Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis.

Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted. Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies. Results and Conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.

Serial direct sodium removal in patients with heart failure and diuretic resistance.

AIMS: Loop diuretics may exacerbate cardiorenal syndrome (CRS) in heart failure (HF). Direct sodium removal (DSR) using the peritoneal membrane, in conjunction with complete diuretic withdrawal, may improve CRS and diuretic resistance. METHODS AND RESULTS: Patients with HF requiring high-dose loop diuretics were enrolled in two prospective, single-arm studies: RED DESERT (n = 8 euvolaemic patients), and SAHARA (n = 10 hypervolaemic patients). Loop diuretics were withdrawn, and serial DSR was utilized to achieve and maintain euvolaemia. At baseline, participants required a median 240 mg (interquartile range [IQR] 200-400) oral furosemide equivalents/day, which was withdrawn in all participants during DSR (median time of DSR 4 weeks [IQR 4-6]). Diuretic response (queried by formal 40 mg intravenous furosemide challenge and 6 h urine sodium quantification) increased substantially from baseline (81 ± 37 mmol) to end of DSR (223 ± 71 mmol, p < 0.001). Median time to re-initiate diuretics was 87 days, and the median re-initiation dose was 8% (IQR 6-10%) of baseline. At 1 year, diuretic dose remained substantially below baseline (30 [IQR 7.5-40] mg furosemide equivalents/day). Multiple dimensions of kidney function such as filtration, uraemic toxin excretion, kidney injury, and electrolyte handling improved (p < 0.05 for all). HF-related biomarkers including N-terminal pro-B-type natriuretic peptide, carbohydrate antigen-125, soluble ST2, interleukin-6, and growth differentiation factor-15 (p < 0.003 for all) also improved. CONCLUSIONS: In patients with HF and diuretic resistance, serial DSR therapy with loop diuretic withdrawal was feasible and associated with substantial and persistent improvement in diuretic resistance and several cardiorenal parameters. If replicated in randomized controlled studies, DSR may represent a novel therapy for diuretic resistance and CRS. CLINICAL TRIAL REGISTRATION: RED DESERT (NCT04116034), SAHARA (NCT04882358).

Pragmatic Trial of Messaging to Providers About Treatment of Hyperlipidemia (PROMPT-LIPID): A Randomized Clinical Trial.

BACKGROUND: Lipid-lowering therapy (LLT) is underutilized for very high-risk atherosclerotic cardiovascular disease. PROMPT-LIPID (PRagmatic Trial of Messaging to Providers about Treatment of HyperLIPIDemia) sought to determine whether electronic health record (EHR) alerts improve 90-day LLT intensification in patients with very high-risk atherosclerotic cardiovascular disease. METHODS: PROMPT-LIPID was a pragmatic trial in which cardiovascular and internal medicine clinicians within Yale New Haven Health (New Haven, CT) were cluster-randomized to receive an EHR alert with individualized LLT recommendations or no alert for outpatients with very high-risk atherosclerotic cardiovascular disease and LDL-C (low-density lipoprotein cholesterol), ≥70 mg/dL. The primary outcome was 90-day LLT intensification (change to high-intensity statin and addition of ezetimibe or PCSK9i [proprotein subtilisin/kexin type 9 inhibitors]). Secondary outcomes included LDL-C level, proportion of patients with LDL-C of <70 or < 55 mg/dL, rate of major adverse cardiovascular events, ED visit incidence, and 6-month mortality. Results were analyzed using logistic and linear regression clustered at the provider level. RESULTS: The no-alert group included 47 clinicians and 1370 patients (median age, 71 years; 50.1% female, median LDL-C, 93 mg/dL); the alert group included 49 clinicians and 1130 patients (median age, 72 years; 47% female, median LDL-C 91, mg/dL). The primary outcome was observed in 14.1% of patients in the alert group as compared with 10.4% in the no-alert group. There were no differences in any secondary outcomes at 6 months. Among 542 patients whose clinicians (n=46) did not dismiss the EHR alert recommendations, LLT intensification was significantly greater (21.2% versus 10.4%, odds ratio, 2.33 [95% CI, 1.48-3.66]). CONCLUSIONS: With a real-time, targeted, individualized EHR alert as compared with usual care, the proportion of patients with atherosclerotic cardiovascular disease with LLT intensification was numerically higher but not statistically significant. Among clinicians who did not dismiss the alert, there was a > 2-fold increase in LLT intensification. EHR alerts, coupled with strategies to reduce clinician dismissal, may help address persistent gaps in LDL-C management. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04394715, https://www.clinicaltrials.gov/ct2/show/study/NCT04394715.

