Hypertension Control During the Coronavirus Disease 2019 Pandemic: A Cohort Study Among US Veterans.

DESIGN: Retrospective cohort study. OBJECTIVE: We sought to examine whether disruptions in follow-up intervals contributed to hypertension control. BACKGROUND: Disruptions in health care were widespread during the coronavirus disease 2019 pandemic. PATIENTS AND METHODS: We identified a cohort of individuals with hypertension in both prepandemic (March 2019-February 2020) and pandemic periods (March 2020-February 2022) in the Veterans Health Administration. First, we calculated follow-up intervals between the last prepandemic and first pandemic blood pressure measurement during a primary care clinic visit, and between measurements in the prepandemic period. Next, we estimated the association between the maintenance of (or achieving) hypertension control and the period using generalized estimating equations. We assessed associations between follow-up interval and control separately for periods. Finally, we evaluated the interaction between period and follow-up length. RESULTS: A total of 1,648,424 individuals met the study inclusion criteria. Among individuals with controlled hypertension, the likelihood of maintaining control was lower during the pandemic versus the prepandemic (relative risk: 0.93; 95% CI: 0.93, 0.93). Longer follow-up intervals were associated with a decreasing likelihood of maintaining controlled hypertension in both periods. Accounting for follow-up intervals, the likelihood of maintaining control was 2% lower during the pandemic versus the prepandemic. For uncontrolled hypertension, the likelihood of gaining control was modestly higher during the pandemic versus the prepandemic (relative risk: 1.01; 95% CI: 1.01, 1.01). The likelihood of gaining control decreased with follow-up length during the prepandemic but not pandemic. CONCLUSIONS: During the pandemic, longer follow-up between measurements contributed to the lower likelihood of maintaining control. Those with uncontrolled hypertension were modestly more likely to gain control in the pandemic.

The Association of COVID-19 With Acute Kidney Injury Independent of Severity of Illness: A Multicenter Cohort Study.

RATIONALE & OBJECTIVE: Although coronavirus disease 2019 (COVID-19) has been associated with acute kidney injury (AKI), it is unclear whether this association is independent of traditional risk factors such as hypotension, nephrotoxin exposure, and inflammation. We tested the independent association of COVID-19 with AKI. STUDY DESIGN: Multicenter, observational, cohort study. SETTING & PARTICIPANTS: Patients admitted to 1 of 6 hospitals within the Yale New Haven Health System between March 10, 2020, and August 31, 2020, with results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing via polymerase chain reaction of a nasopharyngeal sample. EXPOSURE: Positive test for SARS-CoV-2. OUTCOME: AKI by KDIGO (Kidney Disease: Improving Global Outcomes) criteria. ANALYTICAL APPROACH: Evaluated the association of COVID-19 with AKI after controlling for time-invariant factors at admission (eg, demographic characteristics, comorbidities) and time-varying factors updated continuously during hospitalization (eg, vital signs, medications, laboratory results, respiratory failure) using time-updated Cox proportional hazard models. RESULTS: Of the 22,122 patients hospitalized, 2,600 tested positive and 19,522 tested negative for SARS-CoV-2. Compared with patients who tested negative, patients with COVID-19 had more AKI (30.6% vs 18.2%; absolute risk difference, 12.5% [95% CI, 10.6%-14.3%]) and dialysis-requiring AKI (8.5% vs 3.6%) and lower rates of recovery from AKI (58% vs 69.8%). Compared with patients without COVID-19, patients with COVID-19 had higher inflammatory marker levels (C-reactive protein, ferritin) and greater use of vasopressors and diuretic agents. Compared with patients without COVID-19, patients with COVID-19 had a higher rate of AKI in univariable analysis (hazard ratio, 1.84 [95% CI, 1.73-1.95]). In a fully adjusted model controlling for demographic variables, comorbidities, vital signs, medications, and laboratory results, COVID-19 remained associated with a high rate of AKI (adjusted hazard ratio, 1.40 [95% CI, 1.29-1.53]). LIMITATIONS: Possibility of residual confounding. CONCLUSIONS: COVID-19 is associated with high rates of AKI not fully explained by adjustment for known risk factors. This suggests the presence of mechanisms of AKI not accounted for in this analysis, which may include a direct effect of COVID-19 on the kidney or other unmeasured mediators. Future studies should evaluate the possible unique pathways by which COVID-19 may cause AKI.

