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Effect of Sevelamer on Calciprotein Particles in Hemodialysis Patients: The Sevelamer Versus Calcium to Reduce Fetuin-A-Containing Calciprotein Particles in Dialysis (SCaRF) Randomized Controlled Trial. Kidney Int Rep 2020; 5:1432-1447. [PMID: 32954068 PMCID: PMC7486191 DOI: 10.1016/j.ekir.2020.06.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 06/10/2020] [Accepted: 06/17/2020] [Indexed: 01/03/2023] Open
Abstract
Introduction Calciprotein particles (CPPs) are potentially modifiable mediators of phosphate toxicity in patients with kidney disease. We compared the effects of calcium carbonate (CC) and the non–calcium-based phosphate binder sevelamer on CPP levels in patients undergoing hemodialysis (HD). We hypothesized that treatment with sevelamer would achieve greater reductions in amorphous calcium phosphate–containing CPP (CPP-1) and hydroxyapatite-containing CPP (CPP-2) owing to reduced calcium loading and anti-inflammatory pleiotropic effects. Methods We conducted an open-label, randomized controlled trial (RCT) in which 31 stable prevalent HD patients were allocated to receive either sevelamer hydrochloride (SH), sevelamer carbonate (SC), or CC for 24 weeks. Dual primary endpoints were the between groups differences in serum CPP-1 and CPP-2 levels at 24 weeks in SH + SC–treated versus CC-treated patients. Effects on aortic pulse wave velocity (aPWV), inflammatory cytokines (interleukin-6 and -8), and effects across individual treatment arms were also assessed. Results Serum CPP-1, but not CPP-2, levels were lower in those randomly assigned to the sevelamer (SH + SC) group compared with the CC group at 24 weeks (–70%, 95% confidence interval [CI] –90% to –15%, P = 0.02). In subgroup analysis, this effect was confined to those receiving SC (–83.4%, 95% CI –95.7% to –36.8%, P = 0.01). aPWV and interleukin-8 levels were also lower in those who received sevelamer compared with CC at 24 weeks (–2.0 m/s, 95% CI –2.9 to –1.1; –57%, 95% CI –73% to –30%, respectively, both P = 0.01). Conventional markers of mineral metabolism remained stable across all treatment groups. Discussion Compared with treatment with CC, use of sevelamer for 24 weeks was associated with lower serum CPP-1 levels and a reduction in aPWV and systemic inflammation.
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Bover J, Cozzolino M. Small steps towards the potential of 'preventive' treatment of early phosphate loading in chronic kidney disease patients. Clin Kidney J 2019; 12:673-677. [PMID: 31584564 PMCID: PMC6768463 DOI: 10.1093/ckj/sfz082] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Indexed: 12/31/2022] Open
Abstract
Few clinical studies have investigated the value of phosphate (P)-lowering therapies in early chronic kidney disease (CKD) patients in whom hyperphosphataemia has not yet clearly developed and they report conflicting and even unexpected results. In this issue of Clinical Kidney Journal, de Krijger et al. found that sevelamer carbonate (4.8 g/day for 8 weeks) did not induce a significant reduction of pulse wave velocity (PWV) and that fibroblast growth factor 23 (FGF23) did not decrease despite a decline in 24-h urine P excretion. To some extent these findings challenge the concept that 'preventive' P binder therapy to lower FGF23 is a useful approach, at least over this short period of time. Interestingly, in a subgroup of patients with absent or limited abdominal vascular calcification, treatment did result in a statistically significant reduction in adjusted PWV, suggesting that PWV is amenable to improvement in this subset. Interpretation of the scarce and heterogeneous observations described in early CKD remains difficult and causality and/or the possibility of 'preventive' treatment may not yet be completely disregarded. Moreover, de Krijger et al. contribute to the identification of new sources of bias and methodological issues that may lead to more personalized treatments, always bearing in mind that not all patients and not all P binders are equal.
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Affiliation(s)
- Jordi Bover
- Fundació Puigvert, Department of Nephrology and Cardiology, IIB Sant Pau, RedinRen, Barcelona, Catalonia, Spain
| | - Mario Cozzolino
- Renal Unit, San Paolo Hospital and San Carlo Hospital, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
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Ruggiero B, Trillini M, Tartaglione L, Rotondi S, Perticucci E, Tripepi R, Aparicio C, Lecchi V, Perna A, Peraro F, Villa D, Ferrari S, Cannata A, Mazzaferro S, Mallamaci F, Zoccali C, Bellasi A, Cozzolino M, Remuzzi G, Ruggenenti P, Kohan DE. Effects of Sevelamer Carbonate in Patients With CKD and Proteinuria: The ANSWER Randomized Trial. Am J Kidney Dis 2019; 74:338-350. [PMID: 31027883 DOI: 10.1053/j.ajkd.2019.01.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 01/29/2019] [Indexed: 11/11/2022]
Abstract
RATIONALE & OBJECTIVE Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (RAS) blockers. We investigated whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of RAS inhibitors in patients with CKD. STUDY DESIGN Phase 2, randomized, controlled, open-label, crossover trial. SETTING & PARTICIPANTS Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m2 and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy. INTERVENTION After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period. OUTCOMES The primary outcome was 24-hour proteinuria (n=49patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness. RESULTS Changes in proteinuria during the 3-month treatment with (from 1.36 [IQR, 0.77-2.51] to 1.36 [IQR, 0.77-2.60] g/24h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24h) sevelamer were similar (P=0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol levels without affecting levels of office BP, measured GFR, fibroblast growth factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer. LIMITATIONS Short treatment duration, lower pretreatment proteinuria than expected. CONCLUSIONS 3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal RAS blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria. FUNDING Sanofi (Milan, Italy). TRIAL REGISTRATION Registered at ClinicalTrials.gov with study number NCT01968759.
