Physiologic homeostasis after pig-to-human kidney xenotransplantation.

Demand for kidney grafts outpaces supply, limiting kidney transplantation as a treatment for kidney failure. Xenotransplantation has the potential to make kidney transplantation available to many more patients with kidney failure, but the ability of xenografts to support human physiologic homeostasis has not been established. A brain-dead adult decedent underwent bilateral native nephrectomies followed by 10 gene-edited (four gene knockouts, six human transgenes) pig-to-human xenotransplantation. Physiologic parameters and laboratory values were measured for seven days in a critical care setting. Data collection aimed to assess homeostasis by measuring components of the renin-angiotensin-aldosterone system, parathyroid hormone signaling, glomerular filtration rate, and markers of salt and water balance. Mean arterial blood pressure was maintained above 60 mmHg throughout. Pig kidneys secreted renin (post-operative day three to seven mean and standard deviation: 47.3 ± 9 pg/mL). Aldosterone and angiotensin II levels were present (post-operative day three to seven, 57.0 ± 8 pg/mL and 5.4 ± 4.3 pg/mL, respectively) despite plasma renin activity under 0.6 ng/mL/hr. Parathyroid hormone levels followed ionized calcium. Urine output down trended from 37 L to 6 L per day with 4.5 L of electrolyte free water loss on post-operative day six. Aquaporin 2 channels were detected in the apical surface of principal cells, supporting pig kidney response to human vasopressin. Serum creatinine down trended to 0.9 mg/dL by day seven. Glomerular filtration rate ranged 90-240 mL/min by creatinine clearance and single-dose inulin clearance. Thus, in a human decedent model, xenotransplantation of 10 gene-edited pig kidneys provided physiologic balance for seven days. Hence, our in-human study paves the way for future clinical study of pig-to-human kidney xenotransplantation in living persons.

American Society of Transplant Surgeons-American Society of Transplantation report of FDA meeting on regulatory expectations for xenotransplantation products.

In June 2022, the US Food and Drug Administration Center for Biologics Evaluation and Research held the 73rd meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee for public discussion of regulatory expectations for xenotransplantation products. The members of a joint American Society of Transplant Surgeons/American Society of Transplantation committee on xenotransplantation compiled a meeting summary focusing on 7 topics believed to be key by the committee: (1) preclinical evidence supporting progression to a clinical trial, (2) porcine kidney function, (3) ethical aspects, (4) design of initial clinical trials, (5) infectious disease issues, (6) industry perspectives, and (7) regulatory oversight.

Adverse cardiac remodeling is absent in patients with true controlled resistant hypertension.

Resistant hypertension (RHTN), defined as blood pressure (BP) that is uncontrolled with ≥3 medications, including a long-acting thiazide diuretic, also includes a subset with BP that is controlled with ≥4 medications, so-called controlled RHTN. This resistance is attributed to intravascular volume excess. Patients with RHTN overall have a higher prevalence of left ventricular hypertrophy (LVH) and diastolic dysfunction compared to patients with non-RHTN. We tested the hypothesis that patients with controlled RHTN due to the intravascular volume excess have higher left ventricular mass index (LVMI), higher prevalence of LVH, larger intracardiac volumes, and more diastolic dysfunction compared to patients with controlled non-resistant hypertension (CHTN), defined as BP controlled with ≤3 anti-hypertensive medications. Patients with controlled RHTN (n = 69) or CHTN (n = 63) who were treated at the University of Alabama at Birmingham were offered enrollment and underwent cardiac magnetic resonance imaging. Diastolic function was assessed by peak filling rate, time needed in diastole to recover 80% of stroke volume, E:A ratios and left atrial volume. LVMI was higher in patients with controlled RHTN (64.4 ± 22.5 vs 56.9 ± 11.5; P = .017). Intracardiac volumes were similar in both groups. Diastolic function parameters were not significantly different between groups. There were no significant differences in age, gender, race, body mass index, dyslipidemia between the two groups. The findings show that patients with controlled RHTN have higher LVMI, but comparable diastolic function to those of patients with CHTN.

Assessment of glomerular filtration and tubular secretion in baboons with life-supporting pig kidney grafts.

