Efficacy and safety of sacubitril/valsartan after switching from azilsartan in hemodialysis patients with hypertension.

This study assessed the efficacy and safety of sacubitril/valsartan in 23 hemodialysis patients with hypertension (mean age 70 years; male 69.6%) after switching from azilsartan, an angiotensin receptor blocker. Both at baseline and 3 months after the start of sacubitril/valsartan treatment, home blood pressure (BP), BP values during hemodialysis, and N-terminal pro-brain natriuretic peptide (NT-proBNP) level were measured. The mean dosage of azilsartan was 30 ± 10 mg/day at baseline and that of sacubitril/valsartan after 3 months of treatment was 204 ± 64 mg/day. After 3 months, significant reductions in mean morning home BP (155 ± 17/80 ± 12 to 147 ± 16/76 ± 11 mmHg), mean nighttime home systolic BP (153 ± 19 to 144 ± 16 mmHg), and median (IQRs) NT-proBNP level [8124 (2620-13 394) to 6271 (1570-9591) pg/mL] were observed (all P < .05), whereas BP values during hemodialysis did not change significantly. In hemodialysis patients, except for hypotension, sacubitril/valsartan was generally well tolerated, effectively controlled out-of-office BP, and improved NT-proBNP.

Blood pressure, arterial waveform, and arterial stiffness during hemodialysis and their clinical implications in intradialytic hypotension.

This study included 152 hemodialysis patients (mean age, 69 years; 34.2% female) and investigated serial changes in blood pressure (BP) and arterial stiffness indices during hemodialysis using an oscillometric device, SphygmoCor XCEL, and examined whether assessment of the arterial waveform has clinical implications for the management of intradialytic hypotension (IDH). Measurement was performed every 30 min during hemodialysis, and the threshold defining IDH was systolic BP (SBP) decrease ≥40 mmHg or a requirement for antihypotensive medication in all patients and ≥ the 75th percentile of maximum SBP decrease during hemodialysis (≥34 mmHg) in the subgroup without antihypotensive medication (n = 98). In all patients, a 1-standard deviation (SD) increase in the baseline subendocardial viability ratio (SEVR), an index of myocardial perfusion, was an independent predictor of IDH (odds ratio [OR] 0.43, p < 0.001). In the subgroup analysis, a serial change in SBP and all arterial waveform indices, including the augmentation index, augmented pressure (AP), and SEVR, during hemodialysis were greater for IDH than for non-IDH patients (all p < 0.01 by 2-way repeated-measures ANOVA), with the exception of heart rate (p = 0.40) and diastolic pressure time index (p = 0.21). Diabetes (OR 4.08), a 1-SD increase in ultrafiltration rate (OR 2.07), fractional shortening (OR 0.45), baseline SEVR (OR 0.36) and the first 1-h percent change in AP (OR 0.52) were independent predictors of IDH (all p < 0.05). In conclusion, impaired myocardial perfusion and increased arterial stiffness, particularly poor arteriolar responsiveness to acute dialysis-related changes, are associated with IDH, and predialysis SEVR evaluation can complement screening for IDH.

Urinary Podocyte Excretion Predicts Urinary Protein Selectivity and Renal Prognosis.

Background: Urinary podocyte excretion is related to a reduction in glomerular podocyte numbers, glomerulosclerosis, and urinary protein selectivity. To elucidate the role of urinary podocytes in proteinuria and renal prognosis and to identify the factors that cause podocyte detachment, we examined urinary podocytes in 120 renal biopsy patients. Methods: Podocytes were identified in urinary sediments stained with fluorescent-labeled anti-podocalyxin antibodies in ten high power fields. The amounts of protein bands, separated by SDS-polyacrylamide gel electrophoresis, were calculated using an image software program and the correlation with urinary podocytes was analyzed. Podocyte surface pores were observed using a low-vacuum scanning electron microscope. The renal prognosis, including induction of hemodialysis or 30% reduction in eGFR, was investigated. Results: Urinary podocyte excretion showed a higher positive correlation with albumin excretion compared to IgG, prealbumin, and transferrin. There were no significant correlations between urinary podocyte count and low molecular weight proteins, including ß2-microglobulin and α1-microglobulin. The number of podocyte surface pores was positively correlated with proteinuria, suggesting enhanced albumin transcytosis. The hemodynamic pressure on the glomerular capillary wall, including products of pulse pressure and pulse rate (water hammer pressure), was positively correlated with urinary podocyte excretion. Urinary podocyte excretion and Tamm-Horsfall protein (THP) were independent risk factors for renal prognosis but were not related to response to treatment. Conclusion: Urinary podocyte excretion was correlated with urinary albumin excretion, indicating specific albumin transport by podocytes. Podocytes were detached from the glomerular capillaries by water hammer pressure and THP was involved in the renal prognosis.

