Impact of Renal Denervation on Urinary Peptide-Based Biomarkers in Hypertension.

BACKGROUND: Catheter-based renal denervation (RDN) reduces blood pressure in hypertension. Urinary peptides are associated with cardiovascular and renal disease and provide prognostic information. We aimed to investigate the effect of RDN on urinary peptide-based classifiers associated with chronic kidney and heart disease and to identify urinary peptides affected by RDN. METHODS: This single-arm, single-center study included patients undergoing catheter-based RDN. Urine samples were collected before and 24 months after RDN and were analyzed using capillary electrophoresis coupled with mass spectrometry. Predefined urinary peptide-based classifiers for chronic kidney disease (CKD273), coronary artery disease (CAD238), and heart failure (HF1) were applied. RESULTS: This study included 48 patients (33% female) with uncontrolled hypertension. At 24 months after RDN, systolic blood pressure (165±17 versus 148±20 mm Hg; P<0.0001), diastolic blood pressure (90±17 versus 81±13 mm Hg; P<0.0001), and mean arterial pressure (115±15 versus 103±13 mm Hg; P<0.0001) decreased significantly. A total of 103 urinary peptides from 37 different proteins, mostly collagens, altered following RDN. CAD238, a 238 coronary artery-specific polypeptide-based classifier, significantly improved following RDN (Cohen's d, -0.632; P=0.0001). The classification scores of HF1 (P=0.8295) and CKD273 (P=0.6293) did not change significantly. CONCLUSIONS: RDN beneficially affected urinary peptides associated with coronary artery disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01888315.

Serum Alpha-1-Acid Glycoprotein-1 and Urinary Extracellular Vesicle miR-21-5p as Potential Biomarkers of Primary Aldosteronism.

Primary aldosteronism (PA) is the most common cause of secondary hypertension and reaches a prevalence of 6-10%. PA is an endocrine disorder, currently identified as a broad-spectrum phenotype, spanning from normotension to hypertension. In this regard, several studies have made advances in the identification of mediators and novel biomarkers of PA as specific proteins, miRNAs, and lately, extracellular vesicles (EVs) and their cargo. Aim: To evaluate lipocalins LCN2 and AGP1, and specific urinary EV miR-21-5p and Let-7i-5p as novel biomarkers for PA. Subjects and Methods: A cross-sectional study was performed in 41 adult subjects classified as normotensive controls (CTL), essential hypertensives (EH), and primary aldosteronism (PA) subjects, who were similar in gender, age, and BMI. Systolic (SBP) and diastolic (DBP) blood pressure, aldosterone, plasma renin activity (PRA), and aldosterone to renin ratio (ARR) were determined. Inflammatory parameters were defined as hs-C-reactive protein (hs-CRP), PAI-1, MMP9, IL6, LCN2, LCN2-MMP9, and AGP1. We isolated urinary EVs (uEVs) and measured two miRNA cargo miR-21-5p and Let-7i-5p by Taqman-qPCR. Statistical analyses as group comparisons were performed by Kruskall-Wallis, and discriminatory analyses by ROC curves were performed with SPSS v21 and Graphpad-Prism v9. Results: PA and EH subjects have significantly higher SBP and DBP (p <0.05) than the control group. PA subjects have similar hs-CRP, PAI-1, IL-6, MMP9, LCN2, and LCN2-MMP9 but have higher levels of AGP1 (p <0.05) than the CTL&EH group. The concentration and size of uEVs and miRNA Let-7i-5p did not show any difference between groups. In PA, we found significantly lower levels of miR-21-5p than controls (p <0.05). AGP1 was associated with aldosterone, PRA, and ARR. ROC curves detected AUC for AGP1 of 0.90 (IC 95 [0.79 - 1.00], p <0.001), and combination of AGP1 and EV-miR-21-5p showed an AUC of 0.94 (IC 95 [0.85 - 1.00], p<0.001) to discriminate the PA condition from EH and controls. Conclusion: Serum AGP1 protein was found to be increased, and miR-21-5p in uEVs was decreased in subjects classified as PA. Association of AGP1 with aldosterone, renin activity, and ARR, besides the high discriminatory capacity of AGP1 and uEV-miR-21-5p to identify the PA condition, place both as potential biomarkers of PA.

The Long-Term Study of Urinary Biomarkers of Renal Injury in Spontaneously Hypertensive Rats.

