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Uromodulin, produced exclusively in the kidney's thick ascending limb, is a biomarker of kidney tubular health. However, the relationship between urine uromodulin and histologic changes in the kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histologic findings in humans and mice.We investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histologic features in 364 participants at two academic medical centers from 2015 to 2018 using multivariable linear regression models. This relationship was further examined by comparison of uromodulin staining in murine models of kidney fibrosis and repair.We found urine uromodulin to be correlated with serum creatinine (rho=-0.43;Higher urine uromodulin is independently associated with lower tubulointerstitial fibrosis in both human kidney biopsies and a mouse model of fibrosis.This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_08_10_CJN04360422.mp3.

Background: Following treatment for acute decompensated heart failure, in-hospital observation on oral diuretics (OOD) is recommended, assuming it provides actionable information on discharge diuretic dosing and thus reduces readmissions. Methods: In the Mechanisms of Diuretic Resistance (MDR) cohort, we analyzed in-hospital measures of diuretic response, provider’s decisions, and diuretic response ≈30 days postdischarge. In a Yale multicenter cohort, we assessed if in-hospital OOD was associated with 30-day readmission risk. The main objective of this study was to evaluate the utility of in-hospital OOD. Results: Of the 468 patients in the MDR cohort, 57% (N=265) underwent in-hospital OOD. During the OOD, weight change and net fluid balance correlated poorly with each other ( r =0.36). Discharge diuretic dosing was similar between patients who had increased, stable, or decreased weight (decreased discharge dose from OOD dose in 77% versus 72% versus 70%, respectively), net fluid status (decreased discharge dose from OOD dose in 100% versus 69% versus 74%, respectively), and urine output (decreased discharge dose from OOD dose in 69% versus 79% versus 72%, respectively) during the 24-hour OOD period ( P >0.27 for all). In participants returning at 30 days for formal quantification of outpatient diuretic response (n=98), outpatient and inpatient OOD natriuresis was poorly correlated ( r =0.26). In the Yale multicenter cohort (n=18 454 hospitalizations), OOD occurred in 55% and was not associated with 30-day hospital readmission (hazard ratio, 0.98 [95% CI, 0.93–1.05]; P =0.51). Conclusions: In-hospital OOD did not provide actionable information on diuretic response, was not associated with outpatient dose selection, did not predict subsequent outpatient diuretic response, and was not associated with lower readmission rate. Additional research is needed to replicate these findings and understand if these resources could be better allocated elsewhere. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02546583.

As the biomedical community produces datasets that are increasingly complex and high dimensional, there is a need for more sophisticated computational tools to extract biological insights. We present Multiscale PHATE, a method that sweeps through all levels of data granularity to learn abstracted biological features directly predictive of disease outcome. Built on a coarse-graining process called diffusion condensation, Multiscale PHATE learns a data topology that can be analyzed at coarse resolutions for high-level summarizations of data and at fine resolutions for detailed representations of subsets. We apply Multiscale PHATE to a coronavirus disease 2019 (COVID-19) dataset with 54 million cells from 168 hospitalized patients and find that patients who die show CD16(hi)CD66b(lo) neutrophil and IFN-γ(+) granzyme B(+) Th17 cell responses. We also show that population groupings from Multiscale PHATE directly fed into a classifier predict disease outcome more accurately than naive featurizations of the data. Multiscale PHATE is broadly generalizable to different data types, including flow cytometry, single-cell RNA sequencing (scRNA-seq), single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq), and clinical variables.

Treatment of severe inpatient hypertension (HTN) that develops during hospitalization is not informed by guidelines. Intravenous (i.v.) antihypertensives are used to manage severe HTN even in the absence of acute target organ damage; however they may result in unpredictable blood pressure (BP) reduction and cardiovascular events. Our goal was to assess the association between i.v. antihypertensives and clinical outcomes in this population.This is a multihospital retrospective study of adults admitted for reasons other than HTN who develop severe HTN during hospitalization without acute target end organ damage. We defined severe HTN as BP elevation of systolic180 or diastolic110 mmHg. Treatment was defined as receiving i.v. antihypertensives within 3 h of BP elevation. We used overlap propensity score weighted Cox models to study the association between treatment and clinical outcomes during index hospitalization.Of 224 265 unique, nonintensive care unit hospitalizations, 20 383 (9%) developed severe HTN, of which 5% received i.v. antihypertensives and 79% were untreated within 3 h of severe BP elevation. In the overlap propensity weighted population, patients who received i.v. antihypertensives were more likely to develop myocardial injury (5.9% in treated versus 3.6% in untreated; hazard ratio [HR]: 1.6 [1.13, 2.24]). Treatment was not associated with increased risk of stroke (HR: 0.7 [0.3, 1.62]), acute kidney injury (HR: 0.97 [0.81, 1.17]), or death (HR: 0.86 [0.49, 1.51]).Intravenous antihypertensives were associated with increased risk of myocardial injury in patients who develop severe HTN during hospitalization. These results suggest that i.v. antihypertensives should be used with caution in patients without acute target organ damage.

