α- or ß-Adrenergic blockade does not affect transplanted islet cell responses to hypoglycemia in type 1 diabetes.

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to post-transplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (ß-adrenergic blockage), or placebo infusion. Participants (5 female/4 male) were median (range) age 53 (34-63) years, diabetes duration 29 (18-56) years, post-transplant 7.0 (1.9-8.4) years, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate lower with propranolol vs. placebo (P <0.05). There was no difference in suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and while levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine vs. placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate higher with propranolol vs. placebo during the hypoglycemic phase (P < 0.05). These results indicate that neither physiologic α- nor ß-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic re-innervation of the islet graft is not necessary for post-transplant glucose counterregulation.

Race, Genetic Ancestry, and Estimating Kidney Function in CKD.

BACKGROUND: The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed. METHODS: In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels. RESULTS: Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P10], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m2; 95% CI, -0.29 to 2.54; P10, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m2; 95% CI, -0.12 to 2.33; P10, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m2; 95% CI, -1.43 to 1.92) and accurate (P10, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C. CONCLUSIONS: The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Arterial Stiffness and Diabetes Risk in Framingham Heart Study and UK Biobank.

BACKGROUND: Microvascular damage from large artery stiffness (LAS) in pancreatic, hepatic, and skeletal muscles may affect glucose homeostasis. Our goal was to evaluate the association between LAS and the risk of type 2 diabetes using prospectively collected, carefully phenotyped measurements of LAS as well as Mendelian randomization analyses. METHODS: Carotid-femoral pulse wave velocity (CF-PWV) and brachial and central pulse pressure were measured in 5676 participants of the FHS (Framingham Heart Study) without diabetes. We used Cox proportional hazards regression to evaluate the association of CF-PWV and pulse pressure with incident diabetes. We subsequently performed 2-sample Mendelian randomization analyses evaluating the associations of genetically predicted brachial pulse pressure with type 2 diabetes in the UKBB (United Kingdom Biobank). RESULTS: In FHS, individuals with higher CF-PWV were older, more often male, and had higher body mass index and mean arterial pressure compared to those with lower CF-PWV. After a median follow-up of 7 years, CF-PWV and central pulse pressure were associated with an increased risk of new-onset diabetes (per SD increase, multivariable-adjusted CF-PWV hazard ratio, 1.36 [95% CI, 1.03-1.76]; P=0.030; central pulse pressure multivariable-adjusted CF-PWV hazard ratio, 1.26 [95% CI, 1.08-1.48]; P=0.004). In United Kingdom Biobank, genetically predicted brachial pulse pressure was associated with type 2 diabetes, independent of mean arterial pressure (adjusted odds ratio, 1.16 [95% CI, 1.00-1.35]; P=0.049). CONCLUSIONS: Using prospective cohort data coupled with Mendelian randomization analyses, we found evidence supporting that greater LAS is associated with increased risk of developing diabetes. LAS may play an important role in glucose homeostasis and may serve as a useful marker of future diabetes risk.

White Coat Hypertension & Cardiovascular Outcomes.

PURPOSE OF REVIEW: This review aims to inform the reader of the complexity of blood pressure responses when comparing blood pressure measured in the medical environment to that outside the medical environment. In addition, we summarize what is known about current predictors of white coat hypertension, reevaluate the relationship of white coat hypertension to cardiovascular outcomes, and provide some clinical guidance on management. RECENT FINDINGS: Differences in outcomes exist when white coat effect occurs in unmedicated people versus the white coat effects in those on antihypertensive therapy. White coat hypertension is relatively common, carries a small but definite increase in cardiovascular risk, and is prone to conversion to sustained hypertension. Future research will hopefully tease out the roles of ancillary findings that characterize a white coat hypertensive (like modest elevations in creatinine, glucose and triglycerides) in the elevated cardiovascular risk, and test the effectiveness of mitigation strategies in these patients.

Hypertension management in patients with cardiovascular comorbidities.