COVID-19-Associated Acute Kidney Injury and Longitudinal Kidney Outcomes.

Importance: COVID-19 infection is associated with a high incidence of acute kidney injury (AKI). Although rapid kidney function decline has been reported in the first few months after COVID-19-associated AKI (COVID-AKI), the longer-term association of COVID-AKI with kidney function remains unknown. Objective: To assess long-term kidney outcomes of patients who had COVID-19-associated AKI. Design, Setting, and Participants: This was a retrospective longitudinal multicenter cohort study conducted in a large hospital system using electronic health records data on adult hospitalized patients with AKI and COVID-19 or other illnesses. Included patients were hospitalized during the COVID-19 pandemic (March 2020-June 2022), were screened for SARS-CoV-2, had AKI, and survived to discharge, or had been hospitalized during the 5 years before the pandemic (October 2016-January 2020), had a positive influenza A or B test result, had AKI, and survived to discharge. Patients were followed up for a maximum of 2 years after hospital discharge. Data analyses were performed from December 2022 to November 2023. Exposure: COVID-19 and influenza. Main Outcomes and Measures: The primary outcome was major adverse kidney events (MAKE), defined as a composite of mortality and worsened kidney function (estimated glomerular filtration rate [eGFR] decline by ≥25% from discharge eGFR or kidney failure requiring dialysis). Multivariable time-to-event analyses were performed to compare MAKE between individuals with COVID-AKI and those who had AKI associated with other illnesses hospitalized during the same period. For further comparison, this outcome was assessed for a historic cohort of patients with influenza-associated AKI. Results: The study cohort included 9624 hospitalized patients (mean [SD] age, 69.0 [15.7] years; 4955 [51.5%] females) with AKI, including 987 patients with COVID-AKI, 276 with influenza-associated AKI, and 8361 with AKI associated with other illnesses (other-AKI). Compared with the other 2 groups, patients with COVID-19-associated AKI were slightly younger in age, had a higher baseline eGFR, worse baseline comorbidity scores, higher markers of illness severity, and longer hospital stay. Compared with the other-AKI group, the COVID-AKI group had lower MAKE (adjusted hazard ratio [aHR], 0.67; 95% CI, 0.59-0.75) due to lower all-cause mortality (aHR, 0.31; 95% CI, 0.24-0.39) and lower rates of worsened kidney function (aHR, 0.78; 95% CI, 0.69-0.88). Conclusions and Relevance: The findings of this multicenter cohort study indicate that survivors of hospitalization with COVID-AKI experience lower rates of MAKE, long-term kidney function decline, and mortality compared with patients with AKI associated with other illnesses.

Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects.

SIGNIFICANCE STATEMENT: The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling. BACKGROUND: The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits. METHODS: This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide. RESULTS: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT. CONCLUSIONS: Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov ( NCT03027960 ).

Rationale, Design, and Patient Characteristics of a Cluster-Randomized Pragmatic Trial to Improve Mineralocorticoid Antagonist Use.