Heart failure (HF) is one of the most common causes of hospitalization in the United States and carries a significant risk of morbidity and mortality. Use of evidence-based interventions may improve outcomes, but their use is encumbered in part by limitations in accurate prognostication. The REVeAL-HF (Risk EValuation And its Impact on ClinicAL Decision Making and Outcomes in Heart Failure) trial is the first to definitively evaluate the impact of knowledge about prognosis on clinical decision making and patient outcomes. The REVeAL-HF trial is a pragmatic, completely electronic, randomized controlled trial that has completed enrollment of 3,124 adults hospitalized for HF, defined as having an N-terminal pro–B-type natriuretic peptide level of >500 pg/ml and receiving intravenous diuretic agents within 24 h of admission. Patients randomized to the intervention had their risk of 1-year mortality generated with information in the electronic health record and presented to their providers, who had the option to give feedback on their impression of this risk assessment. The authors are examining the impact of this information on clinical decision-making (use of HF pharmacotherapies, referral to electrophysiology, palliative care referral, and referral for advanced therapies like heart transplantation or mechanical circulatory support) and patient outcomes (length of stay, post-discharge 30-day rehospitalizations, and 1-year mortality). The REVeAL-HF trial will definitively examine whether knowledge about prognosis in HF has an impact on clinical decision making and patient outcomes. It will also examine the relationship between calculated, perceived, and real risk of mortality in this patient population. (Risk EValuation And Its Impact on ClinicAL Decision Making and Outcomes in Heart Failure [REVeAL-HF]; NCT03845660 ).

Background Acute kidney injury (AKI) is a sudden episode of kidney damage or failure affecting up to 15% of hospitalized patients and is associated with serious short- and long-term complications, mortality, and health care costs. Current practices to diagnose and stage AKI are variable and do not factor in our improved understanding of the biological and analytical variability of creatinine. In addition, the emergence of biomarkers, for example, cystatin C, insulin-like growth factor binding protein 7, and tissue inhibitor of metalloproteinases 2, and electronic notification tools for earlier detection of AKI, highlights the need for updated recommendations to address these developments. Content This AACC Academy guidance document is intended to provide laboratorians and clinicians up-to-date information regarding current best practices for the laboratory investigation of AKI. Topics covered include: clinical indications for further investigating potential AKI, analytical considerations for creatinine assays, the impact of biological variability on diagnostic thresholds, defining “baseline” creatinine, role of traditional markers (urine sodium, fractional excretion of sodium, fractional excretion of urea, and blood urea-to-creatinine ratio), urinary microscopic examination, new biomarkers, improving AKI-associated test utilization, and the utility of automated AKI alerts. Summary The previous decade brought us a significant number of new studies characterizing the performance of existing and new biomarkers, as well as potential new tools for early detection and notification of AKI. This guidance document is intended to inform clinicians and laboratorians on the best practices for the laboratory investigation of AKI, based on expert recommendations where the preponderance of evidence is available.

