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Kruglova MP, Ivanov AV, Fedoseev AN, Virus ED, Stupin VA, Parfenov VA, Titova SA, Lazareva PI, Kubatiev AA, Silina EV. The Diagnostic and Prognostic Roles Played by Homocysteine and Other Aminothiols in Patients with Chronic Kidney Disease. J Clin Med 2023; 12:5653. [PMID: 37685718 PMCID: PMC10488590 DOI: 10.3390/jcm12175653] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/22/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
We examined standard clinical and laboratory biochemical parameters, as well as the levels of aminothiols in the blood and urine (homocysteine (Hcy), cysteine (Cys), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH)) via capillary electrophoresis in patients with CKD at stages II-V. Patient outcomes were assessed after five years. To complete forecasting, correlation and ROC analysis were performed. It was found that the levels of Cys and Hcy in blood plasma were earlier markers of CKD starting from stage II, while the levels of SAM and SAM/SAH in urine made it possible to differentiate between CKD at stages II and III. Blood plasma Hcy and urinary SAM and SAM/SAH correlated with mortality, but plasma Hcy concentrations were more significant. Thus, plasma Hcy, urine SAM, and SAM/SAH can be considered to be potential diagnostic and prognostic markers in patients with CKD.
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Affiliation(s)
- Maria Petrovna Kruglova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya St., 8, 119991 Moscow, Russia; (M.P.K.); (V.A.P.); (S.A.T.); (P.I.L.)
| | - Alexander Vladimirovich Ivanov
- Institute of General Pathology and Pathophysiology, Baltiyskaya St., 8, 125315 Moscow, Russia; (A.V.I.); (E.D.V.); (A.A.K.)
| | | | - Edward Danielevich Virus
- Institute of General Pathology and Pathophysiology, Baltiyskaya St., 8, 125315 Moscow, Russia; (A.V.I.); (E.D.V.); (A.A.K.)
| | | | - Vladimir Anatolyevich Parfenov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya St., 8, 119991 Moscow, Russia; (M.P.K.); (V.A.P.); (S.A.T.); (P.I.L.)
| | - Svetlana Andreevna Titova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya St., 8, 119991 Moscow, Russia; (M.P.K.); (V.A.P.); (S.A.T.); (P.I.L.)
| | - Polina Igorevna Lazareva
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya St., 8, 119991 Moscow, Russia; (M.P.K.); (V.A.P.); (S.A.T.); (P.I.L.)
| | - Aslan Amirkhanovich Kubatiev
- Institute of General Pathology and Pathophysiology, Baltiyskaya St., 8, 125315 Moscow, Russia; (A.V.I.); (E.D.V.); (A.A.K.)
| | - Ekaterina Vladimirovna Silina
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya St., 8, 119991 Moscow, Russia; (M.P.K.); (V.A.P.); (S.A.T.); (P.I.L.)
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Zhao W, Gao F, Lv L, Chen X. The interaction of hypertension and homocysteine increases the risk of mortality among middle-aged and older population in the United States. J Hypertens 2022; 40:254-263. [PMID: 34475348 DOI: 10.1097/hjh.0000000000003002] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To investigate the interaction of hypertension and total plasma homocysteine (tHcy) levels on risk of all-cause and cardiovascular disease (CVD) mortality among middle-aged and older population. METHODS This observational cohort study analyzed data from the National Health and Nutrition Examination Survey database (1999-2002 survey cycle). A generalized additive model (GAM) based on Cox proportional hazards models was applied to estimate the relationship of tHcy level with all-cause and CVD mortality. Stratification analyses by sex and renal function were performed. RESULTS Among 5724 individuals aged 40-85, 704 (12.3%) died, with 339 CVD deaths after a median follow-up period of 5.58 years. Mean age was 60.7 ± 13.4 years (49.6% men). In the fully adjusted model, we found that per 1 μmol/l increment of plasma tHcy was associated with 8% increased risk of all-cause mortality and 7% increased risk of CVD mortality in hypertensive participants. The adjusted hazard ratio (95% CIs) for all-cause and CVD mortality were 1.08 (1.06-1.10) and 1.07 (1.04-1.10), respectively. There were pronounced interactive effects between hypertension and tHcy levels on risk of all-cause mortality (P for interaction = 0.031). CONCLUSION Hypertension and tHcy levels can interactively affect the risk of all-cause mortality among middle-aged and older population. Conceivably, hypertension may further enhance the ability of elevated tHcy to provoke the risk of all-cause mortality.
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Affiliation(s)
| | - Faliang Gao
- Department of Neurosurgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College
| | - Laidi Lv
- Department of General Practice, Hangzhou Zhaohui Jiedao Community Healthcare Center, Hangzhou, Zhejiang, China
| | - Xi Chen
- Department of General Practice
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Kruglova MP, Ivanov AV, Virus ED, Bulgakova PO, Samokhin AS, Fedoseev AN, Grachev SV, Kubatiev AA. Urine S-Adenosylmethionine are Related to Degree of Renal Insufficiency in Patients with Chronic Kidney Disease. Lab Med 2021; 52:47-56. [PMID: 32702115 DOI: 10.1093/labmed/lmaa034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE To determine whether urine S-adenosylmethionine (SAM) might be an indicator of chronic kidney disease (CKD). METHODS We investigated urine levels of SAM and related metabolites (S-adenosylhomocysteine and homocysteine cysteine) in 62 patients (average age, 65.9 years) with CKD (stages II-V). RESULTS Patients with stages III-V CKD stages have significantly decreased urine levels and SAM/S-adenosylhomocysteine ratio and also cysteine/homocysteine ratio in blood plasma (P <.05), compared with patients with stage II CKD. Urine SAM levels allowed us to distinguish patients with mildly decreased kidney function from those with moderate to severe renal impairment (AUC, 0.791; sensitivity, 85%; specificity, 78.6%). CONCLUSIONS Our study results demonstrate that urine SAM is a potent biomarker for monitoring renal function decline at early CKD stages. Urine SAM testing confers an additional advantage to healthcare professionals in that it is noninvasive.
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Affiliation(s)
| | | | - Edward Danielevich Virus
- Department of Molecular and Cell Pathophysiology, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Polina Olegovna Bulgakova
- Department of Molecular and Cell Pathophysiology, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Andrey Segeevich Samokhin
- Department of Molecular and Cell Pathophysiology, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | | | | | - Aslan Amirkhanovich Kubatiev
- Department of Molecular and Cell Pathophysiology, Institute of General Pathology and Pathophysiology, Moscow, Russia.,Russian Medical Academy of Postdoctoral Education, Moscow, Russia
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Xiao W, Ye P, Wang F, Cao R, Bai Y, Wang X. Plasma Homocysteine Is a Predictive Factor for Accelerated Renal Function Decline and Chronic Kidney Disease in a Community-Dwelling Population. Kidney Blood Press Res 2021; 46:541-549. [PMID: 34365457 DOI: 10.1159/000514360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/12/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Whether elevated plasma total homocysteine (tHcy) is a risk factor for the progression of kidney disease in general population has not been well established. The purpose of this study was to investigate the prognostic properties of plasma tHcy for renal function decrement and early chronic kidney disease (CKD) in community-dwelling populations with normal renal function at baseline. METHODS A total of 1,426 participants were enrolled and followed for a median of 4.8 years (interquartile range, 4.5-5.2), and estimated glomerular filtration rate (eGFR) was evaluated. One main outcome was the rapid eGFR decline defined as a decline in eGFR of >3 mL/min per 1.73 m2 per year; the other was the new incidence of CKD. RESULTS At the end of follow-up, the incidence of rapid eGFR decline and new-onset CKD was 20.7 and 5.6%, respectively. In multivariate linear regression analysis, age, central pulse pressure, fasting blood glucose, and concentration of tHcy were independent determinants of the change in eGFR. There was a graded association between tHcy quartiles and eGFR decline. Compared with participants with the lowest quartile of tHcy levels, those with the highest quartile had significantly increased risk for rapid eGFR decline (adjusted odds ratio [aOR] = 1.81; 95% confidence interval [CI]: 1.25-2.94) and new onset of CKD (adjusted hazard ratio = 4.29; 95% CI: 1.42-12.99) after adjusting for various confounders. Similarly, significant associations were also found when baseline tHcy was classified as hyperhomocysteinemia (>15 μmol/L) versus normal tHcy level (≤15 μmol/L). However, there was only association between the change in tHcy levels and new occurrence of CKD but not with rapid eGFR decline (aOR = 0.99, p = 0.613). CONCLUSIONS In this prospective cohort of individuals from community-based population, elevated plasma tHcy emerged as an independent predictor of renal function decline and incident CKD, which might support selection of at-risk individuals.