Blood pressure targets for hemodialysis patients.

The association between blood pressure (BP) and mortality is unique in hemodialysis patients compared with that in the general population. This is because of an altered benefit-risk balance associated with BP reduction in these patients. An adequately designed study comparing BP targets in hemodialysis patients remains to be conducted. The current evidence available to guide dialysis providers regarding treatment strategies for managing hypertension in this population is limited to large observational studies and small randomized controlled trials. In this opinion article, we review these data and discuss the key points regarding BP management for hemodialysis patients. Our aim is to provide a practical opinion regarding BP targets that nephrologists can incorporate into clinical practice, with a focus on moving away from dialysis unit BPs and focusing on out-of-dialysis unit BPs.

A translational approach for NMDA receptor profiling as a vulnerability biomarker for depression and schizophrenia.

NEW FINDINGS: What is the central question of this study? Can the change in plasma arginine vasopressin concentration (P[AVP] ) in response to osmotic stimulation (POsm ) serve as a biomarker for NMDA receptor signalling in schizophrenia and depression and thereby distinguish between these mental illnesses? What is the main finding and its importance? In response to hyperosmotic challenge, depressed subjects showed increased P[AVP] response compared with healthy control and schizophrenic subjects. However, schizophrenic subjects were not different from healthy control subjects in this small sample. The 'P[AVP] response to POsm ' is a suitable biomarker to distinguish depressed versus schizophrenic patients when used with psychiatric screening. This is the first objective physiological measure for schizophrenia or depression. Altered NMDA receptor activity and glutamate signalling might underlie the pathogenesis of both schizophrenia and depression in subgroups of patients. In schizophrenia, pharmacological modelling, post-mortem and imaging data suggest reduced NMDA signalling. In contrast, recent clinical trials demonstrating the efficacy of the NMDA antagonist ketamine in severely depressed patients suggest increased NMDA receptor signalling. We conducted a proof-of-concept study to assess whether there is any in vivo evidence for an inverse association in depression and schizophrenia with respect to the NMDA receptor function. For this purpose, we used a translational approach, based on findings from animal studies that NMDA receptor is a key mediator of arginine vasopressin (AVP) release into the bloodstream. Using hypertonic saline to increase plasma osmolality (POsm ) and thereby induce AVP release, as done in animal studies, we found that in depressed patients the NMDA receptor-mediated AVP release induced by hypertonic saline infusion was significantly increased [0.24 (0.15) pg ml-1  mosmol-1 , P < 0.05] compared with schizophrenia patients [0.07 (0.07) pg ml-1  mosmol-1 ]. Slopes for healthy control subjects were 0.11 (0.09) pg ml-1  mosmol-1 which was less than the depressed group. These findings are consistent with implicated NMDA receptor-related abnormalities in depression and schizophrenia in subgroups of patients and provide the first in vivo evidence of this dichotomy.

We Hold Antihypertensives Prior To Dialysis.