ImportanceGuidelines recommend that all children and adolescents with hypertension undergo evaluation for secondary causes. Identifying clinical factors associated with secondary hypertension may decrease unnecessary testing for those with primary hypertension.ObjectiveTo determine the utility of the clinical history, physical examination, and 24-hour ambulatory blood pressure monitoring for differentiating primary hypertension from secondary hypertension in children and adolescents (aged ≤21 years).Data Sources and Study SelectionThe databases of MEDLINE, PubMed Central, Embase, Web of Science, and Cochrane Library were searched from inception to January 2022 without language limits. Two authors identified studies describing clinical characteristics in children and adolescents with primary and secondary hypertension.Data Extraction and SynthesisFor each clinical finding in each study, a 2 × 2 table was created that included the number of patients with and without the finding who had primary vs secondary hypertension. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool.Main Outcomes and MeasuresRandom-effects modeling was used to calculate sensitivity, specificity, and likelihood ratios (LRs).ResultsOf 3254 unique titles and abstracts screened, 30 studies met inclusion criteria for the meta-analysis and 23 (N = 4210 children and adolescents) were used for pooling in the meta-analysis. In the 3 studies conducted at primary care clinics or school-based screening clinics, the prevalence of secondary hypertension was 9.0% (95% CI, 4.5%-15.0%). In the 20 studies conducted at subspecialty clinics, the prevalence of secondary hypertension was 44% (95% CI, 36%-53%). The demographic findings most strongly associated with secondary hypertension were family history of secondary hypertension (sensitivity, 0.46; specificity, 0.90; LR, 4.7 [95% CI, 2.9-7.6]), weight in the 10th percentile or lower for age and sex (sensitivity, 0.27; specificity, 0.94; LR, 4.5 [95% CI, 1.2-18]), history of prematurity (sensitivity range, 0.17-0.33; specificity range, 0.86-0.94; LR range, 2.3-2.8), and age of 6 years or younger (sensitivity range, 0.25-0.36; specificity range, 0.86-0.88; LR range, 2.2-2.6). Laboratory studies most associated with secondary hypertension were microalbuminuria (sensitivity, 0.13; specificity, 0.99; LR, 13 [95% CI, 3.1-53]) and serum uric acid concentration of 5.5 mg/dL or lower (sensitivity range, 0.70-0.73; specificity range, 0.65-0.89; LR range, 2.1-6.3). Increased daytime diastolic blood pressure load combined with increased nocturnal systolic blood pressure load on 24-hour ambulatory blood pressure monitoring was associated with secondary hypertension (sensitivity, 0.40; specificity, 0.82; LR, 4.8 [95% CI, 1.2-20]). Findings associated with a decreased likelihood of secondary hypertension were asymptomatic presentation (LR range, 0.19-0.36), obesity (LR, 0.34 [95% CI, 0.13-0.90]), and family history of any hypertension (LR, 0.42 [95% CI, 0.30-0.57]). Hypertension stage, headache, and left ventricular hypertrophy did not distinguish secondary from primary hypertension.Conclusions and RelevanceFamily history of secondary hypertension, younger age, lower body weight, and increased blood pressure load using 24-hour ambulatory blood pressure monitoring were associated with a higher likelihood of secondary hypertension. No individual sign or symptom definitively differentiates secondary hypertension from primary hypertension.

Background Most acute decompensated heart failure admissions are driven by congestion. However, residual congestion is common and often driven by the lack of reliable tools to titrate diuretic therapy. The authors previously developed a natriuretic response prediction equation (NRPE), which predicts sodium output using a spot urine sample collected 2 h after loop diuretic administration. Objectives The purpose of this study was to validate the NRPE and describe proof-of-concept that the NRPE can be used to guide diuretic therapy. Methods Two cohorts were assembled: 1) the Diagnosing and Targeting Mechanisms of Diuretic Resistance (MDR) cohort was used to validate the NRPE to predict 6-h sodium output after a loop diuretic, which was defined as poor ( 150 mmol); and 2) the Yale Diuretic Pathway (YDP) cohort, which used the NRPE to guide loop diuretic titration via a nurse-driven automated protocol. Results Evaluating 638 loop diuretic administrations, the NRPE showed excellent discrimination with areas under the curve ≥0.90 to predict poor, suboptimal, and excellent natriuretic response, and outperformed clinically obtained net fluid loss (p Conclusions Natriuretic response can be rapidly and accurately predicted by the NRPE, and this information can be used to guide diuretic therapy during acute decompensated heart failure. Additional study of diuresis guided by the NRPE is warranted.

Normally, blood pressure (BP) declines by at least 10% from daytime to nighttime. In adults, blunted nocturnal dipping has been associated with more rapid decline in kidney function. Nondipping is prevalent in children with chronic kidney disease (CKD). We sought to determine whether nondipping is associated with proteinuria and progression to kidney failure in children with CKD.In the prospective CKD in children (CKiD) cohort, Cox proportional hazards models were used to evaluate the relationship between baseline nondipping and progression to kidney failure. Linear mixed effects models were used to evaluate the relationship between nondipping and changes in iohexol glomerular filtration rate (GFR) and urine protein-to-creatinine ratio (log-UPCR, mg/mg) over time.Among 620 participants, mean age was 11 (± 4) years, mean iohexol GFR was 52 (± 22) ml/min per 1.73 mNondipping is not associated with end-stage kidney disease, GFR decline, or change in proteinuria within the CKiD cohort.

