Context:Detecting patients with surgically curable aldosterone-producing adenoma (APA) among hypertensive individuals is clinically pivotal. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the ideal method of measuring plasma aldosterone concentration (PAC) because of the inaccuracy of conventional chemiluminescent enzyme immunoassay (CLEIA). However, LC-MS/MS is expensive and requires expertise. We have developed a novel noncompetitive CLEIA (NC-CLEIA) for measuring PAC in 30 minutes. Objective:This work aimed to validate NC-CLEIA PAC measurements by comparing them with LC-MS/MS measurements and determining screening cutoffs for both measurements detecting APA. Methods:We retrospectively measured PAC using LC-MS/MS and NC-CLEIA in 133 patients with APA, 100 with bilateral hyperaldosteronism, and 111 with essential hypertension to explore the accuracy of NC-CLEIA PAC measurements by comparing with LC-MS/MS measurements and determined the cutoffs for detecting APA. Results:Passing-Bablok analysis revealed that the values by NC-CLEIA (the regression slope, intercept, and correlation coefficient were 0.962, -0.043, and 0.994, respectively) were significantly correlated and equivalent to those by LC-MS/MS. Bland-Altman plot analysis of NC-CLEIA and LC-MS/MS also demonstrated smaller systemic errors (a bias of -0.348 ng/dL with limits of agreement of -4.390 and 3.694 within a 95% CI) in NC-CLEIA than LC-MS/MS. The receiver operating characteristic analysis demonstrated that cutoff values for aldosterone/renin activity ratio obtained by LC-MS/MS and NC-CLEIA were 31.2 and 31.5 (ng/dL per ng/mL/hour), with a sensitivity of 91.0% and 90.2% and specificity of 75.4% and 76.8%, respectively, to differentiate APA from non-APA. Conclusion:This newly developed NC-CLEIA for measuring PAC could serve as a clinically reliable alternative to LC-MS/MS.

This study investigated factors associated with the antihypertensive effects of esaxerenone and the incidence of serum potassium elevation in patients with hypertension. Using pooled data from seven phase III studies, the study analyzed factors associated with changes in office systolic (SBP) and diastolic (DBP) blood pressure from baseline to 12 weeks, and factors associated with incidence of serum potassium levels ≥ 5.5 mEq/L in esaxerenone-treated patients. Overall, 1466 and 1472 patients were included in the full analysis and safety analysis sets, respectively. Male sex (4.02/2.40 mmHg), weight ≥ 78.4 kg (4.62/2.09 mmHg), hypertension duration ≥ 10 years (2.66/1.71 mmHg), prior antihypertensive treatment (2.38/1.40 mmHg), plasma aldosterone concentration ≥ 120 pg/mL (1.66/1.17 mmHg), urinary albumin-to-creatinine ratio (UACR) ≥ 300 mg/gCr (8.94/4.85 mmHg) or 30–299 mg/gCr (5.17/4.15 mmHg), and smoking (2.62/1.27 mmHg) were associated with mean changes in SBP and DBP. Fasting blood glucose ≥ 126 mg/dL (− 2.73 mmHg) was associated with the mean change in SBP only, and older age (65–74 years, − 2.12 mmHg; and ≥ 75 years, − 3.06 mmHg) with mean change in DBP only. Factors significantly associated with incidence of serum potassium levels ≥ 5.5 mEq/L were higher baseline serum potassium (≥ 4.5 mEq/L, odds ratio [OR] 6.702); lower estimated glomerular filtration rate (≥ 90 mL/min/1.73 m2, OR 0.148; 60–89 mL/min/1.73 m2, OR 0.331 vs 30–59 mL/min/1.73 m2, respectively); higher UACR (30–299 mg/gCr, OR 7.317); higher DBP (≥ 100 mmHg, OR 3.248); and grade I hypertension (OR 2.168). Esaxerenone is effective in patients with a broad range of backgrounds, though some factors may predict increased benefit. Regarding elevated serum potassium, careful therapeutic management is recommended for patients with higher baseline serum potassium and reduced renal function. Clinical trial registration: UMIN000047026.