Impact of Percutaneous Transluminal Renal Angioplasty on Autonomic Nervous System and Natriuresis in Hypertensive Patients With Renal Artery Stenosis.

Background We investigated the early postoperative effect of percutaneous transluminal renal angioplasty on ambulatory blood pressure (BP) and the circadian characteristics of natriuresis and autonomic nerve activity. Methods and Results A total of 64 patients with hypertension with hemodynamically significant renal artery stenosis (mean age, 60.0±21.0 years; 31.3% fibromuscular dysplasia) who underwent angioplasty were included, and circadian characteristics of natriuresis as well as heart rate variability indices, including 24-hour BP, low-frequency and high-frequency (HF) components, and the percentage of differences between adjacent normal R-R intervals >50 ms were evaluated using an oscillometric device, TM-2425, both at baseline and 3 days after angioplasty. In both the fibromuscular dysplasia and atherosclerotic stenosis groups, 24-hour systolic BP (fibromuscular dysplasia, -19±14; atherosclerotic renal artery stenosis, -11±9 mm Hg), percentage of differences between adjacent normal R-R intervals >50 ms, HF, brain natriuretic peptide, and nighttime urinary sodium excretion decreased (all P<0.01), and heart rate increased (both P<0.05) after angioplasty. In both groups, revascularization increased the night/day ratios of percentage of differences between adjacent normal R-R intervals >50 ms (both P<0.01) and HF, and decreased those of low frequency/HF (all P<0.05) and nighttime urinary sodium excretion (fibromuscular dysplasia, 1.17±0.15 to 0.78±0.09; atherosclerotic renal artery stenosis, 1.37±0.10 to 0.99±0.06, both P<0.01). Multiple logistic regression analysis indicated that a 1-SD increase in baseline low frequency/HF was associated with at least a 15% decrease in 24-hour systolic BP after angioplasty (odds ratio, 2.30 [95% CI, 1.03-5.67]; P<0.05). Conclusions Successful revascularization results in a significant BP decrease in the early postoperative period. Intrarenal perfusion might be a key modulator of the circadian patterns of autonomic nerve activity and natriuresis, and pretreatment heart rate variability evaluation seems to be important for treatment success.

AL-Kappa Primary Amyloidosis with Apolipoprotein A-IV Deposition.

A 70-year-old woman with complaints of edema, general malaise, and hypotension was diagnosed with renal amyloidosis, and laser microdissection mass spectrometry revealed her amyloidosis to predominantly comprise the apolipoprotein A-IV type. The M-protein turned from negative to positive during the course, and a bone marrow biopsy showed smoldering myeloma. Treatment with bortezomib and dexamethasone failed to save her from heart failure six months after the onset. Western blotting of urine samples at the time of the renal biopsy showed that amyloid light-chain κ amyloidosis had been present since the onset. Unlike the myeloma, Congo red staining was positive in the plasma cells of the bone marrow.

Analysis of purple urine bag syndrome by low vacuum scanning electron microscopy.

Purple urine bag syndrome (PUBS) is seen in the prolonged indwelling bladder catheters, and the mechanism of its onset was investigated using low vacuum scanning electron microscopy (LVSEM), which enables us to study the 3D structure of urinary sediments and urine bag walls. The urinary sediment and urine bags of 2 cases of PUBS were observed by LVSEM. The urine was brown turbid urine with a pH of 8.5, and magnesium phosphate stones and granules were observed in the urinary sediment together with Gram-positive and Gram-negative bacilli. Bacteria that moved by Brownian motion were observed with a dark-field microscope. LVSEM showed granular crystals around the bacilli, cocci, or mycelium that adhered to the walls of the bag. Granular crystals were dissolved in chloroform and presumed to be a mixture of the bacterial metabolites indigo blue and indirubin red. LVSEM also detected unusual tubular and honeycomb-like graphene in the urinary sediments, which were derived from the inner layer of the silicon elastomer-coated rubber catheter. LVSEM revealed purple crystals produced by bacteria or fungi attached to the urine bag that caused PUBS.

