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Wang S, Cheng Y, Zhang Z, Liu W, Ou M, Yin T, Meng Y, Ban H, Gu W, Meng X, Zhang L, Du Y. Association between obstructive sleep apnea and chronic kidney disease: A cross-sectional and Mendelian randomization study. Medicine (Baltimore) 2025; 104:e41437. [PMID: 39928765 PMCID: PMC11812998 DOI: 10.1097/md.0000000000041437] [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: 08/15/2024] [Revised: 01/04/2025] [Accepted: 01/16/2025] [Indexed: 02/12/2025] Open
Abstract
Previous observational studies have shown that obstructive sleep apnea (OSA) was associated with chronic kidney disease(CKD). Early diagnosis of OSA usually helps better prevent the occurrence of CKD. This cross-sectional investigation was conducted using data from the National Health and Nutrition Examination Survey, which was carried out between 2007 to 2008 and 2015 to 2016. Logistic regression model was employed to assess the impact of OSA on CKD. We did a mediation analysis to assess how much of the effect of OSA on CKD was mediated through mediators. Additionally, Mendelian randomization (MR) analysis assessed the causal link between OSA and various measures of renal impairment and possible mediators: obesity, hypertension and type 2 diabetes mellitus. In the cross-sectional study, the results of unadjusted model showed that participants with OSA had a higher risk of CKD compared to non-OSA (OR = 1.14, 95% confidence intervals [CI]: 1.01-1.28, P < .05). In mediation analysis, the proportion of hypertension and obesity mediating the effect of OSA on CKD was 41.83% and 30.74%, respectively. Univariate MR analysis results showed that: genetically predicted OSA was associated with decreased estimated glomerular filtration ratecystatin c (eGFRcystatin c) level (OR = 0.997, 95% CI: 0.995-0.999, P < .05), increased blood urea nitrogen (BUN) levels (OR = 1.023, 95% CI: 1.008-1.038, P < .05), increased serum creatinine levels (OR = 1.010, 95% CI: 1.002-1.018, P < .05), increased serum cystatin C levels (OR = 1.015, 95% CI: 1.005-1.026, P < .05). Multivariable MR results showed that obesity mediated the causal effect of OSA on eGFRcystatin c, BUN levels and serum cystatin C levels. The cross-sectional study revealed a positive relationship between OSA and CKD, which was mediated by hypertension and obesity. The MR analysis suggest that OSA was associated with several measures of renal impairment, which was mediated by obesity. These findings may inform prevention and intervention strategies against CKD.
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Affiliation(s)
- Shaokang Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yupei Cheng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zhe Zhang
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Wei Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Mi Ou
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Tianlong Yin
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yalu Meng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Haipeng Ban
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Wenlong Gu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xianggang Meng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Lili Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yuzheng Du
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Starek RV, Gomes SA, Helou CM. Metabolic Alkalemia in Hypercalciuria Stone Formers: Does It Matter? Kidney Blood Press Res 2024; 49:987-1002. [PMID: 39447551 PMCID: PMC11614309 DOI: 10.1159/000540953] [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: 03/28/2022] [Accepted: 08/08/2024] [Indexed: 10/26/2024] Open
Abstract
INTRODUCTION The literature lacks whether metabolic alkalemia occurs in outpatients with hypercalciuric nephrolithiasis. Thus, we aim to investigate it because these patients are often treated with thiazides to reduce urinary calcium excretion. However, thiazides induce chloride losses due to the inhibition of Na-Cl cotransporter expressed in the renal distal tubule cells. Besides thiazide prescription, many of these patients are also supplemented with potassium citrate, which is an addition of alkali source in their bodies. METHODS We collected clinical, demographic characteristics, and laboratory data from electronic medical charts of outpatients with calcium kidney stones followed in our institution from January 2013 to July 2021. We diagnosed those cases as metabolic alkalemia, in which the venous blood gas tests showed pH ≥7.46 and bicarbonate concentration >26 mEq/L. Then, we applied statistical analysis to compare distinct categories between patients with and without metabolic alkalemia. RESULTS We diagnosed metabolic alkalemia in 4.3% of hypercalciuric nephrolithiasis outpatients, and we verified that thiazides had been used in all of them except in one case. Furthermore, we observed that the amount of thiazide taken daily was higher in patients with metabolic alkalemia than in those without this imbalance. Additionally, hypokalemia was present in 37% of patients who developed metabolic alkalemia. We also found lower chloride, magnesium and ionic calcium serum concentrations in patients with metabolic alkalemia than in those without an acid-base disequilibrium. CONCLUSION Despite the low prevalence of metabolic alkalemia in hypercalciuric kidney stone formers, it is important to monitor these patients due to the high incidence of hypokalemia and the potential presence of other electrolyte disorders.
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Affiliation(s)
- Renato V.M. Starek
- Ambulatório de Nefrolitíase, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Laboratório de Pesquisa Básica da Unidade de Doenças Renais (LIM 12), Nefrologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Samirah A. Gomes
- Ambulatório de Nefrolitíase, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Laboratório de Nefrologia Celular, Genética e Molecular (LIM 29) Nefrologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Claudia M.B. Helou
- Laboratório de Pesquisa Básica da Unidade de Doenças Renais (LIM 12), Nefrologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Mariani LH, Trachtman H, Thompson A, Gillespie BS, Denburg M, Diva U, Geetha D, Greasley PJ, Hladunewich MA, Huizinga RB, Inrig JK, Komers R, Laurin LP, Little DJ, Nachman PH, Smith KA, Walsh L, Gibson KL. Proteinuria as an End Point in Clinical Trials of Focal Segmental Glomerulosclerosis. Am J Kidney Dis 2024:S0272-6386(24)01038-2. [PMID: 39455047 DOI: 10.1053/j.ajkd.2024.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/26/2024] [Accepted: 08/11/2024] [Indexed: 10/28/2024]
Abstract
Focal segmental glomerulosclerosis (FSGS) is a characteristic histopathological lesion that is indicative of underlying glomerular dysfunction. It is not a single disease entity but rather a heterogeneous disorder that is an important cause of nephrotic syndrome and kidney failure in children and adults. The aim of this Kidney Health Initiative project was to evaluate potential end points for clinical trials in FSGS. Our focus is on the data supporting proteinuria as a surrogate end point. Available data support the use of complete remission of proteinuria in patients with heavy proteinuria as a surrogate end point for progression to kidney failure. Substantial treatment effects on proteinuria that are short of a complete remission may also predict the effect of a treatment on progression to kidney failure, but further work is needed to determine how such an end point should be defined. Fortunately, efforts are underway to bring together patient-level data from randomized controlled trials, observational studies, and registries to address this issue.
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Affiliation(s)
- Laura H Mariani
- Renal Division, University of Michigan, Ann Arbor, Michigan.
| | - Howard Trachtman
- Department of Pediatrics/Nephrology, University of Michigan, Ann Arbor, Michigan.
| | - Aliza Thompson
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Barbara S Gillespie
- Fortrea, Durham, North Carolina; Kidney Center, University of North Carolina, Chapel Hill, North Carolina
| | - Michelle Denburg
- Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Duvuru Geetha
- School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Peter J Greasley
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | | | | | | | | | | | - Dustin J Little
- Clinical Development, Late Cardiovascular, Renal and Metabolism, AstraZeneca, Gaithersburg, Maryland
| | | | - Kimberly A Smith
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | | | - Keisha L Gibson
- Kidney Center, University of North Carolina, Chapel Hill, North Carolina
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Lachkar S, Boualaoui I, Ibrahimi A, El Sayegh H, Nouini Y. Laparoscopic Live Donor Nephrectomy: An Initial Moroccan Experience. Cureus 2024; 16:e70713. [PMID: 39493162 PMCID: PMC11530232 DOI: 10.7759/cureus.70713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2024] [Indexed: 11/05/2024] Open
Abstract
Introduction Laparoscopic nephrectomy is the gold standard for kidney removal in living donors, offering advantages such as reduced pain and quicker recovery. In Morocco, where end-stage renal disease (ESRD) is a growing concern, this approach could significantly impact the demand for kidney transplants. This study evaluates the safety and efficacy of laparoscopic live donor nephrectomy in the Moroccan healthcare system. Materials and methods Fifteen laparoscopic nephrectomies were analyzed, focusing on donor demographics, procedure details, and outcomes. Key parameters included donor age, BMI, operative time, warm ischemia time, and blood loss. Complications and graft outcomes were also assessed. Results The procedure was safe and effective, even in obese donors. Donors were predominantly female (80%), with an average age of 49.4 years. Obese donors had longer operative times (282 minutes vs. 220 minutes). Left kidney retrieval was preferred (95%). Warm ischemia averaged 6.27 minutes and blood loss was 207 mL. One donor had elevated creatinine postoperatively, while most maintained stable renal function. Eighteen complications, mostly minor, were reported. Conclusion Laparoscopic live donor nephrectomy is a safe and adaptable procedure in Morocco, offering low complication rates and favorable outcomes. It is effective for a diverse donor population, including older and obese individuals, and may help address the country's growing transplant needs.
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Affiliation(s)
- Salim Lachkar
- Department of Urology A, Ibn Sina University Hospital, Rabat, MAR
| | - Imad Boualaoui
- Department of Urology A, Ibn Sina University Hospital, Rabat, MAR
| | - Ahmed Ibrahimi
- Department of Urology A, Ibn Sina University Hospital, Rabat, MAR
| | - Hachem El Sayegh
- Department of Urology A, Ibn Sina University Hospital, Rabat, MAR
| | - Yassine Nouini
- Department of Urology A, Ibn Sina University Hospital, Rabat, MAR
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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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Guo M, He F, Zhang C. Molecular Therapeutics for Diabetic Kidney Disease: An Update. Int J Mol Sci 2024; 25:10051. [PMID: 39337537 PMCID: PMC11431964 DOI: 10.3390/ijms251810051] [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: 08/26/2024] [Revised: 09/13/2024] [Accepted: 09/15/2024] [Indexed: 09/30/2024] Open
Abstract
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus (DM). With the increasing prevalence of DM worldwide, the incidence of DKD remains high. If DKD is not well controlled, it can develop into chronic kidney disease or end-stage renal disease (ESRD), which places considerable economic pressure on society. Traditional therapies, including glycemic control, blood pressure control, blood lipid control, the use of renin-angiotensin system blockers and novel drugs, such as sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor inhibitors and glucagon-like peptide-1 receptor agonists, have been used in DKD patients. Although the above treatment strategies can delay the progression of DKD, most DKD patients still ultimately progress to ESRD. Therefore, new and multimodal treatment methods need to be explored. In recent years, researchers have continuously developed new treatment methods and targets to delay the progression of DKD, including miRNA therapy, stem cell therapy, gene therapy, gut microbiota-targeted therapy and lifestyle intervention. These new molecular therapy methods constitute opportunities to better understand and treat DKD. In this review, we summarize the progress of molecular therapeutics for DKD, leading to new treatment strategies.
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Affiliation(s)
| | - Fangfang He
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Kanbay M, Guldan M, Ozbek L, Copur S, Covic AS, Covic A. Exploring the nexus: The place of kidney diseases within the cardiovascular-kidney-metabolic syndrome spectrum. Eur J Intern Med 2024; 127:1-14. [PMID: 39030148 DOI: 10.1016/j.ejim.2024.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/25/2024] [Accepted: 07/11/2024] [Indexed: 07/21/2024]
Abstract
Cardiovascular-kidney-metabolic (CKM) syndrome and chronic kidney disease (CKD) are two significant comorbidities affecting a large proportion of the general population with considerable crosstalk. In addition to substantial co-incidence of CKD and CKM syndrome in epidemiological studies, clinical and pre-clinical studies have identified similar pathophysiological pathways leading to both entities. Patients with CKM syndrome are more prone to develop acute kidney injury and CKD, while therapeutic alternatives and their success rates are considerably lower in such patient groups. Nevertheless, the association between CKM syndrome and CKD or ESKD is bidirectional rather than being a cause-effect relationship as patients with CKD are also prone to develop peripheral insulin resistance, high blood pressure, and dyslipidemia. Furthermore, such patients are less likely to receive kidney transplantation in addition to the higher allograft dysfunction risk. We hereby aim to evaluate the association in-between kidney diseases and CKM syndrome, including epidemiological data, pre-clinical studies with pathophysiological pathways, and potential therapeutic perspectives.