Arterial hypertension is a leading cause of death globally. Due to ageing, the rising incidence of obesity, and socioeconomic and environmental changes, its incidence increases worldwide. Hypertension commonly coexists with Type 2 diabetes, obesity, dyslipidaemia, sedentary lifestyle, and smoking leading to risk amplification. Blood pressure lowering by lifestyle modifications and antihypertensive drugs reduce cardiovascular (CV) morbidity and mortality. Guidelines recommend dual- and triple-combination therapies using renin-angiotensin system blockers, calcium channel blockers, and/or a diuretic. Comorbidities often complicate management. New drugs such as angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists improve CV and renal outcomes. Catheter-based renal denervation could offer an alternative treatment option in comorbid hypertension associated with increased sympathetic nerve activity. This review summarises the latest clinical evidence for managing hypertension with CV comorbidities.

Effects of a mitochondrial-targeted ubiquinol on vascular function and exercise capacity in chronic kidney disease: a randomized controlled pilot study.

Mitochondria-derived oxidative stress has been implicated in vascular and skeletal muscle abnormalities in chronic kidney disease (CKD). The purpose of this study was to investigate the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in CKD. In this randomized controlled trial, 18 patients with CKD (means ± SE, age: 62 ± 3 yr and estimated glomerular filtration rate: 45 ± 3 mL/min/1.73 m2) received 4 wk of 20 mg/day MitoQ (MTQ group) or placebo (PLB). Outcomes assessed at baseline and follow-up included macrovascular function measured by flow-mediated dilation, microvascular function assessed by laser-Doppler flowmetry combined with intradermal microdialysis, aortic hemodynamics assessed by oscillometry, and exercise capacity assessed by cardiopulmonary exercise testing. Compared with PLB, MitoQ improved flow-mediated dilation (baseline vs. follow-up: MTQ, 2.4 ± 0.3% vs. 4.0 ± 0.9%, and PLB, 4.2 ± 1.0% vs. 2.5 ± 1.0%, P = 0.04). MitoQ improved microvascular function (change in cutaneous vascular conductance: MTQ 4.50 ± 2.57% vs. PLB -2.22 ± 2.67%, P = 0.053). Central aortic systolic and pulse pressures were unchanged; however, MitoQ prevented increases in augmentation pressures that were observed in the PLB group (P = 0.026). MitoQ did not affect exercise capacity. In conclusion, this study demonstrates the potential for a MitoQ to improve vascular function in CKD. The findings hold promise for future investigations of mitochondria-targeted therapies in CKD.NEW & NOTEWORTHY In this randomized controlled pilot study, we investigated the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in chronic kidney disease. Our novel findings showed that 4-wk supplementation of MitoQ was well tolerated and improved macrovascular endothelial function, arterial hemodynamics, and microvascular function in patients with stage 3-4 chronic kidney disease. Our mechanistic findings also suggest that MitoQ improved microvascular function in part by reducing the NADPH oxidase contribution to vascular dysfunction.

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 Trial.

