Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure
2013; Elsevier BV; Volume: 84; Issue: 3 Linguagem: Inglês
10.1038/ki.2013.110
ISSN1523-1755
AutoresJulien Maizel, Isabelle Six, Sébastien Dupont, Edouard Secq, Bénédicte Dehédin, Fellype Carvalho Barreto, Joyce Benchitrit, Sabrina Poirot, Michel Slama, Christophe Tribouilloy, Gabriel Choukroun, J.C. Mazière, Tilman B. Drüeke, Ziad A. Massy,
Tópico(s)Pancreatitis Pathology and Treatment
ResumoElevated serum phosphate and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease (CVD) in patients with chronic renal failure (CRF). The phosphate-binder sevelamer has been shown to decrease both phosphate and FGF23, but limited data indicate that sevelamer improves CRF-related CVD, such as diastolic dysfunction, left ventricular hypertrophy (LVH), and aortic stiffness. To gain additional information, we measured the effects of sevelamer on CVD in a murine model of CRF. Groups of CRF and sham-operated mice received regular chow or 3% sevelamer–HCl in the chow for 14 weeks, starting 6 weeks after the initiation of CRF or sham operation. After the first 8 weeks of sevelamer treatment, CRF mice had decreased serum phosphate levels and an improved aortic systolic expansion rate, pulse-wave velocity, and diastolic function, although LVH remained unchanged. Following an additional 6-week course of sevelamer, LVH had not progressed. The FGF23 serum level was not reduced by sevelamer until after 14 weeks of treatment. In multiple regression analysis, serum phosphate, but not FGF23, was independently correlated with LV diastolic function and mass. Thus, sevelamer first improved aortic stiffness and diastolic dysfunction and secondarily prevented LVH in mice with CRF. The phosphate-lowering, rather than FGF23-lowering, effect appears to be responsible for the observed cardiovascular improvement. Elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease (CVD) in patients with chronic renal failure (CRF). The phosphate-binder sevelamer has been shown to decrease both phosphate and FGF23, but limited data indicate that sevelamer improves CRF-related CVD, such as diastolic dysfunction, left ventricular hypertrophy (LVH), and aortic stiffness. To gain additional information, we measured the effects of sevelamer on CVD in a murine model of CRF. Groups of CRF and sham-operated mice received regular chow or 3% sevelamer–HCl in the chow for 14 weeks, starting 6 weeks after the initiation of CRF or sham operation. After the first 8 weeks of sevelamer treatment, CRF mice had decreased serum phosphate levels and an improved aortic systolic expansion rate, pulse-wave velocity, and diastolic function, although LVH remained unchanged. Following an additional 6-week course of sevelamer, LVH had not progressed. The FGF23 serum level was not reduced by sevelamer until after 14 weeks of treatment. In multiple regression analysis, serum phosphate, but not FGF23, was independently correlated with LV diastolic function and mass. Thus, sevelamer first improved aortic stiffness and diastolic dysfunction and secondarily prevented LVH in mice with CRF. The phosphate-lowering, rather than FGF23-lowering, effect appears to be responsible for the observed cardiovascular improvement. Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Hyperphosphatemia appears to be one of the most important risk factors identified in this context, as it affects both atherosclerosis and arteriosclerosis in CKD patients and in the general population.1.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8983) Google Scholar, 2.Onufrak S.J. Bellasi A. Shaw L.J. et al.Phosphorus levels are associated with subclinical atherosclerosis in the general population.Atherosclerosis. 2008; 199: 424-431Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 3.Dhingra R. Sullivan L.M. Fox C.S. et al.Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community.Arch Intern Med. 2007; 167: 879-885Crossref PubMed Scopus (674) Google Scholar Furthermore, hyperphosphatemia has been linked to endothelial dysfunction, increased carotid intima-media thickness, the development of atherosclerosis, and cardiovascular mortality in individuals with normal kidney function.2.Onufrak S.J. Bellasi A. Shaw L.J. et al.Phosphorus levels are associated with subclinical atherosclerosis in the general population.Atherosclerosis. 2008; 199: 424-431Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 4.Giachelli C.M. Vascular calcification: In vitro evidence for the role of inorganic phosphate.J Am Soc Nephrol. 2003; 14: S300-S304Crossref PubMed Google Scholar, 5.Jono S. McKee M.D. Murry C.E. et al.Phosphate regulation of vascular smooth muscle cell calcification.Circ Res. 2000; 87: E10-E17Crossref PubMed Google Scholar, 6.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1509) Google Scholar, 7.Shuto E. Taketani Y. Tanaka R. et al.Dietary phosphorus acutely impairs endothelial function.J Am Soc Nephrol. 2009; 20: 1504-1512Crossref PubMed Scopus (287) Google Scholar Finally, hyperphosphatemia is involved in the mineral and bone disorders seen in patients with CKD and promotes the development of vascular calcifications and arterial stiffness.8.Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (948) Google Scholar,9.Lau W.L. Pai A. Moe S.M. et al.Direct effects of phosphate on vascular cell function.Adv Chronic Kidney Dis. 2011; 18: 105-112Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar For the past 40 years, oral phosphate binders have been used to control hyperphosphatemia in CKD patients both before and after the advent of end-stage renal disease. The aluminum-containing phosphate binders used initially have been superseded by calcium-containing binders. However, the high calcium intake associated with the latter is suspected to favor vascular calcification.10.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2436) Google Scholar The calcium-free phosphate-binder sevelamer has since emerged as a promising treatment in CKD and end-stage renal disease patients. Sevelamer not only reduces vascular calcification but also decreases serum levels of low-density lipoprotein cholesterol, C-reactive protein, and uremic toxins, and improves fetuin A and parathyroid hormone levels.11.Goldberg D.I. Dillon M.A. Slatopolsky E.A. et al.Effect of renagel, a non-absorbed, calcium- and aluminium-free phosphate binder, on serum phosphorus, calcium, and intact parathyroid hormone in end-stage renal disease patients.Nephrol Dial Transplant. 1998; 13: 2303-2310Crossref PubMed Scopus (109) Google Scholar,12.Nikolov I.G. Joki N. Maizel J. et al.Pleiotropic effects of the non-calcium phosphate binder sevelamer.Kidney Int Suppl. 2006; : S16-S23Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar At present, most of sevelamer's effects are only partly understood. As the drug is not absorbed from the gut, it cannot exert any direct effects on the vascular endothelium. Recently, investigations into the phosphaturic hormone fibroblast growth factor 23 (FGF23) have prompted questions about the relationships between phosphate and the cardiovascular abnormalities seen in CKD patients.13.Zoppellaro G. Faggin E. Puato M. et al.Fibroblast growth factor 23 and the bone-vascular axis: lessons learned from animal studies.Am J Kidney Dis. 2012; 59: 135-144Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,14.Faul C. Amaral A.P. Oskouei B. et al.FGF23 induces left ventricular hypertrophy.J Clin Invest. 2011; 121: 4393-4408Crossref PubMed Scopus (1469) Google Scholar In both healthy individuals and patients with CKD, FGF23 is secreted by osteocytes and osteoblasts in response to oral phosphate loading.15.Shimada T. Hasegawa H. Yamazaki Y. et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res. 2004; 19: 429-435Crossref PubMed Scopus (1412) Google Scholar, 16.Gutierrez O. Isakova T. Rhee E. et al.Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.J Am Soc Nephrol. 2005; 16: 2205-2215Crossref PubMed Scopus (746) Google Scholar, 17.Antoniucci D.M. Yamashita T. Portale A.A. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men.J Clin Endocrinol Metab. 2006; 91: 3144-3149Crossref PubMed Scopus (354) Google Scholar Furthermore, serum FGF23 levels increase in the very early stages of CKD, and the hormone is probably produced as an initial attempt by the body to counter hyperphosphatemia. As CKD progresses, hyperphosphatemia occurs despite marked increases in serum FGF23 and parathyroid hormone levels. The FGF23 receptor and its co-receptor klotho are expressed in many cell types, including cardiomyocytes, aortic tissue, the kidneys, and the parathyroid glands.14.Faul C. Amaral A.P. Oskouei B. et al.FGF23 induces left ventricular hypertrophy.J Clin Invest. 2011; 121: 4393-4408Crossref PubMed Scopus (1469) Google Scholar, 18Donate-Correa J, Mora-Fernández C, Martínez-Sanz R et al. Expression of FGF23/KLOTHO system in human vascular tissue. Int J Cardiol. e-pub ahead of print 24 September 2011Google Scholar, 19.Urakawa I. Yamazaki Y. Shimada T. et al.Klotho converts canonical FGF receptor into a specific receptor for FGF23.Nature. 2006; 444: 770-774Crossref PubMed Scopus (1450) Google Scholar Interestingly, elevated FGF23 is associated with the development of endothelial dysfunction and cardiac hypertrophy in CKD.14.Faul C. Amaral A.P. Oskouei B. et al.FGF23 induces left ventricular hypertrophy.J Clin Invest. 2011; 121: 4393-4408Crossref PubMed Scopus (1469) Google Scholar,20.Mirza M.A. Larsson A. Lind L. et al.Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community.Atherosclerosis. 2009; 205: 385-390Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar Several recent studies have demonstrated sevelamer's ability to decrease serum FGF23 and phosphate levels.21.Nagano N. Miyata S. Abe M. et al.Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats.Kidney Int. 2006; 69: 531-537Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 22.Koiwa F. Kazama J.J. Tokumoto A. et al.Sevelamer hydrochloride and calcium bicarbonate reduce serum fibroblast growth factor 23 levels in dialysis patients.Ther Apher Dial. 2005; 9: 336-339Crossref PubMed Scopus (124) Google Scholar, 23.Oliveira R.B. Cancela A.L. Graciolli F.G. et al.Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy?.Clin J Am Soc Nephrol. 2010; 5: 286-291Crossref PubMed Scopus (306) Google Scholar, 24.Cancela A.L. Oliveira R.B. Graciolli F.G. et al.Fibroblast growth factor 23 in hemodialysis patients: effects of phosphate binder, calcitriol and calcium concentration in the dialysate.Nephron Clin Pract. 2011; 117: c74-c82Crossref PubMed Scopus (53) Google Scholar It is therefore plausible that a combined reduction of these parameters, both of which are associated with CVD and mortality in patients with CKD, leads to an improvement of this serious complication. Hence, we decided to study the therapeutic effects of sevelamer on the cardiovascular alterations induced by chronic renal failure (CRF). To this end, we used a recently developed CRF mouse model with no arterial hypertension, no hypercholesterolemia, and no calcification of the aorta.25.Maizel J. Six I. Slama M. et al.Mechanisms of aortic and cardiac dysfunction in uremic mice with aortic calcification.Circulation. 2009; 119: 306-313Crossref PubMed Scopus (43) Google Scholar This model is characterized by the development, already after 6 weeks of CRF, of cardiovascular abnormalities, including left ventricular hypertrophy (LVH), diastolic dysfunction, and aortic stiffness, and concomitant endothelial dysfunction.25.Maizel J. Six I. Slama M. et al.Mechanisms of aortic and cardiac dysfunction in uremic mice with aortic calcification.Circulation. 