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Affiliation(s)
- Wenkai Xiao
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ping Ye
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Fan Wang
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ruihua Cao
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yongyi Bai
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaona Wang
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
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Lanthionine, a Novel Uremic Toxin, in the Vascular Calcification of Chronic Kidney Disease: The Role of Proinflammatory Cytokines. Int J Mol Sci 2021; 22:ijms22136875. [PMID: 34206780 PMCID: PMC8269354 DOI: 10.3390/ijms22136875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/24/2021] [Accepted: 06/23/2021] [Indexed: 12/14/2022] Open
Abstract
Vascular calcification (VC) is a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD). Several components influence the occurrence of VC, among which inflammation. A novel uremic toxin, lanthionine, was shown to increase intracellular calcium in endothelial cells and may have a role in VC. A group of CKD patients was selected and divided into patients with a glomerular filtration rate (GFR) of <45 mL/min/1.73 m2 and ≥45 mL/min/1.73 m2. Total Calcium Score (TCS), based on the Agatston score, was assessed as circulating lanthionine and a panel of different cytokines. A hemodialysis patient group was also considered. Lanthionine was elevated in CKD patients, and levels increased significantly in hemodialysis patients with respect to the two CKD groups; in addition, lanthionine increased along with the increase in TCS, starting from one up to three. Interleukin IL-6, IL-8, and Eotaxin were significantly increased in patients with GFR < 45 mL/min/1.73 m2 with respect to those with GFR ≥ 45 mL/min/1.73 m2. IL-1b, IL-7, IL-8, IL-12, Eotaxin, and VEGF increased in calcified patients with respect to the non-calcified. IL-8 and Eotaxin were elevated both in the low GFR group and in the calcified group. We propose that lanthionine, but also IL-8 and Eotaxin, in particular, are a key feature of VC of CKD, with possible marker significance.
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Xiang T, Xiang H, Yan M, Yu S, Horwedel MJ, Li Y, Zeng Q. Systemic risk factors correlated with hyperhomocysteinemia for specific MTHFR C677T genotypes and sex in the Chinese population. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1455. [PMID: 33313200 PMCID: PMC7723589 DOI: 10.21037/atm-20-6587] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Background Methyltetrahydrofolate reductase (MTHFR) is a main regulatory enzyme in homocysteine (Hcy) metabolism. A common C677T mutation in the MTHFR gene results in decreased enzyme activity, which contributes to hyperhomocysteinemia (HHcy). Previous studies have shown that HHcy was correlated with various systemic diseases, such as cardiovascular disease, stroke, cancer, renal failure and so on. However, we hypothesized that HHcy in different genotype and sex groups may have different risk factors, which would lead to various pathologic states. Therefore, the aim of this study was to explore systemic information that are correlated with HHcy for specific MTHFR C677T genotypes and sex, which might be useful for predicting and preventing systemic diseases. Methods This cross-sectional study was performed through November 2017 to July 2019. A total of 4,534 adults aged 20–75 y were selected for this study. All the participants underwent a physical examination, blood tests and MTHFRC677T genotyping. Multivariable linear regression was performed to explore the risk factors for HHcy for each sex and genotype. Results The average of Hcy level is higher in the TT genotype than CC and CT genotypes (P=0.000). Multiple linear regression analysis identified the common protective factors (folate and Vit B12) and risk factor (Cr) for HHcy. Besides that, each group has its specific risk factors—female-CT (age, SBP, and Hb), female-TT (SBP and AST); male-CC (age, AST and Hb), male-CT (age and AST) and male-TT (SBP, AST, and Hb). Conclusions HHcy was associated with different risk factors for each specific sex and genotype. These risk factors might be useful for predicting and preventing systemic diseases.
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Affiliation(s)
- Tianyuan Xiang
- China Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China.,Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Hang Xiang
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA.,Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Muyang Yan
- Department of Hyperbaric-Oxygen, Chinese PLA General Hospital, Beijing, China
| | - Sheng Yu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Matthew John Horwedel
- Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Yang Li
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Qiang Zeng
- China Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
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Homocysteine and chronic kidney disease: an ongoing narrative. J Nephrol 2019; 32:673-675. [DOI: 10.1007/s40620-019-00622-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 06/17/2019] [Indexed: 10/26/2022]
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Vigorito C, Anishchenko E, Mele L, Capolongo G, Trepiccione F, Zacchia M, Lombari P, Capasso R, Ingrosso D, Perna AF. Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium. Int J Mol Sci 2019; 20:E2269. [PMID: 31071929 PMCID: PMC6539355 DOI: 10.3390/ijms20092269] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/03/2019] [Accepted: 05/06/2019] [Indexed: 01/08/2023] Open
Abstract
(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.
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Affiliation(s)
- Carmela Vigorito
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy.
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli," 80138 Naples, Italy.
| | - Evgeniya Anishchenko
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy.
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli," 80138 Naples, Italy.
| | - Luigi Mele
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," 80138 Naples, Italy.
| | - Giovanna Capolongo
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy.
| | - Francesco Trepiccione
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy.
- Biogem A. C. S. R. L. Contrada Camporeale, 83031 Ariano Irpino AV, Italy.
| | - Miriam Zacchia
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy.
| | - Patrizia Lombari
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy.
| | - Rosanna Capasso
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli," 80138 Naples, Italy.
| | - Diego Ingrosso
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli," 80138 Naples, Italy.
| | - Alessandra F Perna
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy.
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Capelli I, Cianciolo G, Gasperoni L, Zappulo F, Tondolo F, Cappuccilli M, La Manna G. Folic Acid and Vitamin B12 Administration in CKD, Why Not? Nutrients 2019; 11:nu11020383. [PMID: 30781775 PMCID: PMC6413093 DOI: 10.3390/nu11020383] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 02/09/2019] [Accepted: 02/11/2019] [Indexed: 12/13/2022] Open
Abstract
Patients affected by chronic kidney disease (CKD) or end-stage renal disease (ESRD) experience a huge cardiovascular risk and cardiovascular events represent the leading causes of death. Since traditional risk factors cannot fully explain such increased cardiovascular risk, interest in non-traditional risk factors, such as hyperhomocysteinemia and folic acid and vitamin B12 metabolism impairment, is growing. Although elevated homocysteine blood levels are often seen in patients with CKD and ESRD, whether hyperhomocysteinemia represents a reliable cardiovascular and mortality risk marker or a therapeutic target in this population is still unclear. In addition, folic acid and vitamin B12 could not only be mere cofactors in the homocysteine metabolism; they may have a direct action in determining tissue damage and cardiovascular risk. The purpose of this review was to highlight homocysteine, folic acid and vitamin B12 metabolism impairment in CKD and ESRD and to summarize available evidences on hyperhomocysteinemia, folic acid and vitamin B12 as cardiovascular risk markers, therapeutic target and risk factors for CKD progression.
