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Spencer S, Bhandari S. Optimizing renin-angiotensin-aldosterone inhibition in advanced chronic kidney disease: balancing benefits and risks. Curr Opin Nephrol Hypertens 2025:00041552-990000000-00226. [PMID: 40207744 DOI: 10.1097/mnh.0000000000001076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
PURPOSE OF REVIEW Renin-angiotensin-aldosterone system inhibitors (RAASi), including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), are fundamental in chronic kidney disease (CKD) management, particularly in proteinuric conditions. However, their use in advanced CKD (eGFR <30 ml/min/1.73 m 2 ) remains debated because of risks of hyperkalaemia, acute kidney injury (AKI), and hypotension. This review evaluates the latest evidence, including the STOP-ACEi trial, to inform the risks and benefits of RAASi in advanced CKD. RECENT FINDINGS The STOP-ACEi trial, a multicentre randomized controlled trial (RCT), investigated RAASi discontinuation in 411 patients with advanced CKD. After 3 years, discontinuation did not slow eGFR decline or reduce mortality, while continuation was associated with a numerical trend towards lower end-stage kidney disease (ESKD) rates. Meta-analyses also indicate that ACEi may offer superior kidney protection compared to ARBs, though both lower cardiovascular risk and this difference may not be clinically significant. Combination ACEi/ARB therapy provides no additional benefits and increases adverse events, such as hyperkalaemia and hypotension. Adjunct therapies like potassium binders and sodium-glucose cotransporter-2 (SGLT2) inhibitors may enable safer RAASi use in high-risk patients. SUMMARY Current evidence supports RAASi continuation in most CKD patients, including those with advanced disease, unless contraindicated. Future studies should refine patient selection criteria and optimize adjunctive strategies to mitigate adverse effects.
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Affiliation(s)
- Sebastian Spencer
- University of Hull
- Hull York Medical School, Department of Medical Science, Hull
- Hull University Teaching Hospitals NHS Trust Academic Renal Department, Hull, UK
| | - Sunil Bhandari
- Hull York Medical School, Department of Medical Science, Hull
- Hull University Teaching Hospitals NHS Trust Academic Renal Department, Hull, UK
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Zhang TY, An DA, Yan H, Wang J, Zhou H, Chen B, Lu R, Fang W, Wang Q, Che X, Huang J, Jin H, Shen J, Zhou Y, Mou S, Chen J, Fang Y, Wu LM. Fractal Analysis of Left Ventricular Trabeculae in Patients with End-Stage Renal Disease: A Random Survival Tree Analysis. J Magn Reson Imaging 2024; 60:1948-1961. [PMID: 38270242 DOI: 10.1002/jmri.29251] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/05/2024] [Accepted: 01/05/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND The complexity of left ventricular (LV) trabeculae is related to the prognosis of several cardiovascular diseases. PURPOSE To evaluate the prognostic value of LV trabecular complexity in patients with end-stage renal disease (ESRD). STUDY TYPE Prospective outcome study. POPULATION 207 participants on maintenance dialysis, divided into development (160 patients from 2 centers) and external validation (47 patients from a third center) cohorts, and 72 healthy controls. FIELD STRENGTH 3.0T, steady-state free precession (SSFP) and modified Look-Locker imaging sequences. ASSESSMENT All participants had their trabecular complexity quantified by fractal analysis using cine SSFP images. Patients were followed up every 2 weeks until April 2023, or endpoint events happened. Random Forest (RF) and Cox regression models including age, diabetes, LV mass index, mean basal fractal dimension (FD), and left atrial volume index, were developed to predict major adverse cardiac events (MACE). Patients were divided into low- and high-risk groups based on scores derived from the RF model and survival compared. STATISTICAL TESTS Receiver operating characteristic curve analysis; Kaplan-Meier survival analysis with log rank tests; Harrel's C-index to assess model performance. A P value <0.05 was considered statistically significant. RESULTS Fifty-five patients (26.57%) experienced MACE during a median follow-up time of 21.83 months. An increased mean basal FD (≥1.324) was associated with a significantly higher risk of MACE. The RF model (C-index: 0.81) had significantly better discrimination than the Cox regression model (C-index: 0.74). Participants of the external validation dataset classified into the high-risk group had a hazard of experiencing MACE increased by 12.29 times compared to those in the low-risk group. DATA CONCLUSION LV basal FD was an independent predictor for MACE in patients with ESRD. Reliable risk stratification models could be generated based on LV basal FD and other MRI variables using RF analysis. LEVEL OF EVIDENCE 2 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Tian-Yi Zhang
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dong-Aolei An
- Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Yan
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jieying Wang
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hang Zhou
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Binghua Chen
- Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Renhua Lu
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Fang
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qin Wang
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiajing Che
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiaying Huang
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haijiao Jin
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianxiao Shen
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yin Zhou
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shan Mou
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Chen
- Department of Radiology, Affiliated Third Hospital of Soochow University, Changzhou, China
| | - Yan Fang
- Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lian-Ming Wu
- Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Forouzanmehr B, Hedayati AH, Gholami E, Hemmati MA, Maleki M, Butler AE, Jamialahmadi T, Kesharwani P, Yaribeygi H, Sahebkar A. Sodium-glucose cotransporter 2 inhibitors and renin-angiotensin-aldosterone system, possible cellular interactions and benefits. Cell Signal 2024; 122:111335. [PMID: 39117253 DOI: 10.1016/j.cellsig.2024.111335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/30/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024]
Abstract
Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a newly developed class of anti-diabetics which exert potent hypoglycemic effects in the diabetic milieu. However, the evidence suggests that they also have extra-glycemic effects. The renin-angiotensin-aldosterone system (RAAS) is a hormonal system widely distributed in the body that is important for water and electrolyte homeostasis as well as renal and cardiovascular function. Therefore, modulating RAAS activity is a main goal in patients, notably diabetic patients, which are at higher risk of complications involving these organ systems. Some studies have suggested that SGLT2is have modulatory effects on RAAS activity in addition to their hypoglycemic effects and, thus, these drugs can be considered as promising therapeutic agents for renal and cardiovascular disorders. However, the exact molecular interactions between SGLT2 inhibition and RAAS activity are not clearly understood. Therefore, in the current study we surveyed the literature for possible molecular mechanisms by which SGLT2is modulate RAAS activity.
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Affiliation(s)
- Behina Forouzanmehr
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Emad Gholami
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Tannaz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Dahel H, Tabbara N, Burry L, Hornstein G, Williamson D, Wang HT. Optimizing Subsequent CARdiovascular Medication Reintroduction in the Intensive Care Unit. Can J Kidney Health Dis 2024; 11:20543581241276361. [PMID: 39247850 PMCID: PMC11378200 DOI: 10.1177/20543581241276361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 06/25/2024] [Indexed: 09/10/2024] Open
Abstract
Importance Hospital admission for a critical illness episode creates communication breakpoints and can lead to medication discrepancies during hospital stays. Due to the patient's underlying condition and the care setting, chronic medications such as cardiovascular medication are often held, discontinued, or changed to alternative administration routes. Unfortunately, data on the optimal timing of cardiovascular drug reinitiation among intensive care unit (ICU) survivors are lacking. Objective The primary objective of this study was to describe the prevalence of chronic cardiovascular medication taken before hospital admission and discontinued at ICU discharge and hospital discharge for critically ill patients. A secondary objective was to assess factors associated with medication discontinuation. Design setting and participants We conducted a multicentered retrospective cohort study at 2 tertiary academic hospitals in Canada. All adult patients taking cardiovascular medication before ICU admission and surviving to hospital discharge between April 1, 2016, and April 1, 2017, were eligible. Main outcomes and measures The main outcome of the study was the discontinuation of cardiovascular medication prescribed before ICU admission. The outcome was assessed through participants' chart review. Results We included 352 patients with a median age of 71.0 years. A total of 155 patients (44.03%) had at least 1 cardiovascular medication discontinued during their stay. Our adjusted model uncovered 3 factors associated with cardiovascular medication discontinuation: male sex (odds ratio [OR] = 0.564, 95% confidence interval [CI] = 0.346-0.919), number of cardiovascular medications taken preadmission (OR = 1.669, 95% CI = 1.003-2.777 for 2 medications and OR = 3.170, 95% CI = 1.325-7.583), and the use of vasopressors (OR = 1.770, 95% CI = 1.045-2.997). Conclusion Our study uncovered that cardiovascular medication discontinuation for ICU patients is frequent, especially for renin-angiotensin system (RAS) blockers. Data from our study could be used to reinforce site-specific protocols of medication reconciliation and optimization, as well as inform future protocols aimed at RAS blocker reinitiation follow-up.
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Affiliation(s)
- Hadjer Dahel
- Faculty of Pharmacy, Université de Montréal, QC, Canada
| | - Najla Tabbara
- Department of Pharmacy, Mount Sinai Hospital, Toronto, ON, Canada
| | - Lisa Burry
- Department of Pharmacy, Mount Sinai Hospital, Toronto, ON, Canada
| | | | | | - Han Ting Wang
- Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada
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Vendeville N, Lepage MA, Festa MC, Mavrakanas TA. Clinical Outcomes of Renin-Angiotensin-Aldosterone Blockade in Patients With Advanced Chronic Kidney Disease: A Systematic Review and Meta-analysis. Can J Cardiol 2024; 40:1718-1728. [PMID: 38458564 DOI: 10.1016/j.cjca.2024.02.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 02/09/2024] [Accepted: 02/13/2024] [Indexed: 03/10/2024] Open
Abstract
BACKGROUND The cardiovascular and renal benefits of renin-angiotensin aldosterone system (RAAS) blockade are not well established in patients with advanced chronic kidney disease (CKD). We conducted a systematic review and meta-analysis to identify potential risks and benefits from RAAS blockade in patients with CKD stage 4-5. METHODS A Medline search from inception to November 2022 was conducted to identify randomised controlled trials (RCTs) in patients with CKD stage 4-5 (estimated glomerular filtration rate ≤ 30 mL/min/1.73 m2) comparing RAAS blockade vs placebo or alternative antihypertensive therapy. Different intervention strategies were assessed (RAAS use vs nonuse, initiation vs placebo/alternative therapy, or discontinuation vs continuation). The primary outcome was progression to end-stage kidney disease (ESKD). Secondary outcomes were all-cause mortality and major adverse cardiovascular events (MACE). The risk ratio (RR) was estimated with the use of a random-effects model. RESULTS Nine RCTs (1150 patients) were included. RAAS blockade was associated with a significant reduction in progression to ESKD: RR 0.84 (95% confidence interval [CI] 0.74-0.96; P = 0.01). There was no benefit from RAAS blockade on all-cause mortality or MACE: RR 1.02 (95% CI 0.63-1.65; P = 0.93) and RR 0.87 (95% CI 0.49-1.57; P = 0.65), respectively. CONCLUSIONS RAAS blockade may be considered in selected patients with CKD stage 4-5 to delay progression to ESKD.
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Affiliation(s)
- Nicolas Vendeville
- Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada; Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada.
| | - Marc-Antoine Lepage
- Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada
| | - M Carolina Festa
- Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada
| | - Thomas A Mavrakanas
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada; Research Institute, McGill University Health Centre, Montréal, Québec, Canada
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Guan Y, Zhang Y, Chen L, Ren Y, Nie H, Ji T, Yan J, Zhang C, Ruan L. Effect of low-dose terazosin on arterial stiffness improvement: A pilot study. J Cell Mol Med 2024; 28:e18547. [PMID: 39044238 PMCID: PMC11265993 DOI: 10.1111/jcmm.18547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 06/26/2024] [Accepted: 07/12/2024] [Indexed: 07/25/2024] Open
Abstract
Arterial stiffness, a prominent hallmark of ageing arteries, is a predictor of all-cause mortality. Strategies for promoting healthy vascular ageing are encouraged. Here we conducted a pilot study to evaluate the potential effects of low-dose Terazosin on arterial stiffness. We enrolled patients aged over 40 with elevated arterial stiffness, defined as a brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s, who were administered Terazosin (0.5 and 1.0 mg/day) from December 2020 to June 2023. Treatment responses were assessed every 3 months. Linear regression analysis was used to characterise the improvement. We matched cases who took Terazosin for 1 year with Terazosin-free controls using propensity score matching (PSM). Our findings demonstrate that Terazosin administration significantly affected arterial stiffness. (1) Arterial stiffness significantly improved (at least a 5% reduction in baPWV) in 50.0% of patients at 3 months, 48.6% at 6 months, 59.3% at 9 months, and 54.4% at 12 months, respectively. (2) Those with higher baseline baPWV and hypertension exhibited a significantly reduced risk of non-response. (3) Terazosin was associated with a reduction of baPWV at 1-year follow-up (linear regression: β = -165.16, p < 0.001). This pilot study offers valuable insights into the potential significance of Terazosin in improving arterial stiffness and paves the way for future randomised clinical trials in combating vascular ageing.