Decreased Podocyte Vesicle Transcytosis and Albuminuria in APC C-Terminal Deficiency Mice with Puromycin-Induced Nephrotic Syndrome.

In minimal change nephrotic syndrome, podocyte vesicle transport is enhanced. Adenomatous polyposis coli (APC) anchors microtubules to cell membranes and plays an important role in vesicle transport. To clarify the role of APC in vesicle transport in podocytes, nephrotic syndrome was induced by puromycin amino nucleoside (PAN) injection in mice expressing APC1638T lacking the C-terminal of microtubule-binding site (APC1638T mouse); this was examined in renal tissue changes. The kidney size and glomerular area of APC1638T mice were reduced (p = 0.014); however, the number of podocytes was same between wild-type (WT) mice and APC1638T mice. The ultrastructure of podocyte foot process was normal by electron microscopy. When nephrotic syndrome was induced, the kidneys of WT+PAN mice became swollen with many hyaline casts, whereas these changes were inhibited in the kidneys of APC1638T+PAN mice. Electron microscopy showed foot process effacement in both groups; however, APC1638T+PAN mice had fewer vesicles in the basal area of podocytes than WT+PAN mice. Cytoplasmic dynein-1, a motor protein for vesicle transport, and α-tubulin were significantly reduced in APC1638T+PAN mice associated with suppressed urinary albumin excretion compared to WT+PAN mice. In conclusion, APC1638T mice showed reduced albuminuria associated with suppressed podocyte vesicle transport when minimal change nephrotic syndrome was induced.

Eucommia ulmoides (Tochu) and its extract geniposidic acid reduced blood pressure and improved renal hemodynamics.

INTRODUCTION: Eucommia ulmoides leaves are used as Tochu tea, which has a blood pressure lowering effect of unknown mechanism. PURPOSE AND METHODS: The effects of Tochu tea and its component, geniposidic acid, on blood pressure and renal hemodynamics were investigated in Dahl salt-sensitive (DS) rats received 1% saline solution from 4 weeks of age. At 9 weeks of age, 1% saline alone (DSHS), Tochu tea extract added 1% saline (DSHS+T), or geniposidic acid added 1% saline (DSHS+G) was administered for another 4 weeks. DS rats fed with tap water were used as controls (DSLS). At 13 weeks, the blood pressure, the renal plasma flow (RPF) and the renal NADPH oxidase, endothelial nitric oxide synthase (eNOS) were examined. RESULTS: Blood pressure in DSHS rats was significantly increased in comparison to DSLS (144 vs. 196 mmHg, p < 0.01), and was significantly reduced in DSHS+T (158 mmHg) and DSHS+G (162 mmHg) rats. RPF in DSHS+T rats was significantly higher than in DSHS rats (p < 0.05). The expression of NADPH oxidase in DSHS rats was enhanced in comparison to DSLS rats; however, it was suppressed in DSHS+T and DSHS+G rats, and the NO production by eNOS was increased; thus, RPF was improved. The urinary Na excretion in DSHS rats was higher than that in DSLS rats; however it was further increased in DSHS+T rats without changes in the tubular Na transporters. CONCLUSION: Tochu tea and geniposidic acid suppressed NADPH oxidase, increased eNOS, and improved blood pressure and renal hemodynamics.

Associations Between Arterial Stiffness Indices and Chronic Kidney Disease Categories in Essential Hypertensive Patients.