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Affiliation(s)
- Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey.
| | - Mustafa Guldan
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Lasin Ozbek
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Division of Internal Medicine, Koç University School of Medicine, Istanbul, Turkey
| | | | - Adrian Covic
- University of Medicine "Grigore T Popa" Iasi, Romania
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Jia G, Lastra G, Bostick BP, LahamKaram N, Laakkonen JP, Ylä-Herttuala S, Whaley-Connell A. The mineralocorticoid receptor in diabetic kidney disease. Am J Physiol Renal Physiol 2024; 327:F519-F531. [PMID: 39024357 PMCID: PMC11460335 DOI: 10.1152/ajprenal.00135.2024] [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: 05/01/2024] [Revised: 07/11/2024] [Accepted: 07/12/2024] [Indexed: 07/20/2024] Open
Abstract
Diabetes mellitus is one of the leading causes of chronic kidney disease and its progression to end-stage kidney disease (ESKD). Diabetic kidney disease (DKD) is characterized by glomerular hypertrophy, hyperfiltration, inflammation, and the onset of albuminuria, together with a progressive reduction in glomerular filtration rate. This progression is further accompanied by tubulointerstitial inflammation and fibrosis. Factors such as genetic predisposition, epigenetic modifications, metabolic derangements, hemodynamic alterations, inflammation, and inappropriate renin-angiotensin-aldosterone system (RAAS) activity contribute to the onset and progression of DKD. In this context, decades of work have focused on glycemic and blood pressure reduction strategies, especially targeting the RAAS to slow disease progression. Although much of the work has focused on targeting angiotensin II, emerging data support that the mineralocorticoid receptor (MR) is integral in the development and progression of DKD. Molecular mechanisms linked to the underlying pathophysiological changes derived from MR activation include vascular endothelial and epithelial cell responses to oxidative stress and inflammation. These responses lead to alterations in the microcirculatory environment, the abnormal release of extracellular vesicles, gut dysbiosis, epithelial-mesenchymal transition, and kidney fibrosis. Herein, we present recent experimental and clinical evidence on the MR in DKD onset and progress along with new MR-based strategies for the treatment and prevention of DKD.
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Affiliation(s)
- Guanghong Jia
- Department of Medicine-Endocrinology and Metabolism, University of Missouri School of Medicine, Columbia, Missouri, United States
- Research Service, Harry S. Trumand Memorial Veterans Hospital, Columbia, Missouri, United States
| | - Guido Lastra
- Department of Medicine-Endocrinology and Metabolism, University of Missouri School of Medicine, Columbia, Missouri, United States
- Research Service, Harry S. Trumand Memorial Veterans Hospital, Columbia, Missouri, United States
| | - Brian P Bostick
- Department of Medicine-Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, Missouri, United States
| | - Nihay LahamKaram
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Johanna P Laakkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
| | - Adam Whaley-Connell
- Department of Medicine-Endocrinology and Metabolism, University of Missouri School of Medicine, Columbia, Missouri, United States
- Research Service, Harry S. Trumand Memorial Veterans Hospital, Columbia, Missouri, United States
- Department of Medicine-Nephrology and Hypertension, University of Missouri School of Medicine, Columbia, Missouri, United States
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Murdoch JE, Lourenço BN, Berghaus RD, Ames MK, Hammond HK, Coleman AE. Characterization of the circulating markers of the renin-angiotensin-aldosterone system in telmisartan- or enalapril-treated dogs with proteinuric chronic kidney disease. J Vet Intern Med 2024; 38:2535-2547. [PMID: 39206534 PMCID: PMC11423453 DOI: 10.1111/jvim.17186] [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: 05/17/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. OBJECTIVES To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. ANIMALS Dogs with pCKD (n = 36) and healthy controls (n = 20). METHODS Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. RESULTS Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P < .001). Mean (95% confidence interval) percentage change from pretreatment value in serum Ang 1-7 concentration was significantly greater in telmisartan- (753% [489%-1134%]) versus enalapril-treated (149% [69%-268%]) dogs (P < .001). Serum aldosterone decreased with treatment (P = .02 for enalapril, P < .001 for telmisartan), with no difference between groups at day 30. CONCLUSIONS AND CLINICAL IMPORTANCE Circulating RAAS activity is higher in dogs with pCKD. Compared with enalapril, treatment with telmisartan caused significantly greater increases in the presumed beneficial peptide Ang 1-7.
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Affiliation(s)
- Joanna E Murdoch
- Department of Small Animal and Surgery, University of Georgia College of Veterinary Medicine, Athens, Georgia, USA
| | - Bianca N Lourenço
- Department of Small Animal and Surgery, University of Georgia College of Veterinary Medicine, Athens, Georgia, USA
| | - Roy D Berghaus
- Department of Population Health, University of Georgia College of Veterinary Medicine, Athens, Georgia, USA
| | - Marisa K Ames
- Department of Medicine and Epidemiology, University of California, Davis School of Veterinary Medicine, Davis, California, USA
| | - Hillary K Hammond
- Department of Clinical Sciences, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, Colorado, USA
| | - Amanda E Coleman
- Department of Small Animal and Surgery, University of Georgia College of Veterinary Medicine, Athens, Georgia, USA
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Mohamed B, Ghareib SA, Alsemeh AE, El-Sayed SS. Telmisartan ameliorates nephropathy and restores the hippo pathway in rats with metabolic syndrome. Eur J Pharmacol 2024; 973:176605. [PMID: 38653362 DOI: 10.1016/j.ejphar.2024.176605] [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: 11/05/2023] [Revised: 04/19/2024] [Accepted: 04/19/2024] [Indexed: 04/25/2024]
Abstract
The main objective of this study was to determine if the telmisartan-ameliorative effects of metabolic syndrome (MetS)-evoked nephropathy are attributed to the Hippo pathway. A secondary objective was to investigate the potential of vitamin D3 to enhance telmisartan-favourable effects. A diet composed of 24% fat and 3% salt, along with drinking water containing 10% fructose, was administered for 12 weeks to induce MetS. MetS-rats were given telmisartan (5 mg/kg/day), vitamin D3 (10 μg/kg/day) or both by gavage, starting in the sixth week of experimental diet administration. Assessments performed at closure included renal function, histological examination, catalase, malondialdehyde (MDA), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6), peroxisome proliferator-activated receptor-γ (PPAR-γ), phosphatase and tensin homolog (PTEN), and transforming growth factor-β (TGF-β). Matrix metalloproteinase-9 (MMP-9) immunostaining was conducted. The expression of the Hippo pathway components, as well as that of angiotensin II type 1 and type 2 (AT1 and AT2), receptors was evaluated. Telmisartan attenuated MetS-evoked nephropathy, as demonstrated by improvement of renal function and histological features, enhancement of catalase, reduction of MDA, inflammation (NF-κB, IL-6), and renal fibrosis (increased PPAR-γ and PTEN and reduced MMP-9 and TGF-β). Telmisartan downregulated AT1-receptor, upregulated AT2-receptor and restored the Hippo pathway. Vitamin D3 replicated most of the telmisartan-elicited effects and enhanced the antifibrotic actions of telmisartan. The alleviative effects of telmisartan on MetS-evoked nephropathy may be related to the restoration of the Hippo pathway. The combination of vitamin D3 and telmisartan exerted more favourable effects on metabolic and nephropathic biomarkers compared with either one administered alone.
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Affiliation(s)
- Badria Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Salah A Ghareib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Amira Ebrahim Alsemeh
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
| | - Shaimaa S El-Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
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Kohan DE, Bedard P, Jenkinson C, Hendry B, Komers R. Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease. Clin Sci (Lond) 2024; 138:645-662. [PMID: 38808486 PMCID: PMC11139641 DOI: 10.1042/cs20240249] [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: 02/19/2024] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/30/2024]
Abstract
Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT1 and ETA receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ETA and AT1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.
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Affiliation(s)
- Donald E. Kohan
- Division of Nephrology, University of Utah Health, Salt Lake City, UT, U.S.A
| | | | | | - Bruce Hendry
- Travere Therapeutics, Inc., San Diego, CA, U.S.A
| | - Radko Komers
- Travere Therapeutics, Inc., San Diego, CA, U.S.A
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12
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Abbas M, Goodney G, Vargas JD, Gaye A. Transcriptome Study of 2 Black Cohorts Reveals cis Long Noncoding RNAs Associated With Hypertension-Related mRNAs. J Am Heart Assoc 2024; 13:e034417. [PMID: 38818927 PMCID: PMC11255619 DOI: 10.1161/jaha.124.034417] [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: 03/21/2024] [Accepted: 05/06/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) have emerged as critical regulators of the expression of genes involved in cardiovascular diseases. This project aims to identify circulating lncRNAs associated with protein-coding mRNAs differentially expressed between hypertensive and normotensive individuals and establish their link with hypertension. METHODS AND RESULTS The analyses were conducted in 3 main steps: (1) an unbiased whole blood transcriptome-wide analysis was conducted to identify and replicate protein-coding genes differentially expressed by hypertension status in 497 and 179 Black individuals from the GENE-FORECAST (Genomics, Environmental Factors and the Social Determinants of Cardiovascular Disease in African-Americans Study) and MH-GRID (Minority Health Genomics and Translational Research Bio-Repository Database) studies, respectively. Subsequently, (2) proximal lncRNAs, termed cis lncRNA quantitative trait loci, associated with each mRNA were identified in the GENE-FORECAST study and replicated in the MH-GRID study. Finally, (3) the lncRNA quantitative trait loci were used as predictors in a random forest model to predict hypertension in both data sets. A total of 129 mRNAs were significantly differentially expressed between normotensive and hypertensive individuals in both data sets. The lncRNA-mRNA association analysis revealed 249 cis lncRNA quantitative trait loci associated with 102 mRNAs, including VAMP2 (vesicle-associated membrane protein 2), mitogen-activated protein kinase kinase 3, CCAAT enhancer binding protein beta, and lymphocyte antigen 6 complex, locus E. The 249 lncRNA quantitative trait loci predicted hypertension with an area under the curve of 0.79 and 0.71 in GENE-FORECAST and MH-GRID studies, respectively. CONCLUSIONS This study leveraged a significant sample of Black individuals, a population facing a disproportionate burden of hypertension. The analyses unveiled a total of 271 lncRNA-mRNA relationships involving mRNAs that play critical roles in vascular pathways relevant to blood pressure regulation. The compelling findings, consistent across 2 independent data sets, establish a reliable foundation for designing in vitro/in vivo experiments.
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Affiliation(s)
- Malak Abbas
- National Human Genome Research Institute, National Institutes of HealthBethesdaMD
| | - Gabriel Goodney
- National Human Genome Research Institute, National Institutes of HealthBethesdaMD
| | | | - Amadou Gaye
- National Human Genome Research Institute, National Institutes of HealthBethesdaMD
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13
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Zhang J, Chen S, Tian Z, Cao J, Jiao Y, Wang B, Feng S, Luo Z, Zhang Q, Deng Y, Cai W, Xu J. Association Between Liver Fibrosis Score and Diabetic Kidney Disease: A Retrospective Cross-Sectional Study of Hospitalized Patients. Exp Clin Endocrinol Diabetes 2024; 132:328-335. [PMID: 38599609 DOI: 10.1055/a-2280-3742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/12/2024]
Abstract
OBJECTIVES To investigate the association between liver fibrosis score and diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). METHODS A total of 897 hospitalized patients with T2DM were included in this study. Each patient completed DKD screening. Logistic regression analysis was used to assess the predictive value of non-alcoholic fatty liver disease fibrosis score (NAFLD-FS) and fibrosis-4 (FIB-4) for the occurrence of DKD and risk for DKD progression, respectively. RESULTS The prevalence of DKD and risk for its progression significantly increased with increasing NAFLD-FS risk category. DKD prevalence also increased with increasing FIB-4 risk category. Multivariate logistic regression analysis showed that the "high-risk" NAFLD-FS had a significantly higher risk of DKD (odds ratio [OR]: 1.89, 95% confidence interval [CI]: 1.16-3.08) and risk for DKD progression (OR: 2.88, 95% CI: 1.23-6.78), and the "intermediate-risk" FIB-4 had a significantly higher risk of DKD (OR: 1.41, 95% CI: 1.00-1.98). Subgroup analysis showed that the association between NAFLD-FS and FIB-4 and DKD was significant in the female subgroup, whereas the association between the "high-risk" NAFLD-FS and risk for DKD progression was significant in the male subgroup. CONCLUSIONS NAFLD-FS and FIB-4 are strongly associated with DKD and risk for DKD progression in patients with T2DM. Additionally, sexual dimorphism exists in this association.