BACKGROUND: The age-related increase in blood pressure in spontaneously hypertensive rats (SHRs) is associated to cardiac hypertrophy, heart failure, and renal injury. Here, we investigated for the first time the urinary enzymatic activities of glutamil aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), dipeptidyl peptidase-4 (DPP4), and Klotho urinary levels, proteins that are strongly expressed in the kidney, as early biomarkers of renal injury in SHRs. METHODS: Male SHR and Wistar Kyoto (WKY) rats were studied from 2 to 8 months old. Systolic blood pressure (SBP), the heart rate (HR), metabolic variables, and urinary markers were measured monthly. At the end of the study, a histopathological evaluation of the kidney was performed. RESULTS: Kidneys of SHR did not develop signs of relevant histopathological changes, but showed increased glomerular area and cellularity. Plasma creatinine was decreased, and creatinine clearance was augmented in SHR at the end of the study. Urinary excretion of Klotho was higher in SHR at 5 and 8 months old, whereas plasma Klotho levels were similar to WKY. GluAp, AlaAp, and DPP4 urinary activities were increased in SHR throughout the time-course study. A positive correlation between glomerular area and cellularity with creatinine clearance was observed. Urinary GluAp, AlaAp, DPP4, and Klotho showed positive correlations with SBP. CONCLUSIONS: GluAp, AlaAp, DPP4, and Klotho in the urine are useful tools for the evaluation of renal damage at early stages, before the whole histopathological and biochemical manifestations of renal disease are established. Moreover, these observations may represent a novel and noninvasive diagnostic approach to assess the evolution of kidney function in hypertension and other chronic diseases.

Blunted natriuretic response to saline loading in sheep with hypertensive kidney disease following radiofrequency catheter-based renal denervation.

Renal sympathetic nerves contribute to renal excretory function during volume expansion. We hypothesized that intact renal innervation is required for excretion of a fluid/electrolyte load in hypertensive chronic kidney disease (CKD) and normotensive healthy settings. Blood pressure, kidney hemodynamic and excretory response to 180 min of isotonic saline loading (0.13 ml/kg/min) were examined in female normotensive (control) and hypertensive CKD sheep at 2 and 11 months after sham (control-intact, CKD-intact) or radiofrequency catheter-based RDN (control-RDN, CKD-RDN) procedure. Basal blood pressure was ~ 7 to 9 mmHg lower at 2, and 11 months in CKD-RDN compared with CKD-intact sheep. Saline loading did not alter glomerular filtration rate in any group. At 2 months, in response to saline loading, total urine and sodium excretion were ~ 40 to 50% less, in control-RDN and CKD-RDN than intact groups. At 11 months, the natriuretic and diuretic response to saline loading were similar between control-intact, control-RDN and CKD-intact groups but sodium excretion was ~ 42% less in CKD-RDN compared with CKD-intact at this time-point. These findings indicate that chronic withdrawal of basal renal sympathetic activity impairs fluid/electrolyte excretion during volume expansion. Clinically, a reduced ability to excrete a saline load following RDN may contribute to disturbances in body fluid balance in hypertensive CKD.

Urine and Plasma Metabolome of Healthy Adults Consuming the DASH (Dietary Approaches to Stop Hypertension) Diet: A Randomized Pilot Feeding Study.

We aimed to identify plasma and urine metabolites altered by the Dietary Approaches to Stop Hypertension (DASH) diet in a post-hoc analysis of a pilot feeding trial. Twenty adult participants with un-medicated hypertension consumed a Control diet for one week followed by 2 weeks of random assignment to either Control or DASH diet. Non-missing fasting plasma (n = 56) and 24-h urine (n = 40) were used to profile metabolites using untargeted gas chromatography/mass spectrometry. Linear models were used to compare metabolite levels between the groups. In urine, 19 identifiable untargeted metabolites differed between groups at p < 0.05. These included a variety of phenolic acids and their microbial metabolites that were higher during the DASH diet, with many at false discovery rate (FDR) adjusted p < 0.2. In plasma, eight identifiable untargeted metabolites were different at p < 0.05, but only gamma-tocopherol was significantly lower on DASH at FDR adjusted p < 0.2. The results provide insights into the mechanisms of benefit of the DASH diet.

An updated systematic review on the association between Cd exposure, blood pressure and hypertension.

BACKGROUND: Since the first report by Perry et al. (1955), most studies affirmed the hypertensive effects of cadmium (Cd) in humans. Nonetheless, conclusions between studies remain inconsistent. OBJECTIVE: The aim of this study was to reevaluate the evidence for a potential relationship between Cd exposure and altered blood pressure and/or hypertension, focusing on studies published between January 2010 and March 2020. METHODS: We reviewed all observational studies from database searches (PubMed and SCOPUS) on Cd exposure and blood pressure or hypertension. We extracted information from studies that provided sufficient data on population characteristics, smoking status, exposure, outcomes, and design. RESULTS: Thirty-eight studies met our inclusion criteria; of those, twenty-nine were cross sectional, three case control, five cohort and one interventional study. Blood or urinary Cd levels were the most commonly used biomarkers. CONCLUSIONS: A positive association between blood Cd levels and blood pressure and/or hypertension was identified in numerous studies at different settings. Limited number of representative population-based studies of never-smokers was observed, which may have confounded our conclusions. The association between urinary Cd and blood pressure and/or hypertension remains uncertain due to conflicting results, including inverse relationships with lack of strong mechanistic support. We point to the urgent need for additional longitudinal studies to confirm our findings.

