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Abstract 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.

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.

Abstract Severe hypertension (HTN) that develops during hospitalization is more common than admission for HTN; however, it is poorly studied, and treatment guidelines are lacking. Our goal is to characterize hospitalized patients who develop severe HTN and assess blood pressure (BP) response to treatment. This is a multi‐hospital retrospective cohort study of adults admitted for reasons other than HTN who developed severe HTN. The authors defined severe inpatient HTN as the first documented BP elevation (systolic BP > 180 or diastolic BP > 110) at least 1 hour after admission. Treatment was defined as receiving antihypertensives (intravenous [IV] or oral) within 6h of BP elevation. As a measure of possible overtreatment, the authors studied the association between treatment and time to mean arterial pressure (MAP) drop ≥ 30% using the Cox proportional hazards model. Among 224 265 hospitalized adults, 10% developed severe HTN of which 40% were treated. Compared to patients who did not develop severe HTN, those who did were older, more commonly women and black, and had more comorbidities. Incident MAP drop ≥ 30% among treated and untreated patients with severe HTN was 2.2 versus 5.7/1000 person‐hours. After adjustment, treated versus. untreated patients had lower rates of MAP drop ≥ 30% (hazard rate [HR]: 0.9 [0.8, 0.99]). However, those receiving only IV treatment versus untreated had greater rates of MAP drop ≥ 30% (1.4 [1.2, 1.7]). Overall, the authors found that clinically significant MAP drop is observed among inpatients with severe HTN irrespective of treatment, with greater rates observed among patients treated only with IV antihypertensives. Further research is needed to phenotype inpatients with severe HTN.

Background The New York Heart Association (NYHA) classification has served as a fundamental tool for risk stratification of heart failure (HF) and determines clinical trial eligibility and candidacy for drugs and devices. However, its ability to adequately stratify risk is unclear. Methods and Results To compare NYHA class with objective assessments and survival in patients with HF, we performed secondary analyses of 4 multicenter National Institutes of Health–funded HF clinical trials that included patients classified as NYHA class II or III: TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), DIG (The Effect of Digoxin on Mortality and Morbidity in Patients With Heart Failure), HF‐ACTION (Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure), and GUIDE‐IT (Guiding Evidence‐Based Therapy Using Biomarker Intensified Treatment in Heart Failure). Twenty‐month cumulative survival was compared between classes using Kaplan–Meier curves and the log rank test. NT‐proBNP (N‐terminal pro–B‐type natriuretic peptide), Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, 6‐minute walk distances, left ventricular ejection fraction, and cardiopulmonary test parameters were compared using Wilcoxon rank sum tests and percentage overlap using kernel density estimations. Cumulative mortality varied significantly across NYHA classes and HF clinical trials (likelihood ratio, P

Background In acute decompensated heart failure, guidelines recommend increasing loop diuretic dose or adding a thiazide diuretic when diuresis is inadequate. We set out to determine the adverse events associated with a diuretic strategy relying on metolazone or high‐dose loop diuretics. Methods and Results Patients admitted to 3 hospitals using a common electronic medical record with a heart failure discharge diagnosis who received intravenous loop diuretics were studied in a propensity‐adjusted analysis of all‐cause mortality. Secondary outcomes included hyponatremia (sodium

Background: Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF., Methods and Results: Fifty AHF patients treated with intravenous bumetanide underwent a 6-h timed urine collection for sodium and bumetanide clearance. Whole-kidney DR was defined as sodium excreted per doubling of administered loop diuretic and represents the sum of defects in drug delivery and renal tubular response. Tubular DR, defined as sodium excreted per doubling of renally cleared (urinary) loop diuretic, captures resistance specifically in the renal tubule. Median administered bumetanide dose was 3.0 (2.0-4.0) mg with 52 (33-77)% of the drug excreted into the urine. Significant between-patient variability was present as the administered dose only explained 39% of variability in the quantity of bumetanide in urine. Cumulatively, factors related to drug delivery such as renal bumetanide clearance, administered dose, and urea clearance explained 28% of the variance in whole-kidney DR. However, resistance at the level of the renal tubule (tubular DR) explained 71% of the variability in whole-kidney DR., Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)