Geographic and Temporal Trends in COVID-Associated Acute Kidney Injury in the National COVID Cohort Collaborative.

BACKGROUND: AKI is associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19); however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied. METHODS: Electronic health record data were obtained from 53 health systems in the United States in the National COVID Cohort Collaborative. We selected hospitalized adults diagnosed with COVID-19 between March 6, 2020, and January 6, 2022. AKI was determined with serum creatinine and diagnosis codes. Time was divided into 16-week periods (P1-6) and geographical regions into Northeast, Midwest, South, and West. Multivariable models were used to analyze the risk factors for AKI or mortality. RESULTS: Of a total cohort of 336,473, 129,176 (38%) patients had AKI. Fifty-six thousand three hundred and twenty-two (17%) lacked a diagnosis code but had AKI based on the change in serum creatinine. Similar to patients coded for AKI, these patients had higher mortality compared with those without AKI. The incidence of AKI was highest in P1 (47%; 23,097/48,947), lower in P2 (37%; 12,102/32,513), and relatively stable thereafter. Compared with the Midwest, the Northeast, South, and West had higher adjusted odds of AKI in P1. Subsequently, the South and West regions continued to have the highest relative AKI odds. In multivariable models, AKI defined by either serum creatinine or diagnostic code and the severity of AKI was associated with mortality. CONCLUSIONS: The incidence and distribution of COVID-19-associated AKI changed since the first wave of the pandemic in the United States. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_08_08_CJN0000000000000192.mp3.

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.

BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; ß-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Adrenal Vein Sampling Lateralization Despite Mineralocorticoid Receptor Antagonists Exposure in Primary Aldosteronism.

Context: Many antihypertensive medications modulate the renin-angiotensin-aldosterone system, possibly skewing the diagnosis and subtyping of primary aldosteronism (PA). Particularly, mineralocorticoid receptor antagonists (MRA) might raise renin and stimulate aldosterone synthesis from nonautonomous areas, potentially obscuring lateralization on adrenal vein sampling (AVS). Withdrawal of MRA in severe PA, however, can precipitate hypokalemia and/or hypertension and therefore is not always practical. Objective: To assess the effects of MRA on the interpretation of AVS data. Design and Participants: A cohort study of all PA patients who underwent AVS at University of Michigan between January 2009 and January 2018 was conducted. Demographics, diagnostic, AVS, surgical pathology, and follow-up data were collected retrospectively. Results: Of 191 patients who underwent AVS, 51 (27%) were exposed to MRA at the time of the procedure. Plasma aldosterone concentration and the daily defined dose of antihypertensives were higher in patients taking vs those not taking MRA. Unilateral PA was more frequent in the MRA group, both precosyntropin and postcosyntropin (P < 0.05). The MRA group included two patients with unsuppressed renin, who demonstrated unequivocal AVS lateralization. To date, 86 patients underwent unilateral adrenalectomy, including 30 patients taking MRA during AVS. The proportion of clinical and biochemical success was not statistically different between patients exposed to and those not exposed to MRA during AVS (P = 0.17 and 0.65, respectively). Conclusion: Our data suggest that conclusive AVS lateralization is often achieved in patients with severe PA despite MRA use.

Discordance between imaging and immunohistochemistry in unilateral primary aldosteronism.