BACKGROUND: Despite robust evidence and strong guideline recommendations supporting use of mineralocorticoid receptor antagonists (MRAs) to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF), these medications remain underused in clinical practice. OBJECTIVES: The goal is to determine if providing a tailored best practice alert (BPA) to outpatient providers suggesting guideline-recommended MRAs or information about available hyperkalemia treatment, if present, for patients with HFrEF will increase short-term MRA prescriptions. METHODS: PROMPT-MRA (Pragmatic Trial of Messaging to Providers About Treatment With Mineralocorticoid Receptor Antagonists) is a pragmatic, cluster-randomized, controlled study. A total of 119 providers were randomized to receive a BPA or usual care. During an outpatient visit with participating providers, the BPA displayed recent laboratory test values and ejection fraction. The alert suggested guideline-recommended MRAs for eligible patients with a serum potassium of <5.0 mEq/L or novel potassium binders for those with a serum potassium of ≥5.0 mEq/L, each linked to an order set containing the corresponding medication and laboratory monitoring. RESULTS: PROMPT-MRA completed enrollment with 1,210 patients. The primary outcome of PROMPT-MRA is to determine if a tailored BPA for outpatients with HFrEF will lead to higher MRA prescriptions 6 months following randomization compared with usual care. Secondary outcomes included incidence of hyperkalemia, use of novel potassium binders, heart failure hospitalizations, and mortality. CONCLUSIONS: If effective, the BPA can be scaled to improve population health outcomes with increased MRA prescribing among eligible patients with HFrEF, with or without a history of hyperkalemia. (Pragmatic Trial of Alerts for Use of Mineralocorticoid Receptor Antagonists [PROMPT-MRA]; NCT04903717).

Impact of Digital Health Technology on Quality of Life in Patients With Heart Failure.

BACKGROUND: Digital health tools may improve quality of life (QoL) in patients with heart failure (HF) by promoting self-care, knowledge, and engagement. OBJECTIVES: This study evaluates the effect of 3 digital technologies on QoL in patients with HF. METHODS: A total of 182 patients were randomized to usual care or one of the technologies promoting self-care: Bodyport (cardiac scale), Conversa (conversational platform), or Noom (smartphone application). The primary outcome was 90-day change in QoL, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score (OSS). RESULTS: A total of 151 participants (83%) completed their 90-day surveys. The median age of enrolled participants was 61 years (IQR: 53-69 years), and 37.9% were women. No group had any significant change in KCCQ OSS or improvement relative to usual care. However, symptoms and physical function at 90 days, as assessed by the Total Symptom Score (TSS) and Clinical Summary Score (CSS), were significantly improved in the Noom group relative to usual care: TSS median change of +4.2 points (IQR -1 to +16.7) vs -1 points (IQR: -13.5 to +7.8; P = 0.006); CSS median change of +2.8 points (IQR: -1 to +14.6) vs -3.1 points (IQR: -10.2 to +3; P = 0.002). CONCLUSIONS: Three digital interventions showed no independent effect on QoL as assessed by the KCCQ OSS. However, participants randomized to the Noom technology demonstrated improved KCCQ TSS and CSS relative to usual care. Although digital tools may be an important component of longitudinal care for patients with HF, larger studies are needed to better understand their effectiveness and optimal deployment. (Evaluating Efficacy of Digital Health Technology in the Treatment of Congestive Heart Failure; NCT04394754).

Deep learning prediction of hospital readmissions for asthma and COPD.

QUESTION: Severe asthma and COPD exacerbations requiring hospitalization are linked to increased disease morbidity and healthcare costs. We sought to identify Electronic Health Record (EHR) features of severe asthma and COPD exacerbations and evaluate the performance of four machine learning (ML) and one deep learning (DL) model in predicting readmissions using EHR data. STUDY DESIGN AND METHODS: Observational study between September 30, 2012, and December 31, 2017, of patients hospitalized with asthma and COPD exacerbations. RESULTS: This study included 5,794 patients, 1,893 with asthma and 3,901 with COPD. Patients with asthma were predominantly female (n = 1288 [68%]), 35% were Black (n = 669), and 25% (n = 479) were Hispanic. Black (44 vs. 33%, p = 0.01) and Hispanic patients (30 vs. 24%, p = 0.02) were more likely to be readmitted for asthma. Similarly, patients with COPD readmissions included a large percentage of Blacks (18 vs. 10%, p < 0.01) and Hispanics (8 vs. 5%, p < 0.01). To identify patients at high risk of readmission index hospitalization data of a subset of 2,682 patients, 777 with asthma and 1,905 with COPD, was analyzed with four ML models, and one DL model. We found that multilayer perceptron, the DL method, had the best sensitivity and specificity compared to the four ML methods implemented in the same dataset. INTERPRETATION: Multilayer perceptron, a deep learning method, had the best performance in predicting asthma and COPD readmissions, demonstrating that EHR and deep learning integration can improve high-risk patient detection.

Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis.

BackgroundAcute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN.MethodsIn a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by an aptamer-based assay with AIN and validated the top protein, CXCL9, using sandwich immunoassay. We externally validated these findings in 2 cohorts with biopsy-confirmed diagnoses, termed the validation cohorts, and examined mRNA expression differences in kidney tissue from patients with AIN and individuals in the control group.ResultsIn aptamer-based assay, urinary CXCL9 was 7.6-fold higher in patients with AIN than in individuals in the control group (P = 1.23 × 10-5). Urinary CXCL9 measured by sandwich immunoassay was associated with AIN in the discovery cohort (n = 204; 15% AIN) independently of currently available clinical tests for AIN (adjusted odds ratio for highest versus lowest quartile: 6.0 [1.8-20]). Similar findings were noted in external validation cohorts, where CXCL9 had an AUC of 0.94 (0.86-1.00) for AIN diagnosis. CXCL9 mRNA expression was 3.9-fold higher in kidney tissue from patients with AIN (n = 19) compared with individuals in the control group (n = 52; P = 5.8 × 10-6).ConclusionWe identified CXCL9 as a diagnostic biomarker for AIN using aptamer-based urine proteomics, confirmed this association using sandwich immunoassays in discovery and external validation cohorts, and observed higher expression of this protein in kidney biopsies from patients with AIN.FundingThis study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awards K23DK117065 (DGM), K08DK113281 (KM), R01DK128087 (DGM), R01DK126815 (DGM and LGC), R01DK126477 (KNC), UH3DK114866 (CRP, DGM, and FPW), R01DK130839 (MES), and P30DK079310 (the Yale O'Brien Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Comparative evaluation of glomerular morphometric techniques reveals differential technical artifacts between focal segmental glomerulosclerosis and normal glomeruli.

Morphometric estimates of mean or individual glomerular volume (MGV, IGV) have biological implications, over and above qualitative histologic data. However, morphometry is time-consuming and requires expertise limiting its utility in clinical cases. We evaluated MGV and IGV using plastic- and paraffin-embedded tissue from 10 control and 10 focal segmental glomerulosclerosis (FSGS) mice (aging and 5/6th nephrectomy models) using the gold standard Cavalieri (Cav) method versus the 2-profile and Weibel-Gomez (WG) methods and a novel 3-profile method. We compared accuracy, bias and precision, and quantified results obtained when sampling differing numbers of glomeruli. In both FSGS and controls, we identified an acceptable precision for MGV of 10-glomerular sampling versus 20-glomerular sampling using the Cav method, while 5-glomerular sampling was less precise. In plastic tissue, 2- or 3-profile MGVs showed greater concordance with MGV when using Cav, versus MGV with WG. IGV comparisons using the same glomeruli reported a consistent underestimation bias with both 2- or 3-profile methods versus the Cav method. FSGS glomeruli showed wider variations in bias estimation than controls. Our 3-profile method offered incremental benefit to the 2-profile method in both IGV and MGV estimation (improved correlation coefficient, Lin's concordance and reduced bias). In our control animals, we quantified a shrinkage artifact of 52% from tissue processed for paraffin-embedded versus plastic-embedded tissue. FSGS glomeruli showed overall reduced shrinkage albeit with variable artifact signifying periglomerular/glomerular fibrosis. A novel 3-profile method offers slightly improved concordance with reduced bias versus 2-profile. Our findings have implications for future studies using glomerular morphometry.

Differences in Mortality Among Patients With Asthma and COPD Hospitalized With COVID-19.