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Affiliation(s)
- Yuqi Guan
- Department of Geriatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yucong Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Liangkai Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yazhi Ren
- Department of Geriatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Hao Nie
- Department of Geriatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Tianyi Ji
- Department of Geriatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jinhua Yan
- Department of Geriatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Cuntai Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Lei Ruan
- Department of Geriatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Sundström J, Norhammar A, Karayiannides S, Bodegård J, Gustafsson S, Cars T, Eriksson Svensson M, Ärnlöv J. Are there lost opportunities in chronic kidney disease? A region-wide cohort study. BMJ Open 2024; 14:e074064. [PMID: 38643002 PMCID: PMC11033666 DOI: 10.1136/bmjopen-2023-074064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 04/03/2024] [Indexed: 04/22/2024] Open
Abstract
OBJECTIVES Identify the windows of opportunity for the diagnosis of chronic kidney disease (CKD) and the prevention of its adverse outcomes and quantify the potential population gains of such prevention. DESIGN AND SETTING Observational, population-wide study of residents in the Stockholm and Skåne regions of Sweden between 1 January 2015 and 31 December 2020. PARTICIPANTS All patients who did not yet have a diagnosis of CKD in healthcare but had CKD according to laboratory measurements of CKD biomarkers available in electronic health records. OUTCOME MEASURES We assessed the proportions of the patient population that received a subsequent diagnosis of CKD in healthcare, that used guideline-directed pharmacological therapy (statins, renin-angiotensin aldosterone system inhibitors (RAASi) and/or sodium-glucose cotransporter-2 inhibitors (SGLT2i)) and that experienced adverse outcomes (all-cause mortality, cardiovascular mortality or major adverse cardiovascular events (MACE)). The potential to prevent adverse outcomes in CKD was assessed using simulations of guideline-directed pharmacological therapy in untreated subsets of the study population. RESULTS We identified 99 382 patients with undiagnosed CKD during the study period. Only 33% of those received a subsequent diagnosis of CKD in healthcare after 5 years. The proportion that used statins or RAASi was of similar size to the proportion that didn't, regardless of how advanced their CKD was. The use of SGLT2i was negligible. In simulations of optimal treatment, 22% of the 21 870 deaths, 27% of the 14 310 cardiovascular deaths and 39% of the 22 224 MACE could have been avoided if every patient who did not use an indicated medication for their laboratory-confirmed CKD was treated with guideline-directed pharmacological therapy for CKD. CONCLUSIONS While we noted underdiagnosis and undertreatment of CKD in this large contemporary population, we also identified a substantial realisable potential to improve CKD outcomes and reduce its burden by treating patients early with guideline-directed pharmacological therapy.
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Affiliation(s)
- Johan Sundström
- Department of Medical Sciences, Clinical Epidemiology, Uppsala University, Uppsala, Sweden
- The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Anna Norhammar
- Cardiology Unit, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden
- Capio S:t Görans Hospital, Stockholm, Sweden
| | - Stelios Karayiannides
- Department of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden
- Center for Diabetes, Academic Specialist Center, Region Stockholm, Stockholm, Sweden
| | - Johan Bodegård
- Cardiovascular, Renal and Metabolism, Medical Department, BioPharmaceuticals, AstraZeneca PLC, Oslo, Norway
| | | | | | - Maria Eriksson Svensson
- Department of Medical Sciences, Renal Medicine, Uppsala University, Uppsala, Sweden
- Uppsala Clinical Research Center, Uppsala, Sweden
| | - Johan Ärnlöv
- Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- School of Health and Social Studies, Dalarna University, Falun, Dalarna, Sweden
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Zhu X, Xue J, Liu Z, Dai W, Xiang J, Xu H, Zhou Q, Zhou Q, Wei X, Chen W. The effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in critically ill patients with acute kidney injury: An observational study using the MIMIC database. Front Pharmacol 2022; 13:918385. [PMID: 36105224 PMCID: PMC9465288 DOI: 10.3389/fphar.2022.918385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 08/02/2022] [Indexed: 11/29/2022] Open
Abstract
Background: The safety of prescribing angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) during acute kidney injury (AKI) remains unclear. We aimed to investigate the associations of ACEI/ARB therapy in AKI with the risk of mortality, acute kidney disease (AKD), and hyperkalemia. Methods: We conducted a retrospective monocentric study, which included patients in Massachusetts between 2008 and 2019 from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Propensity score matching was performed for the endpoint analysis. The association between ACEI/ARB therapy and mortality was assessed using Cox proportional hazards regression models. Logistic regression was used to assess the risk of AKD and hyperkalemia. Results: Among the 19,074 individuals with AKI admitted to the intensive care unit (ICU), 3,244 (17.0%) received ACEI/ARBs, while 15,830 (83.0%) did not. In the propensity score-matched sample of 6,358 individuals, we found a decreased risk of mortality in those who received ACEI/ARBs compared to those who did not (hazard ratio [HR] for ICU mortality: 0.34, 95% confidence interval [CI]: 0.27-0.42); HR for in-hospital mortality: 0.47, 95% CI: 0.39-0.56; HR for 30-day mortality: 0.47, 95% CI: 0.40-0.56; HR for 180-day mortality: 0.53, 95% CI: 0.45-0.62). However, the use of ACEI/ARBs was associated with a higher risk of AKD (risk ratio [RR]: 1.81; 95% CI: 1.55-2.12). There was no significant association between ACEI/ARBs and an increased risk of hyperkalemia (RR: 1.21; 95% CI: 0.96-1.51). Conclusions: ACEI/ARB treatment during an episode of AKI may decrease all-cause mortality, but increases the risk of AKD. Future randomized controlled trials are warranted to validate these findings.
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Affiliation(s)
- Xu Zhu
- Department of Epidemiology and Health Statistics, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Jing Xue
- Department of Scientific Research, Xiangya Hospital, Central South University, Changsha, China
| | - Zheng Liu
- Department of Anesthesiology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Ji’nan, China
| | - Wenjie Dai
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Jingsha Xiang
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Hui Xu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Qiaoling Zhou
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Quan Zhou
- Department of Science and Education, The First People’s Hospital of Changde City, Changde, China
| | - Xinran Wei
- Department of Acupuncture and Massage Rehabilitation, First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Wenhang Chen
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
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Tomaru R. Renin-Angiotensin-Aldosterone System (RAS) Inhibitors May Suppress the Prevalence of Peripheral Arterial Disease (PAD) in Elderly, Chronic Hemodialysis Patients. Cureus 2022; 14:e25087. [PMID: 35600067 PMCID: PMC9113923 DOI: 10.7759/cureus.25087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2022] [Indexed: 11/05/2022] Open
Abstract
According to the hypertension guidelines, calcium antagonists are recommended as antihypertensive drugs for Stage 5 of chronic kidney disease (CKDG5) and late elderly patients, whereas renin-angiotensin-aldosterone system (RAS) inhibitors (RASi) are not recommended. We screened elderly CKDG5D patients at a single outpatient maintenance hemodialysis center for the progression of peripheral arterial disease (PAD) using the ankle-brachial index (ABI) and skin perfusion pressure (SPP) tests, as well as logistic regression analysis, to determine the association between PAD and the treatment with RASi and the association between the treatment with RASi and the need for hospitalization within one year of observation. With the presence of PAD as the explanatory variable and the presence of RASi as the objective variable, the odds ratio was 1.23 (95% confidence interval [CI] 0.37 to 3.82) in univariate analysis. After adjusting for confounding factors (age, gender, and hypertension), the odds ratio in multivariate analysis was 0.83 (95% CI 0.46 to 6.08). The presence or absence of PAD was significantly associated with an odds ratio of 3.24 (p = .04, 95% CI 1.0 to 10.25) and 4.63 (p = .026, 95% CI 1.20 to 17.84) in univariate and multivariate analyses, respectively, when the outcome was hospitalization at one year, regardless of the presence or absence of RASi. However, in univariate analysis, the odds ratio was 1.23 (95% CI 0.37 to 3.82) with RASi status as the explanatory variable and one-year hospitalization as the objective variable. After adjusting for confounders, the odds ratio in multivariate analysis was 0.83 (95% CI 0.46 to 6.08). Although further large-scale, multicenter studies are needed to establish the evidence, our results suggest that RASi treatment may have a suppressive effect on the prevalence of PAD and the need for hospitalization in elderly CKDG5 dialysis (CKDG5D) patients.
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Gentile G, Mckinney K, Reboldi G. Tight Blood Pressure Control in Chronic Kidney Disease. J Cardiovasc Dev Dis 2022; 9:jcdd9050139. [PMID: 35621850 PMCID: PMC9144041 DOI: 10.3390/jcdd9050139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 04/22/2022] [Accepted: 04/27/2022] [Indexed: 12/12/2022] Open
Abstract
Hypertension affects over a billion people worldwide and is the leading cause of cardiovascular disease and premature death worldwide, as well as one of the key determinants of chronic kidney disease worldwide. People with chronic kidney disease and hypertension are at very high risk of renal outcomes, including progression to end-stage renal disease, and, even more importantly, cardiovascular outcomes. Hence, blood pressure control is crucial in reducing the human and socio-economic burden of renal and cardiovascular outcomes in those patients. However, current guidelines from hypertension and renal societies have issued different and sometimes conflicting recommendations, which risk confusing clinicians and potentially contributing to a less effective prevention of renal and cardiovascular outcomes. In this review, we critically appraise existing evidence and key international guidelines, and we finally formulate our own opinion that clinicians should aim for a blood pressure target lower than 130/80 in all patients with chronic kidney disease and hypertension, unless they are frail or with multiple comorbidities. We also advocate for an even more ambitious systolic blood pressure target lower than 120 mmHg in younger patients with a lower burden of comorbidities, to minimise their risk of renal and cardiovascular events during their lifetime.
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Affiliation(s)
- Giorgio Gentile
- College of Medicine and Health, University of Exeter, Exeter EX1 2LU, UK;
- Department of Nephrology, Royal Cornwall Hospitals NHS Trust, Truro TR1 3LQ, UK
| | - Kathryn Mckinney
- Faculty of Biology, College of Letters and Science, University of Wisconsin-Madison, Madison, WI 53706, USA;
| | - Gianpaolo Reboldi
- Centro di Ricerca Clinica e Traslazionale (CERICLET), Department of Medicine, University of Perugia, 06156 Perugia, Italy
- Correspondence:
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11
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Mårup FH, Peters CD, Christensen JH, Birn H. Can patiromer allow for intensified renin-angiotensin-aldosterone system blockade with losartan and spironolactone leading to decreased albuminuria in patients with chronic kidney disease, albuminuria and hyperkalaemia? An open-label randomised controlled trial: MorphCKD. BMJ Open 2022; 12:e057503. [PMID: 35190442 PMCID: PMC8862471 DOI: 10.1136/bmjopen-2021-057503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Chronic kidney disease (CKD) is associated with significantly increased morbidity and mortality. No specific treatment of the underlying condition is available for the majority of patients, but ACE-inhibitors (ACE-I) and angiotensin II-receptor blockers (ARB) slows progression in albuminuric CKD. Adding a mineralocorticoid receptor-antagonist (MRA) like spironolactone has an additive effect. However, renin-angiotensin-aldosterone system (RAAS)-blockade increases the risk of hyperkalaemia which is exacerbated by the presence of CKD. Thus, hyperkalaemia may prevent optimal use of RAAS-blockade in some patients.This project hypothesises that adding a potassium binder (patiromer) allows for improved RAAS-blockade including the use of MRA, thereby reducing albuminuria in patients with albuminuric CKD where full treatment is limited by hyperkalaemia.If successful, the study may lead to improved treatment of this subgroup of patients with CKD. Furthermore, the study will examine the feasibility of potassium binders in patients with CKD. METHODS AND ANALYSIS An open-label, randomised controlled trial including 140 patients with estimated glomerular filtration rate (eGFR) 25-60 mL/min/1.73 m2, a urinary albumin/creatinine ratio (UACR) >500 mg/g (or 200 mg/g if diabetes mellitus) and a current or two previous plasma-potassium >4.5 mmol/L. Patients who develop hyperkaliaemia >5.5 mmol/L during a run-in phase, in which RAAS-blockade is intesified with the possible addition of spironolactone, are randomised to 12-month treatment with maximal tolerated ACE-I/ARB and spironolactone with or without patiromer.The primary endpoint is the difference in UACR measured at randomisation and 12 months compared between the two groups. Secondary endpoints include CKD progression, episodes of hyperkalaemia, blood pressure, eGFR, markers of cardiovascular disease, diet and quality of life. ETHICS AND DISSEMINATION This study is approved by The Central Denmark Region Committees on Health Research Ethics (REFNO 1-10-72-110-20) and is registered in the EudraCT database (REFNO 2020-001595-15). Results will be presented in peer-reviewed journals, at meetings and at international conferences.
