUDY DESIGN AND METHODS: This was a secondary analysis of a randomized clinical trial of early resuscitation, including patients with septic shock at 31 sites. After excluding patients with end-stage kidney disease and missing data, we determined frequencies of the following clinical outcomes: AKI (defined within 24 h as Kidney Disease: Improving Global Outcomes stages 2 or 3 or stage 1 with tissue inhibitor of metalloproteinases-2 × insulin-like growth factor binding protein 7 value of > 2.0), CKD, and AKD (persistence of AKI at any stage on day 7 after enrollment) across four phenotypes. We performed multivariable logistic regression to assess the risk-adjusted association between development of AKI and AKD and phenotype. RESULTS: Among 1,090 eligible patients, 543 patients (50%) had AKI. Across phenotypes, the frequencies of AKI varied, being highest in the δ and ß phenotypes (78% and 71%, respectively) and the lowest in the α phenotype (26%; P < .001). AKD occurred most often in the δ phenotype (41%) and least often in the α phenotype (8%; P < .001). The highest frequencies of CKD and of AKI on CKD were found in the ß phenotype (53% and 38% respectively; P < .001 for both). In the multivariable logistic regression models (α phenotype as reference), δ phenotype showed the strongest association with AKI (OR, 12.33; 95% CI, 7.81-19.47; P < .001) and AKD (OR, 9.18; 95% CI, 5.44-15.51; P < .001). INTERPRETATION: The rates of AKI and AKD differed across clinical sepsis phenotypes and are more common among patients with phenotypes ß and δ. Phenotype ß showed a higher level of underlying CKD that predisposed patients to new AKI. The α and γ phenotypes showed lower frequencies of AKI and less progression to AKD.

Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL).

PURPOSE: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety. METHODS: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition. RESULTS: Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0-24] and 14 [0-24], number of days alive and discharged from the ICU through day 28 were 15 [0-22] and 10 [0-22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group. CONCLUSION: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified.

Acute kidney disease beyond day 7 after major surgery: a secondary analysis of the EPIS-AKI trial.

PURPOSE: Acute kidney disease (AKD) is a significant health care burden worldwide. However, little is known about this complication after major surgery. METHODS: We conducted an international prospective, observational, multi-center study among patients undergoing major surgery. The primary study endpoint was the incidence of AKD (defined as new onset of estimated glomerular filtration rate (eCFR) < 60 ml/min/1.73 m2 present on day 7 or later) among survivors. Secondary endpoints included the relationship between early postoperative acute kidney injury (AKI) (within 72 h after major surgery) and subsequent AKD, the identification of risk factors for AKD, and the rate of chronic kidney disease (CKD) progression in patients with pre-existing CKD. RESULTS: We studied 9510 patients without pre-existing CKD. Of these, 940 (9.9%) developed AKD after 7 days of whom 34.1% experiencing an episode of early postoperative-AKI. Rates of AKD after 7 days significantly increased with the severity (19.1% Kidney Disease Improving Global Outcomes [KDIGO] 1, 24.5% KDIGO2, 34.3% KDIGO3; P < 0.001) and duration (15.5% transient vs 38.3% persistent AKI; P < 0.001) of early postoperative-AKI. Independent risk factors for AKD included early postoperative-AKI, exposure to perioperative nephrotoxic agents, and postoperative pneumonia. Early postoperative-AKI carried an independent odds ratio for AKD of 2.64 (95% confidence interval [CI] 2.21-3.15). Of 663 patients with pre-existing CKD, 42 (6.3%) had worsening CKD at day 90. In patients with CKD and an episode of early AKI, CKD progression occurred in 11.6%. CONCLUSION: One in ten major surgery patients developed AKD beyond 7 days after surgery, in most cases without an episode of early postoperative-AKI. However, early postoperative-AKI severity and duration were associated with an increased rate of AKD and early postoperative-AKI was strongly associated with AKD independent of all other potential risk factors.