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Affiliation(s)
- Irene Capelli
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola Hospital, University of Bologna, 40138 Bologna, Italy.
| | - Giuseppe Cianciolo
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola Hospital, University of Bologna, 40138 Bologna, Italy.
| | - Lorenzo Gasperoni
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola Hospital, University of Bologna, 40138 Bologna, Italy.
| | - Fulvia Zappulo
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola Hospital, University of Bologna, 40138 Bologna, Italy.
| | - Francesco Tondolo
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola Hospital, University of Bologna, 40138 Bologna, Italy.
| | - Maria Cappuccilli
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola Hospital, University of Bologna, 40138 Bologna, Italy.
| | - Gaetano La Manna
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola Hospital, University of Bologna, 40138 Bologna, Italy.
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Perna AF, Glorieux G, Zacchia M, Trepiccione F, Capolongo G, Vigorito C, Anishchenko E, Ingrosso D. The role of the intestinal microbiota in uremic solute accumulation: a focus on sulfur compounds. J Nephrol 2019; 32:733-740. [PMID: 30673975 DOI: 10.1007/s40620-019-00589-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 01/18/2019] [Indexed: 12/11/2022]
Abstract
The gut microbiota is considered to be a novel important factor to take into account in the pathogenesis of chronic kidney disease and uremia. Much attention has been paid to specific uremic retention solutes of microbial origin, such as indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide. However, other novel less well studied compounds, such as hydrogen sulfide and related sulfur metabolites (sulfane sulfur, lanthionine, etc.), should be included in a more comprehensive appraisal of this topic, in light of the potential therapeutic opportunities for the future.
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Affiliation(s)
- Alessandra F Perna
- First Division of Nephrology, Department of Translational Medical Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, Bldg 17, 80131, Naples, Italy.
| | - Griet Glorieux
- Nephrology Section, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium
| | - Miriam Zacchia
- First Division of Nephrology, Department of Translational Medical Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, Bldg 17, 80131, Naples, Italy
| | - Francesco Trepiccione
- First Division of Nephrology, Department of Translational Medical Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, Bldg 17, 80131, Naples, Italy
| | - Giovanna Capolongo
- First Division of Nephrology, Department of Translational Medical Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, Bldg 17, 80131, Naples, Italy
| | - Carmela Vigorito
- First Division of Nephrology, Department of Translational Medical Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, Bldg 17, 80131, Naples, Italy
| | - Evgeniya Anishchenko
- First Division of Nephrology, Department of Translational Medical Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, Bldg 17, 80131, Naples, Italy
| | - Diego Ingrosso
- Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Luigi de Crecchio 7, 80138, Naples, Italy
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The Protective Effects of Enalapril Maleate and Folic Acid Tablets against Contrast-Induced Nephropathy in Diabetic Rats. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4609750. [PMID: 29560361 PMCID: PMC5820582 DOI: 10.1155/2018/4609750] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 01/09/2018] [Indexed: 01/18/2023]
Abstract
Background Renal vasoconstriction, oxidative stress, endothelial dysfunction, and apoptosis are the major causes of contrast-induced nephropathy (CIN). The aim of this study was to evaluate the protective effects of enalapril maleate and folic acid tablets on CIN in diabetic rats. Methods Thirty-two Sprague-Dawley rats were divided into four groups: CIN (C), CIN + enalapril maleate (CE), CIN + folic acid (CF), and CIN + enalapril maleate and folic acid tablets (CEF). CE, CF, and CEF rats were treated orally with enalapril maleate, folic acid, or enalapril maleate and folic acid tablets, respectively, for 5 days. CIN was induced in all groups followed by analyzed biochemical parameters, oxidative stress markers, endothelial dysfunction parameters, renal histopathology, and TUNEL staining. Results Serum creatinine, blood urea nitrogen, and malondialdehyde levels were lower in the CEF group than in the C group. Homocysteine, superoxide dismutase, glutathione peroxidase, and nitric oxide levels were higher in the CEF group than in the C group. Histopathology scores and percentage of apoptotic kidney cells in the CEF group were significantly decreased compared with those in the C group. Conclusions These results suggest that enalapril maleate and folic acid tablets have a protective effect against CIN in diabetic rats.
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Kong X, Ma X, Zhang C, Su H, Xu D. Hyperhomocysteinemia increases the risk of chronic kidney disease in a Chinese middle-aged and elderly population-based cohort. Int Urol Nephrol 2016; 49:661-667. [PMID: 27822673 DOI: 10.1007/s11255-016-1452-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 10/28/2016] [Indexed: 11/26/2022]
Abstract
BACKGROUND Patients either with hyperhomocysteinemia or chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Little is known regarding whether hyperhomocysteinemia can increase the risk of CKD in a Chinese middle-aged and elderly population. To help clarify this we conducted a prospective cohort study to measure the association of hyperhomocysteinemia with CKD. METHODS A total of 5917 adults aged 56.4 ± 9.6 years without CKD at baseline were enrolled. The highest homocysteine quartile (≥15 μmol/L) was defined as hyperhomocysteinemia. CKD was defined as decreased estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) or presence of proteinuria (urine protein ≥ 1+) assessed using a repeated dipstick method. RESULTS During 3 years of follow-up, 143 (2.4%) patients developed CKD, 85 (1.4%) patients with proteinuria and 59 (1.0%) patients with decreased eGFR. After adjusted for potential confounders, both homocysteine (per 1 μmol/L increase) and hyperhomocysteinemia were independently associated with increased risk of decreased eGFR [with a fully adjusted OR of 1.07 (95% CI 1.04-1.10) and 3.05 (95% CI 1.71-5.46)] and CKD [with a fully adjusted OR of 1.04 (95% CI 1.02-1.07) and 1.62 (95% CI 1.11-2.35)], respectively. By contrast, neither homocysteine (per 1 μmol/L increase) nor hyperhomocysteinemia were associated with proteinuria in the multivariable logistic regression analysis. CONCLUSIONS The study revealed that hyperhomocysteinemia increases the risk of decreased eGFR. This suggests that homocysteine could be considered as a useful molecular markers for delaying the development of CKD.
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Affiliation(s)
- Xianglei Kong
- Department of Nephrology, Qianfoshan Hospital, Shandong University, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China
| | - Xiaojing Ma
- Department of Health Examination Center, Qianfoshan Hospital, Shandong University, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China
| | - Chengyin Zhang
- Department of Nephrology, Yidu Central Hospital, Weifang Medical College, No. 4138, South Road of Linglong Mountain, Qingzhou, People's Republic of China
| | - Hong Su
- Department of Nephrology, Qianfoshan Hospital, Shandong University, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China
| | - Dongmei Xu
- Department of Nephrology, Qianfoshan Hospital, Shandong University, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.