With pig kidney xenotransplantation nearing clinical reality, it is imperative to measure pig kidney function in the graft recipients. Our aims were (i) to compare inulin clearance after a short intravenous (IV) bolus with steady-state inulin IV infusion, (ii) to use this method to measure the glomerular filtration rate (GFR), and (iii) to determine the tubular secretory function using cefoxitin in a pig-to-baboon renal transplant model. A short IV infusion of inulin and cefoxitin were followed by a maintenance IV infusion of inulin over 5 h in seven healthy baboons, three healthy pigs, and five baboons after bilateral native nephrectomy and intra-abdominal pig renal transplantation. Blood and urine samples were collected. Serum and urinary inulin and serum cefoxitin concentrations measured by validated assays were used to calculate GFR and renal secretion. GFR calculated were similar by both methods. The body weight normalized total body clearance of inulin was similar in pigs and baboons despite differences in absolute clearances. Pig kidney transplanted into baboons provided similar clearance in baboons when normalized to baboon body weight and sustained filtration and secretory functions. The study documented that pig kidneys support the physiologic needs of baboons and are likely to support human recipients as well.

Renin-angiotensin-aldosterone system function in the pig-to-baboon kidney xenotransplantation model.

After pig-to-baboon kidney transplantation, episodes of hypovolemia and hypotension from an unexplained mechanism have been reported. This study evaluated the renin-angiotensin-aldosterone system post-kidney xenotransplantation. Kidneys from genetically-engineered pigs were transplanted into 5 immunosuppressed baboons after the excision of the native kidneys. Immunosuppressive therapy was based on the blockade of the CD40/CD154 costimulation pathway. Plasma renin, angiotensinogen (AGT), angiotensin II (Ang II), aldosterone levels, and urine osmolality and electrolytes were measured in healthy pigs, healthy nonimmunosuppressed baboons, and immunosuppressed baboons with life-supporting pig kidney grafts. After pig kidney transplantation, plasma renin and Ang II levels were not significantly different, although Ang II trended lower, even though plasma AGT and potassium were increased. Plasma aldosterone levels were unchanged. Urine osmolality and sodium concentration were decreased. Even in the presence of increasing AGT and potassium levels, lower plasma Ang II concentrations may be because of reduced, albeit not absent, the reactivity of pig renin to cleave baboon AGT, suggesting an impaired response of the renin-angiotensin-aldosterone system to hypovolemic and hypotensive episodes. The maintenance of aldosterone may be protective. The reduced urine osmolality and sodium concentration reflect the decreased ability of the pig kidney to concentrate urine. These considerations should not prohibit successful clinical pig kidney xenotransplantation.

What is the clinical relevance of deviant serum calcium and phosphate levels after pig-to-primate kidney xenotransplantation?

Experience from human renal allotransplantation informs us that disturbances in serum calcium and phosphate levels are relatively common. Post-transplant hypercalcemia is associated with an increased risk of recipient mortality, but not of graft loss or nephropathy, and post-transplant hyperphosphatemia with an increased risk of both recipient mortality and death-censored graft failure, but neither post-transplant hypocalcemia nor hypophosphatemia is associated with adverse outcome. Studies after pig-to-nonhuman primate kidney xenotransplantation have demonstrated consistent supranormal serum calcium and subnormal serum phosphate levels. If these trends in serum electrolyte levels were to occur following pig-to-human kidney xenotransplantation, the data from allotransplant studies would indicate an increased risk of recipient mortality (associated with hypercalcemia) but not of graft loss or nephropathy, and no adverse outcome from hypophosphatemia. Furthermore, some nonhuman primates are now surviving in a healthy state for longer than a year after life-supporting pig kidney transplantation, suggesting that chronic hypercalcemia and/or hypophosphatemia are not detrimental to long-term survival, and should not prevent clinical trials of pig kidney transplantation from being undertaken.

Physiological aspects of pig kidney xenotransplantation and implications for management following transplant.

Successful organ transplantation between species is now possible, using genetic modifications. This article aims to provide a comprehensive overview of the differences and similarities in kidney function between humans, primates, and pigs, in preparation for pig-allograft to human xenotransplantation. The kidney, as the principal defender of body homeostasis, acts as a sensor, effector, and regulator of physiologic feedback systems. Considerations are made for anticipated effects on each system when a pig kidney is placed into a human recipient. Discussion topics include anatomy, global kidney function, sodium and water handling, kidney hormone production and response to circulating hormones, acid-base balance, and calcium and phosphorus handling. Based on available data, pig kidneys are anticipated to be compatible with human physiology, despite a few barriers.