Hypertension is the most common complication of end-stage renal disease and chronic hemodialysis and yet, only a third of these patients have adequately controlled blood pressures. Pathogenesis of hypertension in this population is complex and multifactorial and therefore poses numerous treatment challenges. Furthermore, it is common practice among nephrologists to withhold antihypertensives prior to a hemodialysis procedure due to concerns for intradialytic hypotension (IDH). Intradialytic hypertension (ID-HTN) is an increasingly recognized phenomenon and although less common than IDH, portends poor cardiovascular prognosis as well as reflects higher hypertension burden in the dialysis population. Withholding antihypertensives prior to dialysis routinely in patients may worsen interdialytic blood pressure control as well as increase the prevalence of euvolemic ID-HTN. It may also increase the risk of cardiac arrhythmias and further compromise hemodynamic stability during dialysis. In such situations, predialysis administration of antihypertensive is appropriate and necessary and drug choice should be based on the patient's comorbidities, pharmacokinetics of the drug and its dialyzability.

Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.

UNLABELLED: Acute kidney injury (AKI) is common in patients with cirrhosis and associated with significant mortality. The most common etiologies of AKI in this setting are prerenal azotemia (PRA), acute tubular necrosis (ATN), and hepatorenal syndrome (HRS). Accurately distinguishing the etiology of AKI is critical, as treatments differ markedly. However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of AKI and may facilitate more accurate and rapid diagnoses. We conducted a multicenter, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential diagnosis of clinically adjudicated AKI. Patients (n = 36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. In addition, 76 patients with progressive AKI were diagnosed by way of blinded retrospective adjudication. Of these progressors, 39 (53%) patients were diagnosed with ATN, 19 (26%) with PRA, and 16 (22%) with HRS. Median values for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and albumin differed between etiologies and were significantly higher in patients adjudicated with ATN. The fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ between those with PRA, 0.27%, or ATN, 0.31%, P = 0.54. The likelihood of being diagnosed with ATN increased step-wise with the number of biomarkers above optimal diagnostic cutoffs. CONCLUSION: Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS.

Renalase in hypertension and kidney disease.

Renalase, a recently discovered flavoprotein, which is strongly expressed in the kidney and heart, effectively metabolizes catecholamines. It was discovered during the search to identify proteins secreted by the kidney that could help explain the high incidence of cardiovascular disease in patients with chronic kidney disease. Recent advances have led to more detailed knowledge of its biology, structure, enzymatic activity, mechanisms of action, associations with human disease states and potential therapeutic value. In this study, we review these advances with a focus on hypertension and kidney disease.

Adjudication of etiology of acute kidney injury: experience from the TRIBE-AKI multi-center study.

BACKGROUND: Adjudication of patient outcomes is a common practice in medical research and clinical trials. However minimal data exists on the adjudication process in the setting of Acute Kidney Injury (AKI) as well as the ability to judge different etiologies (e.g. Acute Tubular Necrosis (ATN), Pre-renal Azotemia (PRA)). METHODS: We enrolled 475 consecutive patients undergoing cardiac surgery at four sites of the Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) study. Three expert nephrologists performed independent chart review, utilizing clinical variables and retrospective case report forms with pre intra and post-operative data, and then adjudicated all cases of AKI (n = 67). AKI was defined as a > 50% increase in serum creatinine for baseline (RIFLE Risk). We examined the patterns of AKI diagnoses made by the adjudication panel as well as association of these diagnoses with pre and postoperative kidney injury biomarkers. RESULTS: There was poor agreement across the panel of reviewers with their adjudicated diagnoses being independent of each other (Fleiss' Kappa = 0.046). Based on the agreement of the two out of three reviewers, ATN was the adjudicated diagnosis in 41 cases (61%) while PRA occurred in 13 (19%). Neither serum creatinine or any other biomarker of AKI (urine or serum), was associated with an adjudicated diagnosis of ATN within the first 24 post-operative hours. CONCLUSION: The etiology of AKI after cardiac surgery is probably multi-factorial and pure forms of AKI etiologies, such as ATN and PRA may not exist. Biomarkers did not appear to correlate with the adjudicated etiology of AKI; however the lack of agreement among the adjudicators impacted these results. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00774137.

Correlates of Spontaneous Blood Pressure Reduction Following Severe Inpatient Hypertension Development.