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Affiliation(s)
- Frederik Husum Mårup
- Dept. of Biomedicine, Aarhus University, Aarhus, Denmark
- Dept. of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Christian Daugaard Peters
- Dept. of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Dept. of Clinical Medicine, Aarhus University, Aarhus, Midtjylland, Denmark
| | - Jeppe Hagstrup Christensen
- Department of Nephrology, Aalborg University Hospital, Aalborg, North Denmark Region, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Henrik Birn
- Dept. of Biomedicine, Aarhus University, Aarhus, Denmark
- Dept. of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
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12
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Dai D, Sharma A, Alvarez PJ, Woods SD. Multiple comorbid conditions and healthcare resource utilization among adult patients with hyperkalemia: A retrospective observational cohort study using association rule mining. JOURNAL OF MULTIMORBIDITY AND COMORBIDITY 2022; 12:26335565221098832. [PMID: 35586031 PMCID: PMC9112318 DOI: 10.1177/26335565221098832] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 04/19/2022] [Indexed: 12/21/2022]
Abstract
Objectives To estimate the prevalence of specific comorbid conditions (CCs) and multiple comorbid conditions (MCCs) among adult patients with hyperkalemia and examine the associations between MCCs and healthcare resource utilization (HRU) and costs. Methods This retrospective observational cohort study was conducted using a large administrative claims database. We identified patients with hyperkalemia (ICD-10-CM: E87.5; or serum potassium >5.0 mEq/L; or NDC codes for either patiromer or sodium polystyrene sulfonate) during the study period (1/1/2016–6/30/2019). The earliest service/claim date with evidence of hyperkalemia was identified as index date. Qualified patients had ≥12 months of enrolment before and after index date, ≥18 years of age. Comorbid conditions were assessed using all data within 12 months prior to the index date. Healthcare resource utilization and costs were estimated using all data within 12 months after the index date. Association rule mining was applied to identify MCCs. Generalized linear models were used to examine the associations between MCCs and HRU and costs. Results Of 22,154 patients with hyperkalemia, 94% had ≥3 CCs. The most common individual CCs were chronic kidney disease (CKD, 85%), hypertension (HTN, 83%), hyperlipidemia (HLD, 81%), and diabetes mellitus (DM, 47%). The most common dyad combination of CCs was CKD+HTN (71%). The most common triad combination was CKD+HTN+HLD (62%). The most common quartet combination was CKD+HTN+HLD+DM (36%). The increased number of CCs were significantly associated with increased ED visits, length of hospital stays, and total healthcare costs (all p-value < 0.0001). Conclusions MCCs are very prevalent among patients with hyperkalemia and are strongly associated with HRU and costs.
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Affiliation(s)
- Dingwei Dai
- CVS Health Clinical Trial Services LLC, Woonsocket, RI, USA
| | - Ajay Sharma
- CVS Health Clinical Trial Services LLC, Woonsocket, RI, USA
| | - Paula J Alvarez
- Managed Care Health Outcomes, Vifor Pharma Inc., Redwood City, CA, USA
| | - Steven D Woods
- Managed Care Health Outcomes, Vifor Pharma Inc., Redwood City, CA, USA
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13
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Tobe A, Tanaka A, Tokuda Y, Fujii T, Furusawa K, Ishii H, Usui A, Murohara T. Albuminuria predicts worsening renal function after transcatheter aortic valve replacement. J Cardiol 2021; 79:648-654. [PMID: 34903422 DOI: 10.1016/j.jjcc.2021.11.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/26/2021] [Accepted: 11/10/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND The impact of albuminuria on worsening renal function (WRF) and clinical outcomes after transcatheter aortic valve replacement (TAVR) is unknown. METHODS Overall, 142 patients who underwent TAVR for severe aortic stenosis were divided into two groups based on the preoperative urinary albumin-to-creatinine ratio (ACR): high (ACR ≥30 mg/g) and low (ACR <30 mg/g). The incidence of WRF (an absolute increase in serum creatinine level of ≥0.3 mg/dL or ≥1.5-fold from baseline or dialysis initiation) at 6 months after TAVR and the incidence of all-cause death and heart failure readmission during follow-up were investigated. RESULTS Half of the examined patients [n=71/142 (50.0%)] had a high ACR. Patients with a high ACR more frequently had WRF at 6 months than those with a low ACR (17.6% vs. 2.9%, p=0.004). Multivariate analysis showed a high ACR was independently associated with WRF (odds ratio, 7.76; 95% confidence interval, 1.62-37.30; p=0.01), whereas baseline estimated glomerular filtration rate <60 mL/min/1.73m² was not (odds ratio, 0.34; 95% confidence interval, 0.08-1.50; p=0.15). Patients with a high ACR had a higher risk of composite outcomes of all-cause death and heart failure readmission (p=0.002). CONCLUSIONS Preoperative albuminuria (ACR ≥30 mg/g) was independently associated with WRF at 6 months after TAVR. Furthermore, patients with an ACR ≥30 mg/g had higher risks of all-cause death and heart failure readmission than those with an ACR <30 mg/g.
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Affiliation(s)
- Akihiro Tobe
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Akihito Tanaka
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiyuki Tokuda
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Taro Fujii
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenji Furusawa
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Ishii
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Cardiovascular Medicine, Gunma University Graduates School of Medicine, Maebashi, Japan
| | - Akihiko Usui
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Karaboyas A, Robinson BM, James G, Hedman K, Moreno Quinn CP, De Sequera P, Nitta K, Pecoits-Filho R. Hyperkalemia excursions are associated with an increased risk of mortality and hospitalizations in hemodialysis patients. Clin Kidney J 2021; 14:1760-1769. [PMID: 34221383 PMCID: PMC8243282 DOI: 10.1093/ckj/sfaa208] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Hyperkalemia is common among hemodialysis (HD) patients and has been associated with adverse clinical outcomes. Previous studies considered a single serum potassium (K) measurement or time-averaged values, but serum K excursions out of the target range may be more reflective of true hyperkalemia events. We assessed whether hyperkalemia excursions lead to an elevated risk of adverse clinical outcomes. METHODS Using data from 21 countries in Phases 4-6 (2009-18) of the Dialysis Outcomes and Practice Patterns Study (DOPPS), we investigated the associations between peak serum K level, measured monthly predialysis, over a 4-month period ('peak K') and clinical outcomes over the subsequent 4 months using Cox regression, adjusted for potential confounders. RESULTS The analysis included 62 070 patients contributing a median of 3 (interquartile range 2-6) 4-month periods. The prevalence of hyperkalemia based on peak K was 58% for >5.0, 30% for >5.5 and 12% for >6.0 mEq/L. The all-cause mortality hazard ratio for peak K (reference ≤5.0 mEq/L) was 1.15 [95% confidence interval (CI) 1.09, 1.21] for 5.1-5.5 mEq/L, 1.19 (1.12, 1.26) for 5.6-6.0 mEq/L and 1.33 (1.23, 1.43) for >6.0 mEq/L. Results were qualitatively consistent when analyzing hospitalizations and a cardiovascular composite outcome. CONCLUSIONS Among HD patients, we identified a lower K threshold (peak K 5.1-5.5 mEq/L) than previously reported for increased risk of hospitalization and mortality, with the implication that a greater proportion (>50%) of the HD population may be at risk. A reassessment of hyperkalemia severity ranges is needed, as well as an exploration of new strategies for effective management of chronic hyperkalemia.
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Affiliation(s)
| | - Bruce M Robinson
- Arbor Research Collaborative for Health, Ann Arbor, MI, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Glen James
- BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK
| | - Katarina Hedman
- BioPharmaceuticals Business Unit, AstraZeneca, Gothenburg, Sweden
| | | | | | - Kosaku Nitta
- Department of Nephrology, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
| | - Roberto Pecoits-Filho
- Arbor Research Collaborative for Health, Ann Arbor, MI, USA
- School of Medicine, Pontificia Universidade Catolica do Parana, Curitiba, Brazil
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15
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Hirano D, Miwa S, Kakegawa D, Umeda C, Takemasa Y, Tokunaga A, Yuhei K, Ito A. Impact of acute kidney injury in patients prescribed angiotensin-converting enzyme inhibitors over the first two years of life. Pediatr Nephrol 2021; 36:1907-1914. [PMID: 33462699 DOI: 10.1007/s00467-021-04920-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/12/2020] [Accepted: 01/05/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND The association of long-term acute kidney injury (AKI) risk with angiotensin-converting enzyme (ACE) inhibitor use in neonates/infants is poorly understood. We examined this association to identify potential AKI risk factors. METHODS We retrospectively evaluated 119 children aged < 2 years (72 boys; median age, 5.0 months) who received ACE inhibitors for congenital heart disease for ≥ 6 months between January 2009 and June 2019. We monitored the occurrence of AKI, defined according to the Kidney Disease Improving Global Outcomes guidelines. Demographic and clinical data were extracted from medical records. Risk factors associated with AKI onset were identified by a Cox proportional hazards regression analysis of variables previously identified as risk factors of AKI and those significant in a univariate analysis. RESULTS Thirty-three of 119 patients (28%) developed AKI at a median follow-up of 1.3 years (interquartile range, 0.8-3.2 years). AKI incidence was 1257 events per 10,000 patient-years. Concomitant tolvaptan use (hazard ratio [HR], 3.81; 95% confidence interval [CI], 1.82-7.97; P < 0.01) and Down syndrome (HR, 3.22; 95% CI, 1.43-7.29; P < 0.01) were identified as independent risk factors of AKI onset. CONCLUSIONS AKI was strongly associated with concomitant tolvaptan use and Down syndrome in our study population. Physicians should consider these factors when prescribing ACE inhibitors for neonates/infants. Low-dose ACE inhibitors slow CKD progression because of their antifibrotic properties. ACE inhibitors may be beneficial for patients with Down syndrome who have underlying CKD in a non-acute setting. Therefore, they should be administered to such patients with caution.
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Affiliation(s)
- Daishi Hirano
- Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-0003, Japan.
| | - Saori Miwa
- Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-0003, Japan
| | - Daisuke Kakegawa
- Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-0003, Japan
| | - Chisato Umeda
- Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-0003, Japan
| | - Yoichi Takemasa
- Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-0003, Japan.,Division of Nephrology, Saitama Children's Medical Center, Saitama, Japan
| | - Ai Tokunaga
- Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-0003, Japan
| | - Kawakami Yuhei
- Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-0003, Japan
| | - Akira Ito
- Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-0003, Japan
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16
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Ruggenenti P, Podestà MA, Trillini M, Perna A, Peracchi T, Rubis N, Villa D, Martinetti D, Cortinovis M, Ondei P, Condemi CG, Guastoni CM, Meterangelis A, Granata A, Mambelli E, Pasquali S, Genovesi S, Pieruzzi F, Bertoli SV, Del Rosso G, Garozzo M, Rigotti A, Pozzi C, David S, Daidone G, Mingardi G, Mosconi G, Galfré A, Romei Longhena G, Pacitti A, Pani A, Hidalgo Godoy J, Anders HJ, Remuzzi G, on behalf of the ARCADIA Study Organization. Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis: The ARCADIA Multicenter Randomized Controlled Trial. Clin J Am Soc Nephrol 2021; 16:575-587. [PMID: 33782036 PMCID: PMC8092055 DOI: 10.2215/cjn.12940820] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 02/15/2021] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND OBJECTIVES Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25-10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization. RESULTS At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: -16.3 g/m2; 95% confidence interval, -29.4 to -3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls. CONCLUSIONS Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008-003529-17.
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Affiliation(s)
- Piero Ruggenenti
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Manuel Alfredo Podestà
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Matias Trillini
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Annalisa Perna
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Tobia Peracchi
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Nadia Rubis
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Davide Villa
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Davide Martinetti
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Monica Cortinovis
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Patrizia Ondei
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Carmela Giuseppina Condemi
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Carlo Maria Guastoni
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Ovest Milanese, Ospedali di Legnano e Magenta, Milano, Italy
| | - Agnese Meterangelis
- Unit of Nephrology and Dialysis, Policlinico San Pietro, Ponte San Pietro, Bergamo, Italy
| | - Antonio Granata
- Unit of Nephrology and Dialysis, Azienda Ospedaliera per l'Emergenza “Cannizzaro,” Catania, Italy
| | - Emanuele Mambelli
- Unit of Nephrology, Dialysis and Hypertension, Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Sonia Pasquali
- Unit of Nephrology and Dialysis, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
| | - Simonetta Genovesi
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Monza, Ospedale San Gerardo, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
| | - Federico Pieruzzi
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Monza, Ospedale San Gerardo, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
| | - Silvio Volmer Bertoli
- Unit of Nephrology and Dialysis, Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Sesto San Giovanni, Milano, Italy
| | - Goffredo Del Rosso
- Unit of Nephrology and Dialysis, Ospedale Giuseppe Mazzini, Teramo, Italy
| | - Maurizio Garozzo
- Unit of Nephrology and Dialysis, Presidio Ospedaliero S. Marta e S. Venera, Acireale, Catania, Italy
| | - Angelo Rigotti
- Unit of Nephrology and Dialysis, Ospedale Infermi, Rimini, Italy
| | - Claudio Pozzi
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Nord Milano-Ospedale Bassini, Cinisello Balsamo, Milano, Italy
| | - Salvatore David
- Department of Nephrology and Dialysis, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Giuseppe Daidone
- Unit of Nephrology and Dialysis, Ospedale Umberto I, Siracusa, Italy
| | - Giulio Mingardi
- Unit of Nephrology and Dialysis, Humanitas Gavazzeni, Bergamo, Italy
| | - Giovanni Mosconi
- Unit of Nephrology and Dialysis, Ospedale “Morgagni-Pierantoni,” Forlì, Italy
| | - Andrea Galfré
- Unit of Nephrology and Dialysis, Azienda Sanitaria Locale 8, Cagliari, Italy
| | - Giorgio Romei Longhena
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Rhodense-Ospedale Garbagnate Milanese, Milano, Italy
| | - Alfonso Pacitti
- Unit of Nephrology and Dialysis, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy
| | - Antonello Pani
- Unit of Nephrology and Dialysis, Department of Reproduction, Genitourinary and Kidney Disease and Kidney Transplantation, Azienda Ospedaliera Brotzu, Cagliari, Italy
| | - Jorge Hidalgo Godoy
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
- Institute of Medicine, Universidad Austral de Chile, Valdivia, Chile
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilians Universität Munich, Munich, Germany
| | - Giuseppe Remuzzi
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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17
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Garikapati K, Goh D, Khanna S, Echampati K. Uraemic Cardiomyopathy: A Review of Current Literature. CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2021; 15:1179546821998347. [PMID: 33707979 PMCID: PMC7907931 DOI: 10.1177/1179546821998347] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/03/2021] [Indexed: 12/18/2022]
Abstract
Uraemic Cardiomyopathy (UC) is recognised as an intricate and multifactorial disease which portends a significant burden in patients with End-Stage Renal Disease (ESRD). The cardiovascular morbidity and mortality associated with UC is significant and can be associated with the development of arrythmias, cardiac failure and sudden cardiac death (SCD). The pathophysiology of UC involves a complex interplay of traditional implicative factors such as haemodynamic overload and circulating uraemic toxins as well as our evolving understanding of the Chronic Kidney Disease-Mineral Bone Disease pathway. There is an instrumental role for multi-modality imaging in the diagnostic process; including transthoracic echocardiography and cardiac magnetic resonance imaging in identifying the hallmarks of left ventricular hypertrophy and myocardial fibrosis that characterise UC. The appropriate utilisation of the aforementioned diagnostics in the ESRD population may help guide therapeutic approaches, such as pharmacotherapy including beta-blockers and aldosterone-antagonists as well as haemodialysis and renal transplantation. Despite this, there remains limitations in effective therapeutic interventions for UC and ongoing research on a cellular level is vital in establishing further therapies.