BACKGROUND: It remains unclear whether patients with asthma and/or chronic obstructive pulmonary disease (COPD) are at increased risk for severe coronavirus disease 2019 (COVID-19). OBJECTIVE: Compare in-hospital COVID-19 outcomes among patients with asthma, COPD, and no airway disease. METHODS: A retrospective cohort study was conducted on 8,395 patients admitted with COVID-19 between March 2020 and April 2021. Airway disease diagnoses were defined using International Classification of Diseases, 10th Revision codes. Mortality and sequential organ failure assessment (SOFA) scores were compared among groups. Logistic regression analysis was used to identify and adjust for confounding clinical features associated with mortality. RESULTS: The median SOFA score in patients without airway disease was 0.32 and mortality was 11%. In comparison, asthma patients had lower SOFA scores (median 0.15; P < .01) and decreased mortality, even after adjusting for age, diabetes, and other confounders (odds ratio 0.65; P = .01). Patients with COPD had higher SOFA scores (median 0.86; P < .01) and increased adjusted odds of mortality (odds ratio 1.40; P < .01). Blood eosinophil count of 200 cells/µL or greater, a marker of type 2 inflammation, was associated with lower mortality across all groups. Importantly, patients with asthma showed improved outcomes even after adjusting for eosinophilia, indicating that noneosinophilic asthma was associated with protection as well. CONCLUSIONS: COVID-19 severity was increased in patients with COPD and decreased in those with asthma, eosinophilia, and noneosinophilic asthma, independent of clinical confounders. These findings suggest that COVID-19 severity may be influenced by intrinsic immunological factors in patients with airway diseases, such as type 2 inflammation.

Evaluation of Plasma Biomarkers to Predict Major Adverse Kidney Events in Hospitalized Patients With COVID-19.

RATIONALE & OBJECTIVE: Patients hospitalized with COVID-19 are at increased risk for major adverse kidney events (MAKE). We sought to identify plasma biomarkers predictive of MAKE in patients hospitalized with COVID-19. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: A total of 576 patients hospitalized with COVID-19 between March 2020 and January 2021 across 3 academic medical centers. EXPOSURE: Twenty-six plasma biomarkers of injury, inflammation, and repair from first available blood samples collected during hospitalization. OUTCOME: MAKE, defined as KDIGO stage 3 acute kidney injury (AKI), dialysis-requiring AKI, or mortality up to 60 days. ANALYTICAL APPROACH: Cox proportional hazards regression to associate biomarker level with MAKE. We additionally applied the least absolute shrinkage and selection operator (LASSO) and random forest regression for prediction modeling and estimated model discrimination with time-varying C index. RESULTS: The median length of stay for COVID-19 hospitalization was 9 (IQR, 5-16) days. In total, 95 patients (16%) experienced MAKE. Each 1 SD increase in soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 was significantly associated with an increased risk of MAKE (adjusted HR [AHR], 2.30 [95% CI, 1.86-2.85], and AHR, 2.26 [95% CI, 1.73-2.95], respectively). The C index of sTNFR1 alone was 0.80 (95% CI, 0.78-0.84), and the C index of sTNFR2 was 0.81 (95% CI, 0.77-0.84). LASSO and random forest regression modeling using all biomarkers yielded C indexes of 0.86 (95% CI, 0.83-0.89) and 0.84 (95% CI, 0.78-0.91), respectively. LIMITATIONS: No control group of hospitalized patients without COVID-19. CONCLUSIONS: We found that sTNFR1 and sTNFR2 are independently associated with MAKE in patients hospitalized with COVID-19 and can both also serve as predictors for adverse kidney outcomes. PLAIN-LANGUAGE SUMMARY: Patients hospitalized with COVID-19 are at increased risk for long-term adverse health outcomes, but not all patients suffer long-term kidney dysfunction. Identification of patients with COVID-19 who are at high risk for adverse kidney events may have important implications in terms of nephrology follow-up and patient counseling. In this study, we found that the plasma biomarkers soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 measured in hospitalized patients with COVID-19 were associated with a greater risk of adverse kidney outcomes. Along with clinical variables previously shown to predict adverse kidney events in patients with COVID-19, both sTNFR1 and sTNFR2 are also strong predictors of adverse kidney outcomes.

A randomized clinical trial assessing the effect of automated medication-targeted alerts on acute kidney injury outcomes.