BACKGROUND: Despite guideline recommendations to optimize low-density lipoprotein cholesterol (LDL-C) reduction with intensification of lipid-lowering therapy (LLT) in patients with atherosclerotic cardiovascular disease (ASCVD), few of these patients achieve LDL-C < 70 mg/dL in practice. PURPOSE: We developed a real-time, targeted electronic health record (EHR) alert with embedded ordering capability to promote intensification of evidence based LLT in outpatients with very high risk ASCVD. METHODS: We designed a pragmatic, multicenter, single-blind, cluster randomized trial to test the effectiveness of an EHR-based LLT intensification alert. The study will enroll about 100 providers who will be randomized to either receive the alert or undergo usual care for outpatients with high risk ASCVD with LDL-C > 70 mg/dL. Total enrollment will include 2,500 patients. The primary outcome will be the proportion of patients with LLT intensification at 90 days. Secondary outcomes include achieved LDL-C at 6 months and the proportion of patients with LDL-C < 70 mg/dL or < 55 mg/dL at 6 months. RESULTS: Enrollment of 1,250 patients (50% of goal) was reached within 47 days (50% women, mean age 72, median LDL-C 91). At baseline, 71%, 9%, and 3% were on statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 inhibitors, respectively. CONCLUSIONS: PRagmatic Trial of Messaging to Providers about Treatment of HyperLIPIDemia has rapidly reached 50% enrollment of patients with very high risk ASCVD, demonstrating low baseline LLT utilization. This pragmatic, EHR-based trial will determine the effectiveness of a real-time, targeted EHR alert with embedded ordering capability to promote LLT intensification. Findings from this low-cost, widely scalable intervention to improve LDL-C may have important public health implications.

BackgroundIn patients receiving immune checkpoint inhibitor (ICI) therapy, acute kidney injury (AKI) is common, and can occur either from kidney injury unrelated to ICI use or from immune activation resulting in acute interstitial nephritis (AIN). In this study, we test the hypothesis that occurrence of AIN indicates a favorable treatment response to ICI therapy and therefore among patients who develop AKI while on ICI therapy, those with AIN will demonstrate greater survival compared with others with AKI.MethodsIn this observational cohort study, we included participants initiated on ICI therapy between 2013 and 2019. We tested the independent association of AKI and estimated AIN (eAIN) with mortality up to 1 year after therapy initiation as compared with those without AKI using time-varying Cox proportional hazard models controlling for demographics, comorbidities, cancer type, stage, and therapy, and baseline laboratory values. We defined eAIN as those with a predicted probability of AIN >90th percentile derived from a recently validated diagnostic model.ResultsOf 2207 patients initiated on ICIs, 617 (28%) died at 1 year and 549 (25%) developed AKI. AKI was independently associated with higher mortality (adjusted HR, 2.28 (95% CI 1.90 to 2.72)). Those AKI patients with eAIN had more severe AKI as reflected by a higher peak serum creatinine (3.3 (IQR 2.1–6.1) vs 1.4 (1.2–1.9) mg/dL, pConclusionIn patients treated with ICI, mortality was higher in those with AKI unrelated to ICI but lower in those where the underlying etiology was AIN. Future studies could evaluate the association of biopsy-proven or biomarker-proven AIN with mortality in those receiving ICI therapy.

Background We previously demonstrated that urine interleukin (IL)-9 and tumor necrosis factor (TNF)-α can distinguish acute interstitial nephritis (AIN) from other causes of acute kidney injury. Here we evaluated the role of these biomarkers to prognosticate kidney function in patients with AIN. Methods In a cohort of participants with biopsy-proven, adjudicated AIN, we tested the association of histological features and urine biomarkers (IL-9 and TNF-α) with estimated glomerular filtration rate measured 6 months after diagnosis (6 m-eGFR) controlling for eGFR before AIN and albuminuria. We also evaluated subgroups in whom corticosteroid use was associated with 6 m-eGFR. Results In the 51 (93%) of the 55 participants with complete data, median (interquartile range) eGFR before and 6 m after AIN were 41 (27–69) and 28 (13–47) mL/min/1.73 m2, respectively. Patients with higher severity of interstitial fibrosis had lower 6 m-eGFR, whereas those with higher tubulointerstitial infiltrate had higher 6 m-eGFR. IL-9 levels were associated with lower 6 m-eGFR only in the subset of patients who did not receive corticosteroids [6m-eGFR per doubling of IL-9, −6.0 (−9.4 to −2.6) mL/min/1.73 m2]. Corticosteroid use was associated with higher 6 m-eGFR [20.9 (0.2, 41.6) mL/min/1.73 m2] only in those with urine IL-9 above the median (>0.66 ng/g) but not in others. Conclusions Urine IL-9 was associated with lower 6 m-eGFR only in participants not treated with corticosteroids. Corticosteroid use was associated with higher 6 m-eGFR in those with high urine IL-9. These findings provide a framework for IL-9-guided clinical trials to test efficacy of immunosuppressive therapy in patients with AIN.