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Affiliation(s)
- Jie Zhang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shen Chen
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China
| | - Zhendong Tian
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China
| | - Jiarui Cao
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China
| | - Yijie Jiao
- The Third Clinical Medical School, Medical College, Nanchang University, Nanchang 330006, China
| | - Bangqi Wang
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China
| | - Shenghui Feng
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China
| | - Zhanpeng Luo
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China
| | - Qingfang Zhang
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China
| | - Yuanyuan Deng
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Wei Cai
- Department of Medical Genetics and Cell biology, Medical College of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, Jiangxi, 330006, People's Republic of China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, Jiangxi, 330006, People's Republic of China
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14
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Bondi CD, Hartman HL, Rush BM, Tan RJ. Podocyte-Specific Deletion of MCP-1 Fails to Protect against Angiotensin II- or Adriamycin-Induced Glomerular Disease. Int J Mol Sci 2024; 25:4987. [PMID: 38732210 PMCID: PMC11084322 DOI: 10.3390/ijms25094987] [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: 04/01/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD.
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Affiliation(s)
- Corry D. Bondi
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA 152671, USA; (H.L.H.); (B.M.R.); (R.J.T.)
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15
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Wang P, Ren Z, Wang W, Liu M, Jia Y, Zhang M, Xue Y, Zhang C, Xu J, Wang C, Wang X. Candesartan upregulates angiotensin-converting enzyme 2 in kidneys of male animals by decreased ubiquitination. FASEB J 2024; 38:e23537. [PMID: 38498345 DOI: 10.1096/fj.202302707r] [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: 12/30/2023] [Revised: 02/08/2024] [Accepted: 02/21/2024] [Indexed: 03/20/2024]
Abstract
Candesartan is a common angiotensin-II receptor-1 blocker used for patients with cardiovascular and renal diseases. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of blood pressure (BP), and also a major receptor for coronaviruses. To determine whether and how candesartan upregulates ACE2, we examined BP and ACE2 in multi-organs from male and female C57BL/6J mice treated with candesartan (1 mg/kg, i.p.) for 7 days. Relative to the vehicle, candesartan lowered BP more in males than females; ACE2 protein abundances were increased in kidneys, not lungs, hearts, aorta, liver, spleen, brain, or serum, only from males. Ace2-mRNA was similar in kidneys. Candesartan also decreased BP in normal, hypertensive, and nephrotic male rats. The renal ACE2 was increased by the drug in normal and nephrotic male rats but not spontaneously hypertensive ones. In male mouse kidneys, ACE2 was distributed at sodium-hydrogen-exchanger-3 positive proximal-convoluted-tubules; ACE2-ubiquitination was decreased by candesartan, accompanied with increased ubiquitin-specific-protease-48 (USP48). In candesartan-treated mouse renal proximal-convoluted-tubule cells, ACE2 abundances and activities were increased while ACE2-ubiquitination and colocalization with lysosomal and proteosomal markers were decreased. The silence of USP48 by siRNA caused a reduction of ACE2 in the cells. Thus, the sex-differential ACE2 upregulation by candesartan in kidney from males may be due to the decreased ACE2-ubiquitination, associated with USP48, and consequent degradation in lysosomes and proteosomes. This is a novel mechanism and may shed light on candesartan-like-drug choice in men and women prone to coronavirus infections.
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Affiliation(s)
- Ping Wang
- The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
- Department of Nephrology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Zhiyun Ren
- The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwan Wang
- The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Mingda Liu
- The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Yutao Jia
- Department of Nephrology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Mingzhuo Zhang
- The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
- Department of Nephrology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Ying Xue
- The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Chenyang Zhang
- Department of Neurology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Jianteng Xu
- Laboratory Division, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Cheng Wang
- The Department of Pulmonary and Critical Care Medicine, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoyan Wang
- The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
- Department of Nephrology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
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16
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Zhao R, Hong L, Shi G, Ye H, Lou X, Zhou X, Yao J, Shi X, An J, Sun M. Mineralocorticoid promotes intestinal inflammation through receptor dependent IL17 production in ILC3s. Int Immunopharmacol 2024; 130:111678. [PMID: 38368773 DOI: 10.1016/j.intimp.2024.111678] [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: 12/11/2023] [Revised: 02/03/2024] [Accepted: 02/08/2024] [Indexed: 02/20/2024]
Abstract
Aldosterone is a key mineralocorticoid involved in regulating the concentration of blood electrolytes and physiological volume balance. Activation of mineralocorticoid receptor (MR) has been recently reported to participate in adaptive and innate immune responses under inflammation. Here, we evaluated the role of aldosterone and MR in inflammation bowel diseases (IBD). Aldosterone elevated in the colon of DSS-induced colitis mice. Aldosterone addition induced IL17 production and ROS/RNS level in group 3 innate lymphoid cells (ILC3s) and exacerbated intestinal injury. A selective mineralocorticoid receptor antagonism, eplerenone, inhibited IL17-producing ILC3s and its ROS/RNS production, protected mice from DSS-induced colitis. Mice lacking Nr3c2 (MR coding gene) in ILC3s exhibited decreased IL17 and ROS/RNS production, which alleviated colitis and colitis-associated colorectal cancer (CAC). Further experiments revealed that MR could directly bind to IL17A promoter and facilitate its transcription, which could be enhanced by aldosterone. Thus, our findings demonstrated the critical role of aldosterone-MR-IL17 signaling in ILC3s and gut homeostasis, indicating the therapeutic strategy of eplerenone in IBD clinical trial.
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Affiliation(s)
- Rongchuan Zhao
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China
| | - Lei Hong
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China; Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University. Suzhou Science and Technology Town Hospital. No. 1 Lijiang Road, Suzhou 215153, China
| | - Guohua Shi
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China
| | - Hong Ye
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China
| | - Xinqi Lou
- Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University. Suzhou Science and Technology Town Hospital. No. 1 Lijiang Road, Suzhou 215153, China
| | - Xinying Zhou
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China
| | - Jinyu Yao
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China
| | - Xiaohua Shi
- Digestive Department, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou Science and Technology Town Hospital, No. 1 Lijiang Road, Suzhou 215153, China
| | - Jianzhong An
- Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University. Suzhou Science and Technology Town Hospital. No. 1 Lijiang Road, Suzhou 215153, China.
| | - Minxuan Sun
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China.
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17
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Rao A, Bhat SA, Shibata T, Giani JF, Rader F, Bernstein KE, Khan Z. Diverse biological functions of the renin-angiotensin system. Med Res Rev 2024; 44:587-605. [PMID: 37947345 DOI: 10.1002/med.21996] [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: 12/29/2022] [Revised: 08/30/2023] [Accepted: 10/29/2023] [Indexed: 11/12/2023]
Abstract
The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.
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Affiliation(s)
- Adithi Rao
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, USA
| | - Shabir A Bhat
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Tomohiro Shibata
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jorge F Giani
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Florian Rader
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Kenneth E Bernstein
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Zakir Khan
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
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18
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Govender MA, Stoychev SH, Brandenburg JT, Ramsay M, Fabian J, Govender IS. Proteomic insights into the pathophysiology of hypertension-associated albuminuria: Pilot study in a South African cohort. Clin Proteomics 2024; 21:15. [PMID: 38402394 PMCID: PMC10893729 DOI: 10.1186/s12014-024-09458-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 02/06/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND Hypertension is an important public health priority with a high prevalence in Africa. It is also an independent risk factor for kidney outcomes. We aimed to identify potential proteins and pathways involved in hypertension-associated albuminuria by assessing urinary proteomic profiles in black South African participants with combined hypertension and albuminuria compared to those who have neither condition. METHODS The study included 24 South African cases with both hypertension and albuminuria and 49 control participants who had neither condition. Protein was extracted from urine samples and analysed using ultra-high-performance liquid chromatography coupled with mass spectrometry. Data were generated using data-independent acquisition (DIA) and processed using Spectronaut™ 15. Statistical and functional data annotation were performed on Perseus and Cytoscape to identify and annotate differentially abundant proteins. Machine learning was applied to the dataset using the OmicLearn platform. RESULTS Overall, a mean of 1,225 and 915 proteins were quantified in the control and case groups, respectively. Three hundred and thirty-two differentially abundant proteins were constructed into a network. Pathways associated with these differentially abundant proteins included the immune system (q-value [false discovery rate] = 1.4 × 10- 45), innate immune system (q = 1.1 × 10- 32), extracellular matrix (ECM) organisation (q = 0.03) and activation of matrix metalloproteinases (q = 0.04). Proteins with high disease scores (76-100% confidence) for both hypertension and chronic kidney disease included angiotensinogen (AGT), albumin (ALB), apolipoprotein L1 (APOL1), and uromodulin (UMOD). A machine learning approach was able to identify a set of 20 proteins, differentiating between cases and controls. CONCLUSIONS The urinary proteomic data combined with the machine learning approach was able to classify disease status and identify proteins and pathways associated with hypertension-associated albuminuria.
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Affiliation(s)
- Melanie A Govender
- Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
| | - Stoyan H Stoychev
- Council for Scientific and Industrial Research, NextGen Health, Pretoria, South Africa
- ReSyn Biosciences, Edenvale, South Africa
| | - Jean-Tristan Brandenburg
- Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Strengthening Oncology Services, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Michèle Ramsay
- Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - June Fabian
- Wits Donald Gordon Medical Centre, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Medical Research Council/Wits University Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Ireshyn S Govender
- Council for Scientific and Industrial Research, NextGen Health, Pretoria, South Africa.
- ReSyn Biosciences, Edenvale, South Africa.
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19
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Jones A, Swan D, Lisman T, Barnes GD, Thachil J. Anticoagulation in chronic kidney disease: current status and future perspectives. J Thromb Haemost 2024; 22:323-336. [PMID: 37778512 DOI: 10.1016/j.jtha.2023.09.020] [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: 07/02/2023] [Revised: 09/14/2023] [Accepted: 09/21/2023] [Indexed: 10/03/2023]
Abstract
Chronic kidney disease (CKD) is being diagnosed increasingly worldwide. It is often identified in individuals with comorbidities, which may increase the already heightened risk of thrombosis and hemorrhage associated with CKD. Oral anticoagulation is an effective means of reducing rates of ischemic stroke and systemic embolism in patients with atrial fibrillation and minimizes the morbidity and mortality caused by venous thromboembolic disease. Despite the proven benefits in the majority of patients, these have not been so clearly realized in patients with CKD due to the precarious balance between bleeding and thromboembolic complications. In this review, the current status of anticoagulant utilization in CKD is examined, and some practical recommendations are put forward to assist in the decision-making process of safely anticoagulating patients with CKD diagnosed with atrial fibrillation and venous thromboembolism.
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Affiliation(s)
- Alfred Jones
- Department of Haematology, Beaumont Hospital, Dublin, Ireland
| | - Dawn Swan
- Department of Haematology, Beaumont Hospital, Dublin, Ireland.