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Affiliation(s)
- Barbara Ruggiero
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Matias Trillini
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Lida Tartaglione
- Department of Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | - Silverio Rotondi
- Department of Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | - Elena Perticucci
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Rocco Tripepi
- Bianchi-Melacrino-Morelli Hospital, Nephrology Unit, Reggio Calabria, Italy
| | - Carolina Aparicio
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Veruska Lecchi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Annalisa Perna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Francesco Peraro
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Davide Villa
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Silvia Ferrari
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Antonio Cannata
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Sandro Mazzaferro
- Department of Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Carmine Zoccali
- Bianchi-Melacrino-Morelli Hospital, Nephrology Unit, Reggio Calabria, Italy
| | - Antonio Bellasi
- Department of Nephrology and Dialysis, Sant'Anna Hospital, ASST-Lariana, Como, Italy
| | | | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Italy.
| | - Piero Ruggenenti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Donald E Kohan
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT
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Bouma-de Krijger A, van Ittersum FJ, Hoekstra T, Ter Wee PM, Vervloet MG. Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3. Clin Kidney J 2019; 12:678-685. [PMID: 31584563 PMCID: PMC6768309 DOI: 10.1093/ckj/sfz027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Indexed: 12/25/2022] Open
Abstract
Background High concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furthermore, reduction of PWV is reported with sevelamer use as well, but it is unclear if this is mediated by decline of phosphate or FGF23. We investigated if sevelamer induced a decline in PWV and if this was associated with a reduction in FGF23. Methods In all, 24 normophosphataemic CKD Stage 3 patients started treatment with a fixed dose of sevelamer-carbonate (Renvela®) 2.4 g twice daily, with their usual diet for 8 weeks in a single-arm study. PWV was measured and blood samples were obtained before, during and after washout of treatment with sevelamer. Vascular calcification was quantified using the Kauppila Index (KI). The primary outcome was the change of PWV from baseline to 8 weeks of treatment and the secondary endpoint was the difference of FGF23 following treatment with sevelamer. One of the linear mixed models was used to analyse the association between treatment and outcome. Mediation analysis was performed as a sensitivity analysis. The study was registered in the Dutch trial register (http://www.trialregister.nl: NTR2383). Results A total of 18 patients completed 8 weeks of treatment with sevelamer and were analysed. Overall, treatment with sevelamer did not induce a significant reduction of PWV (β = −0.36, P = 0.12). However, in patients with less vascular calcification (lower KI score), there was a statistically significant reduction of PWV, adjusted for mean arterial pressure, after treatment (β = 0.63, P = 0.02). Addition of FGF23 to the model did not alter this association. Mediation analysis yielded similar results. FGF23 did not decrease during treatment with sevelamer. Conclusion In this short-term pilot study in normophosphataemic CKD patients, treatment with sevelamer did not improve PWV. In subgroup analysis, however, PWV improved in patients with no or limited abdominal aorta calcifications. This was not associated with a decline of FGF23.
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Affiliation(s)
- Annet Bouma-de Krijger
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Frans J van Ittersum
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences Institute (ACS), O2
- Building for Human Life Sciences, Amsterdam, The Netherlands
| | - Tiny Hoekstra
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Pieter M Ter Wee
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Marc G Vervloet
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences Institute (ACS), O2
- Building for Human Life Sciences, Amsterdam, The Netherlands
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Miller-Hodges E, Dhaun N. Pulse-wave velocity is associated with cognitive impairment in haemodialysis patients. Clin Sci (Lond) 2017; 131:1495-1498. [PMID: 28659394 PMCID: PMC5869851 DOI: 10.1042/cs20170973] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 05/29/2017] [Accepted: 06/01/2017] [Indexed: 11/21/2022]
Abstract
Chronic kidney disease (CKD) is common, its prevalence increasing with age. Cognitive impairment is common in the elderly, in CKD and in those on maintenance haemodialysis. As cognitive impairment is the precursor to dementia, the identification of reversible risk factors for cognitive decline is the key to reducing dementia risk. Arterial stiffness is one such potential risk factor. It is independently associated with cardiovascular outcome in dialysis patients. Importantly, the recent demonstration of an independent association between arterial stiffness and cognitive impairment in these patients suggests that vascular stiffness might be potentially causative in the development of cognitive impairment and also be an opportune target for interventions. Whether unstiffening of blood vessels in patients on maintenance haemodialysis can reduce the incidence of cognitive impairment or indeed slow its progression to dementia, remain unanswered questions. In this issue of the Clinical Science, Angermann and colleagues present thought-provoking data related to cognitive impairment in haemodialysis patients.