BACKGROUND: Severe hypertension (sHTN) is prevalent in 10% of hospitalized patients and treatment guidelines are lacking. As such, patients who develop sHTN might unnecessarily receive antihypertensive medications which could lead to worse outcomes. Our goal was to investigate correlates of spontaneous blood pressure (BP) reduction to help guide future treatment decisions and avoid harm associated with aggressive BP treatment. METHODS: This is a retrospective cohort study of hospitalized adults between 2016 and 2020 who developed sHTN, SBP >180 or DBP >110 mm Hg, after admission. Spontaneous BP reduction was defined as a SBP <160 and a DBP <100 mm Hg achieved within 3 h of sHTN in the absence of antihypertensive therapy. Multivariable logistic regression was used to identify correlates of spontaneous BP reduction. RESULTS: Of the 12,825 patients who developed sHTN, 44.2% had spontaneous BP reduction. After adjustment, we found that patients most likely to experience a BP drop received steroids before onset of sHTN (Odds ratio [OR]: 1.3 [1.09, 1.56]), had higher potassium levels on admission (OR: 1.2 [1.09, 1.24]) and were more likely to have a history of chronic pulmonary disease (OR: 1.1 [1.01, 1.18]) or cardiac arrythmia (OR: 1.1 [1.01, 1.18]). While numerically different, these differences were not clinically relevant. CONCLUSIONS: Our findings indicate that almost half the patients who develop sHTN have spontaneous BP reduction. Conventional clinical and demographic characteristics were not strong predictors of spontaneous BP reduction following sHTN development. More research is needed to confirm our findings and help guide treatment of sHTN.

Treatment of severe metabolic alkalosis in a patient with congestive heart failure.

Metabolic alkalosis, isolated or in combination with another abnormality, is the most common acid-base disorder in patients with congestive heart failure. In most cases, it is a result of diuretic therapy, which causes activation of the renin-angiotensin system, chloride depletion, increased distal sodium delivery, hypokalemia, and increased urine acidification, all of which contribute to bicarbonate retention. In addition, the disease state itself results in neurohormonal activation (renin-angiotensin system, sympathetic nervous system, and endothelin) that further amplifies the tendency toward alkalosis. Treatment of metabolic alkalosis is based on the elimination of generation and maintenance factors, chloride and potassium repletion, enhancement of renal bicarbonate excretion (such as acetazolamide), direct titration of the base excess (hydrochloric acid), or, if accompanied by kidney failure, low-bicarbonate dialysis. In congestive heart failure, appropriate management of circulatory failure and use of an aldosterone antagonist in the diuretic regimen are integral to treatment.

Does kidney disease cause hypertension?

Hypertension complicates most cases of chronic kidney disease. While the prevalence and severity of hypertension increase as glomerular filtration rate falls, hypertension is often observed in patients with structural kidney disease while renal function is normal, in particular those with polycystic kidney disease or proteinuric glomerular diseases. On the other hand, even severe reductions in renal function may not result in hypertension, especially if there is effective control of extracellular fluid volume. Recent clinical and experimental data indicate that proteinuria may mediate sodium retention and hypertension via plasmin-mediated activation of the epithelial sodium channel. Current evidence supports the notion that chronic kidney disease is a cause of chronic hypertension, even in the absence of detectable changes in glomerular filtration rate.

Thrombocytopenia and in-hospital mortality risk among ischemic stroke patients.