The kidney plays important roles in homeostasis of body fluid and electrolyte balances as well as blood pressure (BP) regulation. For these, two functions are required. One is a stable and huge (150L/day) amount of glomerular filtration rate (GFR) in the face of large variations of BP and dairy salt intake, and the other is pressure natriuresis. Even if BP changed acutely, glomerular capillary pressure of each nephron is maintained relatively stale by myogenic response and tubuloglomerular feedback (TGF). When salt intake is changed, GFR is maintained by exquisitely precise and elegant interplays among the rein-angiotensin-aldosterone (RAA) system, TGF and connecting TGF (cTGF). The cTGF is a recently discovered intrinsic mechanism controlling glomerular hemodynamics. The pressure natriuresis plays a crucial role in the maintenance of body fluid volume, and its site of action is renal medulla. Blood supply to renal medulla is governed by descending vasa recta, the efferent arteriole of the juxtaglomerulus. In outer medulla, thick ascending limb of juxtamedullary nephron makes direct contact with descending vasa recta. Studies indicate that nitric oxide and oxidative stress produced by this tubular segment affect vascular tone of descending vasa recta, a phenomenon called tubulo-vascular crosstalk. The tubule-vascular crosstalk is implicated to play an important role in oxygen metabolism in such conditions as heart failure and high salt intake. In this presentation, I will discuss above mentioned mechanisms that control renal hemodynamics, sodium balances and BP.

Importance Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m 2 (SD, 22 mL/min/1.73 m 2 ) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m 2 (SD, 22 mL/min/1.73 m 2 ) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m 2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m 2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Objective:Blood pressure fluctuates during diastole to create a dicrotic wave but the mechanistic origin remains poorly understood. We sought to investigate the characteristics and determinants of diastolic pressure and flow fluctuations with a focus on stiffness gradients between the central aorta and peripheral arteries. Methods:Using applanation tonometry and duplex ultrasound, pulse waveforms were recorded on the femoral artery in 592 patients (age: 55 +/- 14 years) to estimate the diastolic pressure fluctuation as a residual wave against the mono-exponential decay and the diastolic flow fluctuation as a bidirectional (forward and reverse) velocity wave. The radial, carotid, and dorsalis pedis pressures were also recorded to measure the peripheral/aortic pulse pressure (PP) and pulse wave velocity (PWV) ratios. Results:There were close resemblances between the femoral pressure and flow fluctuation waveforms. The pressure and flow fluctuations were mutually correlated in relative amplitude as indexed to the total pulse height (r = 0.63), and the former temporally followed the latter. In multivariate-adjusted models, higher peripheral/aortic PP and PWV ratios were independently associated with greater pressure and flow fluctuation indices (P < 0.001). Mediation analysis revealed that the associations of PP and PWV ratios with the pressure fluctuation index were largely mediated by the flow fluctuation index [indirect/total effect ratio: 57 (95% CI 42-80)% and 54 (30-100)%, respectively]. Conclusion:These results suggest that central-to-peripheral pulse amplification and stiffness gradients contribute to triphasic flow fluctuations and dicrotic pressure waves. Diminished or inverted stiffness gradients caused by aortic stiffening may thus reduce diastolic runoff leading to ischemic organ damage.