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Geoffrey D Barnes
- Division of Cardiovascular Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Jecko Thachil
- Department of Haematology, Manchester University Hospitals, Oxford Road, Manchester, United Kingdom
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20
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Xiang Y, Yuan Z, Deng Q, Xie L, Yu D, Shi J. Potential therapeutic medicines for renal fibrosis: Small-molecule compounds and natural products. Bioorg Chem 2024; 143:106999. [PMID: 38035515 DOI: 10.1016/j.bioorg.2023.106999] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/16/2023] [Accepted: 11/22/2023] [Indexed: 12/02/2023]
Abstract
Renal fibrosis is the pathological change process of chronic kidney disease deteriorating continuously. When the renal organ is stimulated by external stimuli, it will trigger the damage and phenotypic changes of some intrinsic cells in the kidney. When the body's autoimmune regulation or external treatment is not prompted enough to restore the organ, the pathological process is gradually aggravating, inducing a large amount of intracellular collagen deposition, which leads to the appearance of fibrosis and scarring. The renal parenchyma (including glomeruli and tubules) begins to harden, making it difficult to repair the kidney lesions. In the process of gradual changes in the kidney tissue, the kidney units are severely damaged and the kidney function shows a progressive decline, eventually resulting in the clinical manifestation of end-stage renal failure, namely uremia. This review provides a brief description of the diagnosis, pathogenesis, and potential therapeutic inhibitors of renal fibrosis. Since renal fibrosis has not yet had a clear therapeutic target and related drugs, some potential targets and relevant inhibitors are discussed, especially pharmacological effects and interactions with targets. Some existing natural products have potential efficacy for renal fibrosis, which is also roughly summarized, hoping that this article would have reference significance for the treatment of renal fibrosis.
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Affiliation(s)
- Yu Xiang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Zhuo Yuan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qichuan Deng
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Linshen Xie
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
| | - Dongke Yu
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
| | - Jianyou Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
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Oh JH, Jun DW. Nonalcoholic fatty liver disease–related extrahepatic complications, associated outcomes, and their treatment considerations. METABOLIC STEATOTIC LIVER DISEASE 2024:101-122. [DOI: 10.1016/b978-0-323-99649-5.00007-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Campbell KN, Griffin S, Trachtman H, Geletka R, Wong MG. Practical Considerations for the Use of Sparsentan in the Treatment of Patients with IgAN in Clinical Practice. Int J Nephrol Renovasc Dis 2023; 16:281-291. [PMID: 38149041 PMCID: PMC10750480 DOI: 10.2147/ijnrd.s430377] [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: 07/13/2023] [Accepted: 12/12/2023] [Indexed: 12/28/2023] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is characterized by the mesangial deposition of IgA-containing immune complexes, triggering damage to the glomerular filtration barrier that is amplified by the tandem action of endothelin-1 and angiotensin II at their receptors. Proteinuria and progressive glomerular damage cause loss of kidney function in up to 50% of patients within 10-20 years. The risk of progression is strongly associated with persistent proteinuria (>0.75-1 g/day). Current standard of care involves interventions to decrease proteinuria and control blood pressure. Immunosuppressive agents, used in selected patients at high risk for progression, can be associated with significant side effects. Sparsentan, a novel non-immunosuppressive single-molecule Dual Endothelin Angiotensin Receptor Antagonist (DEARA), received FDA accelerated approval based on interim results from the PROTECT trial, which demonstrated that sparsentan-treated patients achieved a significantly greater reduction in proteinuria from baseline versus the active control irbesartan and that sparsentan was generally safe and well tolerated. Sparsentan is the first non-immunosuppressive treatment to be FDA-approved for the reduction of proteinuria in adults with IgAN at high risk of disease progression. We provide practical guidance for the clinical use of sparsentan in adults with IgAN.
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Affiliation(s)
- Kirk N Campbell
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Siân Griffin
- Department of Nephrology, University Hospital of Wales, Cardiff, UK
| | - Howard Trachtman
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Rob Geletka
- Travere Therapeutics, Inc., San Diego, CA, USA
| | - Muh Geot Wong
- Department of Renal Medicine, Concord Repatriation General Hospital, Concord, NSW, Australia
- Concord Clinical School, University of Sydney, Concord, NSW, Australia
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23
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Tian L, Fu S, Li M, Zhao X, Li H. Cost-effectiveness analysis of sodium zirconium cyclosilicate for treating hyperkalemia among Chinese patients. Front Public Health 2023; 11:1196789. [PMID: 38145082 PMCID: PMC10740179 DOI: 10.3389/fpubh.2023.1196789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 11/14/2023] [Indexed: 12/26/2023] Open
Abstract
Objectives Hyperkalemia most commonly develops in chronic kidney disease (CKD) or heart failure (HF) patients. Sodium zirconium cyclosilicate (SZC) is a new selective potassium (K+) binder for treating hyperkalemia. The aim of this study was to evaluate the cost-effectiveness of SZC vs. usual care for the treatment of hyperkalemia among CKD patients or HF patients in China. Methods Individual patient microsimulation models were constructed to simulate a CKD cohort until the initiation of renal replacement therapy (RRT) and a HF cohort across the lifetime horizon. K+ levels were based on two phase 3 clinical trials. Health state utility and event incidence rates were retrieved from literature. Drug costs and healthcare utilization costs were obtained from negotiated price, literature, and expert interviews. Costs and quality-adjusted life-years (QALYs) were both discounted at 5%. The main outcomes were overall costs, QALYs, and incremental cost-effectiveness ratio (ICER). The willingness-to-pay (WTP) threshold in China is CNY 80,976-242,928/QALY, which is one to three times the gross domestic product per capita. Sensitivity analyses were performed to characterize the models' uncertainty. Results In the HF cohort, the base case results revealed that SZC was associated with 2.86 QALYs and the total cost was CNY 92671.58; usual care was associated with 1.81 QALYs and CNY 54101.26. In the CKD cohort, SZC was associated with 3.23 QALYs and CNY 121416.82 total cost; usual care was associated with 2.91 QALYs and CNY 111464.57. SZC resulted in an ICER of CNY 36735.87/QALY for the HF cohort and CNY 31181.55/QALY for the CKD cohort, respectively. The one-way and probability sensitivity analyses found that the results were robust. Conclusion SZC is a cost-effective treatment compared to usual care in HF and CKD patients. SZC is an important novel treatment option for managing patients with hyperkalemia in China.
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Affiliation(s)
| | | | | | | | - Hongchao Li
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
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Junho CVC, Frisch J, Soppert J, Wollenhaupt J, Noels H. Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology. Clin Kidney J 2023; 16:1786-1803. [PMID: 37915935 PMCID: PMC10616472 DOI: 10.1093/ckj/sfad085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Indexed: 11/03/2023] Open
Abstract
The cardiorenal syndrome (CRS) is described as a multi-organ disease encompassing bidirectionally heart and kidney. In CRS type 4, chronic kidney disease (CKD) leads to cardiac injury. Different pathological mechanisms have been identified to contribute to the establishment of CKD-induced cardiomyopathy, including a neurohormonal dysregulation, disturbances in the mineral metabolism and an accumulation of uremic toxins, playing an important role in the development of inflammation and oxidative stress. Combined, this leads to cardiac dysfunction and cardiac pathophysiological and morphological changes, like left ventricular hypertrophy, myocardial fibrosis and cardiac electrical changes. Given that around 80% of dialysis patients suffer from uremic cardiomyopathy, the study of cardiac outcomes in CKD is clinically highly relevant. The present review summarizes clinical features and biomarkers of CKD-induced cardiomyopathy and discusses underlying pathophysiological mechanisms recently uncovered in the literature. It discloses how animal models have contributed to the understanding of pathological kidney-heart crosstalk, but also provides insights into the variability in observed effects of CKD on the heart in different CKD mouse models, covering both "single hit" as well as "multifactorial hit" models. Overall, this review aims to support research progress in the field of CKD-induced cardiomyopathy.
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Affiliation(s)
| | - Janina Frisch
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany
| | - Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Julia Wollenhaupt
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
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25
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Blazek O, Bakris GL. Slowing the Progression of Diabetic Kidney Disease. Cells 2023; 12:1975. [PMID: 37566054 PMCID: PMC10417620 DOI: 10.3390/cells12151975] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/12/2023] Open
Abstract
Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal disease worldwide, and diabetic kidney disease is significantly related to unfavorable cardiovascular outcomes. Since the 1990s, specific therapies have emerged and been approved to slow the progression of diabetic kidney disease, namely, renin-angiotensin-aldosterone system blockers (including angiotensin-converting enzyme inhibitors (ACEi) angiotensin receptor blockers (ARBs), the non-steroidal mineralocorticoid receptor antagonist (NS-MRA), finerenone, and sodium-glucose cotransporter-2 (SGLT2) inhibitors). Mechanistically, these different classes of agents bring different anti-inflammatory, anti-fibrotic, and complementary hemodynamic effects to patients with diabetic kidney disease such that they have additive benefits on slowing disease progression. Within the coming year, there will be data on renal outcomes using the glucagon-like peptide-1 receptor agonist, semaglutide. All the aforementioned medications have also been shown to improve cardiovascular outcomes. Thus, all three classes (maximally dosed ACEi or ARB, low-dose SGLT-2 inhibitors, and the NS-MRA, finerenone) form the "pillars of therapy" such that, when used together, they maximally slow diabetic kidney disease progression. Ongoing studies aim to expand these pillars with additional medications to potentially normalize the decline in kidney function and reduce associated cardiovascular mortality.
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Affiliation(s)
| | - George L. Bakris
- Department of Medicine, American Heart Association Comprehensive Hypertension Center, The University of Chicago Medicine, Chicago, IL 60637, USA;
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Kosaki K, Park J, Matsui M, Sugaya T, Kuro-O M, Saito C, Yamagata K, Maeda S. Elevated urinary angiotensinogen excretion links central and renal hemodynamic alterations. Sci Rep 2023; 13:11518. [PMID: 37460637 PMCID: PMC10352254 DOI: 10.1038/s41598-023-38507-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/11/2023] [Indexed: 07/20/2023] Open
Abstract
Inappropriate activation of intrarenal renin-angiotensin system (RAS) may contribute to the pathogenesis of cardio-renal syndrome (CRS). We aimed to examine the cross-sectional associations of urinary angiotensinogen (AGT) excretion, a biomarker of intrarenal RAS activity, with central (aortic) and renal hemodynamic parameters in middle-aged and older adults, including patients with chronic kidney disease. Aortic and renal hemodynamic parameters were measured using applanation tonometry and duplex ultrasonography in 282 participants. Urinary AGT, liver-type fatty acid-binding protein (L-FABP), and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured for each participant. Multiple linear regression analyses demonstrated that urinary AGT levels were associated with aortic blood pressures, pulsatile measures of renal blood flow, plasma NT-proBNP and urinary L-FABP levels after adjusting for potential covariates, including age, sex, body mass index, estimated glomerular filtration rate (GFR), and medication use. Additionally, when classified based on GFR stages and urinary AGT levels, plasma NT-proBNP and urinary L-FABP levels increased in participants with lower GFR and higher AGT groups. Our findings suggest that urinary AGT excretion is a shared determinant of central (aortic) and renal hemodynamics in middle-aged and older adults, providing clinical evidence for the potential role of intrarenal RAS activity in the development of CRS.
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Affiliation(s)
- Keisei Kosaki
- Institute of Health and Sport Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan.
