Hypertension (HTN) is a major public health issue in Sri Lanka, influenced by genetic predisposition and lifestyle factors. Despite high general literacy, gaps in health literacy and suboptimal HTN management persist. Understanding knowledge, attitudes, and practices (KAP) in HTN is crucial for developing targeted public health interventions to improve awareness and management. A cross-sectional online survey was conducted among Sri Lankan adults from February to September 2024. Participants were recruited via social media, and data were collected using a structured questionnaire assessing socio-demographic characteristics, knowledge of HTN, attitudes toward prevention and treatment, and health-related practices. Knowledge scores were analysed using descriptive statistics, chi-square tests, ANOVA, and regression models. A total of 2,013 participants were included, with 47

Hypertension is the leading cause of death globally, primarily due to its strong association with cardiovascular disease. The global prevalence of hypertension has surged over the past three decades, driven by rising rates of diabetes mellitus and obesity. Despite current antihypertensive therapies, only a small proportion of patients with hypertension achieve adequate blood pressure control, necessitating novel therapeutic strategies. In this Review we explore the challenges and emerging opportunities in hypertension management. Aprocitentan, a dual endothelin receptor antagonist, is the first agent from a novel class of antihypertensive drug to be licensed since 2007 and exemplifies innovative treatments on the horizon. Here we also address the complex factors contributing to poor hypertension control, including genetic influences, lifestyle factors, therapeutic inertia and poor patient adherence. We discuss the limitations of existing therapies and highlight promising new pharmacological approaches to hypertension management. Integrating these novel treatments alongside current pharmaceuticals combined with improved diagnostic and management strategies could substantially reduce the global burden of hypertension and associated cardiovascular disease. Hypertension is the leading cause of death globally but has low rates of diagnosis and treatment. In this Review, Dhaun and colleagues discuss the reasons for poor control of hypertension, such as therapeutic inertia and poor patient adherence, as well as novel pharmacological approaches to blood pressure lowering.

Over the past 25 years, the UK has adopted health technology assessment (HTA) as a mechanism to ensure that new medicines, and new indications for existing medicines, are assessed in an open, objective and robust way so that when the UK National Health Service (NHS) adopts these therapeutic developments, it does so in a cost-effective manner, accepting those agents with an acceptable cost per quality-adjusted life year (QALY) or a discount that brings the cost below the threshold. Usually, pharmacoeconomic modelling is used to justify pricing, often relying on surrogate endpoints or extrapolation beyond the duration of existing trials data. Although cost-effectiveness is often based on robust clinical trials, there are other issues to consider, which require an understanding of clinical pharmacology and clinical judgement. Key considerations include the justification of use of surrogates and extrapolation, the appropriateness of any comparator drug studied, the difference between efficacy in trials and clinical effectiveness in real-world use, the additional costs of providing a service to deliver the medicine, and the cost of any important adverse effects that are likely to occur. Although the process in the UK is now well established, with support from clinicians and the public, there remain questions about whether the currently accepted cost/QALY is set too high, whether a special case should be made for some drugs commanding a higher cost/QALY (such as in cancer and end-of-life situations), and whether HTA should be used more broadly to assess other activities undertaken by the NHS.

BACKGROUND: UMOD (uromodulin) has been linked to hypertension through potential activation of Na + -K + -2Cl − cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction. METHODS: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline ( ClinicalTrials.gov : NCT03354897). RESULTS: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m 2 ), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, −6.57 mm Hg [95% CI, −8.44 to −4.69]; P <0.0001; AG/GG, −3.22 [95% CI, −5.93 to −0.51]; P =0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of −3.35 mm Hg ([95% CI, −6.64 to −0.05]; P =0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group ( P =0.004 for difference in trajectories). CONCLUSIONS: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03354897.