Association between urinary polycyclic aromatic hydrocarbons and hypertension in the Korean population: data from the Second Korean National Environmental Health Survey (2012-2014).

Polycyclic aromatic hydrocarbons (PAHs) are environmental and occupational pollutants derived from incomplete combustion of organic materials, including wood and fossil fuels. Epidemiological studies have evaluated the association between PAH exposure and hypertension or cardiovascular disease in the general population, but the evidence is limited. In this study, we evaluated the association between urinary PAH metabolites and hypertension in the Korean adult population. A total of 6478 adults who participated in the Second Korean National Environmental Health Survey (2012-2014) were included. The differences in urinary concentrations of four PAH metabolites, including 1-hydroxypyrene, 2-hydroxyfluorene, 1-hydroxyphenanthrene, and 2-naphthol, were compared according to hypertension status using a general linear model. Adjusted odds ratios (aORs) for hypertension were calculated according to the quartile groups of urinary PAH metabolites after adjusting for age, sex, body mass index (BMI), smoking, and alcohol consumption in multiple logistic regression analyses. The estimated mean concentrations of urinary 1-hydroxyphenanthrene were significantly higher in the hypertension group than in the non-hypertension group. In 1-hydroxyphenanthrene, the OR for hypertension was significantly higher in the third and fourth quartile groups than in the first quartile group (third: OR 1.707, 95% CI 1.203-2.423, fourth: OR 1.604, 95% CI 1.158-2.223). No significant associations were detected for the other metabolites. Our results suggest an association between exposure to PAHs and hypertension in a Korean adult population. Further studies are required to evaluate the effects of low-dose long-term exposure to PAHs on hypertension and cardiovascular disease.

Tubular Biomarkers and Chronic Kidney Disease Progression in SPRINT Participants.

BACKGROUND: Kidney tubular atrophy on biopsy is a strong predictor of chronic kidney disease (CKD) progression, but tubular health is poorly quantified by traditional measures including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of impaired tubule function would be associated with faster eGFR declines in persons with CKD. METHODS: We measured baseline urine concentrations of uromodulin, ß2-microglobulin (ß2m), and α1-microglobulin (α1m) among 2,428 participants of the Systolic Blood Pressure Intervention Trial with an eGFR <60 mL/min/1.73 m2. We used linear mixed models to evaluate biomarker associations with annualized relative change in eGFR, stratified by randomization arm. RESULTS: At baseline, the mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. In the standard blood pressure treatment arm, each 2-fold higher urinary uromodulin was associated with slower % annual eGFR decline (0.34 [95% CI: 0.08, 0.60]), whereas higher urinary ß2m was associated with faster % annual eGFR decline (-0.10 [95% CI: -0.18, -0.02]) in multivariable-adjusted models including baseline eGFR and albuminuria. Associations were weaker and did not reach statistical significance in the intensive blood pressure treatment arm for either uromodulin (0.11 [-0.13, 0.35], p value for interaction by treatment arm = 0.045) or ß2m (-0.01 [-0.08, 0.08], p value for interaction = 0.001). Urinary α1m was not independently associated with eGFR decline in the standard (0.01 [-0.22, 0.23]) or intensive (0.03 [-0.20, 0.25]) arm. CONCLUSIONS: Among trial participants with hypertension and CKD, baseline measures of tubular function were associated with subsequent declines in kidney function, although these associations were diminished by intensive blood pressure control.

Urinary sodium-to-potassium ratio and body mass index in relation to high blood pressure in a national health survey in Chile.

Several lifestyle and sociodemographic factors are associated with blood pressure (BP). The authors conducted a retrospective study of 4870 subjects from the National Health Survey 2009 in Chile to identify exposure factors associated with increasing BP levels. Subjects with isolated urinary excretion of sodium (n = 2873), potassium, and creatinine were included to estimate daily salt intake and urinary sodium/potassium (Na/K) ratio. Hypertension was defined according to European guidelines 2018 and American guidelines ACC/AHA 2017. Proportional odds models were developed to analyze education level, sedentarism, smoking, alcohol intake, estimated urinary Na/K ratio, estimated daily salt intake, and body mass index (BMI) as factors associated with increasing BP levels (from high-normal BP to hypertension). Logistic regression models were checked for overdispersion. Mean age and BMI of the population were 42 years old and 27 kg/m2 , respectively; 19% had low education level and 27% had hypertension according to European guidelines, whereas 47% according to ACC/AHA criteria. Mean estimated urinary Na/K ratio was 4 ± 2, and mean salt consumption was 10 ± 2 g/day. Estimated urinary Na/K ratio (OR, 1.11; 95% CI, 1.01-1.21), BMI (OR, 1.10; 95% CI, 1.07-1.13), estimated daily salt intake (OR, 1.10; 95% CI, 1.03-1.17), and alcohol intake (OR, 1.03; 95% CI, 1.01-1.05) were significantly associated with hypertension. This study highlights that a healthy diet and weight control should be important components of BP management plans, and it suggests that public policies should include close monitoring of these factors to reduce hypertension prevalence and improve its management in a Latino population.