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Affiliation(s)
- Eve Miller-Hodges
- University/British Heart Foundation Centre of Research Excellence, University of Edinburgh, The Queen's Medical Research Institute and Department of Renal Medicine, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, U.K
| | - Neeraj Dhaun
- University/British Heart Foundation Centre of Research Excellence, University of Edinburgh, The Queen's Medical Research Institute and Department of Renal Medicine, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, U.K.
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Korjian S, Daaboul Y, El-Ghoul B, Samad S, Salameh P, Dahdah G, Hariri E, Mansour A, Spielman K, Blacher J, Safar ME, Bahous SA. Change in Pulse Wave Velocity and Short-Term Development of Cardiovascular Events in the Hemodialysis Population. J Clin Hypertens (Greenwich) 2016; 18:857-63. [PMID: 27226148 PMCID: PMC8032091 DOI: 10.1111/jch.12843] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 02/27/2016] [Accepted: 03/03/2016] [Indexed: 11/28/2022]
Abstract
The association between single measurements of carotid-femoral pulse wave velocity (cfPWV) and cardiovascular (CV) events is driven by late events beyond 12 months of follow-up. This prospective study compares single measurements of cfPWV vs the 2-year delta cfPWV and the association with short-term development of CV events in hemodialysis patients. cfPWV was performed at t=0 and t=1 two years later, and patients were followed-up for development of CV events through 12 months (n=66). In Cox regression models adjusted for CV risk factors, history of CV events and delta cfPWV remained associated with the development of CV events (hazard ratio for prior CV events=8.9, P=.03; hazard ratio for delta cfPWV=1.14; P=.002). When delta cfPWV was substituted for single cfPWV measurement, none of the single measures were associated with new CV events. The change in cfPWV, but not single measurements of cfPWV, was associated with the development of CV events through 12 months.
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Affiliation(s)
- Serge Korjian
- Lebanese American University School of Medicine, Lebanon
| | - Yazan Daaboul
- Lebanese American University School of Medicine, Lebanon
| | | | - Salam Samad
- North Hospital Center, Zgharta, North Lebanon, Lebanon
| | - Pascale Salameh
- School of Public Health, Lebanese University, Byblos-Jbeil, Lebanon
| | | | - Essa Hariri
- Lebanese American University School of Medicine, Lebanon
| | | | - Kathryn Spielman
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
| | | | | | - Sola Aoun Bahous
- Lebanese American University School of Medicine, Lebanon.
- Lebanese American University Medical Center - Rizk Hospital, Beirut, Lebanon.
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Ohno Y, Kanno Y, Takenaka T. Central blood pressure and chronic kidney disease. World J Nephrol 2016; 5:90-100. [PMID: 26788468 PMCID: PMC4707173 DOI: 10.5527/wjn.v5.i1.90] [Citation(s) in RCA: 15] [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: 08/30/2015] [Revised: 11/17/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023] Open
Abstract
In this review, we focused on the relationship between central blood pressure and chronic kidney diseases (CKD). Wave reflection is a major mechanism that determines central blood pressure in patients with CKD. Recent medical technology advances have enabled non-invasive central blood pressure measurements. Clinical trials have demonstrated that compared with brachial blood pressure, central blood pressure is a stronger risk factor for cardiovascular (CV) and renal diseases. CKD is characterized by a diminished renal autoregulatory ability, an augmented direct transmission of systemic blood pressure to glomeruli, and an increase in proteinuria. Any elevation in central blood pressure accelerates CKD progression. In the kidney, interstitial inflammation induces oxidative stress to handle proteinuria. Oxidative stress facilitates atherogenesis, increases arterial stiffness and central blood pressure, and worsens the CV prognosis in patients with CKD. A vicious cycle exists between CKD and central blood pressure. To stop this cycle, vasodilator antihypertensive drugs and statins can reduce central blood pressure and oxidative stress. Even in early-stage CKD, mineral and bone disorders (MBD) may develop. MBD promotes oxidative stress, arteriosclerosis, and elevated central blood pressure in patients with CKD. Early intervention or prevention seems necessary to maintain vascular health in patients with CKD.