Evaluation of feasibility and safety of percutaneous radiofrequency ablation using bipolar radiofrequency devices in a prospective multicenter cohort of patients with benign aldosterone-producing adenoma. A total of five institutions participated. CT-guided percutaneous RFA was performed for patients diagnosed as APA. The safety of the procedure was evaluated using the Common Terminology Criteria for Adverse Events. During the 84-day follow-up period, serial changes in plasma aldosterone concentration and plasma renin activity were measured. The percentage of patients with normalized hormonal activity after the procedure, was calculated with 95% confidence intervals. Forty patients were enrolled, and two patients were excluded for cerebral hemorrhage and no safe puncture root. In another patients, RFA was tried, but an intraprocedural intercostal arterial injury occurred. Consequently, RFA was completed in thirty-seven patients (20 men, 17 women; mean age, 50.4 ± 10.0 year). The tumor size was 14.8 ± 3.8 mm. The treatment success rate of the ablation was 94.6% (35/37), and a 2nd session was performed in 2.7% (1/37) patients. Grade 4 adverse events were observed in 4 out of 38 sessions (10.5%). The normalization of plasma aldosterone concentration or aldosterone-renin ratio was 86.5% (72.0–94.1: 95% confidence interval) on day 84. Percutaneous CT-guided RFA for APA using a bipolar radiofrequency system was safe and feasible with clinical success rate of 86.5% on day 84.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are recommended as first-line drugs for hypertension with diabetic nephropathy owing to their renoprotective effect; however, their effect beyond lowering blood pressure (BP) has not been confirmed. Recent studies have shown that aldosterone plays a key role in causing renal injury; therefore, it is likely that mineralocorticoid receptor (MR) blockers inhibit aldosterone-induced renal damage in different ways from ACE inhibitors and ARBs. Therefore, we investigated the mechanism of the effect of an MR blocker on reducing the urinary albumin-to-creatinine ratio (UACR) using data from a randomized, double-blind, placebo-controlled phase 3 study (ESAX-DN) of a new nonsteroidal MR blocker, esaxerenone. This post hoc analysis used a novel statistical method to quantitatively estimate the effect of esaxerenone on UACR reduction mediated, or not mediated, by changes in systolic BP (SBP) and/or estimated glomerular filtration rate (eGFR). The proportion of the mediated effect by SBP changes to the total effect on UACR reduction was 9.8–10.7%; the UACR was reduced to 0.903–0.911 times the baseline at the end of treatment through the SBP-related pathway and to 0.422–0.426 times the baseline through the non-SBP-related pathway. Even considering both SBP and eGFR simultaneously, the proportion of the mediated effect was 21.9–28.1%. These results confirm that esaxerenone has a direct UACR-lowering effect independent of BP lowering and that its magnitude is much larger than that of the BP-dependent effect. Thus, esaxerenone could be a UACR-reducing treatment option for patients with diabetic nephropathy.

Ectopic calcification is a risk of cardiovascular disease in chronic kidney disease (CKD) patients, and impaired endothelial nitric oxide synthase (eNOS) is involved in the CKD complications. However, whether eNOS dysfunction is a cause of ectopic calcification in CKD remains to be elucidated. To address this issue, we investigated the role of eNOS in ectopic calcification in mice with renal injury caused by an adenine and high-phosphorus (Ade + HP) diet. DBA/2J mice, a calcification-sensitive strain, were fed Ade + HP for 3 weeks. Expression levels of eNOS-related genes were reduced significantly in their calcified aorta. C57BL/6J is a calcification-resistant strain, and wild-type mice showed mild calcified lesions in the aorta and kidney when given an Ade + HP diet for 4 weeks. In contrast, a lack of eNOS led to the development of severe aortic calcification accompanied by an increase in runt-related transcription factor 2, an osteochondrogenic marker. Increased renal calcium deposition and the tubular injury score were remarkable in mice lacking eNOS-fed Ade + HP. Exacerbation of ectopic calcification by a lack of eNOS is associated with increased oxidative stress markers such as nicotinamide adenine dinucleotide phosphate oxidases. In conclusion, eNOS is critically important in preventing ectopic calcification. Therefore, the maintenance of eNOS is useful to reduce cardiovascular disease events and to improve prognosis in CKD patients.

Background It is uncertain whether risk classification under the nationwide program on screening and lifestyle modification for metabolic syndrome captures well high‐risk individuals who could benefit from lifestyle interventions. We examined the validity of risk classification by linking the incidence of cardiovascular disease (CVD). Methods and Results Individual‐level data of 29 288 Japanese individuals aged 40 to 74 years without a history of CVD from 10 prospective cohort studies were used. Metabolic syndrome was defined as the presence of high abdominal obesity and/or overweight plus risk factors such as high blood pressure, high triglyceride or low high‐density lipoprotein cholesterol levels, and high blood glucose levels. The risk categories for lifestyle intervention were information supply only, motivation‐support intervention, and intensive support intervention. Sex‐ and age‐specific hazard ratios and population attributable fractions of CVD, which were also further adjusted to consider non–high density lipoprotein cholesterol levels, were estimated with reference to nonobese/overweight individuals, using Cox proportional hazard regression. Since the reference category included those with risk factors, we set a supernormal group (nonobese/overweight with no risk factor) as another reference. We documented 1023 incident CVD cases (565 men and 458 women). The adjusted CVD risk was 60% to 70% higher in men and women aged 40 to 64 years receiving an intensive support intervention, and 30% higher in women aged 65 to 74 years receiving a motivation‐support intervention, compared with nonobese/overweight individuals. The population attributable fractions in men and women aged 40 to 64 years receiving an intensive support intervention were 17.7% and 6.6%, respectively, while that in women aged 65 to 74 years receiving a motivation‐support intervention was 9.4%. Compared with the supernormal group, nonobese/overweight individuals with risk factors had similar hazard ratios and population attributable fractions as individuals with metabolic syndrome. Conclusions Similar CVD excess and attributable risks among individuals with metabolic syndrome components in the absence and presence of obesity/overweight imply the need for lifestyle modification in both high‐risk groups.