Background: Sodium-glucose cotransporter-2 inhibitors improve heart failure–related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations. Methods: Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated. Results: Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours ( P P =0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P =0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (−208 mL [interquartile range, −536 to 153 mL] versus −14 mL [interquartile range, −282 to 335 mL]; P =0.035) and plasma volume (−138 mL, interquartile range, −379 to 154±453 mL; P =0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior ( P =0.02) and all other neurohormones were similar ( P P =0.20) or renal dysfunction ( P >0.11 for all biomarkers), whereas both serum magnesium ( P P =0.008) improved. Conclusions: Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03027960.

Background Timely prediction of AKI in children can allow for targeted interventions, but the wealth of data in the electronic health record poses unique modeling challenges. Methods We retrospectively reviewed the electronic medical records of all children younger than 18 years old who had at least two creatinine values measured during a hospital admission from January 2014 through January 2018. We divided the study population into derivation, and internal and external validation cohorts, and used five feature selection techniques to select 10 of 720 potentially predictive variables from the electronic health records. Model performance was assessed by the area under the receiver operating characteristic curve in the validation cohorts. The primary outcome was development of AKI (per the Kidney Disease Improving Global Outcomes creatinine definition) within a moving 48-hour window. Secondary outcomes included severe AKI (stage 2 or 3), inpatient mortality, and length of stay. Results Among 8473 encounters studied, AKI occurred in 516 (10.2%), 207 (9%), and 27 (2.5%) encounters in the derivation, and internal and external validation cohorts, respectively. The highest-performing model used a machine learning-based genetic algorithm, with an overall receiver operating characteristic curve in the internal validation cohort of 0.76 [95% confidence interval (CI), 0.72 to 0.79] for AKI, 0.79 (95% CI, 0.74 to 0.83) for severe AKI, and 0.81 (95% CI, 0.77 to 0.86) for neonatal AKI. To translate this prediction model into a clinical risk-stratification tool, we identified high- and low-risk threshold points. Conclusions Using various machine learning algorithms, we identified and validated a time-updated prediction model of ten readily available electronic health record variables to accurately predict imminent AKI in hospitalized children.

Background: Loop diuretics have well-described toxicities, and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Nonrenal removal of sodium directly across the peritoneal membrane (direct sodium removal [DSR]) with a sodium-free osmotic solution should result in extraction of large quantities of sodium with limited off-target solute removal. Methods: This article describes the preclinical development and first-in-human proof of concept for DSR. Sodium-free 10% dextrose was used as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, and scalability and to determine the effect of experimental heart failure. In the human study, participants with end-stage renal disease on peritoneal dialysis (PD) underwent randomization and crossover to either a 2-hour dwell with 1 L DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary end point was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary end point was difference in sodium removal between DSR and standard PD solution. Results: Porcine experiments revealed that 1 L DSR solution removed 4.1±0.4 g sodium in 2 hours with negligible off-target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume ( P =0.005). In the setting of experimental heart failure with elevated right atrial pressure, sodium removal was ≈4 times greater than in healthy animals ( P P Conclusions: DSR was well tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in heart failure is warranted. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03801226.