OBJECTIVE: Correct subtyping of primary aldosteronism (PA) is essential for good surgical outcomes. Adrenal vein sampling (AVS) and/or computed tomography (CT) are used for PA subclassification. Clinical and/or biochemical improvement after surgery, however, is not always achieved in patients with presumed unilateral PA. We aimed to identify the pitfalls in PA subclassification leading to surgical treatment failures. PATIENTS AND DESIGN: We retrospectively studied 208 patients who underwent adrenal vein sampling (AVS) for PA subclassification in a tertiary referral centre, between January 2009 and August 2016. Simultaneous bilateral AVS was performed before and after cosyntropin administration. We implemented immunohistochemistry for aldosterone synthase (CYP11B2) and 17α-hydroxylase/17,20 lyase (CYP17A1) in adrenal glands resected from patients without improvement of PA after surgical treatment and from those with limitations in AVS interpretation. RESULTS: Of 55 patients who underwent adrenalectomy, three (5.5%) had no improvement of PA. All three patients underwent partial adrenalectomy to remove a CT-detected nodule present on the same side with AVS lateralization. Immunohistochemistry revealed a CYP11B2-negative nodule in both cases available. All patients who underwent total adrenalectomy based on AVS lateralization benefitted from surgery, including three patients with unilateral unsuccessful AVS and aldosterone suppression in the catheterized side vs inferior vena cava. CONCLUSIONS: Radiographically identified adrenal nodules are not always a source of PA, even when ipsilateral with AVS lateralization. These data caution against reliance on imaging findings, either alone or in conjunction with AVS, to guide surgery for PA.

EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research.

We argue that the field of extracellular vesicle (EV) biology needs more transparent reporting to facilitate interpretation and replication of experiments. To achieve this, we describe EV-TRACK, a crowdsourcing knowledgebase (http://evtrack.org) that centralizes EV biology and methodology with the goal of stimulating authors, reviewers, editors and funders to put experimental guidelines into practice.

Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema.

BACKGROUND: The B2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema in 1 study of European patients. OBJECTIVE: We sought to test the hypothesis that a bradykinin B2 receptor antagonist would shorten time-to-resolution from ACE inhibitor-associated angioedema. METHODS: Patients with ACE inhibitor-associated angioedema (defined as swelling of lips, tongue, pharynx, or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and patients with bowel edema only were excluded. Patients were randomized within 6 hours of presentation to subcutaneous icatibant 30 mg or placebo at 0 and 6 hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge. RESULTS: Thirty-three patients were randomized and 31 received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded from analyses. Two-thirds of patients were black and two-thirds were women. Time-to-resolution of symptoms was similar in placebo and icatibant treatment groups (P = .19 for the primary symptom and P > .16 for individual symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the 2 treatment groups. Time-to-resolution of symptoms was similar in black and white patients. CONCLUSIONS: This study does not support clinical efficacy of a bradykinin B2 receptor antagonist in ACE inhibitor-associated angioedema.

Serum Cortisol-to-Cortisone Ratio and Blood Pressure in Severe Obesity before and after Weight Loss.

BACKGROUND/AIMS: The pathogenesis of obesity-associated hypertension is poorly understood. Serum cortisol-to-cortisone ratio (F/E ratio) is a marker of cortisol metabolism. Our objective was to determine whether the serum F/E ratio is associated with blood pressure (BP) in patients after significant weight loss (≥15% from baseline weight). METHODS: Sera from 43 nondiabetic, severely obese males participating in a weight management program were assayed for F and E by mass spectrometry. We assessed whether changes in the F/E ratio accompanying weight loss correlate with changes in the systolic (SBP) and diastolic BP (DBP). Linear regression was used to evaluate change in the F/E ratio as a predictor of change in BP. RESULTS: The body mass index decreased from 40.8 ± 5.6 to 33.7 ± 4.8 (p < 0.001); also, SBP (133.2 ± 13.8 vs. 124.1 ± 14.3 mm Hg; p < 0.001) and DBP (69.8 ± 8.0 vs. 66.6 ± 9.4 mm Hg; p = 0.026) decreased during the study. The baseline F/E ratio tended to associate with baseline DBP (Spearman's r = -0.29, p = 0.06), and change in the serum F/E ratio correlated with change in DBP (Spearman's r = -0.32, p = 0.036). Change in the F/E ratio also tended to associate with change in SBP (Spearman's r = -0.27, p = 0.08). A multiple linear regression model adjusted for change in the F/E ratio and age explained 22% of the variance in SBP change (R(2) = 0.22, p = 0.007). Change in the F/E ratio independently predicted change in SBP (p = 0.036). CONCLUSION: In our sample of nondiabetic, severely obese males, change in the serum F/E ratio was associated with change in BP after weight loss.