Obstructive sleep apnea is more severe in men but not women with refractory hypertension compared with controlled resistant hypertension.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with treatment-resistant hypertension (RHTN) and may contribute to refractory hypertension (RfHTN). The objective of the current study was to test the hypothesis that patients with RfHTN have more severe OSA compared with patients with controlled RHTN. METHODS: Patients (n = 187) referred to the University of Alabama at Birmingham Hypertension Clinic for evaluation and treatment of RHTN, defined as uncontrolled blood pressure (BP) (SBP ≥ 130 mmHg or DBP ≥ 80 mmHg) despite the use of at least three antihypertensive medications including a diuretic, were enrolled following completion of at least three follow-up clinic visits. RfHTN was defined as uncontrolled high BP despite treatment with five or more antihypertensive agents of different classes, including a long-acting thiazide-type diuretic and a mineralocorticoid receptor antagonist. Following enrollment, all patients (n = 130) completed 24-h ambulatory BP measurement and overnight diagnostic polysomnography during normal nightly use of continuous positive airway pressure. Analyses examined the severity of OSA and related sleep characteristics among patients with RfHTN versus controlled RHTN. RESULTS: Of the 130 evaluated patients, 37 (28.5%) had RfHTN and 93 (71.5%) had controlled RHTN. In unadjusted analyses, there was not a significant difference in OSA severity, oxygen saturation, or hypoxemia time in patients with RfHTN versus controlled RHTN (P > 0.05). Men with RfHTN had more severe OSA compared with men with controlled RHTN (P = 0.044). In adjusted analyses, OSA severity was associated with sex (P < 0.0001), but not hypertension phenotype (P = 0.17). CONCLUSION: The severity of OSA may contribute to RfHTN status in men but not women.

AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19.

BACKGROUND: AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT). METHODS: We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients. RESULTS: A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission. CONCLUSIONS: AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission.

Masked Uncontrolled Hypertension Is Accompanied by Increased Out-of-Clinic Aldosterone Secretion.

Masked uncontrolled hypertension (MUCH) in treated patients is defined as controlled office blood pressure (BP) but uncontrolled out-of-clinic ambulatory BP. Previously, we have shown that patients with MUCH have evidence of heightened out-of-clinic sympathetic nervous system activity. The aim is to test the hypothesis that MUCH patients have higher aldosterone secretion compared with patients with true controlled hypertension. Two hundred twenty-two patients were recruited after having controlled office BP readings at ≥3 clinic visits. Patients taking MR (mineralocorticoid receptor) antagonists and epithelial sodium channel blockers were excluded. All patients were evaluated by clinic automated office BP and morning serum aldosterone and plasma renin activity. Out-of-clinic ambulatory BP monitoring and 24-hour urinary aldosterone, catecholamines, and metanephrines were also measured. Sixty-four patients had MUCH, and the remaining 48 patients had true controlled hypertension. MUCH patients had significantly higher out-of-clinic levels of 24-hour urinary aldosterone, catecholamines, and metanephrines compared with true controlled hypertension. The 2 groups did not differ in serum aldosterone, plasma renin activity, or aldosterone-renin ratio collected in clinic. In addition, 32.8% of MUCH patients had high out-of-clinic 24-hour urinary aldosterone (≥12 µg) but normal clinic serum aldosterone (<15 ng/dL) and aldosterone-renin ratio (<20). Further, in correlation matrix analysis, higher 24-hour urinary catecholamines and metanephrines were associated with higher 24-hour urinary aldosterone and plasma renin activity levels in MUCH patients. Patients with MUCH have higher out-of-clinic urinary aldosterone levels compared with patients with true controlled hypertension. This study suggests that patients with MUCH likely have higher out-of-clinic sympathetic nervous system tone increases aldosterone secretion mediated by increased renin release that may contribute to their higher out-of-clinic BP.

Reserpine Substantially Lowers Blood Pressure in Patients With Refractory Hypertension: A Proof-of-Concept Study.