OBJECTIVE: To estimate the prevalence of secondary hypertension among otherwise healthy children with hypertension diagnosed in the outpatient setting. STUDY DESIGN: MEDLINE, PubMed Central, Embase, Web of Science, and Cochrane Library were systematically searched for observational studies reporting the prevalence of secondary hypertension in children who underwent evaluation for hypertension and had no known comorbidities associated with hypertension at the time of diagnosis. Two authors independently extracted the study-specific prevalence of secondary hypertension in children evaluated for hypertension. Prevalence estimates for secondary hypertension were pooled in a random effects meta-analysis. RESULTS: Nineteen prospective and 7 retrospective studies including 2575 children with hypertension were analyzed, with a median of 65 (min-max range, 9–486) participants in each study. Studies conducted in primary care or school settings reported a lower prevalence of secondary hypertension (3.7% [95% CI: 1.2–7.2%]) than studies conducted in referral clinics (20.1% [95% CI: 11.5–30.3%]). When stratified by study setting, there were no significant subgroup differences according to study design, country, participant age range, hypertension definition, blood pressure device, or study quality. Although studies applied different approaches to diagnose secondary hypertension, diagnostic evaluations were at least as involved as the limited testing recommended by current guidelines. CONCLUSIONS: The low prevalence of secondary hypertension among children with a new diagnosis of hypertension identified on screening reinforces clinical practice guidelines to avoid extensive testing in the primary care setting for secondary causes in most children with hypertension.

Inferior vena cava (IVC) measurements correlate only modestly with right atrial pressure (RAP). Part of this inaccuracy is due to the high compliance of the venous system, where a large change in blood volume may result in only a small change in pressure. As such, the information provided by the IVC may be different rather than redundant.We analyzed patients in the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial who had both pulmonary artery catheter and IVC measurements at baseline (n = 108). There was only a modest correlation between baseline RAP and IVC diameter (r = 0.41; P0.001). Hemoconcentration, defined as an increase in hemoglobin levels between admission and discharge, was correlated with decrease in IVC diameter (r = 0.35; P = 0.02) but not with a decrease in RAP (r = 0.01; P = 0.95). When patients had both IVC and RAP measurements that were below the median, survival rates were superior to the rates of those who had only 1 measurement below the median, and when both rates were above the median, patients fared the worst (P = 0.002).IVC and RAP have limited correlation with each another, and changes in intravascular volume appear to correlate better with IVC diameter rather than with RAP. Furthermore, complementary information is provided by pressure and volume assessments in acute decompensated heart failure.

Introduction Animal models of renal ischemia-reperfusion injury (IRI) demonstrate that interferon (IFN)-γ producing T-helper (Th)-1 cells worsen acute kidney injury (AKI), whereas interleukin (IL)-4– and IL-13–producing Th2 cells lead to repair. We tested the association of these cytokines with AKI and mortality in patients who underwent cardiac surgery. Methods In 1444 participants of a multicenter, prospective, observational cohort, we measured 10 plasma biomarkers before and after cardiac surgery (IFN-γ, IL-4, IL-13, tumor necrosis factor [TNF]-α, IL-1β, IL-2, IL-6, IL-8, IL-10, and IL-12p70) and combined these biomarkers using principal component analysis (PCA). We also tested independent associations of Th1 (IFN-γ) and Th2 (IL-4 and IL-13) biomarkers with clinical outcomes of postoperative AKI and 1-year mortality. Results AKI occurred in 492 participants (34%), and 1-year mortality occurred in 81 participants (6%). Within 6 hours after surgery, IFN-γ, IL-4, and IL-13 increased 2.1-, 6.0-, and 4.6-fold, respectively, from their preoperative levels. Patients with higher levels of IFN-γ had higher odds of AKI (adjusted odds ratio per log change, 1.35 [1.13, 1.6]) and mortality (1.51 [1.17, 1.94]). Patients with higher levels of IL-4 and IL-13 also had higher odds of AKI (1.26 [1.09, 1.46] and 1.4 [1.16, 1.69], respectively) and mortality (1.46 [1.18, 1.82] and 1.71 [1.27, 2.31], respectively). Adding biomarkers to the clinical variables through use of PCA improved the area under the curve by 0.01 for AKI and 0.04 for mortality, resulting in final areas under the curve of 0.85 (0.83–0.87) and 0.76 (0.70–0.81), respectively. Conclusion Both Th1 and Th2 cytokines increased immediately after cardiac surgery and were associated with AKI and 1-year mortality. Our findings indicate activation of both Th1 and Th2 pathways after cardiac surgery rather than predominance of either pathway., Graphical abstract

Background: Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors. Methods: One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics. Results: FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis ( P ≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [ P ≥0.33 for all]) or neurohormonal activation (plasma or urine renin [ P ≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis ( P =0.44). Conclusions: FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.