We aimed to examine associations between ultraviolet (UV) exposure and mortality among older adults in the United Kingdom (UK). We used data from UK Biobank participants with two UV exposures, validated with measured vitamin D levels: solarium use and annual average residential shortwave radiation. Associations between the UV exposures, all-cause and cause-specific mortality were examined as adjusted hazard ratios. The UV exposures were inversely associated with all-cause, cardiovascular disease (CVD) and cancer mortality. Solarium users were also at a lower risk of non-CVD/non-cancer mortality. The benefits of UV exposure may outweigh the risks in low-sunlight countries.

3D printing has emerged as a revolutionary technique for producing products with specific shapes and mechanical properties tailored to various needs. Its ability to fabricate intricate structures and forms has garnered considerable attention, leading to numerous research efforts exploring its potential benefits in geotechnical applications. These endeavours highlight the possibilities of utilizing 3D printing technology to create innovative and customized materials for soil reinforcement, such as geosynthetics, and fibres, as well as replicating soil particles, physical models of soil structures, and drainage systems in geo-structures. Additionally, beyond its role in geotechnical engineering, the interaction between geo-structures (foundations, retaining walls, embankments, tunnels, piles, infrastructures, etc.) and the surrounding soil under different loading and environmental conditions is of paramount importance. The interface between these structures and the soil plays a critical role in load transfer and overall stability. Therefore, this study focuses on investigating the interface between soil and 3D printed components through direct shear testing. The experimental campaign aims to examine how different factors, including the type of 3D printing materials, material rigidity, and surface texture of the printed components, influence the shear behaviour of the soil-3D printing material interface. The findings suggest that Young’s modulus of the 3D printed materials plays a crucial role in determining the response of the soil-3D printed parts interface. Furthermore, an optimized design is proposed to achieve the desired shearing resistance at the interface. The insights gained from this investigation have practical implications for optimizing the design of 3D-printed components in geotechnical engineering applications.

AIMS:Endothelin-1 (ET-1) is elevated in patients with obesity and adipose tissue of obese mice fed high-fat diet (HFD); however, its contribution to the pathophysiology of obesity is not fully understood. Genetic loss of endothelin type B receptors (ETB) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ETB activation on adipocytes may contribute to obesity pathophysiology. We hypothesized that elevated ET-1 in obesity promotes insulin resistance by reducing the secretion of insulin sensitizing adipokines, via ETB receptor. METHODS:Male adipocyte-specific ETB receptor knockout (adETBKO), overexpression (adETBOX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks. RESULTS:RNA-sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (p < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adETBKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adETBKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adETBKO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. Treatment of primary adipocytes with ET-1 caused a reduction in adiponectin production that was attenuated in cells pretreated with an ETB antagonist. CONCLUSION:These data indicate elevated ET-1 in adipose tissue of mice fed HFD inhibits adiponectin production and causes insulin resistance through activation of the ETB receptor on adipocytes.

Drug-induced liver injury (DILI) is a challenge in clinical medicine and drug development. Highly sensitive novel biomarkers have been identified for detecting DILI following a paracetamol overdose. The study objective was to evaluate biomarker performance in a 14-day trial of therapeutic dose paracetamol. The PATH-BP trial was a double-blind, placebo-controlled, crossover study. Individuals (n = 110) were randomized to receive 1 g paracetamol 4× daily or matched placebo for 2 weeks followed by a 2-week washout before crossing over to the alternate treatment. Blood was collected on days 0 (baseline), 4, 7, and 14 in both arms. Alanine transaminase (ALT) activity was measured in all patients. MicroRNA-122 (miR-122), cytokeratin-18 (K18), and glutamate dehydrogenase (GLDH) were measured in patients who had an elevated ALT on paracetamol treatment (≥50% from baseline). ALT increased in 49 individuals (45%). All 3 biomarkers were increased at the time of peak ALT (K18 paracetamol arm: 18.9 ± 9.7 ng/ml, placebo arm: 11.1 ± 5.4 ng/ml, ROC-AUC = 0.80, 95% CI 0.71-0.89; miR-122: 15.1 ± 12.9fM V 4.9 ± 4.7fM, ROC-AUC = 0.83, 0.75-0.91; and GLDH: 24.6 ± 31.1U/l V 12.0 ± 11.8U/l, ROC-AUC = 0.66, 0.49-0.83). All biomarkers were correlated with ALT (K18 r = 0.68, miR-122 r = 0.67, GLDH r = 0.60). To assess sensitivity, biomarker performance was analyzed on the visit preceding peak ALT (mean 3 days earlier). K18 identified the subsequent ALT increase (K18 ROC-AUC = 0.70, 0.59-0.80; miR-122 ROC-AUC = 0.60, 0.49-0.72, ALT ROC-AUC = 0.59, 0.48-0.70; GLDH ROC-AUC = 0.70, 0.50-0.90). Variability was lowest for ALT and K18. In conclusion, K18 was more sensitive than ALT, miR-122, or GLDH and has potential significant utility in the early identification of DILI in trials and clinical practice.