BACKGROUND: Thrombocytopenia has been associated with increased mortality in nonstroke conditions. Because its role in acute ischemic stroke is less well understood, we sought to determine whether thrombocytopenia at admission for acute ischemic stroke was associated with in-hospital mortality. METHODS: We used data from a retrospective cohort of stroke patients (1998-2003) at 5 U.S. hospitals. Risk factors considered included conditions that can lead to thrombocytopenia (e.g., liver disease), increase bleeding risk (e.g., hemophilia), medications with antiplatelet effects (e.g., aspirin), and known predictors of mortality (e.g., National Institutes of Health Stroke Scale and Charlson Comorbidity Index scores). Logistic regression modeling evaluated the adjusted association between thrombocytopenia, defined as platelets <100,000/µL, and in-hospital mortality. RESULTS: Among 1233 acute ischemic stroke patients, thrombocytopenia was present in 2.3% (n = 28). A total of 6.1% (n = 75) of patients died in the hospital. In unadjusted analyses, thrombocytopenia was associated with higher mortality (8/28 [28.6%] v 67/1205 [5.6%]; P < .0001). Thrombocytopenia was also independently associated with in-hospital mortality after adjustment for National Institutes of Health Stroke Scale score and comorbidities, with an odds ratio of 6.6 (95% confidence interval 2.3-18.6). CONCLUSIONS: Admission thrombocytopenia among patients presenting with acute ischemic stroke predicts in-hospital mortality.

Anemia is associated with poor outcomes in patients with less severe ischemic stroke.

Anemia is a known predictor of in-hospital mortality among patients with such vascular conditions as acute myocardial infarction, congestive heart failure, and chronic kidney disease. The role of anemia in patients with acute ischemic stroke is less well understood. We sought to examine the association between anemia at hospital admission and the combined outcome of in-hospital mortality and discharge to hospice in patients with acute ischemic stroke. We evaluated data from a retrospective cohort of consecutive ischemic stroke patients presenting within 48 hours of symptom onset at 5 hospitals between 1998 and 2003. Anemia was defined as an admission hematocrit value of <30%. Less severe stroke was defined as an admission National Institutes of Health Stroke Scale score of <10. The outcome was the combined endpoint of in-hospital mortality or discharge to hospice. Among 1306 patients with stroke, anemia was present on admission in 6.4%, and the combined outcome of death or discharge to hospice was present in 10.1%. Anemia was not associated with outcome in patients with severe stroke (anemia, 17.2% [5 of 29] vs no anemia, 28,4% [98 of 345]; P = .20), but was associated with outcome in patients with less severe stroke (anemia, 13.0% [7 of 54] vs no anemia, 2.5% [22 of 878]; P < .0001). After adjustment for stroke severity, admission anemia was independently associated with outcome in patients with less severe stroke (adjusted odds ratio, 4.17; 95% confidence interval, 1.47-11.90), but not in patients with more severe strokes (adjusted odds ratio, 0.82; 95% confidence interval, 0.30-2.22). Our data indicate that anemia is associated with in-hospital mortality or discharge to hospice in patients with less severe ischemic stroke.

Effect of intravenous antihypertensives on outcomes of severe hypertension in hospitalized patients without acute target organ damage.

BACKGROUND: 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. METHODS: 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 systolic >180 or diastolic >110 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. RESULTS: 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]). CONCLUSIONS: 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.

Evaluation and management of orthostatic hypotension: Limited data, limitless opportunity.

Although orthostatic hypotension is common and can have serious consequences, recommendations about its evaluation and management are based on limited data. Here, the author outlines a systematic approach, noting the areas that pose an opportunity for improvement.

Neurogenic orthostatic hypotension after treatment with sorafenib.

A man in his 70s with a history of fatigue, abdominal pain, and a palpable abdominal mass was found to have a peritoneal desmoid tumour. One year after diagnosis, he was prescribed sorafenib to limit tumour growth. Two months later, he developed dyspnoea on exertion and lower extremity weakness and was reported to have supine hypertension and orthostatic hypotension. On formal autonomic testing, he was noted to have severely impaired sympathetic responses and marked orthostatic hypotension without appropriate chronotropic response. A decision to hold sorafenib was made, and treatment was started with graduated compression stockings, liberal fluid and sodium intake, and midodrine. The patient had a modest and gradual improvement in his symptoms. To our knowledge, this is the first reported case of orthostatic hypotension related to sorafenib or any vascular endothelial growth factor inhibitors.