BACKGROUND: This study investigated the association between arterial stiffness indices and asymptomatic chronic kidney disease (CKD) risk categories in hypertensive patients. METHODS: Arterial stiffness indices, including 24-hour brachial and aortic systolic blood pressure (SBP) and pulse wave velocity (PWV), were measured by an oscillometric Mobil-O-Graph device, brachial-ankle PWV (baPWV) by a volume-plethysmographic method, and renal resistive index (RI) by ultrasonography, in 184 essential hypertensive patients (66.0 ± 17.1 years, 47.3% male). CKD was categorized into 3 stages based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria, using a combination of estimated glomerular filtration and albuminuria. RESULTS: The 24-hour aortic PWV (aPWV), baPWV, and RI increased with worsening severity of CKD risk category (all P < 0.01 for trend). Multivariate logistic regression analysis found that a 1 SD increase of nighttime aortic SBP (odds ratio [OR] 1.52), PWV (OR 4.80), or RI (OR 1.75) was an independent predictor of high or very-high CKD stage (all P < 0.05). After adjustment for potential confounders, day-to-night change in brachial SBP as well as in aPWV differed among groups (P < 0.05, respectively). In a multivariate regression model, day-to-night changes in aortic SBP and PWV, and RI were independently associated with day-to-night brachial SBP change. CONCLUSIONS: In hypertension, circadian hemodynamics in high CKD stage are characterized by higher nighttime values of aortic SBP and PWV and disturbed intrarenal hemodynamics. Further, the blunted nocturnal BP reduction in these patients might be mediated via disturbed intrarenal hemodynamics and circadian hemodynamic variation in aortic SBP and arterial stiffness.

Comparing the Heart-Thigh and Thigh-Ankle Arteries with the Heart-Ankle Arterial Segment for Arterial Stiffness Measurements.

PURPOSE: The cardio-ankle vascular index, applying the stiffness parameter ß theory, was calculated using the pulse-wave velocity and blood pressure from the aortic orifice to the ankle. Accordingly, the impact of the stiffness of the aorta [heart-thigh ß (htBETA)] and medium-sized muscular artery [thigh-ankle ß (taBETA)] on the stiffness of the heart-ankle ß (haBETA) was investigated; further, whether the htBETA (haBETA - taBETA) improved the power of diagnosis of coronary artery disease (CAD) was examined. MATERIALS AND METHODS: Segmental ßs were calculated using VaSela with an additional thigh cuff and compared using the receiver operating characteristic (ROC) curve analysis to evaluate CAD. RESULTS: Overall, 90 healthy subjects and 41 patients with CAD were included. In both groups, haBETA and htBETA, but not taBETA, correlated with age, and taBETA was three times higher than htBETA (p < 0.01). Multiple regression analysis revealed that haBETA can be estimated using htBETA and taBETA in healthy subjects and patients with CAD (r = 0.86, r = 0.67, respectively, p < 0.01), and two-thirds of the haBETA components can be estimated by htBETA using the component analysis. The area under the ROC curve (AUC) for CAD in taBETA (0.493, p = n.s.) was smaller than that in haBETA (0.731, p < 0.01) or htBETA (0.757, p < 0.01); no difference was observed in AUC between haBETA and htBETA. CONCLUSION: The stiffness of medium-sized muscular arteries of the age-independent thigh-ankle segment (taBETA) was constant, which was three times greater than that of the elastic artery of the heart-thigh artery (htBETA). Two-thirds of the haBETA components could be estimated using htBETA. The ROC curve analysis revealed that the AUC of haBETA could be replaced by that of htBETA, prolonging the measurement segment without affecting the diagnostic power for CAD.

Hypertension and related diseases in the era of COVID-19: a report from the Japanese Society of Hypertension Task Force on COVID-19.

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than seven million people worldwide, contributing to 0.4 million deaths as of June 2020. The fact that the virus uses angiotensin-converting enzyme (ACE)-2 as the cell entry receptor and that hypertension as well as cardiovascular disorders frequently coexist with COVID-19 have generated considerable discussion on the management of patients with hypertension. In addition, the COVID-19 pandemic necessitates the development of and adaptation to a "New Normal" lifestyle, which will have a profound impact not only on communicable diseases but also on noncommunicable diseases, including hypertension. Summarizing what is known and what requires further investigation in this field may help to address the challenges we face. In the present review, we critically evaluate the existing evidence for the epidemiological association between COVID-19 and hypertension. We also summarize the current knowledge regarding the pathophysiology of SARS-CoV-2 infection with an emphasis on ACE2, the cardiovascular system, and the kidney. Finally, we review evidence on the use of antihypertensive medication, namely, ACE inhibitors and angiotensin receptor blockers, in patients with COVID-19.