Clopidogrel prescription filling delays and cardiovascular outcomes in a pharmacy system integrating inpatient and outpatient care: insights from the Veterans Affairs CART Program.

BACKGROUND: Delays in filling clopidogrel prescriptions after percutaneous coronary intervention (PCI) have been demonstrated previously and associated with adverse outcomes. METHODS: This was a retrospective cohort study of 11,418 patients undergoing PCI with stent placement in Veterans Affairs (VA) hospitals between January 1, 2005, and September 30, 2010. Data were obtained from the national VA Clinical Assessment, Reporting, and Tracking Program, including post-PCI clopidogrel prescription fill date and outcomes of myocardial infarction and death within 90 days of discharge. Patients who did not fill a clopidogrel prescription on the day of discharge were considered to have a delay. Multivariable models assessed the association between clopidogrel delay and myocardial infarction/death using clopidogrel delay as a time-varying covariate. RESULTS: Of the patients, 7.2% had a delay in filling their clopidogrel prescription. Delay in filling clopidogrel was associated with increased risk of major adverse events (hazard ratio 2.34, 95% CI 1.66-3.29, P < .001). The percentage of patients who delayed filling varied by hospital, ranging from 0 to 43.5% with a median of 6.2% (P < .001, χ(2) for difference across hospitals) and a median odds ratio of 2.13 (95% CI 1.85-2.68) suggesting large site variation in clopidogrel delay across hospitals. CONCLUSIONS: In a health care system with integrated inpatient and outpatient pharmacy services, 1 in 14 patients delays filling a clopidogrel prescription. The large site variation suggests a need to identify best practices that allow hospitals to optimize prescription filling at discharge to potentially improve patient outcomes.

Arm position during ambulatory blood pressure monitoring: a review of the evidence and clinical guidelines.

Ambulatory blood pressure monitoring (ABPM) offers advantages over clinic blood pressure measurement. Supporting the arm at the level of the right atrium has long been standard in clinic blood pressure measurement. In contrast, there is no consensus regarding arm position in the guidelines addressing ABPM. Research studies have used a variety of arm positions during ABPM. Discussed in this review are the merits of ABPM and a review of the several arm positions recommended in ABPM guidelines, suggested by cuff manufacturers, and used in research studies. To address this lack of standardization, a rationale for a clinically reasonable arm position during ABPM is offered. Specifically, the authors recommend advising the patient to keep the arm still and relaxed straight down at the side of the body when the cuff is going to inflate, when safe to do so.

Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema.

OBJECTIVE: The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. PARTICIPANTS AND METHODS: We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). RESULTS: There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P<10) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans. CONCLUSION: Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema.

Detection and recognition of hypertension in anxious and depressed patients.

OBJECTIVE: Hypertension management requires detection (i.e. confirmation of persistently high blood pressure (BP) after an initial elevated measurement) and recognition of the condition (evidenced by a formal diagnosis and/or initiation of treatment). Our objective was to determine whether disparities exist in detection of elevated BP and recognition (i.e. diagnosis or treatment) of hypertension in patients with depression and anxiety. METHODS: Using data from the Cardiovascular Research Network Hypertension Registry, we assessed time-to-detection of elevated BP and recognition of hypertension in patients with comorbid anxiety and depression compared with patients with neither disorder. We performed multivariable survival analysis of time to detection and recognition in patients who entered the registry in 2002-2006. We adjusted for primary care visit rate and other relevant clinical factors. RESULTS: In 168,630 incident hypertension patients, detection occurred earlier among patients with anxiety and depression compared with patients without these diagnoses [adjusted hazard ratio for anxiety and depression 1.30, 95% confidence interval (CI) 1.26-1.35]. Recognition of hypertension within 12 months of the second elevated BP was similar (adjusted hazard ratio for anxiety and depression 0.94, 95% CI 0.89-1.00) or delayed (adjusted hazard ratio for anxiety 0.93, 95% CI 0.88-0.99 and for depression 0.93, 95% CI 0.90-0.97). CONCLUSIONS: Detection of elevated BP occurred earlier in patients with anxiety and depression. Time from detection to diagnosis or treatment was similar or delayed in patients with and without these diagnoses. Our findings suggest that as-yet-unidentified factors contribute to disparities in hypertension detection and recognition.

