Novel biomarkers in patients with uncontrolled hypertension with and without kidney damage.

INTRODUCTION: Estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (ACR) are insensitive biomarkers for early detection of hypertension-mediated organ damage (HMOD). In this nationwide cross-sectional study, we assessed potential biomarkers for early HMOD in healthy persons and patients with hypertension. We hypothesised that plasma levels of biomarkers: (1) are different between healthy controls and patients with hypertension, (2): can classify patients with hypertension according to the degree of hypertension severity. DESIGN AND METHODS: Patients with hypertension prescribed ≥2 antihypertensive agents were selected from a multicentre study. Healthy controls were selected from an ongoing study of living kidney donor candidates. Uncontrolled hypertension was defined as systolic daytime ambulatory blood pressure ≥135 mmHg. Kidney HMOD was defined by ACR > 3.0 mg/mmol or eGFR < 60 mL/min/1.73 m2. Patients with hypertension were categorised into three groups: (1) controlled hypertension; (2) uncontrolled hypertension without kidney HMOD; (3) uncontrolled hypertension with kidney HMOD. Fifteen biomarkers were analysed using a Luminex bead-based immunoassay, and nine fell within the specified analytical range. RESULTS: Plasma levels of Interleukin 1 receptor antagonist (IL-1RA), neutrophil gelatinase-associated lipocalin (NGAL) and uromodulin were significantly different between healthy controls (n = 39) and patients with hypertension (n = 176). In regression models, with controlled hypertension (n = 55) as the reference category, none of the biomarkers were associated with uncontrolled hypertension without (n = 59) and with (n = 62) kidney HMOD. In models adjusted for cardiovascular risk factors and eGFR, osteopontin (OPN) was associated with uncontrolled hypertension without kidney HMOD (odds ratio (OR) 1.77 (1.05-2.98), p = 0.03), and regulated upon activation normal T-cell expressed and secreted (RANTES) with uncontrolled hypertension with kidney HMOD (OR 0.57 (0.34-0.95), p = 0.03). CONCLUSIONS: None of the biomarkers could differentiate our hypertension groups when established risk factors were considered. Plasma OPN may identify patients with uncontrolled hypertension at risk for kidney HMOD.

What is the context? In order to tailor individualised hypertension treatment, a risk assessment for cardiovascular disease (CVD) must be performed. This includes evaluation of established hypertension-mediated organ damage (HMOD), such as the presence of kidney damage and associated risk factors. Today, kidney function is assessed by blood and urine samples. However, today's blood and urine samples are not sensitive enough to capture kidney damage due to hypertension at a stage when prevention may be most effective.What is new? In this study, we evaluated plasma levels of biomarkers related to endothelial and kidney cell pathology, inflammation and fibrosis in healthy patients and patients with hypertension. We hypothesised that plasma levels of biomarkers could differentiate between different degrees of hypertension severity.Healthy controls had lower Interleukin 1 receptor antagonist (IL-1RA) and neutrophil gelatinase-associated lipocalin (NGAL) levels, but higher uromodulin compared to patients with hypertension. Except for osteopontin (OPN), all biomarkers showed significant trends in median biomarker levels across study groups. However, as hypertension severity increased, the median plasma OPN levels also rose. None of the biomarker could consistently differentiate the hypertension severity groups after considering established risk factors. However, OPN may be an early biomarker for kidney damage in hypertension.What is the impact? Biomarkers for early detection of organ damage in hypertension may guide targeted treatment. Plasma OPN may have potential to identify those at risk for hypertensive kidney damage. However, the studied biomarkers lack consistent discrimination across hypertension severity levels.

Development of UHPLC-MS/MS methods to quantify 25 antihypertensive drugs in serum in a cohort of patients treated for hypertension.

We developed three ultra-high pressure liquid chromatography coupled to mass spectrometry detection (UHPLC-MS/MS) methods to quantify 25 antihypertensive drugs in serum samples. Patient-reported drug lists were collected, and drug concentrations were analysed in samples from 547 patients, half with uncontrolled hypertension, and all treated with ≥ 2 antihypertensive drugs. For sample preparation, serum was mixed with deuterated internal standards and acetonitrile and precipitated. Aliquots of the supernatant were injected on UHPLC-MSMS with a C18 reversed phase column. The mobile phase was 0.1 % HCOOH (formic acid) in water and 0.1 % HCOOH in acetonitrile (except in methanol for spironolactone/canrenone) at a flow rate of 0.4 mL/min. The calibrators and internal controls were prepared in Autonorm™. The calibration ranges were wide, and the models were linear or quadratic with squared correlation coefficients ≥ 0.97. The limits of detection and quantification, specificity, carry-over, and matrix effects were acceptable. The accuracy of the internal controls was in the range 85-121 %, and the intermediate precision for all drugs was 4-28 %. The patient-reported antihypertensive drug use and the detected serum drug concentrations were in accordance with that most frequently prescribed nationally. The percent non-detectable level was 5-10 % for bendroflumethiazide, doxazosin, nifedipine, and ramipril. Often the drug dose chosen was lower than the recommended maximum daily dose. We report the maximum (Cmax) and minimum (Cmin) drug concentrations after drug intake. The inter-individual pharmacokinetic variability at Cmin was 18-fold for hydrochlorothiazide, 22-fold for losartan carboxyl acid, 26-fold for amlodipine, 44-fold for candesartan, and 50-fold for valsartan. Our methods are suitable for measuring antihypertensive drugs in patient serum for therapy control.

Detection of Nonadherence to Antihypertensive Treatment by Measurements of Serum Drug Concentrations.

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The randomised Oslo study of renal denervation vs. Antihypertensive drug adjustments: efficacy and safety through 7 years of follow-up.

PURPOSE: The blood pressure (BP) lowering effect of renal sympathetic denervation (RDN) in treatment-resistant hypertension shows variation amongst the existing randomised studies. The long-term efficacy and safety of RDN require further investigation. For the first time, we report BP changes and safety up to 7 years after RDN, compared to drug adjustment in the randomised Oslo RDN study. MATERIALS AND METHODS: Patients with treatment-resistant hypertension, defined as daytime systolic ambulatory BP ≥135 mmHg after witnessed intake of ≥3 antihypertensive drugs including a diuretic, were randomised to either RDN (n = 9) or drug adjustment (n = 10). The initial primary endpoint was the change in office BP after 6 months. The RDN group had their drugs adjusted after 1 year using the same principles as the Drug Adjustment group. Both groups returned for long-term follow-up after 3 and 7 years. RESULTS: The decrease in office BP and ambulatory BP (ABPM) after 6 months did not persist, but gradually increased in both groups. From 6 months to 7 years follow-up, mean daytime systolic ABPM increased from 142 ± 10 to 145 ± 15 mmHg in the RDN group, and from 133 ± 11 to 137 ± 13 mmHg in the Drug Adjustment group, with the difference between them decreasing. In a mixed factor model, a significantly different variance was found between the groups in daytime systolic ABPM (p = .04) and diastolic ABPM (p = .01) as well as office diastolic BP (p<.01), but not in office systolic BP (p = .18). At long-term follow-up we unveiled no anatomical- or functional renal impairment in either group. CONCLUSIONS: BP changes up to 7 years show a tendency towards a smaller difference in BPs between the RDN and drug adjustment patients. Our data support RDN as a safe procedure, but it remains non-superior to intensive drug adjustment 7 years after the intervention.