Adherence to consensus guidelines for screening of primary aldosteronism in an urban healthcare system.

BACKGROUND: Primary aldosteronism is a common cause of secondary hypertension. Treatment with adrenalectomy or mineralocorticoid receptor-blockers can prevent long-term adverse outcomes. This study aimed to determine primary aldosteronism screening rats in patients with hypertension in an underserved urban healthcare system. METHODS: We reviewed records of outpatient adults in an urban healthcare system from 2013 to 2017. Chart review along with International Statistical Classification of Diseases, 9th and 10th editions, diagnosis codes were used to identify patients meeting inclusion criteria for screening according to the 2016 Endocrine Society guidelines. The corresponding aldosterone, plasma renin activity, and 24-hour urine aldosterone values were identified. Multivariate logistic regression was performed to determine positive predictors of screening. RESULTS: Of 15,511 hypertensive patients seen, 6,809 (43.8%) met criteria for screening. Blacks were the most common racial group, and Medicare and Medicaid were the most frequent insurers. The aldosterone-to-renin ratio level was checked in 86 (1.3%) patients; 22 (25.6%) had an aldosterone-to-renin ratio >20. Of the 77 patients with hypertension and incidentaloma, 14 (18.2%) had an aldosterone-to-renin ratio checked. Additional positive predictors for being screened were hypertension and hypokalemia and sustained hypertension. CONCLUSION: Screening rates for primary aldosteronism in an underserved population are low. Proper identification of primary aldosteronism in those at risk could help ameliorate long-term effects of disease.

Salt Preference is Linked to Hypertension and not to Aging / A Preferência ao Sal está Relacionada à Hipertensão e não ao Envelhecimento

Abstract Background: Seasoning is one of the recommended strategies to reduce salt in foods. However, only a few studies have studied salt preference changes using seasoning. Objectives: The aim of this study was to compare preference for salty bread, and if seasoning can change preference in hypertensive and normotensive, young and older outpatients. Methods: Outpatients (n = 118) were classified in four groups: older hypertensive subjects (OH) (n = 32), young hypertensive (YH) (n = 25); older normotensive individuals (ON) (n = 28), and young normotensive (YN) (n = 33). First, volunteers random tasted bread samples with three different salt concentrations. After two weeks, they tasted the same types of breads, with seasoning added in all. Blood pressure (BP), 24-hour urinary sodium and potassium excretion (UNaV, UKV) were measured twice. Analysis: Fisher exact test, McNamer's test and ANCOVA. Statistical significance: p < 0.05. Results: Systolic BP, UNaV, and UKV were greater in HO and HY and they had a higher preference for saltier samples than normotensive groups (HO: 71.9%, HY: 56% vs. NO: 25%, NY; 6%, p<0.01). With oregano, hypertensive individuals preferred smaller concentrations of salt, with reduced choice for saltier samples (HO: 71.9% to 21.9%, and HY: 56% to 16%, p = 0.02), NO preferred the lowest salt concentration sample (53.6% vs. 14.3%, p < 0.01), and NY further increased the preference for the lowest one (63.6% vs. 39.4%, p = 0.03). Conclusions: Older and younger hypertensive individuals prefer and consume more salt than normotensive ones, and the seasoned bread induced all groups to choose food with less salt. Salt preference is linked to hypertension and not to aging in outpatients.