Background: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension. Methods: The TIME study is a prospective, pragmatic, decentralised, parallel group study in the UK, that recruited adults with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned 1 to 1, without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning, 0600 to 1000 h, or in the evening, 2000 to 0000 h.. Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non fatal myocardial infarction or non fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention to treat population i.e. all participants randomly assigned to a treatment group. Findings: Between Dec 17, 2011, and June 5, 2018, 24610 individuals were screened and 21104 were randomly assigned 10503 to evening and 10601 to morning dosing groups. Mean age at study entry was 65·1 years, SD 9·3, 12136 or 57·5 percent participants were men; 8968, 90·5 percent were White, and 2725 or 13·0 percent had a previous cardiovascular disease. By the end of study follow up on March 31, 2021, median follow up was 5·2 years, IQR 4·9, 5·7, 529 of 10503 participants assigned to evening treatment and 318 of 10601 assigned to morning treatment had withdrawn from all follow up. A primary endpoint event occurred in 362 participants assigned to evening treatment that is 0·69 events per 100 patient years and 390 assigned to morning treatment that is 0·72 events per 100 patient years, unadjusted hazard ratio 0·95, 95percent CI 0·83 to 1·10, p 0·53. No safety concerns were identified. An analysis of outcome by adherence to dosing time will be presented at the meeting. Interpretation Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects. Funding British Heart Foundation and the British and Irish Hypertension Society.

IntroductionHypertension is the main global risk factor for cardiovascular disease. Despite this, less than half of treated hypertensive patients are controlled. One reason for this is nonadherence, a major unmet need in hypertension pharmacotherapy. Small interfering RNA (small interfering ribonucleic acid) therapies inhibit protein translation, and, when linked to N-acetylgalactosamine, allow liver-specific targeting, and durability over several months. Targeted knockdown of hepatic angiotensinogen, the source of all angiotensins, offers a precision medicine approach.Areas coveredThis article describes the molecular basis for durability over months and the 24-h tonic target inhibition observed after one administration. We present an analysis of the published phase I trials using zilebesiran, a siRNA targeting hepatic angiotensinogen, which reduces blood pressure (BP) by up to 20 mmHg, lasting 24 weeks. Finally, we examine data evaluating reversibility of angiotensinogen knockdown and its relevance to the future clinical utility of zilebesiran.Expert opinionFurther studies should assess safety, efficacy, and outcomes in larger, more broadly representative groups. An advantage of zilebesiran is the potential for bi-annual dosing, thereby reducing nonadherence and improving control rates. It may also reduce nighttime BP due to 24-h tonic control. The provision of adherence assessment services will maximize the clinical value of zilebesiran.