BACKGROUND: The SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial showed the safety but not efficacy of the Symplicity system (Medtronic, Santa Rosa, CA, USA) at 6 months follow-up in patients with treatment-resistant hypertension. This final report presents the 36-month follow-up results. METHODS: SYMPLICITY HTN-3 was a single-blind, multicentre, sham-controlled, randomised clinical trial, done in 88 centres in the USA. Adults aged 18-80 years, with treatment-resistant hypertension on stable, maximally tolerated doses of three or more drugs including a diuretic, who had a seated office systolic blood pressure of 160 mm Hg or more and 24 h ambulatory systolic blood pressure of 135 mm Hg or more were randomly assigned (2:1) to receive renal artery denervation using the single electrode (Flex) catheter or a sham control. The original primary endpoint was the change in office systolic blood pressure from baseline to 6 months for the renal artery denervation group compared with the sham control group. Patients were unmasked after the primary endpoint assessment at 6 months, at which point eligible patients in the sham control group who met the inclusion criteria (office blood pressure ≥160 mm Hg, 24 h ambulatory systolic blood pressure ≥135 mm Hg, and still prescribed three or more antihypertensive medications) could cross over to receive renal artery denervation. Changes in blood pressure up to 36 months were analysed in patients in the original renal artery denervation group and sham control group, including those who underwent renal artery denervation after 6 months (crossover group) and those who did not (non-crossover group). For comparisons between the renal artery denervation and sham control groups, follow-up blood pressure values were imputed for patients in the crossover group using their most recent pre-crossover masked blood pressure value. We report long-term blood pressure changes in renal artery denervation and sham control groups, and investigate blood pressure control in both groups using time in therapeutic blood pressure range analysis. The primary safety endpoint was the incidence of all-cause mortality, end stage renal disease, significant embolic event, renal artery perforation or dissection requiring intervention, vascular complications, hospitalisation for hypertensive crisis unrelated to non-adherence to medications, or new renal artery stenosis of more than 70% within 6 months. The trial is registered with ClinicalTrials.gov, NCT01418261. FINDINGS: From Sep 29, 2011, to May 6, 2013, 1442 patients were screened, of whom 535 (37%; 210 [39%] women and 325 [61%] men; mean age 57·9 years [SD 10·7]) were randomly assigned: 364 (68%) patients received renal artery denervation (mean age 57·9 years [10·4]) and 171 (32%) received the sham control (mean age 56·2 years [11·2]). 36-month follow-up data were available for 219 patients (original renal artery denervation group), 63 patients (crossover group), and 33 patients (non-crossover group). At 36 months, the change in office systolic blood pressure was -26·4 mm Hg (SD 25·9) in the renal artery denervation group and -5·7 mm Hg (24·4) in the sham control group (adjusted treatment difference -22·1 mm Hg [95% CI -27·2 to -17·0]; p≤0·0001). The change in 24 h ambulatory systolic blood pressure at 36 months was -15·6 mm Hg (SD 20·8) in the renal artery denervation group and -0·3 mm Hg (15·1) in the sham control group (adjusted treatment difference -16·5 mm Hg [95% CI -20·5 to -12·5]; p≤0·0001). Without imputation, the renal artery denervation group spent a significantly longer time in therapeutic blood pressure range (ie, better blood pressure control) than patients in the sham control group (18% [SD 25·0] for the renal artery denervation group vs 9% [SD 18·8] for the sham control group; p≤0·0001) despite a similar medication burden, with consistent and significant results with imputation. Rates of adverse events were similar across treatment groups, with no evidence of late-emerging complications from renal artery denervation. The rate of the composite safety endpoint to 48 months, including all-cause death, new-onset end-stage renal disease, significant embolic event resulting in end-organ damage, vascular complication, renal artery re-intervention, and hypertensive emergency was 15% (54 of 352 patients) for the renal artery denervation group, 14% (13 of 96 patients) for the crossover group, and 14% (10 of 69 patients) for the non-crossover group. INTERPRETATION: This final report of the SYMPLICITY HTN-3 trial adds to the totality of evidence supporting the safety of renal artery denervation to 36 months after the procedure. From 12 months to 36 months after the procedure, patients who were originally randomly assigned to receive renal artery denervation had larger reductions in blood pressure and better blood pressure control compared with patients who received sham control. FUNDING: Medtronic.

Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.

BACKGROUND: Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group. METHODS: This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial. FINDINGS: Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was -18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and -8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference -10·0 mm Hg, 95% CI -16·6 to -3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were -5·9 mm Hg (95% CI -10·1 to -1·8; p=0·0055) for mean ambulatory diastolic blood pressure, -11·0 mm Hg (-19·8 to -2·1; p=0·016) for morning systolic blood pressure, and -11·8 mm Hg (-19·0 to -4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation. INTERPRETATION: Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension. FUNDING: Medtronic.

One more step in the renal denervation trek.

Is This REALLY Required?

Socioeconomic characteristics of those with peripheral artery disease in the chronic renal insufficiency cohort.