Resumo Fundamento: Adicionar temperos aos alimentos é umas das estratégias recomendadas para diminuir a quantidade de sal nos alimentos. No entanto, poucos estudos investigaram alterações na preferência ao sal através do uso de temperos. Objetivos: O objetivo deste estudo foi comparar a preferência pelo pão salgado, e até que ponto o uso de temperos pode alterar as preferências dos indivíduos hipertensos e normotensos, pacientes ambulatoriais jovens e idosos. Métodos: Os pacientes ambulatoriais (n = 118) foram classificados em quatro grupos: idosos com hipertensão (IH) (n = 32), jovens hipertensos (JH) (n = 25); indivíduos idosos normotensos (IN) (n = 28), e jovens normotensos (JN) (n = 33). Primeiro, os voluntários provaram amostras aleatórias de pão com três diferentes concentrações de sal. Após duas semanas, eles provaram os mesmos tipos de pão, porém acrescidos de temperos. A pressão arterial (PA), e a excreção urinária de sódio e potássio de 24 horas (UNaV, UKV) foram medidas duas vezes. Análise: Teste exato de Fisher, teste de McNemar e teste ANCOVA. Significância estatística: p < 0,05. Resultados: A PA sistólica e a excreção urinária de sódio e potássio foram maiores nos grupos IH e JH, e eles tiveram maior preferência por amostras mais salgadas quando comparados com os grupos de normotensos (IH: 71,9%, JH: 56% vs. IN: 25%, JN; 6%, p < 0,01). Quando o orégano foi adicionado, a preferência dos indivíduos hipertensos foi pelas amostras com menores concentrações de sal, com uma diminuição da escolha por amostras mais salgadas (IH: 71,9% a 21,9%, e JH: 56% a 16%, p = 0,02); o grupo IN preferiu a amostra com a concentração de sal mais baixa (53,6% vs. 14,3%, p < 0,01) e no grupo JN aumentou ainda mais o número de indivíduos com preferência pela amostra com concentrações mais baixas de sal (63,6% vs. 39,4%, p = 0,03). Conclusões: Os idosos e jovens hipertensos preferem e consomem mais sal do que os normotensos, e o pão adicionado de tempero ajudou todos os grupos a escolher alimentos menos salgados. A preferência ao sal está ligada à hipertensão e não à idade nos pacientes ambulatoriais.

Association Between Urinary Catecholamine Excretion and Urine Volume.

Several confounders must be considered in the evaluation of urinary catecholamine excretion. However, literature is contradictory about potential confounders. The aim of the present study was to assess correlations between catecholamine excretion and anthropometric or clinical parameters with special attention to urine volume. A total of 967 24-h urinary catecholamine measurements were performed in 593 patients for diagnostic purposes. The indication for urine examination was suspicion of secondary hypertension, phaeochromocytoma, or paraganglioma. From the patients examined, 57% were females and 43% were males. The patients' age ranged between 15 and 87 years with a median [Q1; Q3] of 51 [39; 62] years. Seventy-eight percent of the patients suffered from hypertension. Seventy percent of patients took one or more antihypertensive drugs. The most commonly used drugs were ACE inhibitors (43%), while α-blockers (15%) were the least used drugs. Urinary excretion was between 500 and 11 950 ml/24 h with a median of 2200 [1600; 2685] ml/24 h. The median body mass index (BMI) was 26.7 [24.0; 30.4] kg/m2. The excretion of all catecholamines was greater in men than in women (all p<0.0001). Epinephrine (p=0.0026), dopamine (p<0.0001), and metanephrine (p=0.0106) excretion decreased with age. BMI was associated with urinary excretion of dopamine (p<0.0001), norepinephrine (p=0.0026), normetanephrine (p<0.0001), and homovanillylmandelic acid (HVMA; p=0.0251). Urine volume correlated with urinary dopamine (p=0.0127), metanephrine (p<0.0001), normetanephrine (p=0.0070), and HVMA (p<0.0028) excretion. In addition to the established associations between urinary catecholamine excretion and age, gender, and BMI in the present study, urinary catecholamine excretion correlated also with urine volume.

The concentration of tumor necrosis factor in the blood serum and in the urine and selected early organ damages in patients with primary systemic arterial hypertension.

Arterial hypertension is considered to be an inflammatory condition with low intensity. Therefore, an elevated concentration of inflammatory cytokines can be expected in patients with systemic arterial hypertension, including tumor necrosis factor (TNF).The study included a group of 96 persons aged 18 to 65 years: 76 patients with primary arterial hypertension and 20 healthy individuals (control group). Blood pressure was measured in all individuals using the office and ambulatory blood pressure monitoring (ABPM) measurement, blood was collected for laboratory tests [tumor necrosis factor (TNF), tumor necrosis factor receptor 1 (TNFR1)], and 24-hour urine collection was performed in which albuminuria and TNF concentration were assessed. Moreover, assessment of the intima-media thickness (IMT) in ultrasonography and left ventricular mass index (LVMI) in echocardiography were carried out.Statistically elevated TNF concentration in the blood serum (P = .0001) and in the 24-hour urine collection (P = .0087) was determined in patients with hypertension in comparison with the control group. The TNF and TNFR1 concentration in the serum and TNF in the 24-hour urine in the group of patients with arterial hypertension and organ damages and without such complications did not differ statistically significantly.We observed a positive and statistically significant correlation between TNFR1 concentration in the serum and TNF urine excretion in patients with hypertension (r = 0.369, P < .05)Patients with arterial hypertension are characterized by higher TNF concentrations in blood serum and higher TNF excretion in 24-hour urine than healthy persons.TNF and TNFR1 concentration in blood serum and TNF excretion in 24-hour urine in patients with early organ damages due to arterial hypertension do not differ significantly from those parameters in patients with arterial hypertension without organ complications.There is a positive correlation between TNFR1 concentration in the serum and TNF urine excretion in patients with hypertension.