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Affiliation(s)
- Neeraj Dhaun
- University/British Heart Foundation Centre of Research Excellence, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; and Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - David J Webb
- University/British Heart Foundation Centre of Research Excellence, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; and
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Arterial Stiffness and Renal Replacement Therapy: A Controversial Topic. Int J Nephrol 2015; 2015:729609. [PMID: 26064684 PMCID: PMC4439473 DOI: 10.1155/2015/729609] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 04/13/2015] [Indexed: 11/18/2022] Open
Abstract
The increase of arterial stiffness has been to have a significant impact on predicting mortality in end-stage renal disease patients. Pulse wave velocity (PWV) is a noninvasive, reliable parameter of regional arterial stiffness that integrates the vascular geometry and arterial wall intrinsic elasticity and is capable of predicting cardiovascular mortality in this patient population. Nevertheless, reports on PWV in dialyzed patients are contradictory and sometimes inconsistent: some reports claim the arterial wall stiffness increases (i.e., PWV increase), others claim that it is reduced, and some even state that it augments in the aorta while it simultaneously decreases in the brachial artery pathway. The purpose of this study was to analyze the literature in which longitudinal or transversal studies were performed in hemodialysis and/or peritoneal dialysis patients, in order to characterize arterial stiffness and the responsiveness to renal replacement therapy.
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Rastogi A. Sevelamer revisited: pleiotropic effects on endothelial and cardiovascular risk factors in chronic kidney disease and end-stage renal disease. Ther Adv Cardiovasc Dis 2014; 7:322-42. [PMID: 24327730 PMCID: PMC3917706 DOI: 10.1177/1753944713513061] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in CKD or end-stage renal disease (ESRD) patients include uremic toxins, serum uric acid, hyperphosphatemia, reactive oxygen species, and advanced glycation endproducts (AGEs). Sevelamer carbonate, a calcium-free intestinally nonabsorbed polymer, is approved for hyperphosphatemic dialysis patients in the US and hyperphosphatemic stage 3-5 CKD patients in many other countries. Sevelamer has been observed investigationally to reduce absorption of AGEs, bacterial toxins, and bile acids, suggesting that it may reduce inflammatory, oxidative, and atherogenic stimuli in addition to its on-label action of lowering serum phosphate. Some studies also suggest that noncalcium binders may contribute less to vascular calcification than calcium-based binders. Exploratory sevelamer carbonate use in patients with stages 2-4 diabetic CKD significantly reduced HbA1c, AGEs, fibroblast growth factor (FGF)-23, and total and low-density lipoprotein (LDL) cholesterol versus calcium carbonate; inflammatory markers decreased and defenses against AGEs increased. Sevelamer has also been observed to reduce circulating FGF-23, potentially reducing risk of left ventricular hypertrophy. Sevelamer but not calcium-based binders in exploratory studies increases flow-mediated vasodilation, a marker of improved endothelial function, in patients with CKD. In contrast, lanthanum carbonate and calcium carbonate effects on FMV did not differ in hemodialysis recipients. The recent independent-CKD randomized trial compared sevelamer versus calcium carbonate in predialysis CKD patients (investigational in the US, on-label in European participants); sevelamer reduced 36-month mortality and the composite endpoint of mortality or dialysis inception. Similarly, independent-HD in incident dialysis patients showed improved survival with 24 months of sevelamer versus calcium-based binders. This review discusses recent exploratory evidence for pleiotropic effects of sevelamer on endothelial function in CKD or ESRD. Endothelial effects of sevelamer may contribute mechanistically to the improved survival observed in some studies of CKD and ESRD patients.
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Affiliation(s)
- Anjay Rastogi
- Division of Nephrology, Department of Medicine, 10630 Santa Monica Boulevard, Los Angeles, CA 90025, USA
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Abstract
The vasculopathy of ESRD affects both arteries and veins. The arteries develop arteriosclerosis, which is
largely a disease of the media characterized by increased collagen content, calcification, and both hypertrophy and
hyperplasia of vascular smooth muscle cells. Veins may exhibit increased width of the intimal and medial layers, and may
develop neointimal hyperplasia and calcification. Successful fistula maturation depends upon dilatation and remodeling of
the artery and vein, but the stiff and thickened vessels of ESRD patients may respond poorly to signals that promote these
adaptations. There is intense interest in accurately predicting fistula maturation outcome and preventing maturation
failure. However, definitive criteria for preoperative testing of vessel elasticity have not yet been established. Tests that
are adopted for widespread clinical use will need to be easy to apply - a standard that many of these tests may not meet.
Finally, effective treatments are needed that prevent or reduce the stiffness of vessels. In conclusion, although there are
many promising developments in this emerging field, effective methods of predicting fistula maturation outcome and
preventing maturation failure remain to be established.
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TOUSSAINT NIGELD, PEDAGOGOS EUGENIE, TAN SVENJEAN, BADVE SUNILV, HAWLEY CARMELM, PERKOVIC VLADO, ELDER GRAHAMEJ. Phosphate in early chronic kidney disease: Associations with clinical outcomes and a target to reduce cardiovascular risk. Nephrology (Carlton) 2012; 17:433-44. [DOI: 10.1111/j.1440-1797.2012.01618.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Bellasi A, Ferramosca E, Ratti C. Arterial stiffness in chronic kidney disease: the usefulness of a marker of vascular damage. Int J Nephrol 2011; 2011:734832. [PMID: 21660313 PMCID: PMC3108158 DOI: 10.4061/2011/734832] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Accepted: 03/27/2011] [Indexed: 11/20/2022] Open
Abstract
Increased arterial stiffness is a marker of vasculopathy in chronic kidney disease (CKD) patients, suggesting a significant cardiovascular damage. Detection of arterial stiffness provides physicians with useful prognostic information independent of traditional cardiovascular (CV) risk factors. In addition, this knowledge may help guide appropriate therapeutic choices and monitor the effectiveness of antihypertensive therapies. We review the relationship between arterial stiffness and CKD, as well as the prognostic implications of increased arterial stiffness and the potential therapeutic strategies to ameliorate arterial compliance and outcome in CKD.