BACKGROUND: Refractory hypertension (RfHTN), a phenotype of antihypertensive treatment failure, is defined as uncontrolled automated office blood pressure (AOBP) ≥130/80 mm Hg and awake ambulatory blood pressure (ABP) ≥130/80 mm Hg on ≥5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist. Previous studies suggest that RfHTN is attributable to heightened sympathetic tone. The current study tested whether reserpine, a potent sympatholytic agent, lowers blood pressure (BP) in patients with RfHTN. METHODS: Twenty-one out of 45 consecutive patients with suspected RfHTN were determined to be fully adherent with their antihypertensive regimen. Seven patients agreed to participate in the current clinical trial with reserpine and 6 patients completed the study. Other sympatholytic medications, such as clonidine or guanfacine, were tapered and discontinued before starting reserpine. Reserpine 0.1 mg daily was administered in an open-label fashion for 4 weeks. All patients were evaluated by AOBP and 24-hour ABP at baseline and after 4 weeks of treatment. RESULTS: Reserpine lowered mean systolic and diastolic AOBP by 29.3 ± 22.2 and 22.0 ± 15.8 mm Hg, respectively. Mean 24-hour systolic and diastolic ABPs were reduced by 21.8 ± 13.4 and 15.3 ± 9.6 mm Hg, mean awake systolic and diastolic ABPs by 23.8 ± 11.8 and 17.8 ± 9.2 mm Hg, and mean asleep systolic and diastolic ABPs by 21.5 ± 11.4 and 13.7 ± 6.4 mm Hg, respectively. CONCLUSIONS: Reserpine, a potent sympatholytic agent, lowers BP in patients whose BP remained uncontrolled on maximal antihypertensive therapy, lending support to the hypothesis that excess sympathetic output contributes importantly to the development of RfHTN.

Aortic blood pressure and arterial stiffness in patients with controlled resistant and non-resistant hypertension.

The purpose of the current study was to determine whether aortic blood pressure (BP) and arterial stiffness are greater in patients with controlled resistant hypertension (RHTN) than controlled non-resistant hypertension (non-RHTN) despite similar clinic BP level. Participants were recruited from University of Alabama at Birmingham (UAB) Hypertension Clinic. Controlled hypertension was defined as automated office BP measurement with BP < 135/85 mm Hg. A total of 141 participants were evaluated by pulse wave analysis (PWA) and carotid-femoral pulse wave velocity (cf-PWV). Among them, 75 patients had controlled RHTN with use of 4 or more antihypertensive medications and 56 patients had controlled non-RHTN with use of 3 or less antihypertensive medications. Compared to patients with controlled non-RHTN, those with controlled RHTN were more likely to be African American and had a higher prevalence of diabetes mellitus and congestive heart failure. The mean number of antihypertensive medications was greater in patients with controlled RHTN (4.4 ± 0.8 vs 2.3 ± 0.7, P < .001). Clinic brachial BP, aortic BP, augmentation pressure (AP), augmentation index normalized for heart rate of 75 beats per minute (AIx@75) and cf-PWV were similar in both groups. In summary, there was no significant difference in central BP or arterial stiffness between patients with controlled RHTN and controlled non-RHTN. These findings suggest that the higher residual cardiovascular risk observed in patients with RHTN after achieving BP control compared to patients with more easily controlled hypertension is not likely attributable to persistent differences in central BP and arterial stiffness.

Antihypertensive Medication Adherence and Confirmation of True Refractory Hypertension.

Refractory hypertension (RfHTN) is a phenotype of antihypertensive treatment failure defined as uncontrolled BP despite the use of effective doses of ≥5 antihypertensive medications including a long-acting thiazide-like diuretic (chlorthalidone) and a mineralocorticoid receptor antagonist. The degree of medication nonadherence is unknown among patients with RfHTN. In this prospective evaluation, 54 patients with apparent RfHTN were recruited from the University of Alabama at Birmingham Hypertension Clinic after having uncontrolled BP at 3 or more clinic visits. All patients' BP was evaluated by automated office BP and 24-hour ambulatory BP monitoring (n=49). Antihypertensive medication adherence was determined by measuring 24-hour urine specimens for antihypertensive medications and their metabolites by high-performance liquid chromatography-tandem mass spectrometry (n=45). Of the 45 patients who completed 24-hour ambulatory BP monitoring, 40 (88.9%) had confirmed RfHTN based on an elevated automated office BP (≥130/80 mm Hg), mean 24-hour ABP (≥125/75 mm Hg), and mean awake (day-time) ABP (≥130/80 mm Hg). Out of the 40 fully evaluated patients with RfHTN, 16 (40.0%) were fully adherent with all prescribed medications. Eighteen (45.0%) patients were partially adherent and 6 (15.0%) had none of the prescribed agents detected in their urine. Of 18 patients who were partially adherent, 5 (12.5%) were adherent with at least 5 medications, including chlorthalidone and the mineralocorticoid receptor antagonist, consistent with true RfHTN. Of patients identified as having apparent RfHTN, 52.5% were adherent with at least 5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist, confirming true RfTHN. These findings validate RfHTN as a rare, but true phenotype of antihypertensive treatment failure.