Drinking Water Salinity, Urinary Macro-Mineral Excretions, and Blood Pressure in the Southwest Coastal Population of Bangladesh.

Background Sodium (Na+) in saline water may increase blood pressure ( BP ), but potassium (K+), calcium (Ca2+), and magnesium (Mg2+) may lower BP . We assessed the association between drinking water salinity and population BP . Methods and Results We pooled 6487 BP measurements from 2 cohorts in coastal Bangladesh. We used multilevel linear models to estimate BP differences across water salinity categories: fresh water (electrical conductivity, <0.7 mS/cm), mild salinity (electrical conductivity ≥0.7 and <2 mS/cm), and moderate salinity (electrical conductivity ≥2 and <10 mS/cm). We assessed whether salinity categories were associated with hypertension using multilevel multinomial logistic models. Models included participant-, household-, and community-level random intercepts. Models were adjusted for age, sex, body mass index ( BMI ), physical activity, smoking, household wealth, alcohol consumption, sleep hours, religion, and salt consumption. We evaluated the 24-hour urinary minerals across salinity categories, and the associations between urinary minerals and BP using multilevel linear models. Compared with fresh water drinkers, mild-salinity water drinkers had lower mean systolic BP (-1.55 [95% CI : -3.22-0.12] mm Hg) and lower mean diastolic BP (-1.26 [95% CI : -2.21--0.32] mm Hg) adjusted models. The adjusted odds ratio among mild-salinity water drinkers for stage 1 hypertension was 0.60 (95% CI : 0.43-0.84) and for stage 2 hypertension was 0.56 (95% CI : 0.46-0.89). Mild-salinity water drinkers had high urinary Ca2+, and Mg2+, and both urinary Ca2+ and Mg2+ were associated with lower BP. Conclusions Drinking mild-salinity water was associated with lower BP , which can be explained by higher intake of Ca2+ and Mg2+ through saline water.

Ethnic Differences in Nighttime Melatonin and Nighttime Blood Pressure: A Study in European Americans and African Americans.

BACKGROUND: Ethnic differences in nighttime blood pressure (BP) have long been documented with African Americans (AAs) having higher BP than European Americans (EAs). At present, lower nighttime melatonin, a key regulator of circadian rhythms, has been associated with higher nighttime BP levels in EAs. This study sought to test the hypothesis that AAs have lower nighttime melatonin secretion compared with EAs. We also determined if this ethnic difference in melatonin could partially explain the ethnic difference in nighttime BP. METHODS: A total of 150 young adults (71 AA; 46% females; mean age: 27.7 years) enrolled in the Georgia Stress and Heart study provided an overnight urine sample for the measurement of 6-sulfatoxymelatonin, a major metabolite of melatonin. Urine melatonin excretion (UME) was calculated as the ratio between 6-sulfatoxymelatonin concentration and creatinine concentration. Twenty-four-hour ambulatory BP was assessed and nighttime systolic BP (SBP) was used as a major index of BP regulation. RESULTS: After adjustment of age, sex, body mass index, and smoking, AAs had significantly lower UME (P = 0.002) and higher nighttime SBP than EAs (P = 0.036). Lower UME was significantly associated with higher nighttime SBP and this relationship did not depend on ethnicity. The ethnicity difference in nighttime SBP was significantly attenuated after adding UME into the model (P = 0.163). CONCLUSION: This study is the first to document the ethnic difference in nighttime melatonin excretion, demonstrating that AAs have lower melatonin secretion compared with EAs. Furthermore, the ethnic difference in nighttime melatonin can partially account for the established ethnic difference in nighttime SBP.

Improving proteinuria screening with mailed smartphone urinalysis testing in previously unscreened patients with hypertension: a randomized controlled trial.