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Affiliation(s)
- Antonio Bellasi
- Division of Nephrology, S.Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy
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Takenaka T, Mimura T, Kikuta T, Kato N, Inoue T, Kanno Y, Ohno Y, Kobayashi T, Miyawaki Y, Suzuki H. Time for reflection predicts the progression of renal dysfunction in patients with nondiabetic chronic kidney disease. Clin Exp Hypertens 2009; 31:220-30. [PMID: 19387898 DOI: 10.1080/10641960902822476] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Our previous data indicated that both home blood pressure and arterial stiffness predicted the progression of renal dysfunction in the patients with chronic kidney diseases. In the present study, we examined both home blood pressure and the parameters of arterial stiffness as the indicator to the progression of chronic kidney diseases. Forty-two nondiabetic chronic kidney disease patients were enrolled and followed for 1 year. Anti-hypertensive therapy was adjusted to achieve office blood pressure below 130/80 mmHg. Home blood pressure was examined twice a day in the morning and evening. Pulse wave velocity (PWV) and augmentation index (AI) were measured as the index of arterial stiffness. The time for reflection (TR) was also determined. The relationship of annual changes in serum creatinine (Scr) with the above parameters was assessed. Multivariate regression analysis revealed that TR inversely correlated to annual increase in Scr (beta = -0.03, p < 0.05). Home blood pressure did not correlate to annual changes in Scr in the present study. The present data indicated that arterial stiffness is elevated despite good blood pressure control in chronic kidney disease, especially among the dippings. In addition, our data suggest that PWV and AI correlated to each other, while they were influenced differently by hemodynamic factors. Finally, the present findings provide the evidence that the arterial stiffness parameter is more sensitive than home blood pressure as an indicator to the progression of chronic kidney disease.
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Affiliation(s)
- Tsuneo Takenaka
- Department of Nephrology, Saitama Medical University, School of Medicine, 38 Moro-Hongo Moroyama, Iruma, Saitama, Japan
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Takenaka T, Hoshi H, Kato N, Kobayashi K, Takane H, Shoda J, Suzuki H. Cardio-ankle vascular index to screen cardiovascular diseases in patients with end-stage renal diseases. J Atheroscler Thromb 2008; 15:339-44. [PMID: 19060424 DOI: 10.5551/jat.e584] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Cardiovascular diseases constitute major causes of death in patients with chronic kidney diseases. An increase in arterial stiffness predicts the presence of cardiovascular diseases; however, non-invasive arterial stiffness parameters such as pulse wave velocity are confounded by blood pressure. METHODS A new arterial stiffness parameter beta for the arterial tree, cardio-ankle vascular index (CAVI), was measured. To examine the usefulness of CAVI to screen for the presence of cardiovascular diseases, cross-sectional studies were performed on 68 patients undergoing chronic hemodialysis. RESULTS Stepwise regression analysis indicated that CAVI significantly correlated to age (beta=0.05, p<0.01) but not blood pressure. In addition, CAVI was higher in diabetics than non-diabetics (8.39+/-0.37 vs 7.63+/-0.57, p<0.05). Furthermore, CAVI was markedly elevated in patients with a history of cardiovascular diseases (8.69+/-0.23 vs 6.66+/-0.28, p<0.01). Analysis using the ROC curve has demonstrated that CAVI of 7.55 constitutes the cut-off value for the presence of cardiovascular diseases with both sensitivity and specificity of 0.79. CONCLUSION The present findings suggest that CAVI can be used as a screening test to detect for the presence of cardiovascular diseases in patients undergoing hemodialysis.