2009; 119: 306-313Crossref PubMed Scopus (43) Google Scholar Biochemical, hematocrit, and body weight data are presented in Table 1. At baseline (i.e., 6 weeks after the initiation of CRF creation or sham operation), the two CRF groups differed significantly from the two non-CRF groups in terms of body weight, serum urea, total calcium, total cholesterol, and hematocrit. Serum phosphate did not differ significantly between the groups at that time. After 8 weeks, CRF in non-treated animals was associated with a decrease in body weight and hematocrit and an increase in serum total calcium, serum phosphate, urea, total cholesterol, and FGF23. By contrast, serum calcium was increased and serum phosphate was decreased in the sevelamer-treated groups. Serum FGF23 was not different in response to sevelamer treatment. After 14 weeks of treatment, body weight, serum urea, serum total cholesterol, and hematocrit were still significantly different when comparing the non-treated CRF and sham groups. The serum phosphate level, which was higher in the CRF groups, was decreased by sevelamer treatment. Serum FGF23 was elevated in both the CRF groups and decreased in response to sevelamer treatment. However, at this time point, sevelamer treatment was associated with an increase in the serum urea level and a decrease in body weight. The increase in serum urea between 8 and 14 weeks in sevelamer-treated CRF mice was also highly significant (P=0.001).Table 1Effects of CRF and sevelamer–HCl treatment on body weight, routine serum biochemistry, hematocrit, and serum FGF23Sham non-treatedSham sevelamerCRF non-treatedCRF sevelamerEffect of the CRF/sevelamer/interactionBaseline (after 6 weeks of CRF) Body weight (g)22.4 (21.8–22.8)22 (21–22.4)21.0 (20.3–21.8)20.9 (20.2–21.4)0.001/0.019/048 Urea (mmol/l)9.0 (8.3–10)9.4 (7.9–10.7)30.3 (27.6–34.5)31.8 (28.3–35.7)0.001/0.61/0.86 Total calcium (mmol/l)2.14 (2.04–2.19)2.09 (2.02–2.16)2.49 (2.38–2.6)2.55 (2.39–2.69)0.001/0.7/0.46 Phosphate (mmol/l)2.1 (1.86–2.43)1.96 (1.86–2.7)2.29 (2.08–2.57)2.23 (1.92–2.65)0.39/0.56/0.21 Total cholesterol (mmol/l)1.97 (1.83–2.08)1.97 (1.87–2.06)2.62 (2.36–2.87)2.7 (2.51–2.95)0.001/0.68/0.5 Hematocrit (%)38 (34–40)38 (37–40)28 (27–31)29 (25–31)0.001/0.96/0.84After 8 weeks of treatment Body weight (g)23.3 (23–24.4)23 (22.1–24.1)22 (20.9–22.9)22.0 (20.9–23.0)0.001/0.52/0.18 Urea (mmol/l)9.4 (9–10.6)7.8 (7.2–8.8)24.6 (21.8–29.4)27.3 (24.9–30.8)0.001/0.83/0.41 Total calcium (mmol/l)2.01 (1.8–2.1)2.1 (2.0–2.2)2.28 (2.2–2.4)2.3 (2.2–2.4)0.001/0.01/0.07 Phosphate (mmol/l)2.54 (2.31–2.84)2.11 (1.65–2.26)2.8 (2.43–3.66)2.28 (2.02–2.62)0.001/0.001/0.12 Total cholesterol (mmol/l)1.99 (1.91–2.13)2.05 (1.9–2.13)2.59 (2.41–2.76)2.62 (2.5–2.87)0.001/0.32/0.99 Hematocrit (%)39 (37–42)38 (36–40)31 (29–32)30 (27–30)0.001/0.15/0.84 FGF23 (pg/ml)332 (305–505)454 (407–494)1172 (763–1852)1215 (905–1545)0.001/0.84/0.7After 14 weeks of treatment Body weight (g)24 (23.5–25)23 (22.7–24.8)22.5 (21.6–23.3)21.3 (20.8–22.6)0.001/0.007/0.39 Urea (mmol/l)9.1 (8–10.8)9.4 (8.1–11.3)27.9 (26.2–32)34.6 (29.8–38.3)0.001/0.009/0.026 Total calcium (mmol/l)2.09 (2.04–2.18)2.08 (2.01–2.13)2.37 (2.3–2.57)2.5 (2.3–2.6)0.001/0.89/0.032 Phosphate (mmol/l)2.41 (1.79–2.74)2.03 (1.61–2.73)3.29 (2.25–3.79)2.1 (1.73–2.74)0.001/0.003/0.006 Total cholesterol (mmol/l)1.89 (1.7–2.05)1.89 (1.6–1.99)2.34 (2.18–2.63)2.47 (2.24–2.85)0.001/0.73/0.049 Hematocrit (%)38 (34–40)39 (37–41)28 (26–32)25 (23–27)0.001/0.51/0.031 FGF23 (pg/ml)522 (390–561)369 (199–531)1996 (1268–3554)1091 (812–1201)0.001/0.001/0.004Abbreviations: CRF, chronic renal failure; FGF23, fibroblast growth factor 23.At baseline, n=36–43 mice per group; after 8 weeks of treatment, n=18–22, except for FGF23, n=4–6; after 14 weeks of treatment, n=20–23, except for FGF23, n=12–18. Open table in a new tab Abbreviations: CRF, chronic renal failure; FGF23, fibroblast growth factor 23. At baseline, n=36–43 mice per group; after 8 weeks of treatment, n=18–22, except for FGF23, n=4–6; after 14 weeks of treatment, n=20–23, except for FGF23, n=12–18. Comparisons between the four groups at each time point in the protocol are shown in Table 2. As expected, a decrease in aortic distensibility (systolic aortic expansion rate (ESAo)), a diastolic dysfunction (isovolumic relaxation time (IVRT) and Tei