Background: Incident severe HTN during hospitalization is far more common than admission for HTN, however treatment guidelines are lacking. Severe inpatient HTN is poorly studied, therefore our goal is to characterize inpatients who develop severe HTN and assess BP response to antihypertensive treatment. Methods: This is a cohort study of adults admitted for reasons other than HTN and developed severe HTN within a single healthcare system. We defined severe inpatient HTN as the first documentation of BP elevation (>180 systolic or >110 diastolic) at least 1 hour after hospital admission. Treatment was defined as receiving antihypertensive medications within 6 hours of BP elevation. We studied the association between treatment and BP drop ≥30%. Results: Among 224,265 hospitalized adults, 23,147 developed severe HTN of which 40% were treated. Compared to inpatients who did not develop severe HTN, those who did were older, more commonly women and Black, and had more comorbidities. Of the treated and untreated patients, 45.5 and 46.4% had a MAP drop ≥30% (p-value= 0.2). Risk factors for severe MAP drop include older age, Black race, HTN, and diabetes. Additionally, treatment vs. no treatment and treatment with intravenous vs. oral medications were associated with greater odds of MAP drop ≥30% ( Table 1 ). Conclusion: While there was no difference in the proportion of treated and untreated patients with severe MAP reduction, after adjustment for factors independently associated with HTN we found that treatment was associated with severe BP drop. Further research is needed to phenotype inpatients with severe HTN to help establish treatment guidelines.

Background: BP elevations in the hospital are commonly treated with intravenous medications, specifically hydralazine. However, treatment guidelines are lacking. Our goal is to assess the effect of intravenous hydralazine on BP following severe inpatient HTN development. Methods: This is a cohort study of adults admitted for reasons other than HTN and developed severe HTN within a single healthcare system. We defined severe inpatient HTN as the first documentation of BP elevation (>180 systolic or >110 diastolic) at least 1 hour after admission. Pregnant women were excluded. Mixed-effects models with nonlinear time trend were used to assess and visualize the time-dependent effect of intravenous hydralazine on BP within 6 hours of BP elevation. Results: Of the 23,147 inpatients who developed severe HTN, 13,753 were untreated and 9,166 were treated of which 12% received intravenous hydralazine. Of the treated and untreated patients, 57 and 46% had a severe MAP reduction (drop ≥30%) (p-valueFigure 1 ). Conclusion: Severe MAP reduction is observed in both treated and untreated inpatients with severe HTN, however adjusted absolute decrease in MAP is greater in inpatients treated with intravenous hydralazine.

Heart failure is a major cause of morbidity and mortality worldwide. The use of risk scores has the potential to improve targeted use of interventions by clinicians that improve patient outcomes, but this hypothesis has not been tested in a randomized trial.To evaluate whether prognostic information in heart failure translates into improved decisions about initiation and intensity of treatment, more appropriate end-of-life care, and a subsequent reduction in rates of hospitalization or death.This was a pragmatic, multicenter, electronic health record-based, randomized clinical trial across the Yale New Haven Health System, comprising small community hospitals and large tertiary care centers. Patients hospitalized for heart failure who had N-terminal pro-brain natriuretic peptide (NT-proBNP) levels of greater than 500 pg/mL and received intravenous diuretics within 24 hours of admission were automatically randomly assigned to the alert (intervention) or usual-care groups.The alert group had their risk of 1-year mortality calculated using an algorithm that was derived and validated using similar historic patients in the electronic health record. This estimate, including a categorical risk assessment, was presented to clinicians while they were interacting with a patient's electronic health record.The primary outcome was a composite of 30-day hospital readmissions and all-cause mortality at 1 year.Between November 27, 2019, through March 7, 2021, 3124 patients were randomly assigned to the alert (1590 [50.9%]) or usual-care (1534 [49.1%]) group. The alert group had a median (IQR) age of 76.5 (65-86) years, and 796 were female patients (50.1%). Patients from the following race and ethnicity groups were included: 13 Asian (0.8%), 324 Black (20.4%), 136 Hispanic (8.6%), 1448 non-Hispanic (91.1%), 1126 White (70.8%), 6 other ethnicity (0.4%), and 127 other race (8.0%). The usual-care group had a median (IQR) age of 77 (65-86) years, and 788 were female patients (51.4%). Patients from the following race and ethnicity groups were included: 11 Asian (1.4%), 298 Black (19.4%), 162 Hispanic (10.6%), 1359 non-Hispanic (88.6%), 1077 White (70.2%), 13 other ethnicity (0.9%), and 137 other race (8.9%). Median (IQR) NT-proBNP levels were 3826 (1692-8241) pg/mL in the alert group and 3867 (1663-8917) pg/mL in the usual-care group. A total of 284 patients (17.9%) and 270 patients (17.6%) were admitted to the intensive care unit in the alert and usual-care groups, respectively. A total of 367 patients (23.1%) and 359 patients (23.4%) had a left ventricular ejection fraction of 40% or less in the alert and usual-care groups, respectively. The model achieved an area under the curve of 0.74 in the trial population. The primary outcome occurred in 619 patients (38.9%) in the alert group and 603 patients (39.3%) in the usual-care group (P = .89). There were no significant differences between study groups in the prescription of heart failure medications at discharge, the placement of an implantable cardioverter-defibrillator, or referral to palliative care.Provision of 1-year mortality estimates during heart failure hospitalization did not affect hospitalization or mortality, nor did it affect clinical decision-making.ClinicalTrials.gov Identifier NCT03845660.