Fibroblastic reticular cell-derived exosomes are a promising therapeutic approach for septic acute kidney injury.

Sepsis-induced acute kidney injury (S-AKI) is highly lethal, and effective drugs for treatment are scarce. Previously, we reported the robust therapeutic efficacy of fibroblastic reticular cells (FRCs) in sepsis. Here, we demonstrate the ability of FRC-derived exosomes (FRC-Exos) to improve C57BL/6 mouse kidney function following cecal ligation and puncture-induced sepsis. In vivo imaging confirmed that FRC-Exos homed to injured kidneys. RNA-Seq analysis of FRC-Exo-treated primary kidney tubular cells (PKTCs) revealed that FRC-Exos influenced PKTC fate in the presence of lipopolysaccharide (LPS). FRC-Exos promoted kinase PINK1-dependent mitophagy and inhibited NLRP3 inflammasome activation in LPS-stimulated PKTCs. To dissect the mechanism underlying the protective role of Exos in S-AKI, we examined the proteins within Exos by mass spectrometry and found that CD5L was the most upregulated protein in FRC-Exos compared to macrophage-derived Exos. Recombinant CD5L treatment in vitro attenuated kidney cell swelling and surface bubble formation after LPS stimulation. FRCs were infected with a CD5L lentivirus to increase CD5L levels in FRC-Exos, which were then modified in vitro with the kidney tubular cell targeting peptide LTH, a peptide that binds to the biomarker protein kidney injury molecule-1 expressed on injured tubule cells, to enhance binding specificity. Compared with an equivalent dose of recombinant CD5L, the modified CD5L-enriched FRC-Exos selectively bound PKTCs, promoted kinase PINK-ubiquitin ligase Parkin-mediated mitophagy, inhibiting pyroptosis and improved kidney function by hindering NLRP3 inflammasome activation, thereby improving the sepsis survival rate. Thus, strategies to modify FRC-Exos could be a new avenue in developing therapeutics against kidney injury.

Designing acute kidney injury clinical trials.

Acute kidney injury (AKI) is a common clinical condition with various causes and is associated with increased mortality. Despite advances in supportive care, AKI increases not only the risk of premature death compared with the general population but also the risk of developing chronic kidney disease and progressing towards kidney failure. Currently, no specific therapy exists for preventing or treating AKI other than mitigating further injury and supportive care. To address this unmet need, novel therapeutic interventions targeting the underlying pathophysiology must be developed. New and well-designed clinical trials with appropriate end points must be subsequently designed and implemented to test the efficacy of such new interventions. Herein, we discuss predictive and prognostic enrichment strategies for patient selection, as well as primary and secondary end points that can be used in different clinical trial designs (specifically, prevention and treatment trials) to evaluate novel interventions and improve the outcomes of patients at a high risk of AKI or with established AKI.

Endotoxemia Correlates with Kidney Function and Length of Stay in Critically Ill Patients.

INTRODUCTION: Endotoxin is a key driver of sepsis, which frequently causes acute kidney injury (AKI). However, endotoxins may also be found in non-bacteremic critically ill patients, likely from intestinal translocation. Preclinical models show that endotoxins can directly injure the kidneys, and in COVID-19 patients, endotoxemia correlated with AKI. We sought to determine correlations between endotoxemia and kidney and hospital outcomes in a broad group of critically ill patients. METHODS: In this single-center, serial prospective study, 124 predominantly Caucasian adult patients were recruited within 48 h of admission to Stony Brook University Hospital Intensive Care Unit (ICU). Demographics, vital signs, laboratory data, and outcomes were collected. Circulating endotoxin was measured on days 1, 4, and 8 using the endotoxin activity assay (EAA). The association of EAA with outcomes was examined with EAA: (1) categorized as <0.6, ≥0.6, and nonresponders (NRs); and (2) used as a continuous variable. RESULTS: Patients with EAA ≥0.6 had a higher prevalence of proteinuria, and lower arterial oxygen saturation (SaO2) to fraction of inspired oxygen (FiO2) (SaO2/FiO2) ratio versus patients with EAA <0.6. EAA levels positively correlated with serum creatinine (sCr) levels on day 1. Patients whose EAA level stayed ≥0.6 had a slower decline in sCr compared to those whose EAA started at ≥0.6 and subsequently declined. Patients with AKI stage 1 and EAA ≥0.6 on day 1 showed slower decline in sCr compared to patients with stage 1 AKI and EAA <0.6. EAA ≥0.6 and NR patients had longer hospital stay and delayed ICU discharge versus EAA <0.6. CONCLUSIONS: High EAA levels correlated with worse kidney function and outcomes. Patients whose EAA levels fell, and those with AKI stage I and day 1 EAA <0.6 recovered more quickly compared to those with EAA ≥0.6, suggesting that removal of circulating endotoxins may be beneficial in critically ill patients.