index), and a LVH was seen in placebo-treated CRF mice at baseline (i.e., after 6 weeks of CRF).Table 2Effects of CRF and sevelamer on echocardiographic and invasive hemodynamic parameters at baseline, after 8 weeks, and after 14 weeks of treatment, respectivelySham non-treatedSham sevelamerCRF non-treatedCRF sevelamerEffect of the CRF/sevelamer/interactionBaseline (after 6 weeks of CRF) ESAo (%)16 (12–19)17 (13–19)8 (7–11)8 (5–12)0.001/0.52/0.28 IVRT (ms)15 (15–16)15 (15–17)19 (17–20)19 (18–20)0.001/0.74/0.99 Tei index245 (220–287)238 (220–282)322 (277–360)343 (312–379)0.001/0.26/0.14 LVM (mg)73 (66–81)79 (66–89)97 (89–108)96 (89–108)0.001/0.23/0.7After 8 weeks of treatment ESAo (%)19 (15–24)18 (13–22)8 (6–10)13 (12–16)0.001/0.05/0.001 IVRT (ms)15 (15–16)15 (14–16)19 (19–20)17 (15–19)0.001/0.01/0.33 Tei index270 (255–290)256 (236–285)332 (253–380)287 (251–321)0.001/0.08/0.36 LVM (mg)82 (76–86)78 (71–88)106 (98–110)95 (91–118)0.001/0.27/0.72 SAP, mmHg95 (87–101)96 (90–103)89 (70–97)97 (92–102)0.44/0.25/0.07 DAP, mmHg69 (57–72)66 (53–73)65 (44–69)65 (51–68)0.21/0.67/0.29 MAP, mmHg78 (67–82)76 (65–82)71 (51–78)75 (68–79)0.26/0.49/0.18 PP, mmHg29 (26–32)29 (28–34)28 (23–31)29 (28–38)0.42/017/0.16 PWV, m/s2.6 (2.3–2.8)3.1 (2.7–3.4)4.1 (3.7–4.2)3.3 (3.1–3.4)0.001/0.86/0.001After 14 weeks of treatment ESAo (%)14 (9–18)15 (12–17)7 (3–9)15 (7–21)0.005/0.023/0.03 IVRT (ms)15 (14–17)15 (14–16)20 (19–21)19 (17–20)0.001/0.045/0.35 Tei index237 (216–292)269 (240–284)357 (327–386)292 (240–327)0.001/0.038/0.03 LVM (mg)99 (97–105)88 (80–96)112 (104–122)95 (88–103)0.001/0.001/0.29 SAP, mmHg88 (76–92)90 (82–96)80 (75–88)75 (67–103)0.65/0.21/0.48 DAP, mmHg54 (49–65)59 (45–70)45 (37–49)38 (32–50)0.27/0.46/0.82 MAP, mmHg58 (53–75)57 (54–78)56 (51–61)57 (47–79)0.34/0.29/0.65 PP, mmHg34 (26–59)39 (28–54)33 (32–55)46 (37–59)0.58/0.43/0.53 PWV, m/s2.3 (2–2.4)3 (2.9–3.1)4.5 (4–4.6)3.6 (3–3.8)0.001/0.69/0.001Abbreviations: CRF, chronic renal failure; DAP, diastolic arterial pressure; ESAo, systolic aortic expansion rate; IVRT, isovolumic relaxation time; LVM, left ventricular mass; MAP, mean arterial pressure; PP, pulse pressure; PWV, pulse-wave velocity; SAP, systolic arterial pressure.At baseline, n=24–32 mice per group; after 8 weeks of treatment, n=14–16, except for blood pressure and PWV, n=8–12; after 14 weeks of treatment, n=8–14, except for blood pressure, n=6–9 and PWV, n=4–5. Open table in a new tab Abbreviations: CRF, chronic renal failure; DAP, diastolic arterial pressure; ESAo, systolic aortic expansion rate; IVRT, isovolumic relaxation time; LVM, left ventricular mass; MAP, mean arterial pressure; PP, pulse pressure; PWV, pulse-wave velocity; SAP, systolic arterial pressure. At baseline, n=24–32 mice per group; after 8 weeks of treatment, n=14–16, except for blood pressure and PWV, n=8–12; after 14 weeks of treatment, n=8–14, except for blood pressure, n=6–9 and PWV, n=4–5. After 8 weeks of treatment, ESAo and IVRT were improved by sevelamer (P=0.05 and P=0.01, respectively, vs. placebo). Aortic distensibility was markedly higher in the sevelamer-treated CRF group (P=0.001 for the interaction). Sevelamer treatment was also associated with a trend toward a significant decrease in the Tei index (P=0.08). LV mass was not significantly affected by sevelamer treatment at this time point. After 14 weeks of treatment, the effect of sevelamer on ESAo in CRF mice remained significant (P=0.03 for interaction). Similarly, IVRT was still improved. For the Tei index, the effect of sevelamer (P=0.038) appeared to be most marked in CRF mice (P=0.03 for the interaction). At this time point, LV mass was found to be lower in the sevelamer-treated groups (P=0.001). The change over time in the echocardiographic parameters in each group is shown in Figure 1. In the CRF sevelamer group, ESAo increased significantly and diastolic function (IVRT and Tei index) improved. The LV mass increased in all the groups except in the CRF sevelamer group, where it remained stable. After 