BACKGROUND: Proteinuria screening is recommended for patients with hypertension to screen for kidney disease and identify those at elevated risk for cardiovascular disease. However, screening rates among hypertensive patients are low. Home testing strategies may be useful in improving proteinuria screening adherence. METHODS: We conducted an individual-level, randomized trial at 55 primary care clinic sites in the Geisinger Health System to evaluate the effectiveness of a strategy using home smartphone urinalysis test (Dip.io) to complete proteinuria screening in previously unscreened non-diabetic patient portal users with hypertension. All patients received an educational letter and a standing urinalysis lab order, and then were randomized to control (usual care) or intervention. Intervention arm participants were invited to complete proteinuria screening with a mailed home smartphone urinalysis test. Co-primary outcomes were completion of proteinuria screening and number of albuminuria cases (albumin/creatinine ratio [ACR] ≥ 30 mg/g or protein/creatinine ratio ≥ 150 mg/g) at the end of 3 months. We also evaluated patient satisfaction with the home test, and compliance with recommendations for patients with newly detected albuminuria. RESULTS: A total of 999 patients were randomized to intervention or control. Out of 499 patients assigned to the intervention arm, 253 were reached by phone, and 69/97 (71.1%) consented patients completed the home test. Overall, the intervention increased proteinuria screening completion (28.9% vs. 18.0%; p < 0.001) with no effect on the number of albuminuria cases (4 vs. 4) although only 6/57 (10.5%) patients with trace or 1+ urine dipstick protein had a follow-up quantitative test. Among the 55 patients who completed a survey after the home test, 89% preferred testing at home rather than the physician's office. CONCLUSIONS: A strategy using a home urinalysis smartphone test increased proteinuria screening rates in previously unscreened patients with hypertension and may be useful in increasing rates of proteinuria screening compliance. Future studies should evaluate use of home testing kits to screen for and confirm albuminuria, and determine whether improving early detection of kidney disease can improve future kidney health. TRIAL REGISTRATION: Clinical Trial Registry: NCT03470701 (First posted 3/20/2018) https://clinicaltrials.gov/ct2/show/NCT03470701 . This study was retrospectively registered.

Urinary Biomarkers of Tubular Damage Are Associated with Mortality but Not Cardiovascular Risk among Systolic Blood Pressure Intervention Trial Participants with Chronic Kidney Disease.

BACKGROUND: Kidney tubulointerstitial fibrosis on biopsy is a strong predictor of chronic kidney disease (CKD) progression, and CKD is associated with elevated risk of cardiovascular disease (CVD). Tubular health is poorly quantified by traditional kidney function measures, including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of tubular injury, inflammation, and repair would be associated with higher risk of CVD and mortality in persons with CKD. METHODS: We measured urinary concentrations of interleukin-18 (IL-18), kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and chitinase-3-like protein-1 (YKL-40) at baseline among 2,377 participants of the Systolic Blood Pressure Intervention Trial who had an eGFR < 60 mL/min/1.73 m2. We used Cox proportional hazards models to evaluate biomarker associations with CVD events and all-cause mortality. RESULTS: At baseline, the mean age of participants was 72 ± 9 years, and eGFR was 48 ± 11 mL/min/1.73 m2. Over a median follow-up of 3.8 years, 305 CVD events (3.6% per year) and 233 all-cause deaths (2.6% per year) occurred. After multivariable adjustment including eGFR, albuminuria, and urinary creatinine, none of the biomarkers showed statistically significant associations with CVD risk. Urinary IL-18 (hazard ratio [HR] per 2-fold higher value, 1.14; 95% CI 1.01-1.29) and YKL-40 (HR per 2-fold higher value, 1.08; 95% CI 1.02-1.14) concentrations were each incrementally associated with higher mortality risk. Associations were similar when stratified by randomized blood pressure arm. CONCLUSIONS: Among hypertensive trial participants with CKD, higher urinary IL-18 and YKL-40 were associated with higher risk of mortality, but not CVD.

Renal injury after uninephrectomy in male and female intrauterine growth-restricted aged rats.

Epidemiological studies report an inverse association between birth weight and risk for kidney disease that may differ between males and females, but studies investigating this association are limited. This study tested the hypothesis that male intrauterine growth-restricted offspring in a model of low birth weight induced by placental insufficiency in the rat exhibit enhanced renal injury in response to a persistent secondary renal insult while female growth-restricted offspring are protected. For this study, control offspring from sham-operated dams and growth-restricted offspring from reduced uterine perfusion dams underwent uninephrectomy or a sham procedure at 18 months of age. One month later, urinary markers of renal injury, renal function, and histological damage were measured. Results were analyzed using 2-way ANOVA. Male and female offspring were assessed separately. Proteinuria and urinary neutrophil gelatinase-associated lipocalin were significantly elevated in male growth-restricted offspring exposed to uninephrectomy when compared to male uninephrectomized control. Urinary kidney injury marker-1 was elevated in male uninephrectomized growth-restricted offspring relative to male sham growth-restricted but not to male uninephrectomized controls. Likewise, urinary neutrophil gelatinase-associated lipocalin was elevated in female uninephrectomized growth-restricted offspring but only when compared to female sham growth-restricted offspring. Markers of renal function including glomerular filtration rate and serum creatinine were impaired after uninephrectomy in female offspring regardless of birth weight. Histological parameters did not differ between control and growth-restricted offspring. Collectively, these studies suggest that both male and female growth-restricted offspring demonstrate susceptibility to renal injury following uninephrectomy; however, only male growth-restricted offspring exhibited an increase in renal markers of injury in response to uninephrectomy relative to same-sex control counterparts. These findings further suggest that urinary excretion of protein, kidney injury marker-1, and neutrophil gelatinase-associated lipocalin may be early markers of kidney injury in growth-restricted offspring exposed to a secondary renal insult such as reduction in renal mass.