Masked Uncontrolled Hypertension Is Not Attributable to Medication Nonadherence.

Masked uncontrolled hypertension (MUCH) in treated hypertensive patients is defined as controlled automated office blood pressure (BP; <135/85 mm Hg) in-clinic but uncontrolled out-of-clinic BP by ambulatory BP monitoring (awake [daytime] readings ≥135/85 mm Hg or 24-hour readings ≥130/80 mm Hg). To determine whether MUCH is attributable to antihypertensive medication nonadherence. One hundred eighty-four enrolled patients were confirmed to have controlled office BP; of these, 167 patients were with adequate 24-hour ambulatory BP recordings. Of 167 patients, 86 were controlled by in-clinic BP assessment but had uncontrolled ambulatory awake BP, indicative of MUCH. The remaining 81 had controlled in-clinic and ambulatory awake BP, consistent with true controlled hypertension. After exclusion of 9 patients with missing 24-hour urine collections, antihypertensive medication adherence was determined based on the detection of urinary drugs or drug metabolites by high-performance liquid chromatography-tandem mass spectrometry. Of the 81 patients with MUCH, 69 (85.2%) were fully adherent and 12 (14.8%) were partially adherent (fewer medications detected than prescribed). Of the 77 patients with true controlled hypertension, 69 (89.6%) were fully adherent with prescribed antihypertensive medications and 8 (10.4%) were partially adherent. None of the patients in either group were fully nonadherent. There was no statistically significant difference in complete or partial adherence between the MUCH and true controlled groups (P=0.403). Measurement of urinary drug and drug metabolite levels demonstrates a similarly high level of antihypertensive medication adherence in both MUCH and truly controlled hypertensive patients. These findings indicate that MUCH is not attributable to antihypertensive medication nonadherence.

Out-of-Clinic Sympathetic Activity Is Increased in Patients With Masked Uncontrolled Hypertension.

Masked uncontrolled hypertension (MUCH) is defined as controlled automated office blood pressure (BP; AOBP <135/85 mm Hg) in-clinic in patients receiving antihypertensive medication(s) but uncontrolled BP out-of-clinic by 24-hour ambulatory BP monitoring (ABPM; awake ≥135/85 mm Hg). We hypothesized that MUCH patients have greater out-of-clinic sympathetic activity compared with true controlled hypertensives. Patients being treated for hypertension were prospectively recruited after 3 or more consecutive clinic visits. All patients were evaluated by in-clinic automated office BP, plasma catecholamines, and spot-urine/plasma metanephrines. In addition, out-of-clinic 24-hour ABPM, 24-hour urinary for catecholamines and metanephrines was done. Out of 237 patients recruited, 169 patients had controlled in-clinic BP of which 156 patients had completed ABPM. Seventy-four were true controlled hypertensives, that is controlled by clinic automated office BP and by out-of-clinic ABPM. The remaining 82 were controlled by clinic automated office BP, but uncontrolled during out-of-clinic ABPM, indicative of MUCH. After exclusion of 4 patients because of inadequate or lack of 24-hour urinary collections, 72 true controlled hypertensive and 80 MUCH patients were analyzed. MUCH patients had significantly higher out-of-clinic BP variability and lower heart rate variability compared with true controlled hypertensives, as well as higher levels of out-of-clinic urinary catecholamines and metanephrines levels consistent with higher out-of-clinic sympathetic activity. In contrast, there was no difference in in-clinic plasma catecholamines and spot-urine/plasma levels of metanephrines between the 2 groups, consistent with similar levels of sympathetic activity while in clinic. MUCH patients have evidence of heightened out-of-clinic sympathetic activity compared with true controlled hypertensives, which may contribute to the development of MUCH.

Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association.

Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the "white-coat effect" (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.

Refractory Hypertension Is not Attributable to Intravascular Fluid Retention as Determined by Intracardiac Volumes.