Contrast-associated acute kidney injury and cardiovascular events: a secondary analysis of the PRESERVE cohort.

Background: Contrast-associated acute kidney injury (CA-AKI) has been associated with a higher risk of cardiovascular (CV) events. We studied the risk of CV events in chronic kidney disease (CKD) patients undergoing angiography and whether biomarkers can predict such events. We also explored whether CA-AKI mediates the association of pre-angiography estimated glomerular filtration rate (eGFR) on CV events. Methods: We analysed participants from the Prevention of Serious Adverse Events following the Angiography (PRESERVE) trial. Urinary tissue inhibitor of matrix metalloproteinase [TIMP]-2 and insulin growth factor binding protein [IGFBP]-7, plasma brain-type natriuretic peptide (BNP), high sensitivity C-reactive protein (hs-CRP), and serum cardiac troponin-I (Tn-I) were assayed before and after angiography. We assessed the composite risk of CV events by day 90. Results: Of the 922 participants, 119 (12.9%) developed CV events, and 73 (7.9%) developed CA-AKI. Most cases of CA-AKI (90%) were stage 1. There were no differences in urinary [TIMP-2]•[IGFBP7] concentrations or the proportion of patients with CA-AKI among those with and without CV events. Higher BNP, Tn-I, and hs-CRP were associated with CV events, but their discriminatory capacity was modest (AUROC <0.7). CA-AKI did not mediate the association of the pre-angiography eGFR on CV events. Conclusions: Most episodes of CA-AKI are stage 1 AKI and are not associated with CV events. Less severe CA-AKI episodes also did not mediate the risk of pre-angiography eGFR on CV events. Our findings suggest that most CV events after contrast procedures are due to underlying CKD and CV risk factors rather than less severe CA-AKI episodes and should help enhance the utilization of clinically indicated contrast procedures among high-risk patients with CKD. Further research is required to examine whether moderate-to-severe CA-AKI episodes are associated with CV events.

Nomenclature of Extracorporeal Blood Purification Therapies for Acute Indications: The Nomenclature Standardization Conference.

The development of new extracorporeal blood purification (EBP) techniques has led to increased application in clinical practice but also inconsistencies in nomenclature and misunderstanding. In November 2022, an international consensus conference was held to establish consensus on the terminology of EBP therapies. It was agreed to define EBP therapies as techniques that use an extracorporeal circuit to remove and/or modulate circulating substances to achieve physiological homeostasis, including support of the function of specific organs and/or detoxification. Specific acute EBP techniques include renal replacement therapy, isolated ultrafiltration, hemoadsorption, and plasma therapies, all of which can be applied in isolation and combination. This paper summarizes the proposed nomenclature of EBP therapies and serves as a framework for clinical practice and future research.

Bayesian methods: a potential path forward for sepsis trials.

BACKGROUND: Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods. METHODS: We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment. RESULTS: In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored. CONCLUSIONS: Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive.

Moving toward a contemporary classification of drug-induced kidney disease.