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Affiliation(s)
- Kartheek Garikapati
- Department of Internal Medicine,
Toowoomba Hospital, Toowoomba, QLD, Australia
| | - Daniel Goh
- Department of Internal Medicine,
Toowoomba Hospital, Toowoomba, QLD, Australia
- University of New South Wales, Sydney,
NSW, Australia
| | - Shaun Khanna
- Department of Internal Medicine,
Toowoomba Hospital, Toowoomba, QLD, Australia
- University of New South Wales, Sydney,
NSW, Australia
| | - Krishna Echampati
- Department of Internal Medicine,
Toowoomba Hospital, Toowoomba, QLD, Australia
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18
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Lamprea-Montealegre JA, Shlipak MG, Estrella MM. Chronic kidney disease detection, staging and treatment in cardiovascular disease prevention. Heart 2021; 107:1282-1288. [PMID: 33568433 DOI: 10.1136/heartjnl-2020-318004] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 11/03/2022] Open
Abstract
Globally, nearly 10% of the population has chronic kidney disease (CKD), defined as a glomerular filtration rate less than 60 mL/min/1.73 m2 and/or a urinary albumin to creatinine ratio greater than 30 mg/g (3 mg/mmol). Persons with CKD have a substantially high risk of cardiovascular disease. Indeed, most persons with CKD are far more likely to develop a cardiovascular event than to progress to end-stage kidney disease. Although early detection and staging of CKD could help prevent its cardiovascular consequences, current rates of testing for CKD are very low, even among high-risk populations such as persons with diabetes, hypertension and cardiovascular disease. In this review, we first describe the need to test for both estimated glomerular filtration rate and albuminuria among persons at high risk of CKD in order to properly stage CKD and enhance cardiovascular risk stratification. We then discuss how detection and staging for CKD could help prioritise patients at high risk of atherosclerotic cardiovascular disease and heart failure who could derive the largest benefit from cardiovascular preventive interventions. In addition, we discuss the central role of CKD detection and staging in the initiation of cardiorenal preventive therapies, such as the sodium-glucose cotransporter 2 inhibitors, which have shown overwhelming evidence of cardiorenal protection. We conclude by discussing strategies to overcome historical barriers to CKD detection and treatment.
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Affiliation(s)
| | - Michael G Shlipak
- Division of General Internal Medicine and Kidney Health Research Collaborative, University of California, San Francisco, California, USA.,San Francisco VA Health Care System, San Francisco, California, USA
| | - Michelle M Estrella
- Division of Nephrology and Kidney Health Research Collaborative, University of California, San Francisco, California, USA.,San Francisco VA Healthcare System, San Francisco, California, USA
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19
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Kadesjö E, Roos A, Siddiqui AJ, Sartipy U, Holzmann MJ. Treatment With Cardiovascular Medications: Prognosis in Patients With Myocardial Injury. J Am Heart Assoc 2021; 10:e017239. [PMID: 33372527 PMCID: PMC7955454 DOI: 10.1161/jaha.120.017239] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/13/2020] [Indexed: 12/15/2022]
Abstract
Background There is no clinical guidance on treatment in patients with non-ischemic myocardial injury and type 2 myocardial infarction (T2MI). Methods and Results In a cohort of 22 589 patients in the emergency department at Karolinska University Hospital in Sweden during 2011 to 2014 we identified 3853 patients who were categorized into either type 1 myocardial infarction, T2MI, non-ischemic acute and chronic myocardial injury. Data from all dispensed prescriptions within 180 days of the visit to the emergency department were obtained concerning β-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, statins, and platelet inhibitors. We estimated adjusted hazard ratios (HR) with 95% CI for all-cause mortality in relationship to the number of medications (categorized into 0-1 [referent], 2-3 and 4 medications) in the groups of myocardial injury. In patients with T2MI, treatment with 2 to 3 and 4 medications was associated with a 50% and 56% lower mortality, respectively (adjusted HR [95% CI], 0.50 [0.25-1.01], and 0.43 [0.19-0.96]), while corresponding associations in patients with acute myocardial injury were 24% and 29%, respectively (adjusted HR [95% CI], 0.76 [0.59-0.99] and 0.71 [0.5-1.02]), and in patients with chronic myocardial injury 27% and 37%, respectively (adjusted HR [95% CI], 0.73 [0.58-0.92] and 0.63 [0.46-0.87]). Conclusions Patients with T2MI and non-ischemic acute or chronic myocardial injury are infrequently prescribed common cardiovascular medications compared with patients with type 1 myocardial infarction. However, treatment with guideline recommended drugs in patients with T2MI and acute or chronic myocardial injury is associated with a lower risk of death after adjustment for confounders.
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Affiliation(s)
- Erik Kadesjö
- Department of MedicineKarolinska InstitutetSolnaSweden
- Department of Emergency and Reparative MedicineKarolinska University HospitalHuddinge, StockholmSweden
| | - Andreas Roos
- Department of MedicineKarolinska InstitutetSolnaSweden
- Department of Emergency and Reparative MedicineKarolinska University HospitalHuddinge, StockholmSweden
| | - Anwar J. Siddiqui
- Department of MedicineKarolinska InstitutetSolnaSweden
- Department of Emergency and Reparative MedicineKarolinska University HospitalHuddinge, StockholmSweden
| | - Ulrik Sartipy
- Department of Cardiothoracic SurgeryKarolinska University HospitalStockholmSweden
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
| | - Martin J. Holzmann
- Department of MedicineKarolinska InstitutetSolnaSweden
- Department of Emergency and Reparative MedicineKarolinska University HospitalHuddinge, StockholmSweden
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20
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ACE Inhibitor Benefit to Kidney and Cardiovascular Outcomes for Patients with Non-Dialysis Chronic Kidney Disease Stages 3-5: A Network Meta-Analysis of Randomised Clinical Trials. Drugs 2020; 80:797-811. [PMID: 32333236 PMCID: PMC7242277 DOI: 10.1007/s40265-020-01290-3] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background The advantages of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in reducing risk of cardiovascular events (CVEs) and delaying end-stage kidney disease (ESKD) in patients with chronic kidney disease (CKD) is well-known. However, the efficacy and safety of these agents in non-dialysis CKD stages 3–5 patients are still a controversial issue. Methods Two investigators (Yaru Zhang and Dandan He) independently searched and identified relevant studies from MEDLINE (from 1950 to October 2018), EMBASE (from 1970 to October 2018), and the Cochrane Library database. Randomised clinical trials in non-dialysis CKD3–5 patients treated with renin-angiotensin system (RAS) inhibitors were included. We used standard criteria (Cochrane risk of bias tool) to assess the inherent risk of bias of trials. We calculated the odds ratio (OR) and 95% confidence interval (CI) for each outcome by random-effects model. A 2-sided p value < 0.05 was considered statistically significant, and all statistical analyses were performed using STATA, version 15.0. This network meta-analysis was undertaken by the frequency model. Results Forty-four randomised clinical trials with 42,319 patients were included in our network meta-analysis. ACEIs monotherapy significantly decreased the odds of kidney events (OR 0.54, 95% CI 0.41–0.73), cardiovascular events (OR 0.73, 95% CI 0.64–0.84), cardiovascular death (OR 0.73, 95% CI 0.63–0.86) and all-cause death (OR 0.77, 95% CI 0.66–0.91) when compared to placebo. According to the cumulative ranking area (SUCRA), ACEI monotherapy had the highest probabilities of their protective effects on outcomes of kidney events (SUCRA 93.3%), cardiovascular events (SUCRA 77.2%), cardiovascular death (SUCRA 86%), and all-cause death (SUCRA 94.1%), even if there were no significant differences between ACEIs and other antihypertensive drugs, including calcium channel blockers (CCBs), β-blockers and diuretics on above outcomes except for kidney events. ARB monotherapy and combination therapy of an ACEI plus an ARB showed no more advantage than CCBs, β-blockers and diuretics in all primary outcomes. In the subgroup of non-dialysis diabetic kidney disease patients, no drugs, including ACEIs or ARBs, significantly lowered the odds of cardiovascular events and all-cause death. However, ACEIs were still better than other antihypertensive drugs including ARBs in all-cause death but not ARBs in cardiovascular events according to the SUCRA. Only ARBs had significant differences in preventing the occurrence of kidney events compared with placebo (OR 0.82, 95% CI 0.72–0.95). Both ACEI/ARB monotherapy and combination therapy had higher odds of hyperkalaemia. ACEIs had 3.81 times higher odds than CCBs (95% CI 1.58–9.20), ARBs had 2.08–5.10 times higher odds than placebo and CCBs and combination therapy of an ACEI and an ARB had 4.80–24.5 times higher odds than all other treatments. Compared with placebo, CCBs and β blockers, ACEI therapy significantly increased the odds of cough (OR 2.90, 95% CI 1.76–4.77; OR 8.21, 95% CI 3.13–21.54 and OR 1.80, 95% CI 1.08–3.00). There were no statistical differences in hypotension among all comparisons except ACEIs versus placebo. Conclusions Although ACEIs increased the odds of hyperkalaemia, cough and hypotension, they were still superior to ARBs and other antihypertensive drugs and had the highest benefits for the prevention of kidney events, cardiovascular outcomes, cardiovascular death and all-cause mortality in non-dialysis CKD3–5 patients. In patients with advanced diabetic kidney disease, ACEIs were superior to ARBs in lowering risk of all-cause death but not in kidney events and cardiovascular events. Electronic supplementary material The online version of this article (10.1007/s40265-020-01290-3) contains supplementary material, which is available to authorized users.
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21
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Baruah VJ, Paul R, Gogoi D, Mazumder N, Chakraborty S, Das A, Mondal TK, Sarmah B. Integrated computational approach toward discovery of multi-targeted natural products from Thumbai ( Leucas aspera) for attuning NKT cells. J Biomol Struct Dyn 2020; 40:2893-2907. [PMID: 33179569 DOI: 10.1080/07391102.2020.1844056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
A multi-omics-based approach targeting the plant-based natural products from Thumbai (Leucas aspera), an important yet untapped potential source of many therapeutic agents for myriads of immunological conditions and genetic disorders, was conceptualized to reconnoiter its potential biomedical application. A library of 79 compounds from this plant was created, out of which 9 compounds qualified the pharmacokinetics parameters. Reverse pharmacophore technique for target fishing of the screened compounds was executed through which renin receptor (ATP6AP2) and thymidylate kinase (DTYMK) were identified as potential targets. Network biology approaches were used to comprehend and validate the functional, biochemical and clinical relevance of the targets. The target-ligand interaction and subsequent stability parameters at molecular scale were investigated using multiple strategies including molecular modeling, pharmacophore approaches and molecular dynamics simulation. Herein, isololiolide and 4-hydroxy-2-methoxycinnamaldehyde were substantiated as the lead molecules exhibiting comparatively the best binding affinity against the two putative protein targets. These natural lead products from L. aspera and the combinatorial effects may have plausible medical applications in a wide variety of neurodegenerative, genetic and developmental disorders. The lead molecules also exhibit promising alternative in diagnostics and therapeutics through immuno-modulation targeting natural killer T-cell function in transplantation-related pathogenesis, autoimmune and other immunological disorders.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Vishwa Jyoti Baruah
- Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam, India
| | - Rasana Paul
- Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam, India
| | - Dhrubajyoti Gogoi
- Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam, India
| | - Nirmal Mazumder
- Department of Biophysics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | | | - Aparoopa Das
- Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam, India
| | - Tapan Kumar Mondal
- ICAR-National Institute for Plant Biotechnology, LBS Centre, IARI Campus, New Delhi, India
| | - Bhaswati Sarmah
- Department of Plant Breeding and Genetics, Assam Agricultural University, Jorhat, Assam, India
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22
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Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A. Incretin-based therapies and renin-angiotensin system: Looking for new therapeutic potentials in the diabetic milieu. Life Sci 2020; 256:117916. [PMID: 32534034 DOI: 10.1016/j.lfs.2020.117916] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 05/27/2020] [Accepted: 06/04/2020] [Indexed: 02/08/2023]
Abstract
Incretin-based therapies include pharmacologic agents such as glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors which exert potent anti-hyperglycemic effects in the diabetic milieu. They are also shown to have extra-pancreatic effects. Renin-angiotensin system is part of the endocrine system which is widely distributed in the body and is closely involved in water and electrolyte homeostasis as well as renal and cardiovascular functions. Hence the renin-angiotensin system is the main target for treating patients with various renal and cardiovascular disorders. There is growing evidence that incretins have modulatory effects on renin-angiotensin system activity; thereby, can be promising therapeutic agents for the management of renal and cardiovascular disorders. But the exact molecular interactions between incretins and renin-angiotensin system are not clearly understood. In this current study, we have reviewed the possible molecular mechanisms by which incretins modulate renin-angiotensin system activity.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Mina Maleki
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull
| | - Tannaz Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran.