Urine Haptoglobin and Haptoglobin-Related Protein Predict Response to Spironolactone in Patients With Resistant Hypertension.

Resistant hypertension prevalence is progressively increasing, and prolonged exposure to suboptimal blood pressure control results in higher cardiovascular risk and end-organ damage. Among various antihypertensive agents, spironolactone seems the most effective choice to treat resistant hypertension once triple therapy including a diuretic fails. However success in blood pressure control is not guaranteed, adverse effects are not negligible, and no clinical tools are available to predict patient's response. Complementary to our previous study of resistant hypertension metabolism, here we investigated urinary proteome changes with potential capacity to predict response to spironolactone. Twenty-nine resistant hypertensives were included. A prospective study was conducted and basal urine was collected before spironolactone administration. Patients were classified in responders or nonresponders in terms of blood pressure control. Protein quantitation was performed by liquid chromatography-mass spectrometry; ELISA and target mass spectrometry analysis were performed for confirmation. Among 3310 identified proteins, HP (haptoglobin) and HPR (haptoglobin-related protein) showed the most significant variations, with increased levels in nonresponders compared with responders before drug administration (variation rate, 5.98 and 7.83, respectively). Protein-coordinated responses were also evaluated by functional enrichment analysis, finding oxidative stress, chronic inflammatory response, blood coagulation, complement activation, and regulation of focal adhesions as physiopathological mechanisms in resistant hypertension. In conclusion, protein changes able to predict patients' response to spironolactone in basal urine were here identified for the first time. These data, once further confirmed, will support clinical decisions on patients' management while contributing to optimize the rate of control of resistant hypertensives with spironolactone.

Effects of Intensive Blood Pressure Lowering on Kidney Tubule Injury in CKD: A Longitudinal Subgroup Analysis in SPRINT.

BACKGROUND: Random assignment to the intensive systolic blood pressure (SBP) arm (<120mmHg) in the Systolic Blood Pressure Intervention Trial (SPRINT) resulted in more rapid declines in estimated glomerular filtration rates (eGFRs) than in the standard arm (SBP<140mmHg). Whether this change reflects hemodynamic effects or accelerated intrinsic kidney damage is unknown. STUDY DESIGN: Longitudinal subgroup analysis of clinical trial participants. SETTINGS & PARTICIPANTS: Random sample of SPRINT participants with prevalent chronic kidney disease (CKD) defined as eGFR<60mL/min/1.73m2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline. OUTCOMES & MEASUREMENTS: Urine biomarkers of tubule function (ß2-microglobulin [B2M], α1-microglobulin [A1M]), and uromodulin), injury (interleukin 18, kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin), inflammation (monocyte chemoattractant protein 1), and repair (human cartilage glycoprotein 40) at baseline, year 1, and year 4. Biomarkers were indexed to urine creatinine concentration and changes between arms were evaluated using mixed-effects linear models and an intention-to-treat approach. RESULTS: 978 SPRINT participants (519 in the intensive and 459 in the standard arm) with prevalent CKD were included. Mean age was 72±9 years and eGFR was 46.1±9.4mL/min/1.73m2 at baseline. Clinical characteristics, eGFR, urinary albumin-creatinine ratio, and all 8 biomarker values were similar across arms at baseline. Compared to the standard arm, eGFR was lower by 2.9 and 3.3mL/min/1.73m2 in the intensive arm at year 1 and year 4. None of the 8 tubule marker levels was higher in the intensive arm compared to the standard arm at year 1 or year 4. Two tubule function markers (B2M and A1M) were 29% (95% CI, 10%-43%) and 24% (95% CI, 10%-36%) lower at year 1 in the intensive versus standard arm, respectively. LIMITATIONS: Exclusion of persons with diabetes, and few participants had advanced CKD. CONCLUSIONS: Among participants with CKD in SPRINT, random assignment to the intensive SBP arm did not increase any levels of 8 urine biomarkers of tubule cell damage despite loss of eGFR. These findings support the hypothesis that eGFR declines in the intensive arm of SPRINT predominantly reflect hemodynamic changes rather than intrinsic damage to kidney tubule cells.