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Padullés A, Rama I, Llaudó I, Lloberas N. Developments in renal pharmacogenomics and applications in chronic kidney disease. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2014; 7:251-66. [PMID: 25206311 PMCID: PMC4157401 DOI: 10.2147/pgpm.s52763] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Chronic kidney disease (CKD) has shown an increasing prevalence in the last century. CKD encompasses a poor prognosis related to a remarkable number of comorbidities, and many patients suffer from this disease progression. Once the factors linked with CKD evolution are distinguished, it will be possible to provide and enhance a more intensive treatment to high-risk patients. In this review, we focus on the emerging markers that might be predictive or related to CKD progression physiopathology as well as those related to a different pattern of response to treatment, such as inhibitors of the renin–angiotensin system (including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers; the vitamin D receptor agonist; salt sensitivity hypertension; and progressive kidney-disease markers with identified genetic polymorphisms). Candidate-gene association studies and genome-wide association studies have analyzed the genetic basis for common renal diseases, including CKD and related factors such as diabetes and hypertension. This review will, in brief, consider genotype-based pharmacotherapy, risk prediction, drug target recognition, and personalized treatments, and will mainly focus on findings in CKD patients. An improved understanding will smooth the progress of switching from classical clinical medicine to gene-based medicine.
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Affiliation(s)
- Ariadna Padullés
- Pharmacy Department, IDIBELL-Hospital Universitari Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Inés Rama
- Nephrology Department, IDIBELL-Hospital Universitari Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Inés Llaudó
- Nephrology Department, IDIBELL-Hospital Universitari Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Núria Lloberas
- Nephrology Department, IDIBELL-Hospital Universitari Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
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Orimadegun BE, Orimadegun AE, Ademola AD, Agbedana EO. Plasma homocysteine and B vitamins levels in Nigerian children with nephrotic syndrome. Pan Afr Med J 2014; 18:107. [PMID: 25404967 PMCID: PMC4232175 DOI: 10.11604/pamj.2014.18.107.3678] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 05/26/2014] [Indexed: 11/11/2022] Open
Abstract
INTRODUCTION Available data on plasma homocysteine level in patients with nephrotic syndrome (NS) are controversial with increased, decreased and unchanged values reported. Therefore, plasma homocysteine and serum B vitamins in Nigerian children with NS were assessed in this study. METHODS Fasting blood samples were analysed for plasma homocysteine, serum folate and B vitamins in 42 children with NS and 42 age and sex-matched healthy controls in this case control study. Data were compared between NS and control using t test and Chi square. Relationships were tested with regression analysis with p set at 0.05. RESULTS Prevalence of hyperhomocysteinaemia, low folate and cyanocobalamin in NS was 57.1%, 14.3% and 9.5% respectively. The mean homocysteine level was significantly higher in NS than control (11.3±2.6 µmol/L versus 5.5±2.3 µmol/L). Also, NS had lower folate and cyanocobalamin than control: 9.1±3.9 ng/mL versus 11.2±3.1 ng/dL and 268.5±95.7 pg/mL versus 316±117.2 pg/mL respectively. Weak but significant correlation between homocysteine and serum albumin (r = 0.347), folate (r = -0.607) and vitamin B12 (r = -0.185) were found in the NS group. Significant relationship was also found between homocysteine and vitamin B12 (ß = -0.64, 95% CI = -1.20, -0.08) after controlling for folate and vitamin B6 levels. CONCLUSION Clinically important hyperhomocysteinaemia and low B vitamins occur in Nigerian children with nephrotic syndrome. This data suggest that potential usefulness of folate and vitamin B supplementation for reducing high homocysteine levels in nephrotic syndrome need to be further investigated.
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Tbahriti HF, Messaoudi A, Kaddous A, Bouchenak M, Mekki K. [The degree of chronic renal failure is associated with the rate of pro-inflammatory cytokines, hyperhomocysteinemia and with oxidative stress]. Ann Cardiol Angeiol (Paris) 2014; 63:135-139. [PMID: 24857797 DOI: 10.1016/j.ancard.2014.04.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 04/15/2014] [Indexed: 06/03/2023]
Abstract
AIM To evaluate pro-inflammatory cytokines, homocysteinemia and markers of oxidative status in the course of chronic renal failure. PATIENTS AND METHODS One hundred and two patients (male/female: 38/64; age: 45±07 years) with chronic renal failure were divided into 4 groups according to the National Kidney Foundation classification. They included 28 primary stage renal failure patients, 28 moderate stage renal failure, 28 severe stage renal failure and 18 end stage renal failure. The inflammatory status was evaluated by the determination of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) and total homocysteine. Pro-oxidant status was assessed by assaying thiobarbituric acid reactive substances, hydroperoxides, and protein carbonyls. Antioxidant defence was performed by analysis of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase. RESULTS Inflammatory markers were elevated in the end stage renal failure group compared to the other groups (P<0.001). Indeed, an increase in thiobarbituric acid reactive substances, hydroperoxides and protein carbonyls was noted in the end stage renal failure group in comparison with the other groups (P<0.001), while the levels of antioxidants enzymes activity were decreased in the study population (P<0.001). CONCLUSION Impaired renal function is closely associated with the elevation of inflammatory markers leading to both increased markers of oxidative stress and decreased antioxidant defense.
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Affiliation(s)
- H F Tbahriti
- Laboratoire de nutrition clinique et métabolique, faculté des sciences de la nature et de la vie, université d'Oran, Oran 31100, Algérie
| | - A Messaoudi
- Service de biochimie, établissement hospitalier universitaire (EHU) d'Oran, Oran 31037, Algérie
| | - A Kaddous
- Service de nephrologie, établissement hospitalier universitaire (EHU) d'Oran, Oran 31037, Algérie
| | - M Bouchenak
- Laboratoire de nutrition clinique et métabolique, faculté des sciences de la nature et de la vie, université d'Oran, Oran 31100, Algérie
| | - K Mekki
- Laboratoire de nutrition clinique et métabolique, faculté des sciences de la nature et de la vie, université d'Oran, Oran 31100, Algérie.
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Tbahriti HF, Meknassi D, Moussaoui R, Messaoudi A, Zemour L, Kaddous A, Bouchenak M, Mekki K. Inflammatory status in chronic renal failure: The role of homocysteinemia and pro-inflammatory cytokines. World J Nephrol 2013; 2:31-37. [PMID: 24175263 PMCID: PMC3782222 DOI: 10.5527/wjn.v2.i2.31] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 03/21/2013] [Accepted: 05/18/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate determinants of inflammatory markers in chronic renal failure patients according to the level of glomerular filtration rate.
METHODS: One hundred fifty four patients (Age: 44 ± 06 years; male/female: 66/88) with chronic renal failure (CRF) were divided into 6 groups according to the National Kidney Foundation (NKF) classification. They included 28 primary stage renal failure patients (CRF 1), 28 moderate stage renal failure patients (CRF 2), 28 severe stage renal failure patients (CRF 3), 18 end-stage renal failure patients (CRF 4), 40 hemodialysis (HD) patients, and 12 peritoneal dialysis (PD) patients. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and C-reactive protein (CRP) were analyzed by immunosorbent assay kit (ELISA) (Cayman Chemical’s ACETM EIA kit). Immunoassay methods were used for total homocysteine (tHcy) (fluorescence polarization immunoanalysis HPLC, PerkinEmer 200 series), transferrin (MININEPHTM human transferin kit: ZK070.R), ferritin (ADVIA Centaur) and fibrinogen analysis (ACL 200). Differences between groups were performed using SPSS 20.0 and data are expressed as the mean ± SD.