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23
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Caravaca-Fontán F, Valladares J, Díaz-Campillejo R, Barroso S, Luna E, Caravaca F. Efecto negativo del bloqueo del sistema renina-angiotensina sobre la progresión de la enfermedad renal crónica avanzada: ¿una cuestión de ajuste de dosis? Nefrologia 2020; 40:38-45. [DOI: 10.1016/j.nefro.2019.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 11/10/2018] [Accepted: 02/24/2019] [Indexed: 10/26/2022] Open
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24
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Abstract
The term uraemic cardiomyopathy refers to the cardiac abnormalities that are seen in patients with chronic kidney disease (CKD). Historically, this term was used to describe a severe cardiomyopathy that was associated with end-stage renal disease and characterized by severe functional abnormalities that could be reversed following renal transplantation. In a modern context, uraemic cardiomyopathy describes the clinical phenotype of cardiac disease that accompanies CKD and is perhaps best characterized as diastolic dysfunction seen in conjunction with left ventricular hypertrophy and fibrosis. A multitude of factors may contribute to the pathogenesis of uraemic cardiomyopathy, and current treatments only modestly improve outcomes. In this Review, we focus on evolving concepts regarding the roles of fibroblast growth factor 23 (FGF23), inflammation and systemic oxidant stress and their interactions with more established mechanisms such as pressure and volume overload resulting from hypertension and anaemia, respectively, activation of the renin-angiotensin and sympathetic nervous systems, activation of the transforming growth factor-β (TGFβ) pathway, abnormal mineral metabolism and increased levels of endogenous cardiotonic steroids.
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Affiliation(s)
- Xiaoliang Wang
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Joseph I Shapiro
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.
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25
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Aiumtrakul N, Euswas K, Phichedwanichskul K, Rangsin R, Kaewput W, Satirapoj B. Cardiovascular and Renal Outcomes in an Excellent Chronic Kidney Disease Clinic Compared with an Outpatient Clinic in a Primary Care Setting: A Retrospective Cohort Study. KIDNEY DISEASES (BASEL, SWITZERLAND) 2019; 5:144-152. [PMID: 31259176 PMCID: PMC6587207 DOI: 10.1159/000495464] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 11/15/2018] [Indexed: 11/19/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. In standard care, the physician attempts to control all known risk factors, but treatment goals are achieved with difficulty. Assistance by a multidisciplinary care team may improve outcomes. OBJECTIVE To compare the cardiovascular and renal endpoints between patients with CKD receiving care from excellent CKD and outpatient clinics. METHODS A retrospective cohort study was conducted in a primary care setting in Thailand. Patients with CKD stages 3 and 4 in excellent CKD (n = 96) and outpatient clinics (n = 192) were matched in a 1: 2 ratio with the propensity score. We collected data from electronic medical records concerning the incidences of primary composite outcomes including rapid renal progression, end-stage renal disease, myocardial infarction, congestive heart failure, stroke, and mortality. Multidisciplinary team care in the excellent CKD clinic consisted of physician, nurse, pharmacist, dietitian, physical therapist, and applied Thai traditional physician. The outpatient clinic consisted of physician care only. RESULTS Subjects' mean age was 64.54 ± 10.96 years, and 52.1% were female. During an average 49.63 ± 8.36 months of follow-up, 74 events occurred including 35 (47.30%) patients who experienced renal events, 29 (39.19%) who experienced cardiovascular events, and 10 (13.51%) who experienced loss of life. The Kaplan-Meier curve indicated a higher percentage of subjects without primary composite outcomes in the excellent CKD clinic than those in the outpatient clinic (66.85%; 95% CI 0.48-0.80 vs. 44.71%; 95% CI 0.29-0.60; p = 0.005). From multivariate analysis, the excellent CKD clinic group had a 64% lower risk for primary composite outcomes compared with those in the outpatient clinic (adjusted HR 0.36; 95% CI 0.18-0.74; p = 0.005). CONCLUSION A multidisciplinary care system can reduce composition outcomes including cardiovascular and renal outcomes for the growing CKD population. The optimal outcomes arise from the medical personnel's teamwork, not from one physician alone.
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Affiliation(s)
- Noppawit Aiumtrakul
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
| | - Krischon Euswas
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
| | - Kitinan Phichedwanichskul
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
| | - Ram Rangsin
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
| | - Wisit Kaewput
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
| | - Bancha Satirapoj
- Department of Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
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26
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Cardiovascular Screening and Early Detection of Heart Disease in Adults With Chronic Kidney Disease. J Nurse Pract 2019. [DOI: 10.1016/j.nurpra.2018.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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27
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Brar S, Ye F, James MT, Hemmelgarn B, Klarenbach S, Pannu N. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury. JAMA Intern Med 2018; 178:1681-1690. [PMID: 30422153 PMCID: PMC6583606 DOI: 10.1001/jamainternmed.2018.4749] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
IMPORTANCE Patients with acute kidney injury (AKI) are at an increased long-term risk of death. Effective strategies that improve long-term outcomes in patients with AKI are unknown. OBJECTIVE To evaluate whether the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) after hospital discharge is associated with better outcomes in patients with AKI. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used data from the Alberta Kidney Disease Network population database to evaluate 46 253 adults 18 years or older with an episode of AKI during a hospitalization between July 1, 2008, and March 31, 2015, in Alberta, Canada. All patients who survived to hospital discharge were followed up for a minimum of 2 years. EXPOSURES Use of an ACEI or ARB within 6 months after hospital discharge. MAIN OUTCOMES AND MEASURES The primary outcome was mortality; secondary outcomes included hospitalization for a renal cause, end-stage renal disease (ESRD), and a composite outcome of ESRD or sustained doubling of serum creatinine concentration. An AKI was defined as a 50% increase between prehospital and peak in-hospital serum creatinine concentrations. Propensity scores were used to construct a matched-pairs cohort of patients who did and did not have a prescription for an ACEI or ARB within 6 months after hospital discharge. RESULTS The study evaluated 46 253 adults (mean [SD] age, 68.6 [16.4] years; 24 436 [52.8%] male). Within 6 months of discharge, 22 193 (48.0%) of the participants were prescribed an ACEI or ARB. After adjustment for comorbidities, ACEI or ARB use before admission, demographics, baseline kidney function, other factors related to index hospitalization, and prior health care services, ACEI or ARB use was associated with lower mortality in patients with AKI after 2 years (adjusted hazard ratio, 0.85; 95% CI, 0.81-0.89). However, patients who received an ACEI or ARB had a higher risk of hospitalization for a renal cause (adjusted hazard ratio, 1.28; 95% CI, 1.12-1.46). No association was found between ACEI or ARB use and progression to ESRD. CONCLUSIONS AND RELEVANCE Among patients with AKI, ACEI or ARB therapy appeared to be associated with lower mortality but a higher risk of hospitalization for a renal cause. These results suggest a potential benefit of ACEI or ARB use after AKI, but cautious monitoring for renal-specific complications may be warranted.
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Affiliation(s)
- Sandeep Brar
- Department of Nephrology, University of Toronto, Toronto, Ontario, Canada
| | - Feng Ye
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Matthew T James
- Department of Medicine, Division of Nephrology, University of Calgary, Calgary, Alberta, Canada.,Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Brenda Hemmelgarn
- Department of Medicine, Division of Nephrology, University of Calgary, Calgary, Alberta, Canada.,Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Scott Klarenbach
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Institute of Health Economics, Edmonton, Alberta, Canada
| | - Neesh Pannu
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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28
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Brar S, Ye F, James MT, Hemmelgarn B, Klarenbach S, Pannu N. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury. JAMA Intern Med 2018. [PMID: 30422153 DOI: 10.1001/jamainternmed_2018.4749] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
IMPORTANCE Patients with acute kidney injury (AKI) are at an increased long-term risk of death. Effective strategies that improve long-term outcomes in patients with AKI are unknown. OBJECTIVE To evaluate whether the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) after hospital discharge is associated with better outcomes in patients with AKI. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used data from the Alberta Kidney Disease Network population database to evaluate 46 253 adults 18 years or older with an episode of AKI during a hospitalization between July 1, 2008, and March 31, 2015, in Alberta, Canada. All patients who survived to hospital discharge were followed up for a minimum of 2 years. EXPOSURES Use of an ACEI or ARB within 6 months after hospital discharge. MAIN OUTCOMES AND MEASURES The primary outcome was mortality; secondary outcomes included hospitalization for a renal cause, end-stage renal disease (ESRD), and a composite outcome of ESRD or sustained doubling of serum creatinine concentration. An AKI was defined as a 50% increase between prehospital and peak in-hospital serum creatinine concentrations. Propensity scores were used to construct a matched-pairs cohort of patients who did and did not have a prescription for an ACEI or ARB within 6 months after hospital discharge. RESULTS The study evaluated 46 253 adults (mean [SD] age, 68.6 [16.4] years; 24 436 [52.8%] male). Within 6 months of discharge, 22 193 (48.0%) of the participants were prescribed an ACEI or ARB. After adjustment for comorbidities, ACEI or ARB use before admission, demographics, baseline kidney function, other factors related to index hospitalization, and prior health care services, ACEI or ARB use was associated with lower mortality in patients with AKI after 2 years (adjusted hazard ratio, 0.85; 95% CI, 0.81-0.89). However, patients who received an ACEI or ARB had a higher risk of hospitalization for a renal cause (adjusted hazard ratio, 1.28; 95% CI, 1.12-1.46). No association was found between ACEI or ARB use and progression to ESRD. CONCLUSIONS AND RELEVANCE Among patients with AKI, ACEI or ARB therapy appeared to be associated with lower mortality but a higher risk of hospitalization for a renal cause. These results suggest a potential benefit of ACEI or ARB use after AKI, but cautious monitoring for renal-specific complications may be warranted.