Combination therapy as initial treatment for newly diagnosed hypertension.

BACKGROUND: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that clinicians consider the use of multidrug therapy to increase likelihood of achieving blood pressure goal. Little is known about recent patterns of combination antihypertensive therapy use in patients being initiated on hypertension treatment. METHODS: We investigated combination antihypertensive therapy use in newly diagnosed hypertensive patients from the Cardiovascular Research Network Hypertension Registry. Multivariable logistic regression was used to assess the relationship between combination antihypertensive therapy and 12-month blood pressure control. RESULTS: Between 2002 and 2007, a total of 161,585 patients met criteria for incident hypertension and were initiated on treatment. During the study period, an increasing proportion of patients were treated initially with combination rather than with single-agent therapy (20.7% in 2002 compared with 35.8% in 2007, P < .001). This increase in combination therapy use was more pronounced in patients with stage 2 hypertension, whose combination therapy use increased from 21.6% in 2002 to 44.5% in 2007. Nearly 90% of initial combination therapy was accounted for by 2 combinations, a thiazide and a potassium-sparing diuretic (47.6%) and a thiazide and an angiotensin-converting enzyme inhibitor (41.4%). After controlling for relevant clinical factors, including subsequent intensification of treatment and medication adherence, combination therapy was associated with increased odds of blood pressure control at 12 months (odds ratio compared with single-drug initial therapy 1.20; 95% CI 1.15-1.24, P < .001). CONCLUSIONS: Initial treatment of hypertension with combination therapy is increasingly common and is associated with better long-term blood pressure control.

Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema.

BACKGROUND: Angioedema is a rare adverse effect of angiotensin-converting enzyme (ACE) inhibitors, which occurs more commonly in women and black Americans. Angioedema is thought to result from decreased degradation of vasoactive peptides. During ACE inhibition, bradykinin is primarily inactivated by aminopeptidase P (APP). Earlier studies have provided conflicting data with regard to serum APP activity in patients with a history of ACE inhibitor-associated angioedema. A single nucleotide polymorphism, -2399C>A (rs3788853, C-2399A), in XPNPEP2, the X-linked gene that encodes membranous APP, has been reported to associate with APP activity. OBJECTIVE: To test the hypothesis that the relationship between XPNPEP2 C-2399A genotype and APP activity or ACE inhibitor-associated angioedema is sex-dependent and race-dependent. METHODS: We compared C-2399A genotype frequencies in 169 cases with a history of ACE inhibitor-associated angioedema and 397 ACE inhibitor-exposed controls. Controls were prespecified to be 50% white, 50% black, and 50% women. Cases and controls were group matched for age and smoking. RESULTS: XPNPEP2 C-2399A genotype associated with serum APP activity in both men and women. Serum APP activity was lower in men than in women, independent of genotype. XPNPEP2 -2399 A/ genotype was associated with an increased risk of angioedema in men [odds ratio 2.17 (1.09-4.32), P=0.03] in multivariate analysis. The A/ genotype was associated with angioedema in black men (P=0.03) but not in white men. CONCLUSION: APP activity is lower in men and the XPNPEP2 C-2399A polymorphism associates with ACE inhibitor-associated angioedema in men but not women.