RESULTS: Results showed that in comparison with CRF 1 group and other groups, TNF-α and IL-6 levels were respectively more elevated in HD (16.38 ± 5.52 pg/mL vs 0.39 ± 0.03 pg/mL, 11.05 ± 3.59 pg/mL vs 8.20 ± 0.22 pg/mL, P < 0.001) and PD (14.04 ± 3.40 pg/mL vs 0.39 ± 0.03 pg/mL, 10.15 ± 1.66 pg/mL vs 8.20 ± 0.22 pg/mL, P < 0.001). IL-1β levels were increased in HD (9.63 ± 3.50 pg/mL vs 3.24 ± 0.10 pg/mL, P < 0.001) and CRF 4 (7.76 ± 0.66 pg/mL vs 3.24 ± 0.10 pg/mL, P < 0.001) patients than in CRF 1 and in the other groups. Plasma tHcy levels were higher in HD (32.27 ± 12.08 μmol/L) and PD (28.37 ± 4.98 μmol/L) patients compared to the other groups of CRF (P < 0.001). The serum CRP level was significantly increased in HD (18.17 ± 6.38 mg/L) and PD (17.97 ± 4.85 mg/L) patients compared to the other groups of CRF patients (P < 0.001). The plasma fibrinogen level was more elevated in HD (6.86 ± 1.06 g/L) and CRF 4 (6.05 ± 0.57 g/L) than in the other groups (P < 0.001). Furthermore; the ferritin level was higher in HD (169.90 ± 62.16 ng/mL) and PD (90.08 ± 22.09 ng/mL) patients compared to the other groups of CRF (P < 0.001). The serum transferrin value was significantly decreased especially in PD (1.78 ± 0.21 g/L) compared to the other groups (P < 0.001). We found a negative correlation between glomerular filtration rate (GFR), TNF-α levels (r = -0.75, P < 0.001), and tHcy levels (r = -0.68, P < 0.001). We observed a positive correlation between GFR and transferrin levels (r = 0.60, P < 0.001).
CONCLUSION: CRF was associated with elevated inflammatory markers. The inflammation was observed at the severe stage of CRF and increases with progression of renal failure.
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Moorthy D, Peter I, Scott TM, Parnell LD, Lai CQ, Crott JW, Ordovás JM, Selhub J, Griffith J, Rosenberg IH, Tucker KL, Troen AM. Status of vitamins B-12 and B-6 but not of folate, homocysteine, and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults. J Nutr 2012; 142:1554-60. [PMID: 22739363 PMCID: PMC3397340 DOI: 10.3945/jn.112.161828] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene differs in frequency in various ethnic groups that have differing prevalence of age-related cognitive impairments. We used a series of neuro-psychological tests to examine the association of the MTHFR C677T polymorphism with cognition and depression and also to assess whether genotype modifies the association of folate and homocysteine with these outcomes. This study analyzed pooled cross-sectional data from 2 ethnically diverse cohorts of community-living adults: the Boston Puerto Rican Health Study (n = 939) and the Nutrition, Aging, and Memory in Elders study (n = 1017). Individuals in both cohorts underwent anthropometric and laboratory measurements and dietary and health assessments using validated questionnaires between the years 2003 and 2007. Cognitive outcomes included measures of global cognition [Mini-Mental Status Exam (MMSE)], depression (Center for Epidemiological Studies Depression Scale), and 3 factor scores for the domains of attention, executive function, and memory that were derived from a detailed set of neuropsychological tests. Low plasma vitamin B-12 concentrations were associated with poorer MMSE scores and higher depression scores, and low vitamin B-6 concentrations were associated with lower MMSE and worse attention and executive function in the multivariate analysis. In contrast, MTHFR genotype, folate, and homocysteine were not associated with cognition or depression in either ethnicity-pooled or stratified analysis. The current study did not find evidence of an association between the MTHFR C677T TT genotype and impaired cognition or depression in a population with adequate folate status and a high prevalence of cognitive impairment and depression.
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Affiliation(s)
- Denish Moorthy
- Neuroscience and Aging Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY
| | - Tammy M. Scott
- Neuroscience and Aging Laboratory,Department of Psychiatry, and
| | | | | | | | | | - Jacob Selhub
- Vitamin Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA
| | - John Griffith
- Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA; and
| | | | | | - Aron M. Troen
- Neuroscience and Aging Laboratory,Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel,To whom correspondence should be addressed. E-mail:
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Perła-Kaján J, Jakubowski H. Paraoxonase 1 and homocysteine metabolism. Amino Acids 2012; 43:1405-17. [PMID: 22643843 DOI: 10.1007/s00726-012-1321-z] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 05/04/2012] [Indexed: 01/23/2023]
Abstract
Paraoxonase 1 (PON1), a component of high-density lipoprotein (HDL), is a calcium-dependent multifunctional enzyme that connects metabolisms of lipoproteins and homocysteine (Hcy). Both PON1 and Hcy have been implicated in human diseases, including atherosclerosis and neurodegeneration. The involvement of Hcy in disease could be mediated through its interactions with PON1. Due to its ability to reduce oxidative stress, PON1 contributes to atheroprotective functions of HDL in mice and humans. Although PON1 has the ability to hydrolyze a variety of substrates, only one of them-Hcy-thiolactone-is known to occur naturally. In humans and mice, Hcy-thiolactonase activity of PON1 protects against N-homocysteinylation, which is detrimental to protein structure and function. PON1 also protects against neurotoxicity associated with hyperhomocysteinemia in mouse models. The links between PON1 and Hcy in relation to pathological states such as coronary artery disease, stroke, diabetic mellitus, kidney failure and Alzheimer's disease that emerge from recent studies are the topics of this review.
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Affiliation(s)
- Joanna Perła-Kaján
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, Poznan, Poland.
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19
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Chung S, Koh ES, Shin SJ, Park CW. Malnutrition in patients with chronic kidney disease. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/ojim.2012.22018] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Yi F, Jin S, Zhang F, Xia M, Bao JX, Hu J, Poklis JL, Li PL. Formation of lipid raft redox signalling platforms in glomerular endothelial cells: an early event of homocysteine-induced glomerular injury. J Cell Mol Med 2011; 13:3303-14. [PMID: 20196779 PMCID: PMC3752605 DOI: 10.1111/j.1582-4934.2009.00743.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The present study tested the hypothesis that homocysteine (Hcys)-induced ceramide production stimulates lipid rafts (LRs) clustering on the membrane of glomerular endothelial cells (GECs) to form redox signalling platforms by aggregation and activation of NADPH oxidase subunits and thereby enhances superoxide (O2*-) production, leading to glomerular endothelial dysfunction and ultimate injury or sclerosis. Using confocal microscopy, we first demonstrated a co-localization of LR clusters with NADPH oxidase subunits, gp91(phox) and p47(phox) in the GECs membrane upon Hcys stimulation. Immunoblot analysis of floated detergent-resistant membrane fractions found that in LR fractions NADPH oxidase subunits gp91(phox) and p47(phox) are enriched and that the activity of this enzyme dramatically increased. We also examined the effect of elevated Hcys on the cell monolayer permeability in GECs. It was found that Hcys significantly increased GEC permeability, which was blocked by inhibition of LR redox signalling platform formation. Finally, we found that Hcys-induced enhancement of GEC permeability is associated with the regulation of microtubule stability through these LR-redox platforms. It is concluded that the early injurious effect of Hcys on the glomerular endothelium is associated with the formation of redox signalling platforms via LR clustering, which may lead to increases in glomerular permeability by disruption of microtubule network in GECs.