Objective: Elevated serum uric acid were related not only with cardiovascular disease but also with higher incident of chronic kidney disease in many cohort studies. Lower eGFR and higher urine albumin to creatine ratio (UACR) are associated with all-cause and cardiovascular mortality as well as future renal end-stage. Febxostat (FBX) and topiroxostat (TPX), new xanthine oxidase inhibitors with much less side effects as comparison to allopurinol, are available now. To demonstrate the effects of FBX and TPX on renal functions (eGFR and UACR) in well-controlled hypertensive patients. Design and method: We retrospectively collected 252 well-controlled hypertensive patients with hyperuricemia (HU) who newly received a prescription of FBX or TPX and continued 24 weeks without the addition of any other drugs. Those who had other uric acid-lowering drugs, diabetes mellitus or severe proteinuria were excluded. Total 252 Participants were selected and divided into FBX (128 patients) group and TPX (124 patients) group, both of who were matched for % mean dose/dairy conventional dose, age, sex, uric acid (UA), blood pressure (BP), UACR and eGFR. The changes of UA, BP, eGFR and UACR were evaluated between at the baseline and at the 24-week treatment by FBX and TPX. Results: The baseline characteristics were not significantly different between both treatment groups, which were analyzed by Mann-Whitney U test. Administration of FBX and TPX lowered UA significantly (p < 0.0001). Decrements of UA in both group were not significantly different. Diastolic BP of FBX group was only significantly reduced (BP129.3 ± 17.8/78.7 ± 12.4 mmHg to BP126.1 ± 16.3/76.2 ± 11.1 mmHg, p = 0.049). The eGFR in both FBX group and TPX group were significantly increased from 55.2 ± 15.0 to 56.8 ± 15.7 mL/min/1.73m2 (p = 0.0082) and from 57.3 ± 16.3 to 61.5 ± 16.3 mL/min/1.73m2 (p = 0.0002), respectively. In TPX and FBX groups, there were no significant differences in change of eGFR between patients using high and low amount of TPX and FBX, respectively. UACR was significantly decreased only in TPX group(90.0 ± 336 mg/gCr to 48.9 ± 171 mg/gCr, p = 0.027), while UACR in FBX group was not reduced (113 ± 376 mg/gCr to 120 ± 488 mg/gCr). Conclusions: FBX could improve eGFR and diastolic BP, and TPX could renoprotectively reduce UACR as well as increase eGFR.

Electrolyzed hydrogen-rich water (EHW) is known to have suppressive effects on oxidative stress (OS). However, its benefit in type 2 diabetes mellitus (T2DM) remains unclear. This study aimed to investigate the effect of EHW on T2DM. This was a multicenter, prospective, double-blind, randomized controlled trial of 50 patients with T2DM who were assigned to the EHW or filtered water (FW) groups. The primary endpoint was changes in insulin resistance (IR) evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). OS markers such as urinary 8-hydroxy-2′-deoxyguanosine excretion (8-OHdG), plasma diacron-reactive oxygen metabolites (d-ROM), and plasma biological antioxidant potential (BAP) and other clinical data, including serum lactate concentration (lactate), were evaluated. There were no significant differences in the changes in HOMA-IR between the EHW and FW groups. However, lactate levels decreased significantly in the EHW group, and this decrease was significantly correlated with a reduction in HOMA-IR, fasting plasma glucose, and fasting plasma insulin level. Serum lactate level also significantly correlated to decreased insulin bolus secretion after 90 min with glucose loading in the EHW subjects with HOMA-IR > 1.73. No EHW treatment-related adverse effects were observed. There were no significant effect of EHW in the change in HOMA-IR in this study; larger-scale and longer-term study are needed to verify the effects of EHW in T2DM patients.