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Affiliation(s)
- Tsuneo Takenaka
- Department of Medicine, Faculty of Medicine, Saitama Medical University, Saitama, Japan
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Marangon N, Lindholm B, Stenvinkel P. Nonphosphate-Binding Effects of Sevelamer-Are They of Clinical Relevance? Semin Dial 2008; 21:385-9. [DOI: 10.1111/j.1525-139x.2008.00440.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Takenaka T, Mimura T, Kanno Y, Ohno Y, Suzuki H. Arterial wave reflection is elevated in evening hemodialysis patients. Clin Exp Hypertens 2008; 30:173-81. [PMID: 18425697 DOI: 10.1080/10641960802064542] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
AIM Cardiovascular disease constitutes a major cause of death in patients with chronic kidney diseases and is related to enhanced arterial stiffness. It has been reported that daytime hemodialysis patients show better prognosis than evening hemodialysis patients. METHODS Aortic augmentation index (AI) and radial AI were measured in 20 non-diabetic hemodialysis patients, using SphygmoCor (PWV Medical) and HEM-9010AI (Omron Healthcare) as markers of arterial stiffness. Cardiovascular prognosis was followed for two years. RESULTS Mean age, blood pressure, pulse rate, and aortic and radial AI were 52 +/- 4 y/o, 142 +/- 6/74 +/- 4 mmHg, 78 +/- 4 bpm, 21 +/- 2, and 71 +/- 4%, respectively, in 10 daytime hemodialysis patients, and they averaged 52 +/- 3 y/o, 146 +/- 6/76 +/- 4 mmHg, 74 +/- 3 bpm, 26 +/- 2, and 73 +/- 3% in 10 evening hemodialysis patients, respectively. Thus, aortic AI was higher in evening hemodialysis patients (p < 0.05). In all, one patient was hospitalized due to cardiovascular complications in daytime hemodialysis patients, as well as three patients from those dialyzed in the evening. CONCLUSION Although a larger scale study is required to draw a definite conclusion, our findings suggest that a better prognosis in daytime hemodialysis non-diabetic patients is related to the lower AI.
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Affiliation(s)
- Tsuneo Takenaka
- Department of Nephrology, Saitama Medical University, Iruma, Saitama, Japan
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Vascular compliance and arterial calcification: impact on blood pressure reduction. Curr Opin Nephrol Hypertens 2008; 17:93-8. [PMID: 18090677 DOI: 10.1097/mnh.0b013e3282f331d7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
PURPOSE OF REVIEW The aim of this article is to review the relationship between vascular calcification and difficult to control hypertension. This does not address antihypertensive treatment of drug resistant hypertension per se. RECENT FINDINGS Vascular calcification occurs in a variety of common hypertension scenarios. Basic mechanisms of how and why vessels calcify are reviewed including new genetic insights. The potential for contributing to or improving calcification through drug therapies for nonhypertensive disorders is reviewed. SUMMARY Vascular calcification is common and easily recognized. Studies that target its clinical consequences (arterial stiffness) as primary treatment goals are needed.
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DeLoach SS, Townsend RR. Vascular Stiffness: Its Measurement and Significance for Epidemiologic and Outcome Studies. Clin J Am Soc Nephrol 2008; 3:184-92. [PMID: 18178784 DOI: 10.2215/cjn.03340807] [Citation(s) in RCA: 170] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Stephanie S DeLoach
- Renal Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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20
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Othmane TEH, Bakonyi G, Egresits J, Fekete BC, Fodor E, Jarai Z, Jekkel C, Nemcsik J, Szabo A, Szabo T, Kiss I, Tisler A. Effect of sevelamer on aortic pulse wave velocity in patients on hemodialysis: a prospective observational study. Hemodial Int 2007; 11 Suppl 3:S13-21. [PMID: 17897105 DOI: 10.1111/j.1542-4758.2007.00224.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Aortic stiffening and aortic calcification are risk factors for cardiovascular events in hemodialysis (HD) patients, and these 2 risk factors are interrelated. Sevelamer decreases aortic calcification but its effect on aortic stiffness has not been investigated previously. Thirteen HD patients commencing sevelamer treatment and 13 matched controls were followed for 11 months. Aortic pulse wave velocity (PWV), augmentation index (AIx), and levels of inhibitors of vascular calcification (fetuin-A, matrix-GLA-protein, osteoprotegerin/RANKL) were measured at baseline and at the end of follow-up, and the differences between the groups were compared. Determinants of the changes in PWV during follow-up were assessed by multivariate linear regression. At baseline, PWV was 9.93 (2.10) m/s in sevelamer-treated patients and 9.20 (2.84) m/s in control patients (p=0.464). By the end of follow-up, PWV decreased by 0.83 (2.3) m/s in sevelamer-treated patients while it increased by 0.93 (1.88) m/s in controls (p=0.042). The direction of changes in AIx were similar, but not statistically significant. There were no significant differences in the levels of inhibitors of calcification either at baseline or during follow-up. In multivariate linear regression sevelamer treatment, diabetes, heart rate, and C-reactive protein were related to the change in PWV. These data suggest that sevelamer treatment is associated with an improvement in aortic stiffness in HD patients, but it does not seem to affect serum levels of inhibitors of vascular calcification.