BACKGROUND: The association between socioeconomic factors and peripheral arterial disease (PAD) has not been as well characterized as other cardiovascular conditions. We sought to define how annual income and education level are associated with PAD in a well-characterized diverse set of adults with chronic kidney disease (CKD). METHODS: The Chronic Renal Insufficiency Cohort Study (CRIC) is a multi-center, prospective cohort study designed to examine risk factors for progression of CKD and cardiovascular disease. Demographic, income, and education-level data, as well as clinical data including ankle-brachial index (ABI) were collected at baseline. Annual income was categorized as < $25,000, $25,000-50,000, $50,000-100,000, or above $100,000; educational level was categorized as some high school, high school graduate, some college, or college graduate. Participants with missing income data or incompressible ABI (>1.4) were excluded from initial analysis. Logistic regression was used to estimate the association of income and/or education level with PAD, defined as an enrollment ABI of <0.90, history of PAD, or history of PAD intervention. RESULTS: A total of 4122 were included, mean age of participants was 59.5 years, 56% were male, and 44% were Black. There were 763 CRIC participants with PAD at study enrollment (18.5%). In the final multivariable logistic regression model, Black race (OR = 1.3, 95% CI 1.1-1.6, p = 0.004) and level of annual household income remained independently associated with PAD at the time of enrollment (income <$25,000 OR = 1.9, 95% CI 1.3-2.8, p < 0.001; income $25,000-50,000 OR = 1.6, 95% CI 1.1-2.3, p = 0.011; income $50,000-100,000 OR = 1.2, 95% CI 0.9-1.8, p = 0.246), relative to a baseline annual income of >$100,000 (overall p-value <0.001). Decreasing level of educational attainment was not independently associated with increased PAD at enrollment, but lower level of educational attainment was associated with increased PAD when income data was not adjusted for (p = 0.001). Interestingly, Black race (OR = 0.7, 95% CI 0.6-0.8, p < 0.001), female gender (OR = 0.8, 95% CI 0.7-0.9, p = 0.007), and income <$25,000 (OR = 0.7, 95% CI 0.5-0.9, p = 0.008) were significantly associated with decreased statin use even after controlling for cardiovascular conditions. CONCLUSIONS: In this prospectively followed CKD cohort, lower annual household income and Black race were significantly associated with increased PAD at study enrollment. In contrast, educational level was not associated with PAD when adjusted for patient income data. Black race, female gender, and low income were independently associated with decreased statin use, populations which could be targets of future public health programs.

Sex differences in microvascular function and arterial hemodynamics in nondialysis chronic kidney disease.

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). Abnormal arterial hemodynamics contribute to CVD, a relationship that can be mediated by microvascular dysfunction. The purpose of this study was to investigate potential sex differences in arterial hemodynamics and microvascular dysfunction in patients with stages 3 to 4 CKD. Vascular function was assessed in 22 male (mean ± SD; age, 56 ± 13 yr) and 10 female (age, 63 ± 9 yr) patients. Arterial hemodynamics were acquired with combined tonometry and oscillometry. Skin blood flow was used as a model of microvascular function. Participants were instrumented with three microdialysis fibers for the delivery of 1) Ringer's solution; 2) superoxide dismutase mimetic, Tempol; and 3) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin. Blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). Central pulse pressure (mean ± SE; 62 ± 9 vs. 46 ± 3 mmHg; P = 0.01) and augmentation index (36 ± 3 vs. 26 ± 3%; P = 0.03) were higher in females. There was a trend for higher central systolic pressures in females (146 ± 9 vs. 131 ± 3 mmHg; P = 0.06). Females reported higher forward (39 ± 4 vs. 29 ± 2 mmHg; P = 0.004) and reflected (27 ± 3 vs. 19 ± 1 mmHg; P < 0.001) wave amplitudes. Cutaneous vascular function was impaired in females compared with males (77 ± 3 vs. 89 ± 1%, P = 0.001). Microvascular function was improved following the delivery of Tempol and apocynin in females but not in males. Female patients with CKD had poorer central hemodynamics and reduced microvascular function compared with their male counterparts. Oxidative stress may contribute to lower microvascular function observed in females.NEW & NOTEWORTHY There are limited data regarding the physiological mechanisms of potential sex differences in central hemodynamics and vascular function in chronic kidney disease (CKD). We report that older female patients with nondialysis CKD have higher central pulse pressures compared with male patients with CKD. In addition, older females with CKD have lower microvascular function compared with their male counterparts, and oxidative stress contributes to the lower microvascular function in older female patients with CKD.