Objective: Esaxerenone (CS-3150) is a novel, highly potent, selective and long acting non-steroidal mineralocorticoid receptor (MR) blocker with MR blocking action of IC50 3.7 nM, other steroid hormone receptors blocking action of IC50 >5000 nM and half life loss of 18.6 hours. The authors aimed to investigate blood pressure (BP)-lowering ability and safety of esaxerenone in resistant hypertensive patients by add-on or by replacement from spironolactone or eplerenone. Design and method: This study was designed as a prospective observational study in 230 patients, approved by the local ethical committee and followed for 12 weeks. In add-on group, 52 resistant hypertensive patients, whose office BP was > 130/80 (<75 years old) or 140/90 (>75 years old) treated with at least three hypertensive agents (CCBs, RAS inhibitors and diuretics) according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019), were treated by the add-on use of esaxerenone. In replacement group, 208 resistant hypertensive patients, whose BP was controlled by at least 4 antihypertensive drugs including spironolactone or eplerenone, were medicated with esaxerenone by replacement from spironolactone or eplerenone. Results: In add-on group, both systolic and diastolic BP were significantly lowered from 139 ± 16 / 82 ± 14 mmHg (means ± SD) to 129 ± 16 / 79 ± 12 mmHg (p < 0.0001 and p = 0.0185, respectively) with mean esaxerenone dose of 1.44 mg. In replacement group, systolic BP was significantly lowered from 126 ± 16 mmHg (means ± SD) to 120 ± 14 mmHg (p < 0.0001), but diastolic BP was not, with mean esaxerenone dose of 1.58 mg once a day, which was changed from mean spironolactone and eplerenone doses of 34 and 58 mg, respectively. In add-on group, serum potassium concentration was significantly increased from 4.18 ± 0.46 to 4.40 ± 0.58 mmol/L and eGFR was decreased from 74.2 ± 23.9 to 66.9 ± 24.0, but those in replacement group were not significantly changed. Conclusions: This study suggested that esaxerenone has more potent BP lowering ability than spironolactone or eplerenone especially in systolic BP and has the equivalent safety.

To report a series of patients with occlusive retinal vasculitis associated with systemic sclerosis (SSc) and elevated antiphospholipid antibody titers.Case series. Main outcome measures included clinical and fluorescein angiographic findings at presentation and over time.Case 1 - A 61-year-old woman initially diagnosed with idiopathic, bilateral panuveitis and retinal vasculitis causing peripheral nonperfusion was subsequently diagnosed with limited cutaneous systemic sclerosis (lcSSc). Her ocular inflammation and retinal vasculitis were controlled with topical and periocular corticosteroids, but she eventually developed peripheral retinal vascular occlusion that progressed to macular ischemia 11 years after presentation. Repeat serologic evaluation detected interval development of antiphospholipid antibodies. Case 2 – A 58-year-old woman was found to have bilateral peripheral nonperfusion and retinal neovascularization in her right eye. Given her elevated hemoglobin A1c of 8.5%, she was diagnosed with presumed proliferative diabetic retinopathy. Three years after initial presentation, she was diagnosed with lcSSc. Subsequent serum workup detected elevated B2-glycoprotein antibody titers. Her peripheral nonperfusion progressed despite adequate glycemic control, resulting in further neovascularization in each eye. Case 3 – A 40-year-old woman with diffuse cutaneous systemic sclerosis (dcSSc) and elevated titers of anti-cardiolipin antibodies developed multiple branch retinal artery occlusions with subsequent neovascularization of the retina, optic disc, and angle in the right eye.Vision-threatening occlusive retinal vasculitis may develop in select patients with SSc. The presence of elevated anti-phospholipid antibody titers may confer increased risk for this vision-threatening complication.