- Advanced Research Initiative for Human High Performance (ARIHHP), University of Tsukuba, Ibaraki, Japan.
| | - Jiyeon Park
- Institute of Health and Sport Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan
| | - Masahiro Matsui
- Institute of Health and Sport Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan
| | - Takeshi Sugaya
- Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Makoto Kuro-O
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Chie Saito
- Department of Nephrology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kunihiro Yamagata
- Department of Nephrology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
- R&D Center for Smart Wellness City Policies, University of Tsukuba, Tokyo, Japan
| | - Seiji Maeda
- Institute of Health and Sport Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan
- Faculty of Sport Sciences, Waseda University, Saitama, Japan
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Guo H, Bechtel-Walz W. The Interplay of Autophagy and Oxidative Stress in the Kidney: What Do We Know? Nephron Clin Pract 2023; 147:627-642. [PMID: 37442108 DOI: 10.1159/000531290] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 05/19/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Autophagy, as an indispensable metabolism, plays pivotal roles in maintaining intracellular homeostasis. Nutritional stress, amino acid deficiency, oxidative stress, and hypoxia can trigger its initiation. Oxidative stress in the kidney activates essential signal molecules, like mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and silent mating-type information regulation 2 homolog-1 (SIRT1), to stimulate autophagy, ultimately leading to degradation of intracellular oxidative substances and damaged organelles. Growing evidence suggests that autophagy protects the kidney from oxidative stress during acute ischemic kidney injury, chronic kidney disease, and even aging. SUMMARY This review emphasizes the cross talk between reactive oxygen species (ROS) signaling pathways and autophagy during renal homeostasis and chronic kidney disease according to the current latest research and provides therapeutic targets during kidney disorders by adjusting autophagy and suppressing oxidative stress. KEY MESSAGES ROS arise through an imbalance of oxidation and antioxidant defense mechanisms, leading to impaired cellular and organ function. Targeting the overproduction of ROS and reactive nitrogen species, reducing the antioxidant enzyme activity and the recovery of the prooxidative-antioxidative balance provide novel therapeutic regimens to contribute to recovery in acute and chronic renal failure. Although, in recent years, great progress has been made in understanding the molecular mechanisms of oxidative stress and autophagy in acute and chronic renal failure, the focus on clinical therapies is still in its infancy. The growing number of studies on the interactive mechanisms of oxidative stress-mediated autophagy will be of great importance for the future treatment and prevention of kidney diseases.
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Affiliation(s)
- Haihua Guo
- Renal Division, Department of Medicine, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Wibke Bechtel-Walz
- Renal Division, Department of Medicine, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
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Simic J, Mihajlovic M, Zec N, Kovacevic V, Marinkovic M, Mujovic N, Potpara T. The impact of anticoagulation therapy on kidney function in patients with atrial fibrillation and chronic kidney disease. Expert Rev Cardiovasc Ther 2023; 21:937-945. [PMID: 37842943 DOI: 10.1080/14779072.2023.2270909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/11/2023] [Indexed: 10/17/2023]
Abstract
INTRODUCTION Atrial fibrillation (AF) and chronic kidney disease (CKD) are closely related. These diseases share common risk factors and are associated with increased risk of thromboembolic events. Choosing the appropriate oral anticoagulant therapy (OAC) in patients with AF and CKD is challenging. Deterioration of renal function is common in patients with AF treated with OACs, although not all OACs affect the kidneys equally. AREAS COVERED In this review, we aim to summarize the current knowledge of the prevention of thromboembolic events in patients with AF and CKD, focusing on the impact of specific OAC agents on renal function. EXPERT OPINION Consideration of OAC use is mandatory in patients with AF and CKD who are at increased risk of stroke or systemic embolism. Available evidence suggests that the use of non-vitamin K antagonist oral anticoagulants (NOACs) is associated with slower deterioration of renal function in comparison to Vitamin K antagonists (VKAs). Hence, a NOAC should be used in preference to VKAs in all NOAC-eligible patients with AF and CKD. Regarding patients with end-stage renal dysfunction and those on dialysis or renal replacement therapy, the use of NOAC should be considered in line with locally relevant formal recommendations.
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Affiliation(s)
- Jelena Simic
- Cardiology Clinic, University Clinical Centre of Serbia, Belgrade, Serbia
| | | | - Nevena Zec
- School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vladan Kovacevic
- Cardiology Clinic, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Milan Marinkovic
- Cardiology Clinic, University Clinical Centre of Serbia, Belgrade, Serbia
- School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Nebojsa Mujovic
- Cardiology Clinic, University Clinical Centre of Serbia, Belgrade, Serbia
- School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Tatjana Potpara
- Cardiology Clinic, University Clinical Centre of Serbia, Belgrade, Serbia
- School of Medicine, University of Belgrade, Belgrade, Serbia
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Qu L, Jiao B. The Interplay between Immune and Metabolic Pathways in Kidney Disease. Cells 2023; 12:1584. [PMID: 37371054 PMCID: PMC10296595 DOI: 10.3390/cells12121584] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/31/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Kidney disease is a significant health problem worldwide, affecting an estimated 10% of the global population. Kidney disease encompasses a diverse group of disorders that vary in their underlying pathophysiology, clinical presentation, and outcomes. These disorders include acute kidney injury (AKI), chronic kidney disease (CKD), glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetic kidney disease, and many others. Despite their distinct etiologies, these disorders share a common feature of immune system dysregulation and metabolic disturbances. The immune system and metabolic pathways are intimately connected and interact to modulate the pathogenesis of kidney diseases. The dysregulation of immune responses in kidney diseases includes a complex interplay between various immune cell types, including resident and infiltrating immune cells, cytokines, chemokines, and complement factors. These immune factors can trigger and perpetuate kidney inflammation, causing renal tissue injury and progressive fibrosis. In addition, metabolic pathways play critical roles in the pathogenesis of kidney diseases, including glucose and lipid metabolism, oxidative stress, mitochondrial dysfunction, and altered nutrient sensing. Dysregulation of these metabolic pathways contributes to the progression of kidney disease by inducing renal tubular injury, apoptosis, and fibrosis. Recent studies have provided insights into the intricate interplay between immune and metabolic pathways in kidney diseases, revealing novel therapeutic targets for the prevention and treatment of kidney diseases. Potential therapeutic strategies include modulating immune responses through targeting key immune factors or inhibiting pro-inflammatory signaling pathways, improving mitochondrial function, and targeting nutrient-sensing pathways, such as mTOR, AMPK, and SIRT1. This review highlights the importance of the interplay between immune and metabolic pathways in kidney diseases and the potential therapeutic implications of targeting these pathways.
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Affiliation(s)
- Lili Qu
- Division of Nephrology, Department of Medicine, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030-1405, USA
| | - Baihai Jiao
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030-1405, USA
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Nemoto W, Yamagata R, Nakagawasai O, Tan-No K. Angiotensin-Related Peptides and Their Role in Pain Regulation. BIOLOGY 2023; 12:biology12050755. [PMID: 37237567 DOI: 10.3390/biology12050755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/19/2023] [Accepted: 05/20/2023] [Indexed: 05/28/2023]
Abstract
Angiotensin (Ang)-generating system has been confirmed to play an important role in the regulation of fluid balance and blood pressure and is essential for the maintenance of biological functions. Ang-related peptides and their receptors are found throughout the body and exhibit diverse physiological effects. Accordingly, elucidating novel physiological roles of Ang-generating system has attracted considerable research attention worldwide. Ang-generating system consists of the classical Ang-converting enzyme (ACE)/Ang II/AT1 or AT2 receptor axis and the ACE2/Ang (1-7)/MAS1 receptor axis, which negatively regulates AT1 receptor-mediated responses. These Ang system components are expressed in various tissues and organs, forming a local Ang-generating system. Recent findings indicate that changes in the expression of Ang system components under pathological conditions are involved in the development of neuropathy, inflammation, and their associated pain. Here, we summarized the effects of changes in the Ang system on pain transmission in various organs and tissues involved in pain development process.
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Affiliation(s)
- Wataru Nemoto
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Ryota Yamagata
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Osamu Nakagawasai
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Koichi Tan-No
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
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Cho MS, Choi HO, Hwang KW, Kim J, Nam GB, Choi KJ. Clinical benefits and risks of anticoagulation therapy according to the degree of chronic kidney disease in patients with atrial fibrillation. BMC Cardiovasc Disord 2023; 23:209. [PMID: 37098477 PMCID: PMC10131393 DOI: 10.1186/s12872-023-03236-5] [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: 08/07/2022] [Accepted: 04/11/2023] [Indexed: 04/27/2023] Open
Abstract
BACKGROUND The clinical benefits and risks of anticoagulation therapy in patients with chronic kidney disease (CKD) are still inconclusive. We describe the outcomes of patients with atrial fibrillation (AF) after anticoagulation therapy according to differences in creatinine clearance (CrCl). We also aimed to determine the patients who could benefit from anticoagulation therapy. METHODS This is a retrospective observational review of patients with AF who were managed at Asan Medical Center (Seoul, Korea) between January 1, 2006, and December 31, 2018. Patients were categorized into groups according to their baseline CrCl by Cockcroft-Gault equation and their outcomes were evaluated (CKD 1, ≥ 90 mL/min; CKD2, 60-89 mL/min; CKD3, 30-59 mL/min; CKD4, 15-29 mL/min; CKD 5, < 15 mL/min). The primary outcome was NACE (net adverse clinical events), defined as a composite of all-cause mortality, thromboembolic events, and major bleeding. RESULTS We identified 12,714 consecutive patients with AF (mean 64.6 ± 11.9 years, 65.3% male, mean CHA2DS2-VASc score 2.4 ± 1.6 points) between 2006 and 2017. In patients receiving anticoagulation therapy (n = 4447, 35.0%), warfarin (N = 3768, 84.7%) was used more frequently than NOACs (N = 673, 15.3%). There was a higher 3-year rate of NACE with renal function deterioration (14.8%, 18.6%, 30.3%, 44.0%, and 48.8% for CKD stages 1-5, respectively).The clinical benefit of anticoagulation therapy was most prominent in patients with CKD 1 (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.37-0.67), 2 (HR 0.64 CI 0.54-0.76), and 3 (HR 0.64 CI 0.54-0.76), but not in CKD 4 (HR 0.86, CI 0.57-1.28) and 5 (HR 0.81, CI 0.47-1.40). Among patients with CKD, the benefit of anticoagulation therapy was only evident in those with a high risk of embolism (CHA2DS2-VASc score ≥ 4, HR 0.25, CI 0.08-0.80). CONCLUSION Advanced CKD is associated with a higher risk of NACE. The clinical benefit of anticoagulation therapy was reduced with the increasing CKD stage.
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Affiliation(s)
- Min Soo Cho
- Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyung Oh Choi
- Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, 170, Jomaru-ro, Bucheon-si, Gyeonggi-do, 14584, Republic of Korea.
| | - Ki Won Hwang
- Division of Cardiology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University of Medicine, Yangsan, Republic of Korea
| | - Jun Kim
- Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Gi-Byoung Nam
- Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kee-Joon Choi
- Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Cruz NAN, de Oliveira LCG, Fernandes FB, Zaniqueli DDA, Oliosa PR, Mill JG, Casarini DE. Pediatric dyslipidemia is associated with increased urinary ACE activity, blood pressure values, and carotidal-femoral pulse wave velocity. Hypertens Res 2023:10.1038/s41440-023-01240-y. [PMID: 36959504 DOI: 10.1038/s41440-023-01240-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 01/30/2023] [Accepted: 02/10/2023] [Indexed: 03/25/2023]
Abstract
This study aimed to evaluate the enzymatic activity of the angiotensin-converting enzyme (ACE) in children and adolescents to investigate their relationship with dyslipidemia and other cardiometabolic alterations. Anthropometric measurements, blood pressure (BP), and fasting lipid concentrations were taken from 360 subjects. Categorization was done according to the levels of each lipoprotein (total cholesterol, triglycerides (TG), LDL-C, HDL-C, and non-HDL-C) into three groups: normolipidemic (NL), borderline (BL), and dyslipidemic (DL). Enzymatic activity in urine was measured using the substrates Z-FHL-OH and hippuryl-HL-OH (h-HL-OH) and the ACE activity ratio (Z-FHL-OH/h-HL-OH) was calculated. Dyslipidemic levels of HDL-C, TG, and LDL-C were observed in 23%, 9%, and 3% of the participants, respectively, and were more frequent in obese children (Chi-square, p < 0.001). ACE activity ratio was augmented in BL(HDL-C) when compared to NL(HDL-C) (5.06 vs. 2.39, p < 0.01), in DL(LDL-C) in comparison to BL(LDL-C) and NL(LDL-C) (8.7 vs. 1.8 vs. 3.0, p < 0.01), and in DL(non-HDL-C) than in BL(non-HDL-C) and in NL(non-HDL-C) (6.3 vs. 2.1 vs. 2.9, p = 0.02). The groups with impaired HDL-C and TG levels presented an increased diastolic BP percentile, and a higher systolic BP percentile was observed in BL(TG) and DL(TG). The carotidal-femoral pulse wave velocity (cfPWV) was higher in the groups with DL levels of TG and LDL-C than in NL groups. Hypertriglyceridemia was associated with higher cfPWV. No direct impact of the ACE activity on BP values was observed in this cohort, however, there was an association between hyperlipidemia and ACE upregulation which can trigger mechanisms driving to early onset of hypertension and cardiovascular disease. Graphical abstract exemplifying the cohort, categorization of subjects into the groups NL normolipidemic, BL borderline, DL dyslipidemic, methods, and main findings. Pediatric dyslipidemia was consistent with dyslipidemia secondary to obesity (DSO), associated with higher urinary angiotensin-converting enzyme (ACE) activity ratio, BP blood pressure values, and carotidal-femoral pulse wave velocity (cfPWV).