Renal Denervation: A Review.

Uncontrolled hypertension persists as an important health issue despite the availability of many medications and nondrug therapies that lower blood pressure. Increasingly, nonadherence to medication is found in approximately 2 of every 5 patients with uncontrolled hypertension. In the search for interventions that lower blood pressure that do not rely on adherence to a regimen requiring daily ingestion of medication or repeated physical activity, device-based methods that denervate the renal arteries have emerged as a potential complement to standard antihypertensive treatments. At least 3 different approaches to renal artery denervation are under active investigation, including the use of radiofrequency energy, ultrasound, or the injection of neurolytic agents into the renal perivascular tissue. In this review, we cover what is currently known about the mechanisms of antihypertensive effects of renal denervation, summarize the efficacy and safety of renal denervation using recent controlled trial publications in a number of hypertensive populations, and conclude with some thoughts about challenges in the field, including the optimization of patient selection for the procedure and what the reader can expect in the near future in this rapidly developing field.

Home and ambulatory blood pressure levels below target range and clinical effort to detect this condition: a population-based study in older treated hypertensives.

BACKGROUND: With implementation of stricter blood pressure (BP) treatment targets, potential for excessive BP lowering becomes an important issue, especially in older patients. OBJECTIVES: Assess the magnitude, indicators and detection effort of BP levels below-target-range (BTR-BP) recommended by the European hypertension guidelines in older treated hypertensive patients (130-139/70-79 mmHg). DESIGN: Cross-sectional, retrospective study (Seniors-ENRICA-2 cohort). SETTING: General population. SUBJECTS: 1,329 treated hypertensive patients aged ≥65, assessed with three home casual BP measurements and 24-hour ambulatory BP monitoring (ABPM). METHODS: Based on the European hypertension guidelines and the literature, BTR-BPs were defined as mean BP <130/70, <125/65, <130/70 and <110/55 mmHg, for casual BP, 24-hour BP, daytime BP and nighttime BP, respectively, and hypotension as <110/70, <105/65, <110/70 and <90/55 mmHg, respectively. RESULTS: Participants' mean age was 72 ± 4.4 (50.3%, women). Based on casual BP, 7.2% of patients were in target range (130-139/70-79 mmHg), 44.3% in BTR-BP (<130/70) and 20.8% hypotensive (<110/70). Some 44.9, 54.9 and 22.0% of patients were in BTR-BP for 24-hour BP, daytime BP and nighttime BP, respectively, and 11.0, 21.1 and 5.6%, respectively, were hypotensive. The number of patients needed for ABPM to detect one case of 24-hour-, daytime-, and nighttime-BTR-BP was 3, 2 and 5, respectively, and 10, 5 and 18, respectively, for detecting one hypotensive case. Cardiovascular disease and female sex were associated with both BTR-BP and hypotension, and the number of antihypertensive drugs was only associated with hypotension. CONCLUSIONS: BTR-BP levels were common in older treated patients at home and in everyday life, more frequent than many trials report, and daytime ABPM is highly size-efficient for detecting the low ambulatory BP conditions.

The Association Between Socioeconomic Factors and Incident Peripheral Artery Disease in the Chronic Renal Insufficiency Cohort (CRIC).