BACKGROUND:Hyperuricemia is highly prevalent in chronic kidney disease (CKD) patients, but the evidence for a relationship between uric acid (UA) and clinical outcomes in CKD patients is limited and inconsistent. We hypothesized that UA has a different impact on clinical outcomes according to the underlying disease causing CKD.METHODS:This study prospectively investigated the associations between UA and renal and non-renal outcomes according to the underlying disease causing CKD in 2,797 Japanese patients under the care of nephrologists. The patients were categorized into four groups: primary renal disease (n = 1306), hypertensive nephropathy (n = 467), diabetic nephropathy (n = 275), and other nephropathy (n = 749). The renal outcome was defined as end-stage renal disease (ESRD), and the non-renal outcome was defined as a composite endpoint of cardiovascular events (CVEs) and all-cause mortality.RESULTS:During a median 4.8-year follow-up, 359 (12.8%) patients reached the renal outcome, and 260 (9.3%) reached the non-renal outcome. In the all-patient analysis, hyperuricemia was not associated with the risks for renal and non-renal outcomes, but in primary renal disease (PRD) and hypertensive renal disease (HTN) patients, hyperuricemia was significantly associated with non-renal outcomes. Per 1 mg/dl higher UA level, multivariable adjusted hazard ratio was 1.248 (95% CI: 1.003 to 1.553) for PRD, and 1.250 (1.035 to 1.510) for HTN. Allopurinol did not reduce the risks for renal and non-renal outcomes, both in all patients and in the subgroup analysis.CONCLUSIONS:The effect of hyperuricemia on clinical outcomes in CKD patients varies according to the underlying disease causing CKD. Hyperuricemia is an independent risk factor for non-renal outcomes in primary renal disease and hypertensive renal disease patients. Allopurinol did not decrease the risks for renal and non-renal outcomes.

Objective: Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents and detecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results even if measured by inaccurate radioimmunoassay, or we must accept high-cost LC/MS, and development of a more rapid and accurate substitute has been long hoped. We have developed a novel, fully-automated, high-quantitative noncompetitive chemiluminescence immunoassay (NC-CLEIA) for detecting aldosterone in serum and plasma, and its performance is evaluated as compared to LC/MS measurement. Design and method: Recently a unique anti-metatype antibody, which recognizes the immunocomplex of aldosterone and its monoclonal antibody, was established. Using this antibody for sensing permitted the construction of non-competitive assay for the detection of aldosterone. The reaction protocol of novel aldosterone assay is the following. In the 1st reaction, aldosterone in patient's sample is captured on anti-body coated magnetic particles. Alkaline phosphatase-conjugated anti-metatype antibody is added and incubated as 2nd reaction following a wash. Then substrate solution is added after washing immunocomplex. The resulting reaction signals are proportional to the amount of aldosterone in the sample allowing quantitative determination of in serum or plasma sample. The overall reaction is completed within 30 min. Results: Limit of blank (LoB), limit of detection (LoD) and limit of quantitation (LoQ) of our NC-CLEIA aldosterone assay were 0.09 ng/dL, 0.21 ng/dL and 0.57 ng/dL, respectively. NC-CLEIA aldosterone measurements were linearly well correlated with LC/MS aldosterone measurements (N = 130, y = 1.027x - 0.23 ng/dL, Spearman's p = 0.996, p < 0.0001). Bland-Altman plot analysis between NC-CLEIA and LC-MS/MS of aldosterone revealed a bias of 0.40 ng/dL with the limits of agreement of -4.60 and 5.41 ng/dL with 95% confidence interval. Conclusions: Our novel NC-CLEIA aldosterone assay was well-correlated and had only a very low bias with LC-MS/MS method and also was able to accurately quantify low level samples even in essential hypertension patients. This assay may be useful for the routine analysis of aldosterone and for the screening and diagnosis of PA from large number of hypertensive patients.