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Affiliation(s)
| | | | | | | | - Polyana Romano Oliosa
- Postgraduate Program in Public Health, Federal University of Espírito Santo, Vitória, Brazil
| | - José Geraldo Mill
- Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil
| | - Dulce Elena Casarini
- Department of Medicine, Discipline of Nephrology, Federal University of São Paulo, São Paulo, Brazil.
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Alshahrani S. Renin-angiotensin-aldosterone pathway modulators in chronic kidney disease: A comparative review. Front Pharmacol 2023; 14:1101068. [PMID: 36860293 PMCID: PMC9970101 DOI: 10.3389/fphar.2023.1101068] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 01/10/2023] [Indexed: 02/16/2023] Open
Abstract
Chronic kidney disease presents a health challenge that has a complex underlying pathophysiology, both acquired and inherited. The pharmacotherapeutic treatment options available today lower the progression of the disease and improve the quality of life but cannot completely cure it. This poses a challenge to the healthcare provider to choose, from the available options, the best way to manage the disease as per the presentation of the patient. As of now, the recommended first line of treatment to control the blood pressure in chronic kidney disease is the administration of renin-angiotensin-aldosterone system modulators. These are represented mainly by the direct renin inhibitor, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. These modulators are varied in their structure and mechanisms of action, hence showing varying treatment outcomes. The choice of administration of these modulators is determined by the presentation and the co-morbidities of the patient, the availability and affordability of the treatment option, and the expertise of the healthcare provider. A direct head-to-head comparison between these significant renin-angiotensin-aldosterone system modulators is lacking, which can benefit healthcare providers and researchers. In this review, a comparison has been drawn between the direct renin inhibitor (aliskiren), angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. This can be of significance for healthcare providers and researchers to find the particular loci of interest, either in structure or mechanism, and to intervene as per the case presentation to obtain the best possible treatment option.
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Affiliation(s)
- Saeed Alshahrani
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jizan, Saudi Arabia
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Afsar B, Afsar RE. Sodium-glucose cotransporter inhibitors and kidney fibrosis: review of the current evidence and related mechanisms. Pharmacol Rep 2023; 75:44-68. [PMID: 36534320 DOI: 10.1007/s43440-022-00442-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 12/09/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022]
Abstract
Sodium-glucose cotransporter inhibitors (SGLT2i) are a new class of anti-diabetic drugs that have beneficial cardiovascular and renal effects. These drugs decrease proximal tubular glucose reabsorption and decrease blood glucose levels as a main anti-diabetic action. Furthermore, SGLT2i decreases glomerular hyperfiltration by a tubuloglomerular feedback mechanism. However, the renal benefits of these agents are independent of glucose-lowering and hemodynamic factors, and SGLT2i also impacts the kidney structure including kidney fibrosis. Renal fibrosis is a common pathway and pathological marker of virtually every type of chronic kidney disease (CKD), and amelioration of renal fibrosis is of utmost importance to reduce the progression of CKD. Recent studies have shown that SGLT2i impact many cellular processes including inflammation, hypoxia, oxidative stress, metabolic functions, and renin-angiotensin system (RAS) which all are related with kidney fibrosis. Indeed, most but not all studies showed that renal fibrosis was ameliorated by SGLT2i through the reduction of inflammation, hypoxia, oxidative stress, and RAS activation. In addition, less known effects on SGLT2i on klotho expression, capillary rarefaction, signal transducer and activator of transcription signaling and peptidylprolyl cis/trans isomerase (Pin1) levels may partly explain the anti-fibrotic effects of SGLT2i in kidneys. It is important to remember that some studies have not shown any beneficial effects of SGLT2i on kidney fibrosis. Given this background, in the current review, we have summarized the studies and pathophysiologic aspects of SGL2 inhibition on renal fibrosis in various CKD models and tried to explain the potential reasons for contrasting findings.
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Affiliation(s)
- Baris Afsar
- Department of Nephrology, School of Medicine, Suleyman Demirel University, Isparta, Turkey.
| | - Rengin Elsurer Afsar
- Department of Nephrology, School of Medicine, Suleyman Demirel University, Isparta, Turkey
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DANANTO C, SEMBIRING YE, SEDIONO PRIBADI OR, TJEMPAKASARI A. Correlation between the position of double-lumen catheter tip with the incidence of recirculation among patients who undergo hemodialysis: a literature review. ITALIAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY 2023. [DOI: 10.23736/s1824-4777.22.01551-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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View of the Renin-Angiotensin System in Acute Kidney Injury Induced by Renal Ischemia-Reperfusion Injury. J Renin Angiotensin Aldosterone Syst 2022; 2022:9800838. [DOI: 10.1155/2022/9800838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/06/2022] [Accepted: 10/12/2022] [Indexed: 11/17/2022] Open
Abstract
Renal ischemia-reperfusion injury (RIRI) is a sequence of complicated events that is defined as a reduction of the blood supply followed by reperfusion. RIRI is the leading cause of acute kidney injury (AKI). Among the diverse mediators that take part in RIRI-induced AKI, the renin-angiotensin system (RAS) plays an important role via conventional (angiotensinogen, renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptor (AT1R)) and nonconventional (ACE2, Ang 1-7, Ang 1-9, AT2 receptor (AT2R), and Mas receptor (MasR)) axes. RIRI alters the balance of both axes so that RAS can affect RIRI-induced AKI. In overall, the alteration of Ang II/AT1R and AKI by RIRI is important to consider. This review has looked for the effects and interactions of RAS activities during RIRI conditions.
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Yildirim U, Karakayali M, Uslu M, Ezer M, Erihan IB, Artac I, Omar T, Karabag Y, Rencuzogullari I. Association between international index of erectile function-5 scores and circadian patterns of newly diagnosed hypertension in erectile dysfunction patients. Andrologia 2022; 54:e14622. [PMID: 36271752 DOI: 10.1111/and.14622] [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: 07/29/2022] [Revised: 09/17/2022] [Accepted: 10/02/2022] [Indexed: 11/29/2022] Open
Abstract
By the beginning of this study in 2019, it was known that hypertension is a risk factor for erectile dysfunction, and also, there are circadian changes that occur in blood pressure. Further, non-dipping hypertension is known to be linked to poor cardiac outcomes and erectile functions, so the research described in this article was initiated with an aim to explore the potential relationship between erectile dysfunction and circadian patterns of newly diagnosed hypertension. Between April 2019 and May 2022, 583 patients aged 30-70 years were diagnosed with erectile dysfunction (ED) in our outpatient clinic. Applying our exclusion criteria to 583 patients, a group of 371 patients left with us; these patients were referred to the cardiology clinic for hypertension evaluation with consecutive ambulatory blood pressure monitoring (ABPM). Data were collected for the study prospectively. Of the 371 patients evaluated with ABPM, 125 had newly diagnosed hypertension (mean BP ≥135/85 mmHg in ABPM). These patients were divided into two groups according to the pattern of hypertension identified in ABPM: dippers (Group D) and non-dippers (Group ND). They were then compared using clinical and laboratory findings, including erectile function scores. While the number of patients in the ND group was 83, the number in the D group was 42. In the ND group, the mean age was higher (59 ± 10 vs. 54 ± 12, p = 0.0024). IIEF-5 (international index of erectile function) scores were determined to be significantly lower in the ND group (14.4 ± 4.9 vs. 11.5 ± 4.6, p = 0.001). Also, serum creatinine levels were higher in Group ND than in D (0.96 ± 0.12 vs. 1 ± 0.15, p = 0.001). In our multivariate analysis, IIEF-5 scores (OR: 0.880, 95% CI: 0.811-0.955; p = 0.002) and serum creatinine levels (OR: 1027, 95% CI: 1003-1052; p = 0.025) were found to be independent risk factors of non-dipper HT. The cut-off value of the IIEF-5 score for non-dipper HT in a ROC curve analysis was 13.5 with 64.3% sensitivity and 66.1% specificity (area under curve value: 0.673 [95% CI: 0.573-0.772, p < 0.001]). This study showed that, in patients with ED, the non-dipper pattern was associated with poorer erectile function when HT was newly diagnosed. We also found that the severity of erectile dysfunction is an independent marker for non-dipper HT.
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Affiliation(s)
- Umit Yildirim
- Department of Urology, M.D. Kafkas University School of Medicine, Kars, Turkey
| | - Muammer Karakayali
- Department of Cardiology, M.D. Kafkas University School of Medicine, Kars, Turkey
| | - Mehmet Uslu
- Department of Urology, M.D. Kafkas University School of Medicine, Kars, Turkey
| | - Mehmet Ezer
- Department of Urology, M.D. Kafkas University School of Medicine, Kars, Turkey
| | - Ismet Bilger Erihan
- Department of Urology, M.D. Kafkas University School of Medicine, Kars, Turkey
| | - Inanc Artac
- Department of Cardiology, M.D. Kafkas University School of Medicine, Kars, Turkey
| | - Timor Omar
- Department of Cardiology, M.D. Kafkas University School of Medicine, Kars, Turkey
| | - Yavuz Karabag
- Department of Cardiology, M.D. Kafkas University School of Medicine, Kars, Turkey
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Sharma V, Patial V. Peroxisome proliferator-activated receptor gamma and its natural agonists in the treatment of kidney diseases. Front Pharmacol 2022; 13:991059. [PMID: 36339586 PMCID: PMC9634118 DOI: 10.3389/fphar.2022.991059] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/12/2022] [Indexed: 11/19/2022] Open
Abstract
Kidney disease is one of the leading non-communicable diseases related to tremendous health and economic burden globally. Diabetes, hypertension, obesity and cardiovascular conditions are the major risk factors for kidney disease, followed by infections, toxicity and autoimmune causes. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated nuclear receptor that plays an essential role in kidney physiology and disease. The synthetic agonists of PPAR-γ shows a therapeutic effect in various kidney conditions; however, the associated side effect restricts their use. Therefore, there is an increasing interest in exploring natural products with PPARγ-activating potential, which can be a promising solution to developing effective and safe treatment of kidney diseases. In this review, we have discussed the role of PPAR-γ in the pathophysiology of kidney disease and the potential of natural PPAR-γ agonists in treating various kidney diseases, including acute kidney injury, diabetic kidney disease, obesity-induced nephropathy, hypertension nephropathy and IgA nephropathy. PPAR-γ is a potential target for the natural PPAR-γ agonists against kidney disease; however, more studies are required in this direction.