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Affiliation(s)
- Sandeep Brar
- Department of Nephrology, University of Toronto, Toronto, Ontario, Canada
| | - Feng Ye
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Matthew T James
- Department of Medicine, Division of Nephrology, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Brenda Hemmelgarn
- Department of Medicine, Division of Nephrology, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Scott Klarenbach
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
- Institute of Health Economics, Edmonton, Alberta, Canada
| | - Neesh Pannu
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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29
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Garlo KG, Bates DW, Seger DL, Fiskio JM, Charytan DM. Association of Changes in Creatinine and Potassium Levels After Initiation of Renin Angiotensin Aldosterone System Inhibitors With Emergency Department Visits, Hospitalizations, and Mortality in Individuals With Chronic Kidney Disease. JAMA Netw Open 2018; 1:e183874. [PMID: 30646338 PMCID: PMC6324397 DOI: 10.1001/jamanetworkopen.2018.3874] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
IMPORTANCE Renin angiotensin aldosterone system inhibitors (RAASIs) benefit individuals with chronic kidney disease (CKD). Elevations in serum creatinine and potassium levels are common reasons for discontinuation of this therapy, but their incidence and risks are not well characterized in community practice. OBJECTIVE To evaluate associations of increased creatinine levels, hyperkalemia, and therapy continuation with the risk of emergency department (ED) visits, hospitalizations, and mortality within 1 year after RAASI therapy initiation in individuals with CKD. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study included 4661 individuals with nondialysis CKD newly prescribed a RAASI or a diuretic who were treated at 36 outpatient primary care offices affiliated with Brigham & Women's Hospital and Massachusetts General Hospital, Boston, from January 1, 2009, through December 31, 2011. Individuals receiving a new prescription for a diuretic were used to provide context. All participants had a baseline measure of renal function and at least 1 follow-up measurement of creatinine and potassium levels within 90 days of the prescription. Data were analyzed from January 1, 2009, through December 31, 2012. EXPOSURES Changes in creatinine and potassium levels within 90 days after the prescription date and therapy discontinuation. MAIN OUTCOMES AND MEASURES Emergency department visits, hospitalizations, and mortality within 1 year. RESULTS A total of 4661 individuals were included in the analysis (2506 [53.8%] women; mean [SD] age, 71 [14]; 3931 [84.3%] white; and 4198 [90.1%] with CKD stage 3). Of these, 2354 individuals (50.5%) received RAASIs and 2307 (49.5%) received diuretics. Creatinine level increase of at least 30% after RAASI therapy initiation was found in 158 of 2354 individuals (6.7%); hyperkalemia of greater than 5.0 mEq/L, in 251 of 2354 (10.7%). Increases in creatinine level of at least 30% (unadjusted odds ratio [OR], 1.40; 95% CI, 0.89-2.21), hyperkalemia (unadjusted OR, 1.15; 95% CI, 0.64-2.06), and therapy discontinuation (unadjusted OR, 1.01; 95% CI, 0.71-1.46) were not associated with ED visits or hospitalizations, which was consistent with results from competing risk analyses. Initial increases in creatinine level of at least 30% were associated with mortality in the total cohort (adjusted OR [aOR], 2.17; 95% CI, 1.45-3.25). However, the effect was only independent for diuretics (aOR, 2.27; 95% CI, 1.41-3.66) and not for RAASIs (aOR, 1.82; 95% CI, 0.83-3.99). CONCLUSIONS AND RELEVANCE Acute creatinine and potassium level disturbances after initiation of RAASI therapy in individuals with CKD appear to be sustained often often not sustained and not associated with ED visits or hospitalizations, despite therapy continuation. Findings from this study suggest that increases in creatinine level were independently associated with mortality among individuals prescribed diuretics but not RAASIs. Structured laboratory monitoring during RAASI therapy initiation may guide appropriate continuation of therapy in the outpatient setting.
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Affiliation(s)
- Katherine G. Garlo
- Department of Medicine, Renal Division, Brigham & Women’s Hospital, Boston, Massachusetts
| | - David W. Bates
- The Center for Patient Safety Research and Practice, Division of General Internal Medicine and Primary Care, Brigham & Women’s Hospital, Boston, Massachusetts
- Clinical and Quality Analysis, Partners HealthCare, Somerville, Massachusetts
| | - Diane L. Seger
- The Center for Patient Safety Research and Practice, Division of General Internal Medicine and Primary Care, Brigham & Women’s Hospital, Boston, Massachusetts
- Clinical and Quality Analysis, Partners HealthCare, Somerville, Massachusetts
| | - Julie M. Fiskio
- The Center for Patient Safety Research and Practice, Division of General Internal Medicine and Primary Care, Brigham & Women’s Hospital, Boston, Massachusetts
- Clinical and Quality Analysis, Partners HealthCare, Somerville, Massachusetts
| | - David M. Charytan
- Department of Medicine, Renal Division, Brigham & Women’s Hospital, Boston, Massachusetts
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Omboni S, Borghi C. Efficacy of Zofenopril Alone or in Combination with Hydrochlorothiazide in Patients with Kidney Dysfunction. ACTA ACUST UNITED AC 2018; 14:5-15. [PMID: 30360726 DOI: 10.2174/1574884713666181025145404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/24/2018] [Accepted: 10/19/2018] [Indexed: 11/22/2022]
Abstract
Hypertension and kidney disease often coexist, further increasing the risk of future cardiovascular events. Treatment of hypertensive adults with an angiotensin converting enzyme inhibitor in case of concomitant kidney disease may slow disease progression. The third-generation liphophilic angiotensin converting enzyme inhibitor zofenopril, administered alone or combined with a thiazide diuretic, has proved to be effective in lowering blood pressure in hypertensive patients and to reduce the risk of fatal and non-fatal events in post-acute myocardial infarction and heart failure. In almost three-hundred hypertensive patients with kidney impairment zofenopril administered for 12 weeks showed a similar blood pressure-lowering effect irrespective of the stage of the disease, with larger effects in combination with a thiazide diuretic, particularly in patients with slightly or moderately impaired kidney function. In animal models, zofenopril produced a significant and long-lasting inhibition of kidney angiotensin converting enzyme inhibitor and prevented kidney morphological and functional alterations following kidney ischemia-reperfusion injury. Treatment of hypertensive patients for 18 weeks with a combination of zofenopril 30 mg and hydrochlorothiazide 12.5 mg resulted in a reduction in albumin creatinine ratio of 8.4 mg/g (49.6% reduction from baseline values) and no changes in glomerular filtration rate, variations in line with those obtained in the control group treated with a combination of irbesartan 150 mg and hydrochlorothiazide 12.5 mg. Thus, some preliminary evidence exists to support that relatively long-term treatment with the angiotensin converting enzyme inhibitor zofenopril alone or combined with hydrochlorothiazide is effective in controlling blood pressure and may confer some kidney protection due to ACE inhibition properties.
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Affiliation(s)
- Stefano Omboni
- Clinical Research Unit, Italian Institute of Telemedicine, Varese, Italy.,Scientific Research Department of Cardiology, Science and Technology Park for Biomedicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Claudio Borghi
- Unit of Internal Medicine, Policlinico S. Orsola, University of Bologna, Bologna, Italy
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Weir MR, Lakkis JI, Jaar B, Rocco MV, Choi MJ, Kramer HJ, Ku E. Use of Renin-Angiotensin System Blockade in Advanced CKD: An NKF-KDOQI Controversies Report. Am J Kidney Dis 2018; 72:873-884. [PMID: 30201547 DOI: 10.1053/j.ajkd.2018.06.010] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 06/08/2018] [Indexed: 12/21/2022]
Abstract
Multiple clinical trials have demonstrated that renin-angiotensin system (RAS) blockade with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers effectively reduces chronic kidney disease (CKD) progression. However, most clinical trials excluded participants with advanced CKD (ie, estimated glomerular filtration rate [eGFR]<30mL/min/1.73m2). It is acknowledged that initiation of RAS blockade is often associated with an acute reduction in eGFR, which is thought to be functional, but may result in long-term preservation of kidney function through the reductions in glomerular intracapillary pressure conferred by these agents. In this National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) report, we discuss the controversies regarding use of RAS blockade in patients with advanced kidney disease. We review available published data on this topic and provide perspective on the impact of RAS blockade on changes in eGFRs and potassium levels. We conclude that more research is needed to evaluate the therapeutic index of RAS blockade in patients with advanced CKD.
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Affiliation(s)
- Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland, School of Medicine, Baltimore, MD.
| | - Jay I Lakkis
- University of Hawaii John A. Burns School of Medicine, Honolulu, HI
| | - Bernard Jaar
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michael V Rocco
- Division of Nephrology, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC
| | - Michael J Choi
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Holly J Kramer
- Division of Nephrology and Hypertension, Department of Public Health Sciences and Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Elaine Ku
- Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA
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Kloner RA, Gross C, Yuan J, Conrad A, Pergola PE. Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors. J Cardiovasc Pharmacol Ther 2018; 23:524-531. [PMID: 30103622 PMCID: PMC6193203 DOI: 10.1177/1074248418788334] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Introduction: Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin–angiotensin–aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. Methods: Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. Results: Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was −0.67 (0.08) mEq/L in patients taking RAASi and −0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. Conclusions: Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.
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Affiliation(s)
- Robert A Kloner
- 1 Huntington Medical Research Institutes, Pasadena, CA, USA.,2 Division of Cardiovascular Medicine, Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
| | - Coleman Gross
- 3 Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, CA, USA
| | - Jinwei Yuan
- 3 Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, CA, USA
| | - Ansgar Conrad
- 3 Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, CA, USA
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Karaboyas A, Xu H, Morgenstern H, Locatelli F, Jadoul M, Nitta K, Dasgupta I, Tentori F, Port FK, Robinson BM. DOPPS data suggest a possible survival benefit of renin angiotensin-aldosterone system inhibitors and other antihypertensive medications for hemodialysis patients. Kidney Int 2018; 94:589-598. [PMID: 29908836 DOI: 10.1016/j.kint.2018.03.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 02/28/2018] [Accepted: 03/15/2018] [Indexed: 11/25/2022]
Abstract
The benefits of renin angiotensin-aldosterone system inhibitors (RAASi) are well-established in the general population, particularly among those with diabetes, congestive heart failure (CHF), or coronary artery disease (CAD). However, conflicting evidence from trials and concerns about hyperkalemia limit RAASi use in hemodialysis patients, relative to other antihypertensive agents, including beta blockers and calcium channel blockers. Therefore, we investigated prescription patterns and associations with mortality for RAASi and other antihypertensive agents using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS). Cox regression was used to estimate the effect of the prescription of RAASi and other antihypertensive agents at study entry on mortality in 11,421 incident (120 days or less) hemodialysis and 37,124 prevalent (over 120 days) hemodialysis patients from DOPPS phases 2-5 (2002-2015). Over 95% of RAASi were angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. RAASi prevalence was 39% and varied minimally by CHF and CAD. The adjusted hazard ratio for RAASi (vs. no RAASi) was 0.89 (95% confidence interval 0.80-0.99) among incident and 0.94 (0.90-0.99) among prevalent hemodialysis patients, with no convincing evidence of interaction with diabetes, CAD or CHF. Inverse associations with mortality were also observed for beta blockers and calcium channel blockers, and were stronger for angiotensin receptor blockers than angiotensin-converting enzyme inhibitors, but this latter finding requires further study. Thus, our observations suggest a relatively small survival benefit of RAASi and other antihypertensive agents in hemodialysis patients, though randomized prospective studies are needed to potentially change prescribing criteria.
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Affiliation(s)
- Angelo Karaboyas
- Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA.
| | - Hairong Xu
- Global Medical Affairs, AstraZeneca, Gaithersburg, Maryland, USA
| | - Hal Morgenstern
- Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA; University of Michigan, Departments of Epidemiology and Environmental Health Sciences, School of Public Health, and Department of Urology, Medical School, Ann Arbor, Michigan, USA
| | | | - Michel Jadoul
- Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Kosaku Nitta
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | | | | | - Friedrich K Port
- University of Michigan, Department of Internal Medicine, Ann Arbor, Michigan, USA
| | - Bruce M Robinson
- Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA; University of Michigan, Department of Internal Medicine, Ann Arbor, Michigan, USA
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Vejakama P, Ingsathit A, McKay GJ, Maxwell AP, McEvoy M, Attia J, Thakkinstian A. Treatment effects of renin-angiotensin aldosterone system blockade on kidney failure and mortality in chronic kidney disease patients. BMC Nephrol 2017; 18:342. [PMID: 29187194 PMCID: PMC5706339 DOI: 10.1186/s12882-017-0753-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 11/14/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a leading cause of death before and after onset of end-stage renal disease (ESRD). Knowing treatments that can delay disease progression will lead to reduced mortality. We therefore aimed to estimate the effectiveness of renin angiotensin aldosterone system (RAAS) blockade on CKD progression. METHODS We conducted a retrospective CKD cohort at Ubon Ratchathani province, Thailand from 1997 to 2011. ESRD was defined as estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m2, dialysis, or kidney transplantation. All-cause mortality was verified until December 31, 2011. A counterfactual-framework was applied to estimate the effectiveness of RAAS blockade on outcomes, i.e., ESRD, death before and after ESRD. RAAS blockade was categorized according to duration of use <0.25 year, 0.25-1 year (RAAS1), and >1 year (RAAS2). An augmented inverse-probability weighting (AIPW) method was used to estimate potential-outcome mean (POM) and average treatment-effect (ATE). Multi-logit and Poisson regressions were used for treatment and outcome models, respectively. Analyses were stratified by ESRD, death before/after ESRD for diabetic and non-diabetic groups. STATA 14.0 was used for statistical analyses. RESULTS Among 15,032 diabetic patients, 2346 (15.6%), 2351 (18.5%), and 1607 (68.5%) developed ESRD, died before ESRD, and died after ESRD, respectively. Only RAAS2 effect was significant on ESRD, death before and after ESRD. The ESRD rates were 12.9%, versus 20.0% for RAAS2 and non-RAAS, respectively, resulted in significant risk differences (RD) of -7.2% (95% CI: -8.8%, -5.5%), and a numbers needed-to-treat (NNT) of 14. Death rates before ESRD for these corresponding groups were 14.4% (12.9%, 15.9%) and 19.6% (18.7%, 20.4%) with a NNT of 19. Death rates after ESRD in RAAS2 was lower than non-RASS group (i.e., 62.8% (55.5%, 68.9%) versus 68.1% (65.9%, 70.4%)) but this was not significant. RAAS2 effects on ESRD and death before ESRD were persistently significant in non-diabetic patients (n = 17,074) but not for death after ESRD with the NNT of about 15 and 16 respectively. CONCLUSIONS Receiving RAAS blockade for 1 year or longer could prevent both CKD progression to ESRD and premature mortality.