Congestion is the primary pathophysiological lesion in most heart failure (HF) hospitalizations. Renal congestion increases renal tubular pressure, reducing glomerular filtration rate (GFR) and diuresis. Because each nephron is a fluid-filled column, renal negative pressure therapy (rNPT) applied to the urinary collecting system should reduce tubular pressure, potentially improving kidney function. We evaluated the renal response to rNPT in congestive HF. Ten anesthetized ∼80-kg pigs underwent instrumentation with bilateral renal pelvic JuxtaFlow catheters. GFR was determined by iothalamate clearance (mGFR) and renal plasma flow (RPF) by para-aminohippurate clearance. Each animal served as its own control with randomization of left versus right kidney to −30 mmHg rNPT or no rNPT. mGFR and RPF were measured simultaneously from the rNPT and no rNPT kidney. Congestive HF was induced via cardiac tamponade maintaining central venous pressure at 20–22.5 mmHg throughout the experiment. Before HF induction, rNPT increased natriuresis, diuresis, and mGFR compared with the control kidney ( P < 0.001 for all). Natriuresis, diuresis, and mGFR decreased following HF ( P < 0.001 for all) but were higher in rNPT kidney versus control ( P < 0.001 for all). RPF decreased during HF ( P < 0.001) without significant differences between rNPT treatments. During HF, the rNPT kidney had similar diuresis and natriuresis ( P > 0.5 for both) and higher fractional excretion of sodium ( P = 0.001) compared with the non-rNPT kidney in the no HF period. In conclusion, rNPT resulted in significantly increased diuresis, natriuresis, and mGFR, with or without experimental HF. rNPT improved key renal parameters of the congested cardiorenal phenotype.

Background Patients with acute interstitial nephritis (AIN) can present without typical clinical features, leading to a delay in diagnosis and treatment. We therefore developed and validated a diagnostic model to identify patients at risk of AIN using variables from the electronic health record. Methods In patients who underwent a kidney biopsy at Yale University between 2013 and 2018, we tested the association of >150 variables with AIN, including demographics, comorbidities, vital signs and laboratory tests (training set 70%). We used least absolute shrinkage and selection operator methodology to select prebiopsy features associated with AIN. We performed area under the receiver operating characteristics curve (AUC) analysis with internal (held-out test set 30%) and external validation (Biopsy Biobank Cohort of Indiana). We tested the change in model performance after the addition of urine biomarkers in the Yale AIN study. Results We included 393 patients (AIN 22%) in the training set, 158 patients (AIN 27%) in the test set, 1118 patients (AIN 11%) in the validation set and 265 patients (AIN 11%) in the Yale AIN study. Variables in the selected model included serum creatinine {adjusted odds ratio [aOR] 2.31 [95% confidence interval (CI) 1.42–3.76]}, blood urea nitrogen:creatinine ratio [aOR 0.40 (95% CI 0.20–0.78)] and urine dipstick specific gravity [aOR 0.95 (95% CI 0.91–0.99)] and protein [aOR 0.39 (95% CI 0.23–0.68)]. This model showed an AUC of 0.73 (95% CI 0.64–0.81) in the test set, which was similar to the AUC in the external validation cohort [0.74 (95% CI 0.69–0.79)]. The AUC improved to 0.84 (95% CI 0.76–0.91) upon the addition of urine interleukin-9 and tumor necrosis factor-α. Conclusions We developed and validated a statistical model that showed a modest AUC for AIN diagnosis, which improved upon the addition of urine biomarkers. Future studies could evaluate this model and biomarkers to identify unrecognized cases of AIN.