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Affiliation(s)
- Vinesh Sharma
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, HP, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, India
| | - Vikram Patial
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, HP, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, India
- *Correspondence: Vikram Patial, ,
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Navarro J, Sanchez A, Ba Aqeel SH, Ye M, Rehman MZ, Wysocki J, Rademaker A, Molitch ME, Batlle D. Urinary Angiotensinogen in Patients With Type 1 Diabetes With Microalbuminuria: Gender Differences and Effect of Intensive Insulin Therapy. Kidney Int Rep 2022; 7:2657-2667. [PMID: 36506234 PMCID: PMC9727532 DOI: 10.1016/j.ekir.2022.09.010] [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: 07/20/2022] [Revised: 08/25/2022] [Accepted: 09/12/2022] [Indexed: 12/15/2022] Open
Abstract
Introduction Angiotensinogen (AOG) is the precursor of peptides of the renin angiotensin system (RAS). Because insulin up-regulates transcriptional factors that normally repress kidney AOG synthesis, we evaluated urinary AOG (uAOG) in patients with type 1 diabetes (T1D) and microalbuminuria who are receiving either intensive or conventional insulin therapy. Methods Urine samples from participants of the Diabetes Control and Complications Trial (DCCT) were used for the following: (i) uAOG/creatinine measurements in 103 patients with microalbuminuria and 103 patients with normoalbuminuria, matched for age, gender, disease duration, and allocation to insulin therapy; and (ii) uAOG/creatinine measurements from patients with microalbuminuria allocated to intensive insulin therapy (n = 58) or conventional insulin therapy (n = 41) after 3 years on each modality. Results uAOG was higher in patients who started with microalbuminuria than in those with normoalbuminuria (6.65 vs. 4.0 ng/mg creatinine, P < 0.01). uAOG was higher in females than in males with microalbuminuria (11.7 vs. 5.4 ng/mg creatinine, P = 0.015). uAOG was lower in patients with microalbuminuria allocated to intensive insulin therapy than in conventional insulin therapy (3.98 vs. 7.42 ng/mg creatinine, P < 0.01). These differences in uAOG were observed though albumin excretion rate (AER) was not significantly different. Conclusion In patients with T1D and microalbuminuria, uAOG is increased and varies with gender and the type of insulin therapy independently of AER. This suggests that AOG production is increased in females and it is decreased by intensive insulin therapy. The reduction in uAOG with intensive insulin therapy, by kidney RAS downregulation, may contribute to the known renoprotective action associated with intensive insulin and improved glycemic control.
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Affiliation(s)
- Jessica Navarro
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Alejandro Sanchez
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Sheeba H. Ba Aqeel
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Minghao Ye
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Mohammed Z. Rehman
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Jan Wysocki
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Alfred Rademaker
- Division of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Mark E. Molitch
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Daniel Batlle
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA,Correspondence: Daniel Batlle, Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, 320 E Superior, Chicago, Illinois 60611, USA.
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Alexandrou ME, Ferro CJ, Boletis I, Papagianni A, Sarafidis P. Hypertension in kidney transplant recipients. World J Transplant 2022; 12:211-222. [PMID: 36159073 PMCID: PMC9453294 DOI: 10.5500/wjt.v12.i8.211] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/07/2022] [Accepted: 08/05/2022] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation is considered the treatment of choice for end-stage kidney disease patients. However, the residual cardiovascular risk remains significantly higher in kidney transplant recipients (KTRs) than in the general population. Hypertension is highly prevalent in KTRs and represents a major modifiable risk factor associated with adverse cardiovascular outcomes and reduced patient and graft survival. Proper definition of hypertension and recognition of special phenotypes and abnormal diurnal blood pressure (BP) patterns is crucial for adequate BP control. Misclassification by office BP is commonly encountered in these patients, and a high proportion of masked and uncontrolled hypertension, as well as of white-coat hypertension, has been revealed in these patients with the use of ambulatory BP monitoring. The pathophysiology of hypertension in KTRs is multifactorial, involving traditional risk factors, factors related to chronic kidney disease and factors related to the transplantation procedure. In the absence of evidence from large-scale randomized controlled trials in this population, BP targets for hypertension management in KTR have been extrapolated from chronic kidney disease populations. The most recent Kidney Disease Improving Global Outcomes 2021 guidelines recommend lowering BP to less than 130/80 mmHg using standardized BP office measurements. Dihydropyridine calcium channel blockers and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers have been established as the preferred first-line agents, on the basis of emphasis placed on their favorable outcomes on graft survival. The aim of this review is to provide previous and recent evidence on prevalence, accurate diagnosis, pathophysiology and treatment of hypertension in KTRs.
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Affiliation(s)
- Maria-Eleni Alexandrou
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Charles J Ferro
- Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2WB, United Kingdom
| | - Ioannis Boletis
- Department of Nephrology, Laiko General Hospital, National and Kapodistrian University, Athens 11527, Greece
| | - Aikaterini Papagianni
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Pantelis Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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Hofherr A, Williams J, Gan LM, Söderberg M, Hansen PBL, Woollard KJ. Targeting inflammation for the treatment of Diabetic Kidney Disease: a five-compartment mechanistic model. BMC Nephrol 2022; 23:208. [PMID: 35698028 PMCID: PMC9190142 DOI: 10.1186/s12882-022-02794-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 04/20/2022] [Indexed: 12/25/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Mortality and morbidity associated with DKD are increasing with the global prevalence of type 2 diabetes. Chronic, sub-clinical, non-resolving inflammation contributes to the pathophysiology of renal and cardiovascular disease associated with diabetes. Inflammatory biomarkers correlate with poor renal outcomes and mortality in patients with DKD. Targeting chronic inflammation may therefore offer a route to novel therapeutics for DKD. However, the DKD patient population is highly heterogeneous, with varying etiology, presentation and disease progression. This heterogeneity is a challenge for clinical trials of novel anti-inflammatory therapies. Here, we present a conceptual model of how chronic inflammation affects kidney function in five compartments: immune cell recruitment and activation; filtration; resorption and secretion; extracellular matrix regulation; and perfusion. We believe that the rigorous alignment of pathophysiological insights, appropriate animal models and pathology-specific biomarkers may facilitate a mechanism-based shift from recruiting ‘all comers’ with DKD to stratification of patients based on the principal compartments of inflammatory disease activity.
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Affiliation(s)
- Alexis Hofherr
- Research and Early Clinical Development, Cardiovascular, Renal and Metabolism, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, Sweden. .,Renal Division, Department of Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Julie Williams
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolic, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, UK
| | - Li-Ming Gan
- Research and Early Clinical Development, Cardiovascular, Renal and Metabolism, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, Sweden.,Department of Molecular and Clinical Medicine, Department of Cardiology, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Magnus Söderberg
- Cardiovascular, Renal and Metabolic Safety, Clinical Pharmacology and Safety Sciences, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, Sweden
| | - Pernille B L Hansen
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolic, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, UK.,Wallenberg Center for Molecular and Translational Medicine, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kevin J Woollard
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolic, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, UK. .,Centre for Inflammatory Disease, Imperial College London, London, UK.
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Ataga KI, Saraf SL, Derebail VK. The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol 2022; 18:361-377. [PMID: 35190716 PMCID: PMC9832386 DOI: 10.1038/s41581-022-00540-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2022] [Indexed: 01/13/2023]
Abstract
Sickle cell syndromes, including sickle cell disease (SCD) and sickle cell trait, are associated with multiple kidney abnormalities. Young patients with SCD have elevated effective renal plasma flow and glomerular filtration rates, which decrease to normal ranges in young adulthood and subnormal levels with advancing age. The pathophysiology of SCD-related nephropathy is multifactorial - oxidative stress, hyperfiltration and glomerular hypertension are all contributing factors. Albuminuria, which is an early clinical manifestation of glomerular damage, is common in individuals with SCD. Kidney function declines more rapidly in individuals with SCD than in those with sickle cell trait or in healthy individuals. Multiple genetic modifiers, including APOL1, HMOX1, HBA1 and HBA2 variants are also implicated in the development and progression of SCD-related nephropathy. Chronic kidney disease and rapid decline in estimated glomerular filtration rate are associated with increased mortality in adults with SCD. Renin-angiotensin-aldosterone system inhibitors are the standard of care treatment for albuminuria in SCD, despite a lack of controlled studies demonstrating their long-term efficacy. Multiple studies of novel therapeutic agents are ongoing, and patients with SCD and kidney failure should be evaluated for kidney transplantation. Given the high prevalence and severe consequences of kidney disease, additional studies are needed to elucidate the pathophysiology, natural history and treatment of SCD-related nephropathy.
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Affiliation(s)
- Kenneth I Ataga
- Center for Sickle Cell Disease, University of Tennessee Health Scienter Center, Memphis, TN, USA.
| | - Santosh L Saraf
- Division of Hematology/Oncology, University of Illinois, Chicago, IL, USA
| | - Vimal K Derebail
- Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC, USA
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Cardiorenal Syndrome: An Updated Classification Based on Clinical Hallmarks. J Clin Med 2022; 11:jcm11102896. [PMID: 35629022 PMCID: PMC9146647 DOI: 10.3390/jcm11102896] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 02/01/2023] Open
Abstract
Cardiorenal syndrome (CRS) is defined as progressive, combined cardiac and renal dysfunction. In this mini review, a historical note on CRS is presented, the pathomechanisms and clinical hallmarks of both chronic heart failure and chronic kidney disease are discussed, and an updated classification of CRS is proposed. The current consensus classification relies on the assumed etiology and the course of the disease, i.e., acute or chronic CRS. Five types are described: type-I CRS presenting as acute cardiac failure leading to acute renal failure; type-II CRS presenting as chronic cardiac failure leading to chronic renal failure; type-III CRS presenting as acute kidney injury aggravating heart failure; type-IV CRS presenting as chronic kidney failure aggravating heart failure; and type-V CRS presenting as concurrent, chronic cardiac and renal failure. For an updated classification, information on the presence or absence of valvular heart disease and on the presence of hyper- or hypovolemia is added. Thus, CRS is specified as “acute” (type-I, type-III or type-V CRS) or “chronic” (type-II, type-IV or type-V) CRS, as “valvular” or “nonvalvular” CRS, and as “hyper-” or “hypovolemia-associated” CRS if euvolemia is absent. To enable the use of this updated classification, validation studies are mandated.
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Zhong L, Wu C, Li Y, Zeng Q, Lai L, Chen S, Tang S. Nonalcoholic fatty liver disease and health outcomes: An umbrella review of systematic reviews and meta-analyses. Ther Adv Chronic Dis 2022; 13:20406223221083508. [PMID: 35620184 PMCID: PMC9127863 DOI: 10.1177/20406223221083508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 02/09/2022] [Indexed: 11/17/2022] Open
Abstract
Purpose: A large number of systemic reviews and meta-analyses have explored the relationship between nonalcoholic fatty liver disease (NAFLD) and multiple health outcomes. The aim of this study is to conduct an umbrella review to assess the strength and evidence for the association between NAFLD and health outcomes. Methods: We systematically identified the present meta-analyses of observational studies reporting an association between NAFLD and health outcomes. For each meta-analysis, we assessed the quality with AMSTAR2 and graded the epidemiologic evidence. Results: Fifty-four articles comprising 111 unique meta-analyses were included in this study. Eighty-five unique outcomes showed significant associations ( P ← 0.05), whereas 26 unique outcomes showed insignificant associations, and we cannot assess the epidemiologic evidence. For 85 significant health outcomes, four outcomes (carotid intima-media thickness (C-IMT), peak A velocity, left ventricle end-diastolic diameter, incident chronic kidney disease (CKD) in adult patients) was graded as high quality of evidence, 23 outcomes were graded as the moderate quality of evidence, and the remaining 58 outcomes were graded as weak quality of evidence. Fourty-seven (87.03%) studies showed critically low methodological quality. Conclusion: In this umbrella review, only four statistically significant health outcomes showed high epidemiologic evidence. NAFLD seems to relate to an increased risk of C-IMT, peak A velocity, left ventricle end-diastolic diameter, and incident CKD in adult patients.