BACKGROUND: The association between socioeconomic factors and development of peripheral artery disease (PAD) has not been as well characterized compared to other cardiovascular diseases. We sought to define how annual income, sex, race, and education level are associated with newly diagnosed PAD in a well-characterized, diverse set of adults with CKD. METHODS: The Chronic Renal Insufficiency Cohort Study (CRIC) is a multicenter, prospective cohort study designed to examine risk factors for progression of CKD and cardiovascular disease. Demographic and clinical data including ankle brachial index (ABI) and interventions were collected at baseline, as well as yearly during follow-up visits. Annual income was categorized as: <$25,000, $25,000-50,000, $50,000-100,000, or above $100,000. We excluded those with pre-existing PAD, defined as enrollment ABI of <0.9 or >1.4, or missing income data. Cox proportional hazards regression was used to estimate the risk for incident PAD during CRIC enrollment, defined as a drop in ABI to <0.90 or a confirmed PAD intervention, including revascularization or amputation. RESULTS: A total of 3,313 patients met inclusion criteria, the mean age was 58.7 years, 56% were male, and 42% were Black. Over a median follow-up of 10.1 years, 639 participants (19%) were newly diagnosed with PAD. After adjusting for cardiovascular risk factors, all lower levels of annual household income were associated with increased incidence of PAD (income <$25,000 HR 1.7, 95% CI 1.1-2.4, P = 0.008; income $25,000-50,000 HR 1.5, 95% CI 1.1-2.3, P = 0.009; income $50,000-100,000 HR 1.6, 95% CI 1.2-2.4, P = 0.004), relative to a baseline annual income of >$100,000 (overall P-value = 0.02). In the multivariable model, there was no association between education level and PAD incidence (P = 0.80). Black race (HR 1.2, 95% CI 1.0-1.5, P = 0.023) and female sex (HR 1.7, 95% CI 1.4-2.0, P < 0.001) were independently associated with PAD incidence. Multiple imputation analysis provided similar results. CONCLUSIONS: In the CRIC, a multi-center cohort of prospectively followed CKD patients undergoing yearly CVD surveillance, lower annual household income, female sex, and Black race were significantly associated with the PAD incidence. In contrast, level of education was not independently associated with incident PAD.

Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.

BACKGROUND: Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. METHODS: In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749. FINDINGS: From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was -3·9 mm Hg (Bayesian 95% credible interval -6·2 to -1·6) and for office systolic blood pressure the difference was -6·5 mm Hg (-9·6 to -3·5). No major device-related or procedural-related safety events occurred up to 3 months. INTERPRETATION: SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. FUNDING: Medtronic.

Treating Home Versus Predialysis Blood Pressure Among In-Center Hemodialysis Patients: A Pilot Randomized Trial.

RATIONALE & OBJECTIVE: Observational studies have reported a U-shaped association between blood pressure (BP) before a hemodialysis session and death. In contrast, because a linear association between out-of-dialysis-unit BP and death has been reported, home BP may be a better target for treatment. To test the feasibility of this approach, we conducted a pilot trial of treating home versus predialysis BP in hemodialysis patients. STUDY DESIGN: A 4-month, parallel, randomized, controlled trial. SETTINGS & PARTICIPANTS: 50 prevalent hemodialysis patients in San Francisco and Seattle. Participants were randomly assigned using 1:1 block randomization, stratified by site. INTERVENTIONS: To target home systolic BP (SBP) of 100-<140 mm Hg versus predialysis SBP of 100-<140mm Hg. Home and predialysis SBPs were ascertained every 2 weeks. Dry weight and BP medications were adjusted to reach the target SBP. OUTCOMES: Primary outcomes were feasibility, adherence, safety. and tolerability. RESULTS: 50 of 70 (71%) patients who were approached agreed to participate. All enrollees completed the study except for 1 who received a kidney transplant. In the home BP treatment group, adherence to obtaining/reporting home BP was 97.4% (and consistent over the 4 months). There was no increased frequency of high (defined as SBP>200mm Hg; 0.2% vs 0%) or low (defined as<90mm Hg; 1.8% vs 1.2%) predialysis BP readings in the home versus predialysis treatment arms, respectively. However, participants in the home BP arm had higher frequency of fatigue (32% vs 16%). LIMITATIONS: Small sample size. CONCLUSIONS: This pilot trial demonstrates feasibility and high adherence to home BP measurement and treatment in hemodialysis patients. Larger trials to test the long-term feasibility, efficacy, and safety of home BP treatment in hemodialysis patients should be conducted. FUNDERS: National Institutes of Health, Satellite Healthcare, and Northwest Kidney Centers. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03459807.

Mobile Health (mHealth) Technology: Assessment of Availability, Acceptability, and Use in CKD.