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Affiliation(s)
- Phisitt Vejakama
- Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Department of Medicine, Sunpasitthiprasong Hospital, Province, Ubon Ratchathani, Thailand
| | - Atiporn Ingsathit
- Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Gareth J. McKay
- Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland
| | | | - Mark McEvoy
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, Faculty of Health and Medicine, University of New Castle, NSW, Australia
| | - John Attia
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, Faculty of Health and Medicine, University of New Castle, NSW, Australia
| | - Ammarin Thakkinstian
- Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Abstract
PURPOSE OF REVIEW African Americans are over-burdened with hypertension resulting in excess morbidity and mortality. We highlight the health impact of hypertension in this population, review important observations regarding disease pathogenesis, and outline evidence-based treatment, current treatment guidelines, and management approaches. RECENT FINDINGS Hypertension accounts for 50% of the racial differences in mortality between Blacks and Whites in the USA. Genome-wide association studies have not clearly identified distinct genetic causes for the excess burden in this population as yet. Pathophysiology is complex likely involving interaction of genetic, biological, and social factors prevalent among African Americans. Non-pharmacologic and pharmacologic therapy is required and specific treatment guidelines for this population are varied. Combination therapy is most often necessary and single-pill formulations are most successful in achieving BP targets. Racial health disparities related to hypertension in African Americans are a serious public health concern that warrants greater attention. Multi-disciplinary research to understand the inter-relationship between biological and social factors is needed to guide successful treatments. Comprehensive care strategies are required to successfully address and eliminate the hypertension burden.
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Affiliation(s)
- Nomsa Musemwa
- Department of Medicine, Division of Nephrology, Hypertension and Kidney Transplantation, Temple University School of Medicine, Kresge West, Suite 100, 3440 North Broad Street, Philadelphia, PA, 19140, USA
| | - Crystal A Gadegbeku
- Department of Medicine, Division of Nephrology, Hypertension and Kidney Transplantation, Temple University School of Medicine, Kresge West, Suite 100, 3440 North Broad Street, Philadelphia, PA, 19140, USA.
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Pergola PE, Spiegel DM, Warren S, Yuan J, Weir MR. Patiromer Lowers Serum Potassium When Taken without Food: Comparison to Dosing with Food from an Open-Label, Randomized, Parallel Group Hyperkalemia Study. Am J Nephrol 2017; 46:323-332. [PMID: 29017162 PMCID: PMC5804834 DOI: 10.1159/000481270] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 08/30/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Patiromer is a sodium-free, nonabsorbed, potassium binder approved for treatment of hyperkalemia. This open-label study compares the efficacy and safety of patiromer administered without food versus with food. METHODS Adults with hyperkalemia (potassium ≥5.0 mEq/L) were randomized (1:1) to receive patiromer once daily without food or with food for 4 weeks. The dosage was adjusted (maximum: 25.2 g/day) using a prespecified titration schedule to achieve and maintain potassium within a target range (3.8-5.0 mEq/L). The primary efficacy endpoint was the proportion of patients with serum potassium in the target range at either week 3 or week 4. Safety was assessed by adverse events (AEs) and laboratory testing. RESULTS Efficacy was evaluated in 112 patients; 65.2% were ≥65 years of age, 75.9% had chronic kidney disease, and 82.1% had diabetes. Baseline mean serum potassium was similar in the without-food (5.44 mEq/L) and with-food (5.34 mEq/L) groups. The primary endpoint was achieved by 87.3% (95% CI 75.5-94.7) and 82.5% (95% CI 70.1-91.3) of patients in the with-food and without-food groups, respectively; least squares mean changes in serum potassium from baseline to week 4 were -0.65 and -0.62 mEq/L, respectively (p < 0.0001). The most common AEs were diarrhea and constipation. Serum K+ remained ≥3.5 mEq/L in all patients; 5 patients developed serum magnesium <1.4 mg/dL, including 4 whose baseline magnesium was below the lower limit of normal. CONCLUSION Patiromer is equally effective and well tolerated when taken without food or with food, thereby offering the potential for dosing flexibility.
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Affiliation(s)
| | - David M. Spiegel
- Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, California, USA
| | - Suzette Warren
- Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, California, USA
| | - Jinwei Yuan
- Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, California, USA
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Acute kidney injury is a risk factor for subsequent proteinuria. Kidney Int 2017; 93:460-469. [PMID: 28927644 DOI: 10.1016/j.kint.2017.07.007] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 06/20/2017] [Accepted: 07/13/2017] [Indexed: 12/31/2022]
Abstract
Acute kidney injury (AKI) is associated with subsequent chronic kidney disease (CKD), but the mechanism is unclear. To clarify this, we examined the association of AKI and new-onset or worsening proteinuria during the 12 months following hospitalization in a national retrospective cohort of United States Veterans hospitalized between 2004-2012. Patients with and without AKI were matched using baseline demographics, comorbidities, proteinuria, estimated glomerular filtration rate, blood pressure, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ACEI/ARB) use, and inpatient exposures linked to AKI. The distribution of proteinuria over one year post-discharge in the matched cohort was compared using inverse probability sampling weights. Subgroup analyses were based on diabetes, pre-admission ACEI/ARB use, and AKI severity. Among the 90,614 matched AKI and non-AKI pairs, the median estimated glomerular filtration rate was 62 mL/min/1.73m2. The prevalence of diabetes and hypertension were 48% and 78%, respectively. The odds of having one plus or greater dipstick proteinuria was significantly higher during each month of follow-up in patients with AKI than in patients without AKI (odds ratio range 1.20-1.39). Odds were higher in patients with Stage II or III AKI (odds ratios 1.32-1.81) than in Stage I AKI (odds ratios 1.18-1.32), using non-AKI as the reference group. Results were consistent regardless of diabetes status or baseline ACEI/ARB use. Thus, AKI is a risk factor for incident or worsening proteinuria, suggesting a possible mechanism linking AKI and future CKD. The type of proteinuria, physiology, and clinical significance warrant further study as a potentially modifiable risk factor in the pathway from AKI to CKD.
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Logan IR, Tomson C. Managing hypertension in patients with chronic kidney disease. Br J Hosp Med (Lond) 2016; 77:639-644. [PMID: 27828756 DOI: 10.12968/hmed.2016.77.11.639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hypertension is a common clinical problem in patients with chronic kidney disease. This article should equip the non-specialty doctor with the general principles pertaining to the investigation and treatment of hypertension in these patients. It also offers a guide to situations that warrant specialty referral.
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Affiliation(s)
- I R Logan
- Clinical Lecturer and Specialty Registrar in Nephrology, Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH
| | - Crv Tomson
- Consultant Nephrologist in the Urology and Renal Services, Freeman Hospital, Newcastle upon Tyne
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Tyagi S, Perera S, Clarkson BD, Tadic SD, Resnick NM. Nocturnal Polyuria in Older Women with Urge Urinary Incontinence: Role of Sleep Quality, Time in Bed and Medications Used. J Urol 2016; 197:753-758. [PMID: 27678299 DOI: 10.1016/j.juro.2016.09.080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2016] [Indexed: 02/05/2023]
Abstract
PURPOSE Nocturia is common and bothersome in older adults, especially those who are also incontinent. Since nocturnal polyuria is a major contributor, we examined factors associated with nocturnal polyuria in this population to identify those possibly amenable to intervention. MATERIALS AND METHODS We analyzed baseline data from 2 previously completed studies of urge urinary incontinence. The studies involved 284 women (mean age ± SD 72.9 ± 7.9 years) who also completed 3-day voiding diaries. Participants with a nocturnal polyuria index greater than 33% were categorized as having nocturnal polyuria (nocturnal polyuria index = nocturnal urinary volume per 24-hour urine volume). Associations between nocturnal polyuria and various demographic, clinical and sleep related parameters were determined. RESULTS Overall 55% of the participants had nocturnal polyuria. Multivariable regression analysis revealed that age, body mass index, use of angiotensin converting enzyme inhibitor/angiotensin receptor blocker, time spent in bed and duration of first uninterrupted sleep were independent correlates of nocturnal polyuria. Participants with a larger nocturnal excretion reported a shorter duration of uninterrupted sleep before first awakening to void and worse sleep quality despite spending similar time in bed. CONCLUSIONS Body mass index, use of angiotensin converting enzyme inhibitor/angiotensin receptor blockers, time in bed and duration of uninterrupted sleep before first awakening to void are independently associated with nocturnal polyuria in older women with urge urinary incontinence, and are potentially modifiable. These findings also confirm the association between sleep and nocturnal polyuria. Further studies should explore whether interventions to reduce nocturnal polyuria and/or increase the duration of uninterrupted sleep before first awakening to void would help to improve sleep quality in this population and thereby reduce or eliminate the need for sedative hypnotics.
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Affiliation(s)
- Shachi Tyagi
- Division of Geriatrics and Gerontology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
| | - Subashan Perera
- Division of Geriatrics and Gerontology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Becky D Clarkson
- Division of Geriatrics and Gerontology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Stasa D Tadic
- Division of Geriatrics and Gerontology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Neil M Resnick
- Division of Geriatrics and Gerontology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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Mezue K, Puri R, Rangaswami J. Letter by Mezue et al Regarding Article, "Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial". Circulation 2016; 134:e24-5. [PMID: 27462060 DOI: 10.1161/circulationaha.116.022381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Kenechukwu Mezue
- From Department of Medicine, Einstein Medical Center, Philadelphia, PA
| | - Ritika Puri
- From Department of Medicine, Einstein Medical Center, Philadelphia, PA
| | - Janani Rangaswami
- From Department of Medicine, Einstein Medical Center, Philadelphia, PA
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Ismail B, deKemp RA, Hadizad T, Mackasey K, Beanlands RS, DaSilva JN. Decreased renal AT1 receptor binding in rats after subtotal nephrectomy: PET study with [(18)F]FPyKYNE-losartan. EJNMMI Res 2016; 6:55. [PMID: 27339045 PMCID: PMC4919198 DOI: 10.1186/s13550-016-0209-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 06/14/2016] [Indexed: 01/13/2023] Open
Abstract
Background Significant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) is associated with a chain of events that culminates in hypertension and chronic kidney disease (CKD). Numerous studies have provided evidence for the role of angiotensin (Ang) II type 1 receptor (AT1R) in the promotion and progression of the disease; however, conflicting results were reported on intrarenal AT1R levels in CKD models. Methods Male Sprague-Dawley rats (n = 26) underwent Nx or sham operations. Animals were scanned at 8–10 weeks post-surgery with PET using the novel AT1R radioligand [18F]FPyKYNE-losartan. Radioligand binding was quantified by kidney-to-blood ratio (KBR), standard uptake value (SUV), and distribution volume (DV). After sacrifice, plasma and kidney Ang II levels were measured. Western blot and 125I-[Sar1, Ile8]Ang II autoradiography were performed to assess AT1R expression. Results At 8–10 weeks post-surgery, Nx rats developed hypertension, elevated plasma creatinine levels, left ventricle hypertrophy, increased myocardial blood flow (MBF), and reduced Ang II levels compared to shams. PET measurements displayed significant decrease in KBR (29 %), SUV (24 %), and DV (22 %) induced by Nx (p < 0.05), and these findings were confirmed by in vitro assays. Conclusions Reduced renal AT1Rs in hypertensive rats measured with [18F]FPyKYNE-losartan PET at 8–10 weeks following Nx support further use of this non-invasive approach in longitudinal studies to better understand the AT1R role in CKD progression.
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Affiliation(s)
- Basma Ismail
- National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Robert A deKemp
- National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada
| | - Tayebeh Hadizad
- National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada
| | - Kumiko Mackasey
- National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada
| | - Rob S Beanlands
- National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Jean N DaSilva
- National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada. .,Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. .,Department of Radiology, Radio-Oncology and Nuclear Medicine, University of Montreal, University of Montreal Hospital Research Centre (CRCHUM), 900 Rue Saint-Denis, Montréal, Québec, H2X 0A9, Canada.
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Kim RB, Morse BL, Djurdjev O, Tang M, Muirhead N, Barrett B, Holmes DT, Madore F, Clase CM, Rigatto C, Levin A. Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events. Kidney Int 2016; 89:1144-1152. [PMID: 27083288 DOI: 10.1016/j.kint.2016.01.014] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 01/04/2016] [Accepted: 01/07/2016] [Indexed: 11/24/2022]
Abstract
Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82-32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.