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Affiliation(s)
- Lixian Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China
| | - Chutian Wu
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China
| | - Yuting Li
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China
| | - Qiuting Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China
| | - Leizhen Lai
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China
| | - Sisi Chen
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China
| | - Shaohui Tang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, P.R. China
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Okamoto K, Fujii H, Watanabe K, Goto S, Kono K, Nishi S. Changes of FGF23 and the Renin-Angiotensin-System in Male Mouse Models of Chronic Kidney Disease and Cardiac Hypertrophy. J Endocr Soc 2022; 6:bvab187. [PMID: 35047715 PMCID: PMC8758403 DOI: 10.1210/jendso/bvab187] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Indexed: 11/19/2022] Open
Abstract
Serum fibroblast growth factor 23 (FGF23) levels and the renin-angiotensin-aldosterone system (RAAS) are elevated in chronic kidney disease (CKD) patients, and their association with left ventricular hypertrophy (LVH) has been reported. However, whether the FGF23 elevation is the cause or result of LVH remains unclear. At 10 weeks, male C57BL/6J mice were divided into 4 groups: sham, CKD (5/6 nephrectomy), LVH (transaortic constriction), and CKD/LVH group. At 16 weeks, the mice were euthanized, and blood and urine, cardiac expressions of FGF23 and RAAS-related factors, and cardiac histological analyses were performed. Heart weight, serum FGF23 levels, and cardiac expression of FGF23 and RAAS-related factors, except for angiotensin-converting enzyme 2, were more increased in the CKD/LVH group compared to the other groups. A significant correlation between LVH and cardiac expressions of FGF23 and RAAS-related factors was observed. Furthermore, there was a significantly close correlation of the cardiac expression of FGF23 with LVH and RAAS-related factors. The coexisting CKD and LVH increased serum and cardiac FGF23 and RAAS-related factors, and there was a significant correlation between them. A close correlation of cardiac, but not serum FGF23, with LVH and RAAS suggests that local FGF23 levels may be associated with LVH and RAAS activation.
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Affiliation(s)
- Kohei Okamoto
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Hideki Fujii
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Kentaro Watanabe
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Shunsuke Goto
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Keiji Kono
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Shinichi Nishi
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
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46
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Honda N, Ochi A, Uchimoto S, Kakutani Y, Yamazaki Y, Morioka T, Shoji T, Inaba M, Emoto M. Factors associated with atrial fibrillation in Japanese patients with type 2 diabetes mellitus: a cross-sectional study. Diabetol Int 2022; 13:503-512. [PMID: 35693991 PMCID: PMC9174394 DOI: 10.1007/s13340-021-00563-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/09/2021] [Indexed: 01/26/2023]
Abstract
Aims Atrial fibrillation (AF) increases cardiovascular complications and mortality in patients with diabetes. Diabetes is a risk factor for AF; however, risk factors for AF among patients with type 2 diabetes (T2D) remain unknown, especially among Asian people. We clarified the prevalence of AF, regardless of type (i.e., paroxysmal, persistent, or permanent) in Japanese patients with T2D and clarified factors associated with AF. Methods This cross-sectional study was conducted at Fujiidera Municipal Hospital (Osaka, Japan). Patients with T2D (n = 899: 518 men and 381 women with a mean age ± SD of 69.0 ± 12.1 years) were included. Their electrocardiographs were checked during routine examinations between January 2017 and January 2018. A diagnosis of AF was determined from single time-point standard 12-lead electrocardiographic findings. We analyzed clinical parameters (e.g., age, sex, diabetes duration, glycated hemoglobin, body mass index, estimated glomerular filtration rate, albuminuria or proteinuria, use of biguanide, and presence of hypertension) between patients with and without AF. Results The prevalence of AF among patients with T2D was 5.9%; it became higher as age increased and tended to be higher in men than in women. The prevalence became higher as albuminuria or proteinuria progressed and as the eGFR decreased. Multiple logistic regression analyses revealed that older age, male sex, and reduced eGFR were independently and significantly associated with the coexistence of AF. However, multiple logistic regression analysis revealed no significant relationships between AF and the presence of albuminuria or proteinuria. Conclusions Older age, male sex, and reduced eGFR were associated with AF in Japanese patients with T2D. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-021-00563-w.
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Affiliation(s)
- Natsuki Honda
- grid.261445.00000 0001 1009 6411Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan ,Internal Medicine, Fujiidera Municipal Hospital, 2-7-3, Domyozi, Fujiidera City, Osaka 583-0012 Japan
| | - Akinobu Ochi
- grid.261445.00000 0001 1009 6411Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan
| | - Sadahiko Uchimoto
- Internal Medicine, Fujiidera Municipal Hospital, 2-7-3, Domyozi, Fujiidera City, Osaka 583-0012 Japan
| | - Yoshinori Kakutani
- grid.261445.00000 0001 1009 6411Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan
| | - Yuko Yamazaki
- grid.261445.00000 0001 1009 6411Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan
| | - Tomoaki Morioka
- grid.261445.00000 0001 1009 6411Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan
| | - Tetsuo Shoji
- grid.261445.00000 0001 1009 6411Department of Vascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan ,grid.261445.00000 0001 1009 6411Vascular Science Center for Translational Research, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan
| | - Masaaki Inaba
- grid.261445.00000 0001 1009 6411Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan
| | - Masanori Emoto
- grid.261445.00000 0001 1009 6411Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan
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Sodium Thiosulfate Improves Hypertension in Rats with Adenine-Induced Chronic Kidney Disease. Antioxidants (Basel) 2022; 11:antiox11010147. [PMID: 35052651 PMCID: PMC8772748 DOI: 10.3390/antiox11010147] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/29/2021] [Accepted: 01/10/2022] [Indexed: 12/15/2022] Open
Abstract
Hypertension is highly prevalent in chronic kidney disease (CKD). Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with vasodilator properties. We, hence, investigated whether oral administration of sodium thiosulfate (STS), a clinically applicable H2S-based therapy, can exert a protective effect against hypertension in an adenine-induced CKD rat model. Eight-week-old male Sprague–Dawley rats were fed with 0.5% adenine chow for 3 weeks to induce CKD. After 1 week, the rats were divided into two groups: one without and one with STS (2 g/kg body weight/day) in drinking water for 2 weeks. Treatment with STS lowered systolic and diastolic blood pressure by 7 and 9 mm Hg, respectively. Renal H2S-generating enzyme expression was inhibited by CKD, while STS therapy increased plasma levels of H2S and thiosulfate. Additionally, restoration of nitric oxide bioavailability and rebalance of the renin–angiotensin system may contribute to the protective effects of STS. Our data suggest that the oral administration of STS improves hypertension in an adenine-induced CKD model, which brings us closer to the clinical translation of H2S-targeting therapy in CKD-induced hypertension.
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Yaribeygi H, Maleki M, Majeed M, Jamialahmadi T, Sahebkar A. Renoprotective Roles of Curcumin. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1328:531-544. [PMID: 34981504 DOI: 10.1007/978-3-030-73234-9_38] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The use of herb-based therapies is increasing over the past decades. These agents have been reported to provide many beneficial effects in many experimental and clinical studies. Curcumin is one of these agents which has potent pharmacological effects enabling it for the prevent and treatment of many diseases and pathologies such as renal disorders, hyperglycemia, oxidative stress, hypertension, and dyslipidemia. However, the exact molecular mechanisms mediating these renoprotective effects of curcumin are not well established. So, in the current study, we surveyed for possible renoprotective roles of curcumin and concluded how curcumin protects against renal injuries.
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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
| | | | - Tannaz Jamialahmadi
- 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
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Mende CW. Chronic Kidney Disease and SGLT2 Inhibitors: A Review of the Evolving Treatment Landscape. Adv Ther 2022; 39:148-164. [PMID: 34846711 PMCID: PMC8799531 DOI: 10.1007/s12325-021-01994-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/10/2021] [Indexed: 12/31/2022]
Abstract
There is currently an unmet need for effective treatment of chronic kidney disease (CKD) that slows disease progression, prevents development of end-stage kidney disease and cardiovascular disease, and prolongs survival of patients with CKD. In the last 20 years, the only agents to show a reduction in the risk of CKD progression in patients with and without type 2 diabetes (T2D) were angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, but neither drug class has provided a decreased risk of all-cause mortality in patients with CKD and evidence for their use in patients with CKD without T2D is relatively limited. This review discusses the mechanisms underlying the progression of CKD, its associated risk factors, and summarizes the potential therapeutic approaches for managing CKD. There is increasing evidence to support the role of sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy in patients with CKD, including data from the designated kidney outcome trials in patients with T2D (CREDENCE) and in patients with or without T2D (DAPA-CKD). These studies showed a significant reduction in the risk of CKD progression with canagliflozin (in patients with T2D) or dapagliflozin (in patients with or without T2D), respectively, with DAPA-CKD being the first trial to show a reduced risk of all-cause mortality. On the basis of these data, individualized treatment with SGLT2 inhibitors represents a promising therapeutic option for patients with diabetic and nondiabetic CKD to slow disease progression.
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Affiliation(s)
- Christian W Mende
- Department of Medicine, University of California-San Diego, 6950 Fairway Rd, La Jolla, CA, 92037, USA.
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50
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Rieger AC, Tompkins BA, Natsumeda M, Florea V, Banerjee MN, Rodriguez J, Rosado M, Porras V, Valasaki K, Takeuchi LM, Collon K, Desai S, Bellio MA, Khan A, Kashikar ND, Landin AM, Hardin DV, Rodriguez DA, Balkan W, Hare JM, Schulman IH. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:59-72. [PMID: 35641169 PMCID: PMC8895493 DOI: 10.1093/stcltm/szab004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/29/2021] [Indexed: 11/28/2022] Open
Abstract
Background Left ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) are primary manifestations of the cardiorenal syndrome in patients with chronic kidney disease (CKD). Therapies that improve morbidity and mortality in HFpEF are lacking. Cell-based therapies promote cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that cell-based therapy ameliorates CKD-induced HFpEF. Methods and Results Yorkshire pigs (n = 26) underwent 5/6 embolization-mediated nephrectomy. CKD was confirmed by increased creatinine and decreased glomerular filtration rate (GFR). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. HFpEF was evident at 4 weeks by increased LV mass, relative wall thickening, end-diastolic pressure, and end-diastolic pressure-volume relationship, with no change in ejection fraction (EF). Four weeks post-embolization, allogeneic (allo) bone marrow-derived mesenchymal stem cells (MSC; 1 × 107 cells), allo-kidney-derived stem cells (KSC; 1 × 107 cells), allo-cell combination therapy (ACCT; MSC + KSC; 1:1 ratio; total = 1 × 107 cells), or placebo (Plasma-Lyte) was delivered via intra-renal artery. Eight weeks post-treatment, there was a significant increase in MAP in the placebo group (21.89 ± 6.05 mmHg) compared to the ACCT group. GFR significantly improved in the ACCT group. EF, relative wall thickness, and LV mass did not differ between groups at 12 weeks. EDPVR improved in the ACCT group, indicating decreased ventricular stiffness. Conclusions Intra-renal artery allogeneic cell therapy was safe in a CKD swine model manifesting the characteristics of HFpEF. The beneficial effect on renal function and ventricular compliance in the ACCT group supports further research of cell therapy for cardiorenal syndrome.
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Affiliation(s)
- Angela C Rieger
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Bryon A Tompkins
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Makoto Natsumeda
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Victoria Florea
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Monisha N Banerjee
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jose Rodriguez
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Marcos Rosado
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Valeria Porras
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Krystalenia Valasaki
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Lauro M Takeuchi
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kevin Collon
- Department of Orthopedic Surgery, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
| | - Sohil Desai
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Michael A Bellio
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Aisha Khan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Ana Marie Landin
- Cell Therapy and Vaccine Lab, Moffitt Cancer Center, Tampa, FL, USA
| | - Darrell V Hardin
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Daniel A Rodriguez
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ivonne Hernandez Schulman
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
- Corresponding author: Ivonne H. Schulman, MD, Program Director, Translational and Clinical Studies of Acute Kidney Injury, Division of Kidney, Urologic and Hematologic Diseases (KUH), National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Two Democracy Plaza, Room #6077, 6707 Democracy Blvd, Bethesda, MD 20892-5458, USA. Tel: 301-435-3350; Mobile: 301-385-5744; Fax: 301-480-3510, ,
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