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Affiliation(s)
- Fan Yi
- Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, VA, USA
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Dwivedi RS, Herman JG, McCaffrey TA, Raj DSC. Beyond genetics: epigenetic code in chronic kidney disease. Kidney Int 2010; 79:23-32. [PMID: 20881938 DOI: 10.1038/ki.2010.335] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Epigenetics refers to a heritable change in the pattern of gene expression that is mediated by a mechanism specifically not due to alterations in the primary nucleotide sequence. Well-known epigenetic mechanisms encompass DNA methylation, chromatin remodeling (histone modifications), and RNA interference. Functionally, epigenetics provides an extra layer of transcriptional control and plays a crucial role in normal physiological development, as well as in pathological conditions. Aberrant DNA methylation is implicated in immune dysfunction, inflammation, and insulin resistance. Epigenetic changes may be responsible for 'metabolic memory' and development of micro- and macrovascular complications of diabetes. MicroRNAs are critical in the maintenance of glomerular homeostasis and hence RNA interference may be important in the progression of renal disease. Recent studies have shown that epigenetic modifications orchestrate the epithelial-mesenchymal transition and eventually fibrosis of the renal tissue. Oxidative stress, inflammation, hyperhomocysteinemia, and uremic toxins could induce epimutations in chronic kidney disease. Epigenetic alterations are associated with inflammation and cardiovascular disease in patients with chronic kidney disease. Reversible nature of the epigenetic changes gives a unique opportunity to halt or even reverse the disease process through targeted therapeutic strategies.
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Affiliation(s)
- Rama S Dwivedi
- Division of Renal Diseases and Hypertension, The George Washington University, Washington, District of Columbia 20037, USA
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22
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Kerkeni M, Letaief A, Achour A, Miled A, Trivin F, Maaroufi K. Hyperhomocysteinemia, paraoxonase concentration and cardiovascular complications in Tunisian patients with nondiabetic renal disease. Clin Biochem 2009; 42:777-82. [PMID: 19233152 DOI: 10.1016/j.clinbiochem.2009.02.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2008] [Revised: 02/09/2009] [Accepted: 02/09/2009] [Indexed: 11/24/2022]
Abstract
OBJECTIVES Hyperhomocysteinemia is associated with an increased risk of cardiovascular diseases. We determine homocysteine levels (Hcy), paraoxonase (PON1) concentration and their relationship on cardiovascular complications in patients with chronic renal disease (CRD). DESIGN AND METHODS The study population included 100 CRD patients and 120 healthy controls. Renal function was assessed using the eGFR by the MDRD study equation. Patients were considered to have CRD when the eGFR was <60 mL/min/1.73 m(2). Hcy concentrations were determined by direct chemiluminescence assay. PON1 concentration was measured spectrophotometrically using phenylacetate as a substrate. RESULTS We found an increased Hcy levels and a decreased eGFR and PON1 concentration in CRD patients compared to the control group (P<0.001, P<0.001, P<0.01 respectively). Patients with cardiovascular complications showed an increased Hcy levels and a lower PON1 concentration than patients without cardiovascular complications (P<0.001, P<0.01 respectively). CONCLUSION We showed that hyperhomocysteinemia and low PON1 concentration are associated with CRD and markedly associated in patients with cardiovascular complications. Additional effects contribute to the severity of renal disease and increase the incidence of cardiovascular disease.
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Affiliation(s)
- Mohsen Kerkeni
- Research Unit 03/UR/08-14, Faculty of Pharmacy, 5000-Monastir, Tunisia.
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Stopper H, Treutlein AT, Bahner U, Schupp N, Schmid U, Brink A, Perna A, Heidland A. Reduction of the genomic damage level in haemodialysis patients by folic acid and vitamin B12 supplementation. Nephrol Dial Transplant 2008; 23:3272-9. [DOI: 10.1093/ndt/gfn254] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Yi F, Li PL. Mechanisms of homocysteine-induced glomerular injury and sclerosis. Am J Nephrol 2007; 28:254-64. [PMID: 17989498 DOI: 10.1159/000110876] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2007] [Accepted: 09/13/2007] [Indexed: 12/25/2022]
Abstract
Hyperhomocysteinemia (hHcys) has been recognized as a critical risk or pathogenic factor in the progression of end-stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD. Recently, evidence is accumulating that hHcys may directly act on glomerular cells to induce glomerular dysfunction and consequent glomerular sclerosis, leading to ESRD. In this review, we summarize recent findings that reveal the contribution of homocysteine as a pathogenic factor to the development of glomerular sclerosis or ESRD. In addition, we discuss several important mechanisms mediating the pathogenic action of homocysteine in the glomeruli or in the kidney, such as local oxidative stress, endoplasmic reticulum stress, homocysteinylation, and hypomethylation. Understanding these mechanisms may help design new approaches to develop therapeutic strategies for treatment of hHcys-associated end-organ damage and for prevention of deterioration of kidney function and ultimate ESRD in patients with hypertension and diabetes mellitus or even in aged people with hHcys.
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Affiliation(s)
- Fan Yi
- Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA
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Domenici FA, Vannucchi MTI, Simões-Ambrósio LMC, Vannucchi H. Hyperhomocysteinemia and polymorphisms of the methylenetetrahydrofolate gene in hemodialysis and peritoneal dialysis patients. Mol Nutr Food Res 2007; 51:1430-6. [DOI: 10.1002/mnfr.200700114] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Konstantinova SV, Vollset SE, Berstad P, Ueland PM, Drevon CA, Refsum H, Tell GS. Dietary predictors of plasma total homocysteine in the Hordaland Homocysteine Study. Br J Nutr 2007; 98:201-10. [PMID: 17391553 DOI: 10.1017/s0007114507691788] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Established dietary predictors of plasma total homocysteine (tHcy) include folate, riboflavin, and vitamins B6and B12, while information is scarce regarding other dietary components. The aim of this study was to examine the relation between a variety of food groups, food items and nutrients, and plasma tHcy in a large population-based study. The study population included 5812 men and women aged 47–49 and 71–74 years who completed a 169-item FFQ. tHcy was examined across quartiles of dietary components by multiple linear regression analyses adjusting for age, sex, energy intake, various risk factors for elevated tHcy, as well as for dietary and plasma B-vitamins. Among 4578 non-users of vitamin supplements, intake of vegetables, fruits, cereals, eggs, fish and milk, as well as chicken and non-processed meats were inversely associated with tHcy level. The estimated mean difference in tHcy per increasing quartile of intake ranged from − 0·11 (95 % CI − 0·21, − 0·01) μmol/l for milk to − 0·32 (95 % CI − 0·42, − 0·22) μmol/l for vegetables. Positive associations were found for sweets and cakes. Whole-grain bread was significantly inversely related to tHcy only after additional adjustment for dietary and plasma B-vitamins. The nutrients folate, vitamin B6, B12, and riboflavin were inversely related to tHcy. Complex carbohydrates were inversely, and fat positively associated with tHcy, also after adjustment for dietary and plasma B-vitamins. In conclusion, food items rich in B-vitamins and with a low content of fat and sugar were related to lower tHcy levels. Eggs, chicken, non-processed meat, fish and milk were inversely associated with tHcy.
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Affiliation(s)
- Svetlana V Konstantinova
- Section of Epidemiology and Medical Statistics, Department of Public Health and Primary Health Care, University of Bergen, Kalfarveien, 31, Bergen, Norway.