How should we define appropriate patients for percutaneous transluminal renal angioplasty treatment?

Renovascular hypertension (RVH) is one of the most common causes of secondary hypertension and can result in resistant hypertension. RVH is associated with an increased risk for progressive decline in renal function, cardiac destabilization syndromes including "flash" pulmonary edema, recurrent congestive heart failure, and cerebrocardiovascular disease. The most common cause of renal artery stenosis (RAS) is atherosclerotic lesions, followed by fibromuscular dysplasia. The endovascular technique of percutaneous transluminal renal angioplasty (PTRA) with or without stenting is one of the standard treatments for RAS. Randomized controlled trials comparing medical therapy with PTRA to medical therapy alone have failed to show a benefit of PTRA; however, the subjects of these randomized clinical trials were limited to atherosclerotic RAS patients, and patients with the most severe RAS, who would be more likely to benefit from PTRA, might not have been enrolled in these trials. This review compares international guidelines related to PTRA, reevaluates the effects of PTRA treatment on blood pressure and renal and cardiac function, discusses strategies for the management of RVH patients, and identifies factors that may predict which patients are most likely to benefit from PTRA.

Gestational Hypertension as Risk Factor of Hypertension in Middle-Aged and Older Women.

The association of gestational hypertension (GH) with future hypertension in Japanese women is unclear. Hence, this study aimed to examine the association between GH and the risk of future hypertension in middle-aged-to-older Japanese women. A case-control study was performed, including 62 hypertensive women (case) and 75 nonhypertensive women (control). GH during the first pregnancy was diagnosed on the basis of the Maternal and Child Health Handbook record. Hypertensive women were recruited from outpatients in the hospital and residents who completed an annual health check-up in a community. Hypertension was defined as blood pressure with systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, or taking antihypertensive medications. The average age (SD) of the cases and controls at the time of recruitment was 63.1 (8.4) and 57.7 (9.4), respectively. The multivariable-adjusted odds ratio of GH for hypertension in middle-aged-to-older women was 4.2 (95% confidence interval, 1.0-17.5) after adjustment for potential confounding factors such as age and body-mass index (BMI) upon recruitment, prepregnancy BMI, and age at first delivery. In conclusion, GH can be an independent risk factor for future hypertension among Japanese women.

V-ATPase blockade reduces renal gluconeogenesis and improves insulin secretion in type 2 diabetic rats.

Vacuolar H+-adenosine triphosphatase (V-ATPase) stimulates vesicular acidification that may activate cytoplasmic enzymes, hormone secretion and membrane recycling of transporters. We investigated the effect of blockade of V-ATPase by bafilomycin B1 on renal gluconeogenesis, mitochondrial enzymes, and insulin secretion in type 2 diabetic rats. Spontaneous type 2 diabetic Torii rats were treated with intraperitoneal injection of bafilomycin B1 for 1 week, and the kidneys were examined after 24 h of starvation in metabolic cages. The renal expression and activity of V-ATPase were increased in the brush border membrane of the proximal tubules in diabetic rats. The blockade of V-ATPase by bafilomycin B1 reduced renal V-ATPase activity and urinary ammonium in diabetic rats. Treatment with bafilomycin suppressed the enhanced renal gluconeogenesis enzymes and mitochondrial electron transport enzymes in type 2 diabetic rats and reduced the renal cytoplasmic glucose levels. The insulin index and pancreatic insulin granules were decreased in diabetic rats with increased V-ATPase expression in islet cells, and treatment with bafilomycin B1 reversed these changes and increased the insulin secretion index. Hepatosteatosis in type 2 diabetic rats was ameliorated by bafilomycin treatment. As a consequence, treatment with bafilomycin B1 significantly decreased the plasma glucose level after 24 h of starvation in diabetic rats. In conclusion, a V-ATPase inhibitor improved plasma glucose levels in type 2 diabetes by inhibiting renal mitochondrial gluconeogenesis and improving insulin secretion.