The rapid progression of chronic kidney disease and higher incidence of cardiovascular complications are well known in patients with hyperaldosteronism. However, detailed renal histopathologic characteristics of this disease have remained unknown. Therefore, renal biopsy specimens of 19 cases with unilateral hyperaldosteronism were compared with 22 autopsy renal cases of estimated glomerular filtration rate-matched essential hypertension without nephropathy or endocrine disorders to explore the hyperaldosteronism-specific histopathologic renal changes in this study. Global and segmental glomerulosclerosis, interstitial fibrosis, infiltration of inflammatory cells, arteriosclerosis, hyalinization of arterioles and immunoreactivity of mineralocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase type 1 and 2, and renin were all quantitatively evaluated. The ultrastructural analysis was added in 3 hyperaldosteronism cases. Both mineralocorticoid receptor (P<0.01) and 11 beta-hydroxysteroid dehydrogenase type 2 (P<0.01) were significantly higher in renal tubules of hyperaldosteronism, which could result in enhancement of in situ aldosterone effects in hyperaldosteronism kidneys. Interstitial fibrosis was significantly more marked in hyperaldosteronism (P<0.01). The proportion of segmental glomerulosclerosis was also significantly higher in hyperaldosteronism (P<0.01). There were no significant differences of global glomerulosclerosis between 2 groups (P=0.08). Glomerular size was significantly larger in hyperaldosteronism (P<0.01). In medium size artery, luminal stenosis tended to be more marked (P=0.08), and intima-to-media ratio was significantly lower (P=0.02) in hyperaldosteronism. Arteriolar hyalinization was significantly more pronounced (P<0.01), especially at efferent arterioles (P<0.01) in hyperaldosteronism. Results above demonstrated more pronounced whole renal damages in hyperaldosteronism. Results of our present study also indicated the potential clinical significance of early intervention using mineralocorticoid receptorantagonistsor blockers.

BACKGROUND:Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown.METHODS AND FINDINGS:We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure.INTERPRETATION:Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin.FUNDING:Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.

Angioplasty for cases of chronic total occlusion of renal artery with/without atrophic kidney is generally not recommended. We herein report a 57-year-old man who presented with renin-mediated refractory hypertension caused by occlusion of a unilateral renal artery leading to kidney atrophy (length: 69 mm). Angioplasty favorably achieved blood pressure control with normalized renin secretion and enlargement of the atrophic kidney to 85 mm. Timely angioplasty can be beneficial in select patients, even with an atrophic kidney and total occlusion, especially in cases with deterioration of hypertension within six months and the presence of collateral perfusion to the affected kidney.

Abstract Background In recent years, there have been sporadic reports of heart failure with recovered ejection fraction (HFrecEF), wherein the left ventricular EF (LVEF) has been improved by considering temporal changes in the LVEF. Although patients with HFrecEF are known to have a better prognosis than other groups, the type of heart failure associated with reduced EF (HFrEF) that subsequently transitions to HFrecEF is yet to be determined. Purpose In this study, we examined whether it is possible to predict future HFrecEF events by stratifying the HFrEF using machine learning based on previously recorded echocardiographic indices. Methods For 162 patients, with HFrEF and a history of hospitalization owing to heart failure, who underwent echocardiography in a stable hemodynamic state, stratification was performed via machine learning. Regarding temporal changes in the LVEF, 73 patients who underwent another echocardiography under stable conditions were investigated (52 with continued HFrEF and 21 with HFrecEF, with a median follow up of 397 days). HFrEF was defined as a condition for patients with an LVEF of less than 50%, and HFrecEF was defined as a condition for patients who initially had an LVEF of less than 50% but later improved. Patients with severe valvular disease, acute myocardial infarction, acute myocarditis, acute pulmonary embolism, post-cardiac surgery, and pericardial disease were excluded from this group. The random forest method was used as a classification method for machine learning. Results When 162 patients with HFrEF were stratified using machine learning, 63 were classified into Cluster 1 and 99 into Cluster 2. Cluster 1 patients showed a significantly higher tendency to transition to HFrecEF than Cluster 2 patients (p=0.001). The Gini coefficient was calculated to identify echocardiographic indices that are important for the purpose of stratification. As a result, LVEF, left ventricular endo-diastolic volume (LVEDV), the thickness of interventricular septum (IVSth), E/A ratio, and the maximum diameter of the inferior vena cava were found to be particularly important. Compared to Cluster 2 patients, Cluster 1 patients exhibited a significantly higher LVEF (41.5±5.9% vs 27.0±7.6%, p<0.001), lower LVEDV (93.6±36.8 mL vs 141.1±51.7 mL, p<0.001), and a higher IVSth (10.8±2.6 mm vs 9.4±2.5 mm, p<0.001). Conclusion Stratifying HFrEF via machine learning based on echocardiographic indices can help predict temporal changes in the LVEF and deduce the echocardiographic indices useful for improving LVEF. Funding Acknowledgement Type of funding source: None