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27
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Podda GM, Lussana F, Moroni G, Faioni EM, Lombardi R, Fontana G, Ponticelli C, Maioli C, Cattaneo M. Abnormalities of homocysteine and B vitamins in the nephrotic syndrome. Thromb Res 2007; 120:647-52. [PMID: 17276499 DOI: 10.1016/j.thromres.2006.12.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2006] [Revised: 12/06/2006] [Accepted: 12/07/2006] [Indexed: 12/31/2022]
Abstract
INTRODUCTION The nephrotic syndrome is associated with heightened risk for arterial and venous thrombosis. Multiple derangements of hemostasis and acquired risk factors such as hyperlipidemia and hypertension contribute to this risk. The prevalence in the nephrotic syndrome of high circulating levels of homocysteine and of low levels of the B vitamins that are involved in its metabolism, which may play a role in thrombosis, is not well defined. MATERIALS AND METHODS In 84 patients with nephrotic syndrome and 84 sex- and age-matched controls, hemostasis variables and the circulating levels of total homocysteine (tHcy), vitamin B(6), B(12) and folates were measured. RESULTS tHcy levels were higher, vitamin B(6) and vitamin B(12) levels were lower in nephrotic patients than in controls. The association of low vitamin B(6) levels with the nephrotic syndrome was independent of any other alteration associated with the disease. Eighty-two percent of patients with the nephrotic syndrome had vitamin B(6) levels falling in the lowest quartile of the normal distribution. Antithrombin deficiency, factor V Leiden, antiphospholipid antibodies, hypertension, dyslipidemia, were more frequent in patients with the nephrotic syndrome than in controls. CONCLUSIONS Patients with the nephrotic syndrome have multiple risk factors for thrombosis. We report that they frequently have low circulating levels of vitamin B(6), which associate with a heightened risk for venous and arterial thrombosis.
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Affiliation(s)
- Gian Marco Podda
- Centro Emofilia e Trombosi "Angelo Bianchi Bonomi", Dipartmento di Medicina Interna e Dermatologia, Fondazione I.R.C.C.S. Ospedale Maggiore, Mangiagalli e Regina Elena, Università di Milano, Italy
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28
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Robitaille R, Lafrance JP, Leblanc M. Reviews: Altered Laboratory Findings Associated with End-Stage Renal Disease. Semin Dial 2006; 19:373-80. [PMID: 16970737 DOI: 10.1111/j.1525-139x.2006.00192.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Several laboratory parameters can be altered in advanced renal failure. Results may be difficult to interpret and may become misleading and unreliable in such a context. On the other hand, some of the alterations may reflect real abnormalities. Thus sufficient knowledge and careful judgment are required by the clinician. We reviewed different publications related to biochemical anomalies in renal failure and report some of the main findings. The sections are divided as follows: cardiovascular risk factors and markers, inflammation markers, pancreatic and liver function tests, hormones, bone turnover indices and parathyroid hormone assays, tumor markers, carbohydrate metabolism indicators, and others. The information provided should be useful to clinicians involved in the care of renal failure patients.
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Affiliation(s)
- Robert Robitaille
- Department of Biochemistry, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
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29
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Ferguson LR. Nutrigenomics: integrating genomic approaches into nutrition research. Mol Diagn Ther 2006; 10:101-8. [PMID: 16669608 DOI: 10.1007/bf03256449] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
It has been suggested that the supermarket of today will be the pharmacy of tomorrow. Such statements have been derived from recognition of our increasing ability to optimize nutrition, and maintain a state of good health through longer periods of life. The new field of nutrigenomics, which focuses on the interaction between bioactive dietary components and the genome, recognizes that current nutritional guidelines may be ideal for only a relatively small proportion of the population. There is good evidence that nutrition has significant influences on the expression of genes, and, likewise, genetic variation can have a significant effect on food intake, metabolic response to food, individual nutrient requirements, food safety, and the efficacy of disease-protective dietary factors. For example, a significant number of human studies in various areas are increasing the evidence for interactions between single nucleotide polymorphisms (SNPs) in various genes and the metabolic response to diet, including the risk of obesity. Many of the same genetic polymorphisms and dietary patterns that influence obesity or cardiovascular disease also affect cancer, since overweight individuals are at increased risk of cancer development. The control of food intake is profoundly affected by polymorphisms either in genes encoding taste receptors or in genes encoding a number of peripheral signaling peptides such as insulin, leptin, ghrelin, cholecystokinin, and corresponding receptors. Total dietary intake, and the satiety value of various foods, will profoundly influence the effects of these genes. Identifying key SNPs that are likely to influence the health of an individual provides an approach to understanding and, ultimately, to optimizing nutrition at the population or individual level. Traditional methods for identification of SNPs may involve consideration of individual variants, using methodologies such as restriction fragment length polymorphisms or quantitative real-time PCR assays. New developments allow identification of up to 500,000 SNPs in an individual, and with increasingly lowered pricings these developments may explode the population-level potential for dietary optimization based on nutrigenomic approaches.
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Affiliation(s)
- Lynnette R Ferguson
- Discipline of Nutrition/Auckland Cancer Society Research Centre (ACSRC), School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
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30
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Perna AF, Satta E, Acanfora F, Lombardi C, Ingrosso D, De Santo NG. Increased plasma protein homocysteinylation in hemodialysis patients. Kidney Int 2006; 69:869-76. [PMID: 16395265 DOI: 10.1038/sj.ki.5000070] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hyperhomocysteinemia, an independent cardiovascular risk factor, is present in the majority of hemodialysis patients. Among the postulated mechanisms of toxicity, protein homocysteinylation is potentially able to cause significant alterations in protein function. Protein homocysteinylation occurs through various mechanisms, among which is the post-translational acylation of free amino groups (protein-N-homocysteinylation, mediated by homocysteine (Hcy) thiolactone). Another type of protein homocysteinylation occurs through the formation of a covalent -S-S- bond, found primarily with cysteine residues (protein-S-homocysteinylation). Scant data are available in the literature regarding the extent to which alterations in protein homocysteinylation are present in uremic patients on hemodialysis, and the effects of folate treatment are not known. Protein homocysteinylation was measured in a group of hemodialysis patients (n=28) compared to controls (n=14), with a new method combining protein reduction, gel filtration and Hcy derivatization. Chemical hydrolysis was performed, followed by high-pressure liquid chromatography separation. The effects of folate treatment on protein homocysteinylation, as well as in vitro binding characteristics were evaluated. Plasma Hcy, protein-N-homocysteinylation and protein-S-homocysteinylation were significantly higher in patients vs controls. Plasma Hcy and protein-S-homocysteinylation were significantly correlated. After 2 months of oral folate treatment, protein-N-homocysteinylation was normalized, and protein-S-homocysteinylation was significantly reduced. Studies on albumin-binding capacity after in vitro homocysteinylation show that homocysteinylated albumin is significantly altered at the diazepam-binding site. In conclusion, increased protein homocysteinylation is present in hemodialysis patients, with possible consequences in terms of protein function. This alteration can be partially reversed after folate treatment.
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Affiliation(s)
- A F Perna
- Division of Nephrology, Department of Biochemistry and Biophysics, F Cedrangolo and Cardiovascular Research Center, School of Medicine, Second University of Naples, Via Pansini 5, Ed. 17, 80131 Naples, Italy.