In patients with chronic kidney disease (CKD), there is an unmet need for novel biomarkers that reliably track kidney injury, demonstrate treatment-response, and predict outcomes. Here, we investigate the potential of retinal optical coherence tomography (OCT) to achieve these ends in a series of prospective studies of patients with pre-dialysis CKD (including those with a kidney transplant), patients with kidney failure undergoing kidney transplantation, living kidney donors, and healthy volunteers. Compared to health, we observe similar retinal thinning and reduced macular volume in patients with CKD and in those with a kidney transplant. However, the choroidal thinning observed in CKD is not seen in patients with a kidney transplant whose choroids resemble those of healthy volunteers. In CKD, the degree of choroidal thinning relates to falling eGFR and extent of kidney scarring. Following kidney transplantation, choroidal thickness increases rapidly (~10%) and is maintained over 1-year, whereas gradual choroidal thinning is seen during the 12 months following kidney donation. In patients with CKD, retinal and choroidal thickness independently associate with eGFR decline over 2 years. These observations highlight the potential for retinal OCT to act as a non-invasive monitoring and prognostic biomarker of kidney injury.

BACKGROUND:Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis. METHODS:In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring. RESULTS:Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r = -0.56 at week 8; 95% confidence interval, -0.69 to -0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively. CONCLUSIONS:Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.).

Background: Genome-wide association studies identified the major A allele of SNP rs13333226 to be associated with increased BP and uromodulin excretion. Observational studies indicate those with rs13333226-AA genotype have greater BP lowering in response to loop diuretics. Methods: This genotype blinded multi-centre trial (NCT03354897) enrolled hypertensive participants without diabetes aged ≥18 years with home SBP >135 mmHg and/or DBP >85 mmHg despite treatment with ≥1 non diuretic antihypertensive drug for ≥3 months. Participants were prescribed torasemide 5mg daily for 16 weeks with ABPM BP measured at baseline, 8 and 16 weeks. Primary endpoint was change in 24h ABPM SBP between baseline and end of treatment by genotype (AA vs AG/GG). Results: We screened 251 patients, with 222 prescribed torasemide; 174 had genotype data and took ≥80% of dispensed torasemide over the study period. Drop in mean ABPM SBP at 16 weeks compared to baseline was twice as large for AA than AG/GG genotypes (AA -6.57 mmHg change (95% CI -8.44, -4.69), p<0.0001; AG/GG -3.22 (-5.93, -0.51) mmHg change, p=0.021). Mean ABPM SBP in AA group steadily declined from 139 mmHg at baseline to 132.6 mmHg at end of treatment, in contrast, the AG/GG group began with a marginally lower value mean ABPM SBP, showed a marked drop at 8 weeks, followed by a rebound at 16 weeks, ending slightly higher than those in the AA group. Conclusions: The rs13333226-AA genotype identifies a group of hypertensive patients who show a larger, more stable BP reduction in response to torasemide adding further support for a biological uromodulin-NKCC2 interaction, and a role for genotype directed earlier use of loop diuretics in hypertension management.

Hypertension remains the leading cause of cardiovascular disease and premature death globally, affecting half of US adults. A high proportion of hypertensive patients exhibit uncontrolled blood pressure (BP), associated with poor adherence, linked to pill burden and adverse effects. Novel pharmacological strategies are urgently needed to improve BP control. Dysregulation of the renin-angiotensin system increases BP through its primary effector, Ang II (angiotensin II), which results in tissue remodeling and end-organ damage. Silencing liver angiotensinogen (the sole source of Ang II) has been achieved using novel RNA therapeutics, including the antisense oligonucleotide, IONIS-AGT (angiotensinogen)-LRX, and the small-interfering RNA, zilebesiran. Conjugation to N-acetylgalactosamine enables targeted delivery to hepatocytes, where endosomal storage, slow leakage, and small-interfering RNA recycling (for zilebesiran) result in knockdown over several months. Indeed, zilebesiran has an impressive and durable effect on systolic BP, reduced by up to 20 mm Hg and sustained for 6 months after a single administration, likely due to its very effective knockdown of angiotensinogen, without causing acute kidney injury or hyperkalemia. By contrast, IONIS-AGT-LRX caused less knockdown and marginal effects on BP. Future studies should evaluate any loss of efficacy relating to antidrug antibodies, safety issues associated with long-term angiotensinogen suppression, and broader benefits, especially in the context of common comorbidities such as type 2 diabetes and chronic kidney disease.