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Affiliation(s)
- Taha El Hadj Othmane
- 1st Department of Medicine, Semmelweis University, 2/a Korányi S, Budapest, Hungary
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Mimura T, Takenaka T, Kanno Y, Moriwaki K, Okada H, Suzuki H. Vascular compliance is secured under angiotensin inhibition in non-diabetic chronic kidney diseases. J Hum Hypertens 2007; 22:38-47. [PMID: 17653243 DOI: 10.1038/sj.jhh.1002264] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cardiovascular diseases constitute major cause of death in chronic kidney diseases (CKDs). We examined the effects of angiotensin inhibition either with angiotensin-converting enzyme inhibitor or with angiotensin receptor blocker on patient prognosis and heart-ankle pulse wave velocity (haPWV) in CKDs. Randomized controlled study was performed on 102 patients with non-diabetic CKDs. Patients were divided into two groups with or without angiotensin inhibition, and followed until death, creatinine clearance was halved or starting renal replacement therapy, whichever occurred first. For 4 years, haPWV was assessed repeatedly in the surviving patients. While both groups showed well blood pressure control throughout 4 years (129+/-1 to 131+/-2/71+/-1 to 73+/-2 mm Hg), renal prognosis was better in angiotensin inhibition group (P<0.05). In addition, angiotensin inhibition reduced cardiovascular and renal death (P<0.05). Age, sex, heart rate, systolic blood pressure and proteinuria were correlated to haPWV (R(2)=0.76, P<0.0001). Although haPWV was similar between two groups at the start of the study (1098+/-31 vs 1094+/-37 cm/s), it was higher in patients without angiotensin inhibition than that with angiotensin inhibition 4 years later (1034+/-38 cm/s (n=28) vs 1242+/-37 cm/s (n=23), P<0.01). The present results provided the evidence that angiotensin inhibition arrested a time-dependent elevation of haPWV in non-diabetic CKDs, conferring organ protection. Furthermore, our data indicated that angiotensin inhibition improved patient prognosis in non-diabetic chronic kidney diseases with mild-to-moderate renal dysfunction.
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Affiliation(s)
- T Mimura
- Department of Nephrology, Saitama Medical College, Iruma, Saitama, Japan
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Covic A, Gusbeth-Tatomir P, Goldsmith DJA. VASCULAR CALCIFICATION IN PATIENTS WITH KIDNEY DISEASE: Vascular Calcification-A New Window on the Cardiovascular System: Role of Agents Used to Manipulate Skeletal Integrity. Semin Dial 2007; 20:158-69. [PMID: 17374091 DOI: 10.1111/j.1525-139x.2007.00265.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Adrian Covic
- Nephrology Clinic, "Dr. C. I. Parhon" University Hospital, Iasi, Romania.
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Gusbeth-Tatomir P, Covic A. Causes and consequences of increased arterial stiffness in chronic kidney disease patients. Kidney Blood Press Res 2007; 30:97-107. [PMID: 17374960 DOI: 10.1159/000100905] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2006] [Accepted: 02/02/2007] [Indexed: 02/01/2023] Open
Abstract
Cardiovascular (CV) morbidity and mortality is greatly enhanced in patients with chronic kidney disease, compared to the non-renal population. One key element of this high CV burden appears to be arterial stiffness, as an expression of premature vascular aging. Increased arterial stiffness in renal patients may be a consequence of vascular calcification, chronic volume overload, inflammation, endothelial dysfunction, oxidative stress and several other factors. The authors review briefly the main pathophysiological mechanisms leading to reduced arterial compliance. Increased arterial stiffness has significant clinical consequences: isolated systolic hypertension, left ventricular hypertrophy (and failure), and reduced myocardial perfusion. Better knowledge of the mechanisms of arterial functional and morphologic alteration may help in developing more refined therapeutic strategies aimed to reduce the high CV burden in chronic kidney disease. The potential therapeutic interventions - mainly the use of certain antihypertensive drugs and reduction of vascular calcification - are finally discussed.
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Affiliation(s)
- Paul Gusbeth-Tatomir
- Dialysis and Renal Transplantation Center, Parhon University Hospital, Iasi, Romania
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Takenaka T, Kanno Y, Ohno Y, Suzuki H. Key role of insulin resistance in vascular injury among hemodialysis patients. Metabolism 2007; 56:153-9. [PMID: 17224326 DOI: 10.1016/j.metabol.2006.08.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2006] [Accepted: 08/23/2006] [Indexed: 12/16/2022]
Abstract
Insulin resistance prevails not only among diabetic patients but also among hypertensive and obese patients. The relationship between insulin resistance and cardiovascular diseases was investigated in hemodialysis (HD) patients. Eighty-one maintenance HD patients were enrolled. The homeostasis model assessment of insulin resistance (HOMA-IR) method was used to assess insulin resistance. The relationship of HOMA-IR with cardiovascular and all-cause events was assessed. Compared with nondiabetic patients (n = 55), diabetic patients (n = 26) showed higher HOMA-IR (2.5 +/- 0.3 vs 1.4 +/- 0.2, P < .05), lower ankle-brachial pressure index (ABI, 0.85 +/- 0.09 vs 1.12 +/- 0.02, P < .01), and shorter HD duration (3 +/- 1 vs 9 +/- 1 years, P < .01), although their body mass index was similar (22.3 +/- 0.5 vs 21.5 +/- 0.4 kg/m(2)). Nondiabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 36) had lower HOMA-IR (1.2 +/- 0.2 vs 1.8 +/- 0.4, P < .05) and higher ABI (1.18 +/- 0.02 vs 1.02 +/- 0.05, P < .01) than those without (n = 17). Cardiovascular events were less common in HD patients with normal HOMA-IR (P < .05) or ABI (P < .01). Our data indicate that 69% of diabetic and 27% of nondiabetic patients have HOMA-IR greater than 1.6, implying reduced insulin sensitivity in HD patients. The present results provide evidence that angiotensin inhibition improves insulin resistance, possibly preventing vascular injury in HD patients. Finally, our findings suggest that insulin resistance is prognostic of cardiovascular events in HD patients.