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31
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Castro R, Rivera I, Blom HJ, Jakobs C, Tavares de Almeida I. Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. J Inherit Metab Dis 2006; 29:3-20. [PMID: 16601863 DOI: 10.1007/s10545-006-0106-5] [Citation(s) in RCA: 214] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2005] [Accepted: 08/31/2005] [Indexed: 11/26/2022]
Abstract
Hyperhomocysteinaemia has been regarded as a new modifiable risk factor for atherosclerosis and vascular disease. Homocysteine is a branch-point intermediate of methionine metabolism, which can be further metabolised via two alternative pathways: degraded irreversibly through the transsulphuration pathway or remethylated to methionine by the remethylation pathway. Both pathways are B-vitamin-dependent. Plasma homocysteine concentrations are determined by nongenetic and genetic factors. The metabolism of homocysteine, the role of B vitamins and the contribution of nongenetic and genetic determinants of homocysteine concentrations are reviewed. The mechanisms whereby homocysteine causes endothelial damage and vascular disease are not fully understood. Recently, a link has been postulated between homocysteine, or its intermediates, and an alterated DNA methylation pattern. The involvement of epigenetic mechanisms in the context of homocysteine and atherosclerosis, due to inhibition of transmethylation reactions, is briefly overviewed.
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Affiliation(s)
- R Castro
- Centro de Patogénese Molecular, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, Lisbon 1649-003, Portugal
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32
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Austen SK, Fletcher LA, Fassett RG, Booth C, Coombes JS. Acute exposure to cyclosporine does not increase plasma homocysteine in rats. Transplant Proc 2006; 37:4543-6. [PMID: 16387165 DOI: 10.1016/j.transproceed.2005.11.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2004] [Indexed: 10/25/2022]
Abstract
There is interest in the postulate that cyclosporine a (CsA) contributes to the elevated homocysteine levels seen in organ transplant recipients, as hyperhomocysteinemia is now considered an independent risk factor for cardiovascular disease (CVD) and may partially explain the increased prevalence of CVD in this population. The main purpose of this investigation was to determine the effect of CsA administration on plasma homocysteine. Eighteen female Sprague Dawley rats (4 months old) were randomly assigned to either a treatment or a control group. For 18 days the treatment group received of CsA (25 mg/kg/d) while the control group received the same volume of the vehicle. Blood samples obtained following sacrifice to measure CsA, total homocysteine, and plasma creatinine. There were no significant differences in plasma homocysteine (mean values +/- SD: treatment = 4.79 +/- 0.63 micromol/L, control = 4.46 +/- 0.75 micromol/L; P = .37). Homocysteine was not significantly correlated with final CsA concentrations (r = .17; P = .69). There was a significant difference in plasma creatinine values between the two groups (treatment = 60.44 +/- 7.68 micromol/L, control = 46.33 +/- 1.66 micromol/L; P < .001). Furthermore, plasma homocysteine and creatinine were positively correlated with the treatment group (r = .73; P < .05) but not the controls (r = -.10; P = .81). In conclusion, CsA does not influence plasma homocysteine concentrations in rats.
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Affiliation(s)
- S K Austen
- School of Human Movement Studies, University of Queensland, St Luica, Australia
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33
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Fux R, Kloor D, Hermes M, Röck T, Proksch B, Grenz A, Delabar U, Bücheler R, Igel S, Mörike K, Gleiter CH, Osswald H. Effect of acute hyperhomocysteinemia on methylation potential of erythrocytes and on DNA methylation of lymphocytes in healthy male volunteers. Am J Physiol Renal Physiol 2005; 289:F786-92. [PMID: 15855656 DOI: 10.1152/ajprenal.00465.2004] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Homocysteine is a precursor of S-adenosylmethionine (AdoMet) and a metabolite of S-adenosylhomocysteine (AdoHcy). The ratio of AdoMet to AdoHcy, defined as the methylation potential (MP), indicates the flow of methyl groups within the cells. Chronic elevations of total homocysteine (tHcy) in plasma correlate with increased AdoHcy concentrations, decreased MP, and impaired DNA methylation. However, the influence of acute hyperhomocysteinemia on MP is unknown. We induced acute hyperhomocysteinemia in 14 healthy volunteers by oral administration of l-homocysteine (65.1 μmol/kg body wt) in an open, randomized, placebo-controlled two-period crossover study. The kinetics of tHcy in blood and urine, MP in blood, and global DNA methylation in lymphocytes were studied systematically during 48 h. Plasma tHcy concentrations reached a peak at 34 ± 11 min after an oral load with l-homocysteine and decreased with a half-life of 257 ± 41 min (means ± SD). Only 2.3% of the homocysteine dose were recovered in urine. AdoHcy concentrations and MP in whole blood and erythrocytes were not affected by the oral homocysteine load. Furthermore, global DNA methylation in lymphocytes did not change under these conditions. We found no difference between the genotypes of 5,10-methylenetetrahydrofolate reductase in response to the homocysteine load. However, AdoMet content in erythrocytes was significantly higher in the C677T carriers (CT; n = 7) compared with the CC genotype ( n = 7). Although chronic elevation of tHcy has been shown to affect MP and DNA methylation, acute elevation of plasma tHcy above 20 μmol/l for 8 h is not sufficient to change MP and to induce DNA hypomethylation in lymphocytes.
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Affiliation(s)
- R Fux
- Dept. of Pharmacology and Toxicology, Div. of Experimental Pharmacology, Univ. Hospital Tübingen, Wilhelmstr. 56, D-72074 Tübingen, Germany.
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Gonin JM. Folic acid supplementation to prevent adverse events in individuals with chronic kidney disease and end stage renal disease. Curr Opin Nephrol Hypertens 2005; 14:277-81. [PMID: 15821423 DOI: 10.1097/01.mnh.0000165896.98372.f4] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW This review summarizes our current understanding of the role of folate in the treatment of hyperhomocysteindemia and the prevention of cardiovascular disease in patients with chronic kidney disease and end stage renal disease. Relevant papers published between 2003 and 2004 are referenced. RECENT FINDINGS With the exception of one paper, recent therapeutic studies supported previous findings that folate therapy achieves only a modest reduction in plasma homocysteine and seldom normalizes homocysteine. Large prospective studies are under way to evaluate the causal relationship between homocysteine and cardiovascular risk. Recent work supports earlier data that suggested that homocysteine inflicts its damage by oxidative stress. A newly described consequence of hyperhomocysteindemia is DNA hypomethylation and alteration of gene expression. A recent study in the general population suggested that while folate may lower homocysteine it does not improve endothelial function in individuals without cardiovascular disease. SUMMARY The causes of hyperhomocysteindemia in renal failure remain obscure. The possibilities include impairment of both renal and extrarenal metabolic pathways by uraemia. Hyperhomocysteindemia is associated in some but not all studies with an increased risk for cardiovascular disease. A low homocysteine may reflect malnutrition and predict a poor outcome. Folate achieves modest reductions of homocysteine in some but not all studies. There are no data to support therapy with very high-dose folic acid. Hyperhomocysteindemia impairs endothelial function which is not adequately reversed by folate.
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Affiliation(s)
- Joyce M Gonin
- Georgetown University Hospital, Washington, DC 20007, USA.
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Li Vecchi M, Di Lorenzo G. Hyperhomocysteinemia in Hemodialysis Patients: Is it a Risk Factor for Cardiovascular Disease? Int J Artif Organs 2005; 28:207-10. [PMID: 15818542 DOI: 10.1177/039139880502800304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- M Li Vecchi
- Department of Internal Medicine, Cardiovascular and Nephrourological Disease, University of Palermo, Italy.
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