ABSTRACT Objective To examine to what extent UV exposure is associated with all-cause and cause-specific mortality. Design Prospective population-based study. Setting UK Biobank. Participants 376,729 participants with white ancestry and no missing data. Two UV exposures were assessed: sun-seeking behaviour (categorised as less active versus more active) and home latitude. Main outcome measures All-cause, cardiovascular disease (CVD), cancer and non-CVD/non-cancer mortality. Risk of residual confounding was examined using three negative control outcomes. Results The median follow-up was 12.7 years. Participants with more active sun-seeking behaviour were at a lower risk of all-cause mortality (HR=0.86; 95% confidence interval (CI) 0.80 to 0.93), CVD mortality (HR=0.81; 95% CI 0.68 to 0.95) and cancer mortality (HR=0.86; 95% CI 0.77 to 0.95) compared to participants with less active sun-seeking behaviours, adjusted for demographic, socioeconomic, behavioural and clinical confounders. More active sun seekers had around 50 extra days of survival. Participants whose home latitude was 300km farther south were also at a lower risk of all-cause mortality (HR=0.94; 95% CI 0.92 to 0.96), CVD mortality (HR=0.91; 95% CI 0.86 to 0.95) and cancer mortality (HR=0.93; 95% CI 0.90 to 0.96), adjusted for demographic, socioeconomic, behavioural and clinical confounders. Participants whose home latitude was 300km farther south had around 16 extra days of survival. Sun-seeking behaviour was not associated with two of the three negative controls and home latitude was not associated with any of the negative controls. Conclusions Greater behavioural and higher geographically related UV exposures were associated with a lower risk of all-cause, CVD and cancer mortality. This study adds to growing evidence that the benefits of UV exposure may outweigh the risks in low sunlight countries. Tailoring public health advice to both the benefits and hazards of UV exposure may reduce the burden of disease and increase life expectancy in low sunlight countries.

Standard single mode optical fibers (SMFs) have been widely employed to generate and measure ultrasonic signals in remarkable applications. In particular, optoacoustic fiber sensors provide unique features for microscale high resolution ultrasound imaging in biomedicine. However, at specific resonance frequencies, SMFs work as acoustic filters inducing relevant geometrical attenuation bands higher than 10 dB, which limit the sensors' sensitivity and frequency operation, causing image distortions and artifacts. We have numerically demonstrated high frequency axially symmetric ultrasonic resonances inside an optical fiber for the first time. The propagation of resonant axially symmetric acoustic modes along 1 cm fiber is investigated by means of 2D and 3D finite element techniques up to 80 MHz. The dispersion of the modes and induced beatlengths are characterized from the complex multimode interference with the 2D Fourier transform. The simulated spectra are validated with the renowned Pochhammer-Chree analytical equations. The frequency response of the acoustically induced strains in the fiber core is evaluated, and important acoustic parameters relevant for the modulation of phase, wavelength and power in optical fibers and diffractive gratings are derived and discussed. The results show that these resonances are strongly dependent on the modal beatlengths. Solutions to improve the operation of fiber-based devices are proposed, pointing out new alternatives to advance broadband optoacoustic sensors and monolithic acousto-optic modulators.

HomeJournal of the American Heart AssociationVol. 11, No. 20Small Interfering RNA Therapeutics in Hypertension: A Viewpoint on Vasopressor and Vasopressor‐Sparing Strategies for Counteracting Blood Pressure Lowering by Angiotensinogen–Targeting Small Interfering RNA

Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular/physiological pathways are poorly defined. There are no therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6C high monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal proinflammatory Ly6C high monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6C low monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.