Acute kidney injury is common among hospitalized individuals, particularly those exposed to certain medications, and is associated with substantial morbidity and mortality. In a pragmatic, open-label, National Institutes of Health-funded, parallel group randomized controlled trial (clinicaltrials.gov NCT02771977), we investigate whether an automated clinical decision support system affects discontinuation rates of potentially nephrotoxic medications and improves outcomes in patients with AKI. Participants included 5060 hospitalized adults with AKI and an active order for any of three classes of medications of interest: non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, or proton pump inhibitors. Within 24 hours of randomization, a medication of interest was discontinued in 61.1% of the alert group versus 55.9% of the usual care group (relative risk 1.08, 1.04 - 1.14, p = 0.0003). The primary outcome - a composite of progression of acute kidney injury, dialysis, or death within 14 days - occurred in 585 (23.1%) of individuals in the alert group and 639 (25.3%) of patients in the usual care group (RR 0.92, 0.83 - 1.01, p = 0.09). Trial Registration Clinicaltrials.gov NCT02771977.

Expert Consensus on the Nephrotoxic Potential of 195 Medications in the Non-intensive Care Setting: A Modified Delphi Method.

INTRODUCTION: Nephrotoxin exposure is significantly associated with acute kidney injury (AKI) development. A standardized list of nephrotoxic medications to surveil and their perceived nephrotoxic potential (NxP) does not exist for non-critically ill patients. OBJECTIVE: This study generated consensus on the nephrotoxic effect of 195 medications used in the non-intensive care setting. METHODS: Potentially nephrotoxic medications were identified through a comprehensive literature search, and 29 participants with nephrology or pharmacist expertise were identified. The primary outcome was NxP by consensus. Participants rated each drug on a scale of 0-3 (not nephrotoxic to definite nephrotoxicity). Group consensus was met if ≥ 75% of responses were one single rating or a combination of two consecutive ratings. If ≥ 50% of responses indicated "unknown" or not used in the non-intensive care setting, the medication was removed for consideration. Medications not meeting consensus for a given round were included in the subsequent round(s). RESULTS: A total of 191 medications were identified in the literature, with 4 medications added after the first round from participants' recommendations. NxP index rating consensus after three rounds was: 14 (7.2%) no NxP in almost all situations (rating 0); 62 (31.8%) unlikely/possibly nephrotoxic (rating 0.5); 21 (10.8%) possibly nephrotoxic (rating 1); 49 (25.1%) possibly/probably nephrotoxic (rating 1.5); 2 (1.0%) probably nephrotoxic (rating 2); 8 (4.1%) probably/definite nephrotoxic (rating 2.5); 0 (0.0%) definitely nephrotoxic (rating 3); and 39 (20.0%) medications were removed from consideration. CONCLUSIONS: NxP index rating provides clinical consensus on perceived nephrotoxic medications in the non-intensive care setting and homogeneity for future clinical evaluations and research.

Hypertension, Blood Pressure Variability, and Acute Kidney Injury in Hospitalized Children.

Background Although hypertensive blood pressure measurements are common in hospitalized children, the degree of inpatient hypertension and blood pressure variability (BPV) associated with end organ complications like acute kidney injury (AKI) is unknown. Methods and Results All analyses are based on a retrospective cohort of children aged 1 to 17 years with ≥2 creatinine measurements during admission from 2014 to 2018. We used time-updated Cox models to evaluate the association between BPV and hypertension with AKI. Time-varying BPV and hypertension were based on blood pressure in the preceding 72 hours. For the analysis of hypertension and AKI, we excluded patients on vasopressors to ensure comparison between hypertensive and normotensive patients. During 5425 pediatric encounters, 258 430 blood pressure measurements were recorded (median [interquartile range] 22 [11-47] readings per encounter). Among all measurements, 32.7% were ≥95th percentile and 18.9% were ≥99th percentile for age, sex, and height. AKI occurred in 389 (7.2%) encounters. We observed a U-shaped relationship between mean blood pressure and incident AKI. BPV was associated with AKI, with the largest effect sizes in the systolic and mean arterial pressure variability measures. Multiple hypertension thresholds were associated with AKI after controlling for confounders. In an additional multivariable model adjusted for BPV, the association between hypertension and AKI was attenuated but remained significant for hypertension defined as three stage 2 measurements in 1 day (hazard ratio, 1.43 [95% CI, 1.01-2.01]). Conclusions Hypertension and BPV are associated with AKI in hospitalized children. Future studies are needed to determine how pharmacologic and nonpharmacologic interventions modify AKI risk in pediatric inpatients with hypertension.