14 weeks of treatment, serum phosphate was correlated with ESAo (Rho=-0.35; P=0.05), IVRT (Rho=0.56; P=0.001), Tei index (Rho=0.45; P=0.01), and LV mass (Rho=0.44; P=0.01) (Figure 2). At the same time, the serum FGF23 was correlated with ESAo (Rho=-0.48; P=0.01), the LV mass (Rho=0.58; P=0.002), and close to significant correlation with IVRT (Rho=0.38; P=0.06) (Figure 2). By contrast, Tei index was not correlated with serum FGF23 (Rho=0.30; P=0.14). In multiple regression analysis, only serum phosphate but not FGF23 remained significantly correlated with IVRT or LV mass after 14 weeks of treatment as independent variables (Table 3). For Tei index, the correlation with phosphorus level was close to the level of significance. Neither phosphate nor FGF23 appeared independently associated with ESAo.Table 3Results of linear regression analysis for systolic aortic expansion rate (ESAo), isovolumic relaxation time (IVRT), Tei index, and left ventricular mass (LV mass) after 14 weeks of treatmentModelUnstandardized coefficientsStandardized coefficientstP-value95% CI for BBs.e.BetaLower boundUpper boundIndependent variable: ESAo Constant17.9074.4494.0250.0018.47627.338 Phosphate-1.3191.420-0.215-0.9290.367-4.3281.691 FGF23-0.0020.001-0.311-1.3420.198-0.0040.001Independent variable: IVRT Constant11.4281.5337.4540.0008.17814.679 Phosphate1.7650.4890.6413.6080.0020.7282.802 FGF230.0010.0000.2251.2650.2240.0000.001Independent variable: Tei index Constant211.65039.5165.3560.000127.880295.419 Phosphate24.10712.6100.4361.9120.074-2.62450.838 FGF230.0000.0110.0100.0440.965-0.0220.023Independent variable: LV mass Constant81.1368.6089.4250.00062.88799.385 Phosphate6.2482.7470.4682.2740.0370.42412.071 FGF230.0030.0020.2811.3650.191-0.0020.008Abbreviation: FGF23, fibroblast growth factor 23. Open table in a new tab Abbreviation: FGF23, fibroblast growth factor 23. After 8 and 14 weeks of treatment, blood pressure values were generally similar in the four groups. However, the diastolic pressure at 14 weeks was significantly lower in the CRF groups than in the sham groups (Table 2). The PWV was significantly higher in the CRF groups than in the sham groups after both 8 and 14 weeks of treatment (P=0.001 for the effect of CRF). The PWV was also decreased in the CRF sevelamer group than in the CRF non-treated group (P=0.001 and P=0.001 for the interaction after 8 and 14 weeks of treatment, respectively). To examine the effects of CRF and sevelamer treatment in terms of the mechanisms of LVH induction and regression, respectively, we analyzed the expression of several cell-cycle proteins in the heart (Figure 3). Myocardial proliferating cell nuclear antigen (PCNA) expression was higher in non-treated mice (P=0.023) and decreased in response to sevelamer treatment (P=0.006). Similarly, myocardial cyclin D2 expression was significantly higher in CRF mice (P=0.004) but decreased upon sevelamer treatment (P=0.001). The expression of the cyclin-dependent kinase inhibitor p27 was significantly higher in both the CRF groups (P=0.001) but was not affected by sevelamer treatment (P=0.23). No differences were seen in terms of the myocardial expression of cyclin D3, caspase 3, or extracellular signal–regulated kinase (ERK; data not shown). Aortic vasoconstriction with phenylephrine (expressed as percentage of KCl-induced contraction) was similar for the four mouse groups (Figure 4). Exposure to acetylcholine induced an endothelium-dependent dysfunction in CRF non-treated animals. Sevelamer treatment for 8 and 14 weeks improved the endothelium-dependent dysfunction of CRF animals. In the present study, we used a murine CRF model to investigate the therapeutic effects of sevelamer–HCl on CRF-associated cardiovascular complications. We found that sevelamer–HCl administration led to an improvement in cardiovascular abnormalities, initially aortic stiffness, then LV diastolic dysfunction, and finally LVH. The traditional pathogenetic pathway relating the development of CVD in CKD patients is the development of arterial hypertension and vascular calcification. However, this sequence of events cannot explain the cardiovascular changes observed in conditions of CKD where hypertension and vascular calcification are absent. Therefore, the accumulation of uremic toxins has emerged as a promising alternative pathway to better understand the complex interactions between the heart and the kidneys.26.Vanholder R. Massy Z. Argiles A. et al.Chronic kidney disease as cause of cardiovascular morbidity and mortality.Nephrol Dial Transplant. 