Drug-induced kidney disease (DIKD) accounts for about one-fourth of all cases of acute kidney injury (AKI) in hospitalized patients, especially in critically ill setting. There is no standard definition or classification system of DIKD. To address this, a phenotype definition of DIKD using expert consensus was introduced in 2015. Recently, a novel framework for DIKD classification was proposed that incorporated functional change and tissue damage biomarkers. Medications were stratified into four categories, including "dysfunction without damage," "damage without dysfunction," "both dysfunction and damage," and "neither dysfunction nor damage" using this novel framework along with predominant mechanism(s) of nephrotoxicity for drugs and drug classes. Here, we briefly describe mechanisms and provide examples of drugs/drug classes related to the categories in the proposed framework. In addition, the possible movement of a patient's kidney disease between certain categories in specific conditions is considered. Finally, opportunities and barriers to adoption of this framework for DIKD classification in real clinical practice are discussed. This new classification system allows congruencies for DIKD with the proposed categorization of AKI, offering clarity as well as consistency for clinicians and researchers.

Endotoxic Septic Shock: Diagnosis and Treatment.

Endotoxin, also referred to as lipopolysaccharide (LPS), is a potent stimulator of the inflammatory cascade which may progress to sepsis and septic shock. The term endotoxic septic shock has been used for patients who have a clinical phenotype that is characterized by high endotoxin activity in addition to a high burden of organ failure; especially a pattern of organ failure including hepatic dysfunction, acute kidney injury, and various forms of endothelial dysfunction. Endotoxic septic shock has been a target for drug therapy for decades with no success. A likely barrier to their success was the inability to quantify endotoxin in the bloodstream. The Endotoxin Activity Assay (EAA) is positioned to change this landscape. In addition, medical devices using adsorptive technology in an extra-corporeal circulation has been shown to remove large quantities of endotoxin from the bloodstream. Focusing on the use of EAA to determine high concentrations of endotoxin will allow patients with endotoxic septic shock to be identified quickly and these patients may benefit most from removal of endotoxin using extracorporeal methods.

The role of endotoxin in septic shock.

Septic shock can be caused by a variety of mechanisms including direct effects of bacterial toxins such as endotoxin. Annually, approximately 5-7 million patients worldwide develop sepsis with very high endotoxin activity in the blood and more than half die. The term endotoxic septic shock has been used for these patients but it is important to emphasize that endotoxin may be a factor in all forms of septic shock including non-bacterial etiologies like COVID-19 since translocation of bacterial products is a common feature of septic shock. A pattern of organ failure including hepatic dysfunction, acute kidney injury and various forms of endothelial dysfunction ranging from disseminated intravascular coagulation to thrombotic microangiopathy characterize endotoxic septic shock. However, while characteristic, the clinical phenotype is not unique to patients with high endotoxin, and the diagnosis relies on the measurement of endotoxin activity in addition to clinical assessment. Therapies for endotoxic septic shock are limited with immune modulating therapies under investigation and extracorporeal blood purification still controversial in many parts of the world.

Standardization of Nomenclature for the Mechanisms and Materials Utilized for Extracorporeal Blood Purification.

In order to develop a standardized nomenclature for the mechanisms and materials utilized during extracorporeal blood purification, a consensus expert conference was convened in November 2022. Standardized nomenclature serves as a common language for reporting research findings, new device development, and education. It is also critically important to support patient safety, allow comparisons between techniques, materials, and devices, and be essential for defining and naming innovative technologies and classifying devices for regulatory approval. The multidisciplinary conference developed detailed descriptions of the performance characteristics of devices (membranes, filters, and sorbents), solute and fluid transport mechanisms, flow parameters, and methods of treatment evaluation. In addition, nomenclature for adsorptive blood purification techniques was proposed. This report summarizes these activities and highlights the need for standardization of nomenclature in the future to harmonize research, education, and innovation in extracorporeal blood purification therapies.