RATIONALE & OBJECTIVE: Digital and mobile health (mHealth) technologies improve patient-provider communication and increase information accessibility. We assessed the use of technology, attitudes toward using mHealth technologies, and proficiency in using mHealth technologies among individuals with chronic kidney disease (CKD). STUDY DESIGN: Cross-sectional survey with open text responses. SETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort (CRIC) Study participants who completed current use and interest in using mHealth technologies questionnaires and the eHealth literacy Survey (eHEALS). EXPOSURE: Participant characteristics. OUTCOMES: Use of technology (ie, internet, email, smartphone, and mHealth applications [apps]), interest in future mHealth use, and proficiency in using digital and mHealth technologies, or eHealth literacy, determined by eHEALS score. ANALYTICAL APPROACH: Poisson regression and a qualitative content analysis of open-ended responses. RESULTS: Study participants (n = 932) had a mean age of 68 years old and an estimated glomerular filtration rate (eGFR) of 54 mL/min/1.73 m2, and 59% were male. Approximately 70% reported current use of internet, email, and smartphones, and 35% used mHealth apps; only 27% had adequate eHealth literacy (eHEALS score ≥ 32). Participants <65 years of age (vs. ≥65), with more education, higher income, better cognition, and adequate health literacy reported more use of technology, and greater interest in using technologies. Participants of White (vs. non-White) race reported more use of internet and email but less interest in future use of mHealth. Younger age, higher annual income, and greater disease self-efficacy were associated with adequate eHealth literacy. Three themes regarding interest in using digital and mHealth technologies emerged: willingness, concerns, and barriers. LIMITATIONS: Residual confounding, ascertainment bias. CONCLUSIONS: Many individuals with CKD currently use the internet and smartphones and are interested in using mHealth in the future, but few use mHealth apps or have adequate eHealth literacy. mHealth technologies present an opportunity to engage individuals with CKD, especially members of racial or ethnic minority groups because those groups reported greater interest in using mHealth technology than the nonminority population. Further research is needed to identify strategies to overcome inadequate eHealth literacy.

Adiposity, Physical Function, and Their Associations With Insulin Resistance, Inflammation, and Adipokines in CKD.

RATIONALE & OBJECTIVES: Adiposity and physical fitness levels are major drivers of cardiometabolic risk, but these relationships have not been well-characterized in chronic kidney disease (CKD). We examined the associations of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intrahepatic fat, and physical function with inflammation, insulin resistance, and adipokine levels in patients with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Participants with stages 3-5 CKD not receiving maintenance dialysis, followed up at one of 8 clinical sites in the Chronic Renal Insufficiency Cohort (CRIC) Study, and who underwent magnetic resonance imaging of the abdomen at an annual CRIC Study visit (n = 419). PREDICTORS: VAT volume, SAT volume, intrahepatic fat, body mass index, waist circumference, and time taken to complete the 400-m walk test (physical function). OUTCOMES: Markers of inflammation (interleukin 1ß [IL-1ß], IL-6, tumor necrosis factor receptor 1 [TNFR1], and TNFR2), insulin resistance (homeostasis model assessment of insulin resistance), and adipokine levels (adiponectin, total and high molecular weight, resistin, and leptin). ANALYTICAL APPROACH: Multivariable linear regression of VAT and SAT volume, intrahepatic fat, and physical function with individual markers (log-transformed values), adjusting for relevant covariates. RESULTS: Mean age of the study population was 64.3 years; 41% were women, and mean estimated glomerular filtration rate was 53.2±14.6 (SD) mL/min/1.73m2. More than 85% were overweight or obese, and 40% had diabetes. Higher VAT volume, SAT volume, and liver proton density fat fraction were associated with lower levels of total and high-molecular-weight adiponectin, higher levels of leptin and insulin resistance, and lower high-density lipoprotein cholesterol and higher serum triglyceride levels. A slower 400-m walk time was associated only with higher levels of leptin, total adiponectin, plasma IL-6, and TNFR1 and did not modify the associations between fat measures and cardiometabolic risk factors. LIMITATIONS: Lack of longitudinal data and dietary details. CONCLUSIONS: Various measures of adiposity are associated with cardiometabolic risk factors. Physical function was also associated with the cardiometabolic risk factors studied and does not modify associations between fat measures and cardiometabolic risk factors. Longitudinal studies of the relationship between body fat and aerobic fitness with cardiovascular and kidney disease progression are warranted.