2005; 20: 1048-1056Crossref PubMed Scopus (532) Google Scholar,27.Lekawanvijit S. Kompa A.R. Wang B.H. et al.Cardiorenal syndrome: the emerging role of protein-bound uremic toxins.Circ Res. 2012; 111: 1470-1483Crossref PubMed Scopus (141) Google Scholar Hyperphosphatemia as one among the numerous uremic toxins has been recognized as an important factor in the high CVD and mortality rates observed in CKD patients.6.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1509) Google Scholar,28.Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2110) Google Scholar The deleterious effects of hyperphosphatemia may result from the development of vascular calcification.29.Qunibi W. Moustafa M. Muenz L.R. et al.A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study.Am J Kidney Dis. 2008; 51: 952-965Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, 30.Block G.A. Spiegel D.M. Ehrlich J. et al.Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar, 31.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 32.Raggi P. Bellasi A. Ferramosca E. et al.Association of pulse wave velocity with vascular and valvular calcification in hemodialysis patients.Kidney Int. 2007; 71: 802-807Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar However, even though the present CRF mouse model exhibits endothelial dysfunction, the observed harmful effects of hyperphosphatemia occurred in the absence of structural changes of the aorta in general and of vascular calcification in particular.25.Maizel J. Six I. Slama M. et al.Mechanisms of aortic and cardiac dysfunction in uremic mice with aortic calcification.Circulation. 2009; 119: 306-313Crossref PubMed Scopus (43) Google Scholar After 6 weeks of CRF, the serum phosphate was not yet increased in our animal model. The increase became significant only after an additional 8 weeks. This is consistent with several studies in CKD patients showing that phosphate retention is prevented until late stages of CKD, predominantly by an early increase in serum FGF23.15.Shimada T. Hasegawa H. Yamazaki Y. et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res. 2004; 19: 429-435Crossref PubMed Scopus (1412) Google Scholar,16.Gutierrez O. Isakova T. Rhee E. et al.Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.J Am Soc Nephrol. 2005; 16: 2205-2215Crossref PubMed Scopus (746) Google Scholar However, the mechanisms of regulation of FGF23 synthesis and secretion are not yet completely understood. Oliveira et al.23.Oliveira R.B. Cancela A.L. Graciolli F.G. et al.Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy?.Clin J Am Soc Nephrol. 2010; 5: 286-291Crossref PubMed Scopus (306) Google Scholar demonstrated that FGF23 could be reduced in normophosphatemic patients with CKD stages 3–4 in response to sevelamer treatment in the absence of changes in serum phosphate, although they observed a decrease in fractional excretion of phosphate. This points to the possibility that FGF23 is regulated by phosphate load rather than by serum phosphate, in addition to many other factors involved in its regulation.33.Jüppner H. Wolf M. αKlotho: FGF23 coreceptor and FGF23-regulating hormone.J Clin Invest. 2012; 122: 4336-4339Crossref PubMed Scopus (15) Google Scholar Sevelamer is known to decrease serum phosphate in CRF and to prevent the CRF-associated progression of vascular calcification. It also has pleiotropic effects, such as a
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