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Affiliation(s)
- Richard B Kim
- Department of Medicine, Western University, London, Ontario, Canada.
| | - Bridget L Morse
- Department of Medicine, Western University, London, Ontario, Canada
| | - Ognjenka Djurdjev
- Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mila Tang
- Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Norman Muirhead
- Department of Medicine, Western University, London, Ontario, Canada
| | - Brendan Barrett
- Memorial University Newfoundland, St. John's, Newfoundland, Canada
| | - Daniel T Holmes
- Department of Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | | | | | | | - Adeera Levin
- Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
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Ng KP, Jain P, Gill PS, Heer G, Townend JN, Freemantle N, Greenfield S, McManus RJ, Ferro CJ. Results and lessons from the Spironolactone To Prevent Cardiovascular Events in Early Stage Chronic Kidney Disease (STOP-CKD) randomised controlled trial. BMJ Open 2016; 6:e010519. [PMID: 26916697 PMCID: PMC4769397 DOI: 10.1136/bmjopen-2015-010519] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVES To determine whether low-dose spironolactone can safely lower arterial stiffness in patients with chronic kidney disease stage 3 in the primary care setting. DESIGN A multicentre, prospective, randomised, placebo-controlled, double-blinded study. SETTING 11 primary care centres in South Birmingham, England. PARTICIPANTS Adult patients with stage 3 chronic kidney disease. Main exclusion criteria were diagnosis of diabetes mellitus, chronic heart failure, atrial fibrillation, severe hypertension, systolic blood pressure < 120 mm Hg or baseline serum potassium ≥ 5 mmol/L. INTERVENTION Eligible participants were randomised to receive either spironolactone 25 mg once daily, or matching placebo for an intended period of 40 weeks. OUTCOME MEASURES The primary end point was the change in arterial stiffness as measured by pulse wave velocity. Secondary outcome measures included the rate of hyperkalaemia, deterioration of renal function, barriers to participation and expected recruitment rates to a potential future hard end point study. RESULTS From the 11 practices serving a population of 112,462, there were 1598 (1.4%) patients identified as being eligible and were invited to participate. Of these, 134 (8.4%) attended the screening visit of which only 16 (1.0%) were eligible for randomisation. The main reasons for exclusion were low systolic blood pressure (<120 mm Hg: 40 patients) and high estimated glomerular filtration rate (≥ 60 mL/min/1.73 m(2): 38 patients). The trial was considered unfeasible and was terminated early. CONCLUSIONS We highlight some of the challenges in undertaking research in primary care including patient participation in trials. This study not only challenged our preconceptions, but also provided important learning for future research in this large and important group of patients. TRIAL REGISTRATION NUMBER ISRCTN80658312.
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Affiliation(s)
- Khai P Ng
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Poorva Jain
- Department of Primary Care Clinical Sciences, School of Health and Population Sciences, University of Birmingham, Birmingham, UK
| | - Paramjit S Gill
- Department of Primary Care Clinical Sciences, School of Health and Population Sciences, University of Birmingham, Birmingham, UK
| | - Gurdip Heer
- Department of Primary Care Clinical Sciences, School of Health and Population Sciences, University of Birmingham, Birmingham, UK
| | - Jonathan N Townend
- Department of Cardiology, Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Nick Freemantle
- Department of Primary Care and Population Health, UCL Medical School, London, UK
| | - Sheila Greenfield
- Department of Primary Care Clinical Sciences, School of Health and Population Sciences, University of Birmingham, Birmingham, UK
| | - Richard J McManus
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Charles J Ferro
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, UK
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Iyngkaran P, Liew D, McDonald P, Thomas MC, Reid C, Chew D, Hare DL. Phase 4 Studies in Heart Failure - What is Done and What is Needed? Curr Cardiol Rev 2016; 12:216-230. [PMID: 27280303 PMCID: PMC5011189 DOI: 10.2174/1573403x12666160606121458] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/18/2015] [Accepted: 01/11/2016] [Indexed: 02/07/2023] Open
Abstract
Congestive heart failure (CHF) therapeutics is generated through a well-described evidence generating process. Phases 1 - 3 of this process are required prior to approval and widespread clinical use. Phase 3 in almost all cases is a methodologically sound randomized controlled trial (RCT). After this phase it is generally accepted that the treatment has a significant, independent and prognostically beneficial effect on the pathophysiological process. A major criticism of RCTs is the population to whom the result is applicable. When this population is significantly different from the trial cohort the external validity comes into question. Should the continuation of the evidence generating process continue these problems might be identified. Post marketing surveillance through phase 4 and comparative effectiveness studies through phase 5 trials are often underperformed in comparison to the RCT. These processes can help identify remote adverse events and define new hypotheses for community level benefits. This review is aimed at exploring the post-marketing scene for CHF therapeutics from an Australian health system perspective. We explore the phases of clinical trials, the level of evidence currently available and options for ensuring greater accountability for community level CHF clinical outcomes.
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Affiliation(s)
- Pupalan Iyngkaran
- Cardiologist & Senior Lecturer NT Medical School, Flinders University, Australia.
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Norris KC, Nicholas SB. Strategies for Controlling Blood Pressure and Reducing Cardiovascular Disease Risk in Patients with Chronic Kidney Disease. Ethn Dis 2015; 25:515-20. [PMID: 26675050 PMCID: PMC4671428 DOI: 10.18865/ed.25.4.515] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Patients with chronic kidney disease (CKD) suffer from an increased prevalence of cardiovascular disease (CVD) risk factors, and a high rate of premature CV morbidity and mortality. The confluence of CV risk factors, in the context of cardio-metabolic perturbations that vary as renal function declines, complicates strategies for the care of patients with CKD. Understanding the existing evidence for effective CVD treatment strategies can help providers better care for these patients, navigate the complex treatment guidelines, which often differ across major organizations, and minimize the conflicting recommendations that new studies may pose. A pragmatic approach is to target a BP <140/90 mm Hg, which frequently requires more than two or three antihypertensive agents. Most guidelines recommend a combination of diuretic and angiotensin converting enzyme inhibitor or angiotensin receptor blockers, along with a dihydropyridine calcium channel blocker, beta blocker or other agent based on co-existing medical conditions. Consideration for a lower BP goal and/or other therapeutic interventions should be based on the etiology of CKD, stage of CKD, and/or presence of proteinuria. Finally, most patients with CKD, not on dialysis, would benefit from treatment with statins and non-pharmacologic lifestyle interventions should be promoted for all patients with CKD.
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Affiliation(s)
- Keith C. Norris
- 1. Division of General Internal Medicine and Division of Nephrology; Department of Medicine; David Geffen School of Medicine; University of California, Los Angeles
| | - Susanne B. Nicholas
- 2. Division of Nephrology and Division of Endocrinology, Diabetes and Hypertension; Department of Medicine; David Geffen School of Medicine; University of California, Los Angeles
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Ikeda M, Nakao M, Hirano K, Yokoyama K, Yokoo T, Joki N, Ando R, Shinoda T, Inaguma D, Yamaka T, Komatsu Y, Koiwa F, Sakaguchi T, Negi S, Shigematsu T. Possible prevention of dialysis-requiring congestive heart failure by angiotensin-II receptor blockers in non-dialysis Japanese patients with Stage 5 chronic kidney disease. J Renin Angiotensin Aldosterone Syst 2015. [PMID: 26195266 DOI: 10.1177/1470320315592565] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Preventive medications for dialysis-requiring congestive heart failure (CHF) in non-dialysis Japanese patients with Stage 5 chronic kidney disease (CKD) are unknown. Our aim was to explore which CKD medication was associated with a reduced prevalence of dialysis-requiring CHF in non-dialysis Japanese patients with Stage 5 CKD. METHODS The present multicenter, retrospective, cross-sectional study examined the association between CKD medications and the prevalence of dialysis-requiring CHF in non-dialysis Japanese patients with Stage 5 CKD. RESULTS There were 1536 Japanese Stage 5 CKD patients who satisfied our inclusion criteria. We had 309 (20.1%) patients whom had developed dialysis-requiring CHF and 940 patients (60.8%) whom had been using angiotensin-II receptor blockers (ARBs) before initiating dialysis. In our multivariate analysis, only ARB use was significantly associated with a lower risk of CHF (Odds ratio (OR): 0.680, 95% confidence interval (CI): 0.516-0.897; p = 0.0064), of the CKD treatments examined in this study. CONCLUSIONS We found that ARB use during the pre-dialysis period is associated with a lower prevalence of CHF in the non-dialysis Japanese patients with Stage 5 CKD, suggesting a possible prevention of dialysis-requiring CHF by ARBs, in non-dialysis Japanese patients with Stage 5 CKD.
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Affiliation(s)
- Masato Ikeda
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Katsushika medical center, Tokyo, Japan
| | - Masatsugu Nakao
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Katsushika medical center, Tokyo, Japan
| | - Keita Hirano
- Department of Nephrology, Asikaga Red Cross Hospital, Gunma, Japan
| | - Keitaro Yokoyama
- Division of Nephrology and Hypertension, Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Jikei University School of Medicine, Tokyo, Japan
| | - Nobuhiko Joki
- Division of Nephrology, Toho University, Ohashi Medical Center, Tokyo, Japan
| | - Ryoichi Ando
- Department of Nephrology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Toshio Shinoda
- Dialysis Center, Kawakita General Hospital, Tokyo, Japan
| | - Daijo Inaguma
- Kidney Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Toshihiko Yamaka
- Department of Clinical Engineering, Tokyo Yamate Medical Center, Tokyo, Japan
| | - Yasuhiro Komatsu
- Department of Nephrology, Division of Internal Medicine, Saint Luke's International Hospital, Tokyo, Japan
| | - Fumihiko Koiwa
- Division of Nephrology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Toshifumi Sakaguchi
- Division of Nephrology, Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Shigeo Negi
- Division of Nephrology, Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Takashi Shigematsu
- Division of Nephrology, Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
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Bakris GL, Kuritzky L. Monitoring and Managing Urinary Albumin Excretion: Practical Advice for Primary Care Clinicians. Postgrad Med 2015; 121:51-60. [DOI: 10.3810/pgm.2009.07.2031] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Kalaitzidis R, Bakris G. Are Renin-Angiotensin-Aldosterone System Blockers Distinguishable Based on Cardiovascular and Renal Outcomes in Nephropathy? Postgrad Med 2015; 121:77-88. [DOI: 10.3810/pgm.2009.03.1979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Suzuki H, Kikuta T, Inoue T, Hamada U. Time to re-evaluate effects of renin-angiotensin system inhibitors on renal and cardiovascular outcomes in diabetic nephropathy. World J Nephrol 2015; 4:118-26. [PMID: 25664254 PMCID: PMC4317622 DOI: 10.5527/wjn.v4.i1.118] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 11/13/2014] [Accepted: 12/03/2014] [Indexed: 02/06/2023] Open
Abstract
The use of renin-angiotensin system (RAS) inhibitors, such angiotensin converting enzyme inhibitors/angiotensin-II receptor blockers, to slow progression of chronic kidney disease (CKD) in a large group dominated by elderly people in the real world is not supported by available evidence. Large-scale clinical trials had many faults, among them a lack of focus on the elderly. However, it would be difficult to conduct clinical trials of a similar scale in elderly CKD patients. Besides, progression of kidney disease is often slow in elderly persons, and the vast majority of older adults with CKD will die before reaching end stage renal disease. Moreover, since it is not clear that progression of kidney disease, and even of proteinuric diabetic nephropathy, is not inhibited through the use of RAS inhibitors, the most patient-centric goal of therapy for many elderly individuals should be individualized.
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50
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Hwang JH, Chin HJ, Kim S, Kim DK, Kim S, Park JH, Shin SJ, Lee SH, Choi BS, Lim CS. Effects of intensive low-salt diet education on albuminuria among nondiabetic patients with hypertension treated with olmesartan: a single-blinded randomized, controlled trial. Clin J Am Soc Nephrol 2014; 9:2059-69. [PMID: 25332317 DOI: 10.2215/cjn.01310214] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND OBJECTIVES The antiproteinuric effect of a renin-angiotensin-aldosterone system blockade can be magnified by dietary salt restriction. This study sought to determine the effect of intensive low-salt diet education on BP and urine albumin excretion in nondiabetic patients with hypertension and albuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study was conducted between March of 2012 and March of 2013 as an open-label, randomized, controlled trial. After a run-in period of 8 weeks, all patients received the angiotensin II receptor blocker olmesartan (40 mg daily). Patients were then divided into two groups. One group was treated for another 8 weeks with angiotensin II receptor blocker plus conventional low-salt diet education, and the other group was treated for 8 weeks with angiotensin II receptor blocker plus intensive low-salt diet education. The final analyses was performed with 245 completed patients. RESULTS The amount of daily albuminuria was significantly decreased from 0 (566.0 [25.0-5398.6] mg/d) to 8 weeks (282.5 [16.1-4898.5] mg/d; P<0.001). From 8 to 16 weeks, the 24-hour urinary sodium excretion was decreased by 36.0±5.9 mmol/d in the intensive education group and 8.8±4.9 mmol/d in the conventional education group (interaction P<0.001). Patients who completed intensive low-salt diet education exhibited greater decreases in urinary albumin excretion than the control group (change in albuminuria from 8 to 16 weeks, -154.0 versus 0.4 mg/d; P=0.01). Urinary albumin excretion tended to decrease as the 24-hour urinary sodium excretion amount decreased (R=0.32; 95% confidence interval, 0.20 to 0.43; P<0.001). CONCLUSIONS The 24-hour urinary albumin excretion was decreased more in patients in the intensive low-salt diet education group than patients in the conventional education group. Weekly intensive education on a low-salt diet would be a suitable method for clinical practice.
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Affiliation(s)
- Jin Ho Hwang
- Department of Internal Medicine, Chung-Ang University Hospital, Seoul, South Korea
| | - Ho Jun Chin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seong-Nam, South Korea
| | - Sejoong Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seong-Nam, South Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Suhnggwon Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Jung Hwan Park
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - Sung Joon Shin
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, South Korea
| | - Sang Ho Lee
- Department of Internal Medicine, Kyung Hee University Medical Center, Seoul, South Korea
| | - Bum Soon Choi
- Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, South Korea; and
| | - Chun Soo Lim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
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