Changes in sleepiness and 24-h blood pressure following 4 months of CPAP treatment are not mediated by ICAM-1.

OBJECTIVE: Continuous positive airway pressure (CPAP) therapy reduces circulating intercellular adhesion molecule 1 (ICAM-1) in adults with obstructive sleep apnea (OSA). ICAM-1 levels may affect the daytime sleepiness and elevated blood pressure associated with OSA. We evaluated the association of changes from baseline in ICAM-1 with changes of objective and subjective measures of sleepiness, as well as 24-h ambulatory blood pressure monitoring (ABPM) measures, following 4 months of CPAP treatment. METHODS: The study sample included adults with newly diagnosed OSA. Plasma ICAM-1, 24-h ABPM, Epworth Sleepiness Scale (ESS), and psychomotor vigilance task (PVT) were obtained at baseline and following adequate CPAP treatment. The associations between changes in natural log ICAM-1 and changes in the number of lapses on PVT, ESS score, and 24-h mean arterial blood pressure (MAP) were assessed using multivariate regression models, controlling for a priori baseline covariates of age, sex, BMI, race, site, smoking status, physical activity, anti-hypertensive medications, AHI, and daily hours of CPAP use. RESULTS: Among 140 adults (83% men), mean (± SD) body mass index (BMI) was 31.5 ± 4.2 kg/m2, and apnea-hyopnea index (AHI) was 36.8 ± 15.3 events/h. Sleepiness measures, although not ICAM-1 or ABPM measures, improved significantly following CPAP treatment. We observed no statistically significant associations between the change in ICAM-1 and changes in sleepiness, MAP, or other ABPM measures. CONCLUSION: Changes in ICAM-1 levels were not related to changes in sleepiness or ABPM following CPAP treatment of adults with OSA. Future work should explore whether or not other biomarkers may have a role in mediating these treatment outcomes in adults with OSA.

Conversion of Urine Protein-Creatinine Ratio or Urine Dipstick Protein to Urine Albumin-Creatinine Ratio for Use in Chronic Kidney Disease Screening and Prognosis : An Individual Participant-Based Meta-analysis.

BACKGROUND: Although measuring albuminuria is the preferred method for defining and staging chronic kidney disease (CKD), total urine protein or dipstick protein is often measured instead. OBJECTIVE: To develop equations for converting urine protein-creatinine ratio (PCR) and dipstick protein to urine albumin-creatinine ratio (ACR) and to test their diagnostic accuracy in CKD screening and staging. DESIGN: Individual participant-based meta-analysis. SETTING: 12 research and 21 clinical cohorts. PARTICIPANTS: 919 383 adults with same-day measures of ACR and PCR or dipstick protein. MEASUREMENTS: Equations to convert urine PCR and dipstick protein to ACR were developed and tested for purposes of CKD screening (ACR ≥30 mg/g) and staging (stage A2: ACR of 30 to 299 mg/g; stage A3: ACR ≥300 mg/g). RESULTS: Median ACR was 14 mg/g (25th to 75th percentile of cohorts, 5 to 25 mg/g). The association between PCR and ACR was inconsistent for PCR values less than 50 mg/g. For higher PCR values, the PCR conversion equations demonstrated moderate sensitivity (91%, 75%, and 87%) and specificity (87%, 89%, and 98%) for screening (ACR >30 mg/g) and classification into stages A2 and A3, respectively. Urine dipstick categories of trace or greater, trace to +, and ++ for screening for ACR values greater than 30 mg/g and classification into stages A2 and A3, respectively, had moderate sensitivity (62%, 36%, and 78%) and high specificity (88%, 88%, and 98%). For individual risk prediction, the estimated 2-year 4-variable kidney failure risk equation using predicted ACR from PCR had discrimination similar to that of using observed ACR. LIMITATION: Diverse methods of ACR and PCR quantification were used; measurements were not always performed in the same urine sample. CONCLUSION: Urine ACR is the preferred measure of albuminuria; however, if ACR is not available, predicted ACR from PCR or urine dipstick protein may help in CKD screening, staging, and prognosis. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases and National Kidney Foundation.