Refractory hypertension (RfHTN) is an extreme phenotype of antihypertensive treatment failure defined as lack of blood pressure control with ≥5 medications, including a long-acting thiazide and a mineralocorticoid receptor antagonist. RfHTN is a subgroup of resistant hypertension (RHTN), which is defined as blood pressure >135/85 mm Hg with ≥3 antihypertensive medications, including a diuretic. RHTN is generally attributed to persistent intravascular fluid retention. It is unknown whether alternative mechanisms are operative in RfHTN. Our objective was to determine whether RfHTN is characterized by persistent fluid retention, indexed by greater intracardiac volumes determined by cardiac magnetic resonance when compared with controlled RHTN patients. Consecutive patients evaluated in our institution with RfHTN and controlled RHTN were prospectively enrolled. Exclusion criteria included advanced chronic kidney disease and masked or white coat hypertension. All enrolled patients underwent biochemical testing and cardiac magnetic resonance. The RfHTN group (n=24) was younger (mean age, 51.7±8.9 versus 60.6±11.5 years; P=0.003) and had a greater proportion of women (75.0% versus 43%; P=0.02) compared with the controlled RHTN group (n=30). RfHTN patients had a greater left ventricular mass index (88.3±35.0 versus 54.6±12.5 g/m2; P<0.001), posterior wall thickness (10.1±3.1 versus 7.7±1.5 mm; P=0.001), and septal wall thickness (14.5±3.8 versus 10.0±2.2 mm; P<0.001). There was no difference in B-type natriuretic peptide levels and left atrial or ventricular volumes. Diastolic dysfunction was noted in RfHTN. Our findings demonstrate greater left ventricular hypertrophy without chamber enlargement in RfHTN, suggesting that antihypertensive treatment failure is not attributable to intravascular volume retention.

Rationale and design of the ICON-RELOADED study: International Collaborative of N-terminal pro-B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department.

OBJECTIVES: The objectives were to reassess use of amino-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations for diagnosis and prognosis of acute heart failure (HF) in patients with acute dyspnea. BACKGROUND: NT-proBNP facilitates diagnosis, prognosis, and treatment in patients with suspected or proven acute HF. As demographics of such patients are changing, previous diagnostic NT-proBNP thresholds may need updating. Additionally, value of in-hospital NT-proBNP prognostic monitoring for HF is less understood. METHODS: In a prospective, multicenter study in the United States and Canada, patients presenting to emergency departments with acute dyspnea were enrolled, with demographic, medication, imaging, and clinical course information collected. NT-proBNP analysis will be performed using the Roche Diagnostics Elecsys proBNPII immunoassay in blood samples obtained at baseline and at discharge (if hospitalized). Primary end points include positive predictive value of previously established age-stratified NT-proBNP thresholds for the adjudicated diagnosis of acute HF and its negative predictive value to exclude acute HF. Secondary end points include sensitivity, specificity, and positive and negative likelihood ratios for acute HF and, among those with HF, the prognostic value of baseline and predischarge NT-proBNP for adjudicated clinical end points (including all-cause death and hospitalization) at 30 and 180days. RESULTS: A total of 1,461 dyspneic subjects have been enrolled and are eligible for analysis. Follow-up for clinical outcome is ongoing. CONCLUSIONS: The International Collaborative of N-terminal pro-B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department study offers a contemporary opportunity to understand best diagnostic cutoff points for NT-proBNP in acute HF and validate in-hospital monitoring of HF using NT-proBNP.

White-Coat Effect Is Uncommon in Patients With Refractory Hypertension.

Refractory hypertension is a recently described phenotype of antihypertensive treatment failure defined as uncontrolled blood pressure (BP) despite the use of ≥5 different antihypertensive agents, including chlorthalidone and spironolactone. Recent studies indicate that refractory hypertension is uncommon, with a prevalence of ≈5% to 10% of patients referred to a hypertension specialty clinic for uncontrolled hypertension. The prevalence of white-coat effect, that is, uncontrolled automated office BP ≥135/85 mm Hg and controlled out-of-office BP <135/85 mm Hg, by awake ambulatory BP monitor in hypertensive patients overall is ≈30% to 40%. The prevalence of white-coat effect among patients with refractory hypertension has not been previously reported. In this prospective evaluation, consecutive patients referred to the University of Alabama at Birmingham Hypertension Clinic for uncontrolled hypertension were enrolled. Refractory hypertension was defined as uncontrolled automated office BP ≥135/85 mm Hg with the use of ≥5 antihypertensive agents, including chlorthalidone and spironolactone. Automated office BP measurements were based on 6 serial readings, done automatically with the use of a BpTRU device unobserved in the clinic. Out-of-office BP measurements were done by 24-hour ambulatory BP monitor. Thirty-four patients were diagnosed with refractory hypertension, of whom 31 had adequate ambulatory BP monitor readings. White-coat effect was present in only 2 patients, or 6.5% of the 31 patients with refractory hypertension, suggesting that white-coat effect is largely absent in patients with refractory hypertension. These findings suggest that white-coat effect is not a common cause of apparent lack of BP control in patients failing maximal antihypertensive treatment.