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Covic A, Mardare N, Gusbeth-Tatomir P, Prisada O, Sascau R, Goldsmith DJA. Arterial wave reflections and mortality in haemodialysis patients--only relevant in elderly, cardiovascularly compromised? Nephrol Dial Transplant 2006; 21:2859-66. [PMID: 16854850 DOI: 10.1093/ndt/gfl307] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) patients have a 3-30-fold increased risk of death compared with the general population. This mortality difference is even more pronounced in younger subjects. Two markers of aortic stiffness--aortic pulse wave velocity (PWV) and augmentation index (AIx)--have been prospectively related to all-cause and cardiovascular (CV) mortality in end-stage renal disease (ESRD) populations. The aims of our study were first, to confirm the important deleterious effect of arterial stiffness in uraemia and second, to assess the impact on survival of increased AIx in a relatively young non-diabetic dialysis population, with minimal CV disease. METHODS Ninety-two patients (mean age 42.6 +/- 11.2 years) were included in the study and followed for a period of 61 +/- 25 months. None of the patients had diabetes mellitus, and only 3.3% had prior history of CV disease. AIx was determined by applantation tonometry using a SphygmoCor device (AtCor, PWV Inc., Westmead, Sydney, Australia). RESULTS Mean AIx in our study population was 19.9 +/- 13.7%; other significant haemodynamic parameters were: systolic blood pressure (SBP) 129 +/- 24 mmHg, pulse pressure 35.3 +/- 17.5 mmHg with 27.2% of the study population receiving angiotensin-converting enzyme inhibitors (ACE-I). On univariate analysis, in our group AIx correlated with: body weight (P < 0.001), radial SBP (P < 0.001) and haemoglobin levels (P < 0.05). There was no correlation between AIx and any of the echocardiographic parameters. In the stepwise multiple regression analysis, the only independent predictors for AIx were weight (P < 0.001), SBP (P < 0.001) and haemoglobin (P < 0.05) with the model explaining 33% of the AIx variability (adjusted R(2) = 0.33). During the follow-up period, 15 deaths were recorded. In the Cox analysis (P = 0.014; chi square 20.7 for the model) the only independent predictors for all-cause mortality were age (P = 0.001), left ventricular mass index (P = 0.032) and ACE-I therapy (P = 0.039) while AIx did not reach statistical significance. There was no difference in patients' survival when divided by AIx tertiles, assessed by the log rank test (P = 0.78). CONCLUSION Our results fail to support the notion that an increased effect of wave reflections on central arteries is a strong and independent predictor of mortality in all ESRD patients on haemodialysis. The effect of arterial wave reflections might be in fact dependent on patient age and concurrent comorbidity status.
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Affiliation(s)
- Adrian Covic
- Dialysis and Transplantation Center, C. I. PARHON University Hospital, 50 Carol 1st Blvd., Iasi, 700503 Romania.
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Takenaka T, Itaya Y, Suzuki H. Young Hemodialysis Patients Are Exposed to Hyperhomocysteinemia. J Ren Nutr 2005; 15:435-40. [PMID: 16198935 DOI: 10.1053/j.jrn.2005.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2004] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE Homocysteine is one of the cardiovascular risk factors in hemodialysis (HD) patients. Studies were performed to assess the effects of folic acid on pulse wave velocity (PWV) in HD patients. METHODS In a cross-sectional study, plasma total homocysteine (tHcy) was measured in 49 patients on maintenance HD. Ten HD patients younger than 45 years old entered the prospective study. Monthly changes in PWV were compared before and during folic acid treatment. RESULTS Younger HD patients had higher tHcy (r = -0.53, n = 49, P < .001). Patients who manifested myocardial ischemia (37 +/- 3 nmol/mL) possessed higher tHcy than those who did not (30 +/- 3 nmol/mL, P < .05). In prospective study, folic acid treatment (10 to 20 mg/d) failed to alter blood pressure and biochemical parameters, including lipids, calcium, phosphate, and parathormone. However, in association with a decrease in tHcy (46 +/- 5 to 27 +/- 3 nmol/mL, n = 10, P < .005), progressive increases in PWV (33 +/- 8 to 3 +/- 6 cm/sec/month, P < .01) were stopped. CONCLUSIONS The present findings indicate that young HD patients are exposed to severe hyperhomocysteinemia, and suggest that relatively large doses of folic acid attenuate progressive increases in PWV of young or middle-age HD patients.
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