Impact of sevelamer hydrochloride on serum magnesium concentrations in hemodialysis patients.

Serum Mg levels are elevated in patients with renal insufficiency: harmful effects of hypomagnesemia have been reported in patients receiving hemodialysis (HD). In this cross-sectional study, which included 86 HD patients (male : female = 56:30, age 68 ± 12 years), we examined the clinical factors associated with serum Mg levels, with a focus on sevelamer, a phosphate binder widely used to control the hyperphosphatemia of HD patients. The mean serum Mg concentration among our patients was 2.48 ± 0.37 mg/dL (1.02 ± 0.15 mmol/L). Sevelamer was administered to 67 patients (77.9%) at a mean dose of 1.98 ± 1.64 g/day. Sex, diabetes mellitus, cardiovascular disease, anuria, and drugs other than sevelamer were not associated with serum Mg levels. HD duration, serum calcium, albumin, high-density lipoprotein cholesterol, normalized protein catabolic rate (nPCR), creatinine generation rate, and sevelamer dose correlated positively with serum Mg levels, whereas a negative correlation was observed for age and high-sensitivity C-reactive protein. A stepwise multiple regression analysis revealed that age, nPCR, and the dose of sevelamer were independently associated with serum Mg levels. Sevelamer and Mg have been reported to exhibit similar effects, such as an anti-inflammatory effect, inhibition of cardiovascular calcification, and decreased mortality. Therefore, the pleiotropic effects of sevelamer may be partly attributable to the increase in serum Mg levels caused by the drug itself.

Effects of Surgery and Antiplatelet Therapy in Ten-Year Follow-Up from the Registry Study of Research Committee on Moyamoya Disease in Japan.

BACKGROUND: Despite the common practice of surgery and antiplatelet therapy for the prevention of recurrent stroke in patients with moyamoya disease, the benefit of these treatments is controversial. We analyzed the stroke recurrence rate in the Registry Study of Research Committee on Moyamoya Disease in Japan funded by the Health, Labor and Welfare Ministry of Japan. METHODS: An annual follow-up study of the registered cases was continued for 10 years. The rate of recurrent stroke, including cerebral infarction and hemorrhage but not transient ischemic attack and seizure, was evaluated with Kaplan-Meier analysis. RESULTS: The proportion of childhood-onset cases decreased in recently registered cases (within 10 years, n = 541) compared to remote cases (> 10 years, n = 735). Among types at disease onset in adult-onset cases, intracerebral hemorrhage decreased recently. In recent cases, the rate of subsequent cerebral hemorrhage was much higher in the hemorrhagic group (10.9 ± 3.3%/5 years) than in the ischemic group (2.0 ± .9%/5 years). The recurrence rate of cerebral infarction was lower in the surgery group (1.8 ± .9%/5 years) than in the nonsurgery group (3.8 ± 2.2%/5 years). In the adult-onset ischemic group, the proportion of surgically treated patients increased and their recurrence rate was lower than that of nonsurgery patients. In the ischemic group, the rate of cerebral infarction was not significantly different between the antiplatelet subgroup and the non-antiplatelet subgroup, whereas the rate of cerebral hemorrhage was higher in the non-antiplatelet subgroup than in the antiplatelet subgroup. CONCLUSIONS: Our results suggest revascularization surgery may suppress recurrent ischemic attacks in patients with moyamoya disease.

Efficacy and safety of eldecalcitol, a new active vitamin D3 analog, in the bone metabolism of postmenopausal women receiving maintenance hemodialysis.

Eldecalcitol (ELD), a new active vitamin D3 analog developed in Japan, has attracted attention as an effective osteoporotic therapeutic drug. However, because ELD leads to greater calcium absorption than does conventional active vitamin D3, it has yet to be used in patients with renal insufficiency. Therefore, we evaluated the efficacy and safety of ELD treatment in 27 postmenopausal women receiving maintenance dialysis in our institution and underwent ELD treatment (starting at 0.5 µg/day) for 6 months. The mean serum albumin-corrected calcium (Caalb) level was significantly increased following treatment (9.01 ± 0.60 before versus 9.56 ± 0.55 after treatment, mean ± SD). Severe hypercalcemia was prevented through cessation or adjustment of the dosage of calcium-containing phosphate binders or existing active vitamin D. The mean serum phosphorus and intact parathyroid hormone levels were well-controlled throughout. The median levels of bone turnover markers, bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase-5b were significantly decreased. The mean lumbar spine bone mineral density (BMD) was increased, a significant difference being observed in age-matched Z-scores (-0.60 ± 1.6 versus -0.36 ± 1.5, p = 0.018). The average change in lumbar spine BMD after ELD treatment was 3.10%, and in patients with a T-score of <-4.0, it was 5.63%. There was no effect on forearm BMD. Although this study is based on short-term observation in a single institution, our results suggest that ELD could be used to increase bone density in dialysis patients.

Effects of extracranial-intracranial bypass for patients with hemorrhagic moyamoya disease: results of the Japan Adult Moyamoya Trial.

BACKGROUND AND PURPOSE: About one half of those who develop adult-onset moyamoya disease experience intracranial hemorrhage. Despite the extremely high frequency of rebleeding attacks and poor prognosis, measures to prevent rebleeding have not been established. The purpose of this study is to determine whether extracranial-intracranial bypass can reduce incidence of rebleeding and improve patient prognosis. METHODS: This study was a multicentered, prospective, randomized, controlled trial conducted by 22 institutes in Japan. Adult patients with moyamoya disease who had experienced intracranial hemorrhage within the preceding year were given either conservative care or bilateral extracranial-intracranial direct bypass and were observed for 5 years. Primary and secondary end points were defined as all adverse events and rebleeding attacks, respectively. RESULTS: Eighty patients were enrolled (surgical, 42; nonsurgical, 38). Adverse events causing significant morbidity were observed in 6 patients in the surgical group (14.3%) and 13 patients in the nonsurgical group (34.2%). Kaplan-Meier survival analysis revealed significant differences between the 2 groups (3.2%/y versus 8.2%/y; P=0.048). The hazard ratio of the surgical group calculated by Cox regression analysis was 0.391 (95% confidence interval, 0.148-1.029). Rebleeding attacks were observed in 5 patients in the surgical group (11.9%) and 12 in the nonsurgical group (31.6%), significantly different in the Kaplan-Meier survival analysis (2.7%/y versus 7.6%/y; P=0.042). The hazard ratio of the surgical group was 0.355 (95% confidence interval, 0.125-1.009). CONCLUSIONS: Although statistically marginal, Kaplan-Meier analysis revealed the significant difference between surgical and nonsurgical group, suggesting the preventive effect of direct bypass against rebleeding. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

Discrepancy between voluntary movement and motor-evoked potentials in evaluation of motor function during clipping of anterior circulation aneurysms.

BACKGROUND: Various modalities have been used to confirm the blood flow through parent arteries or surrounding perforating arteries during surgical aneurysm clipping, including motor-evoked potentials (MEPs), Doppler ultrasound, and indocyanine green videoangiography. Nonetheless, contralateral hemiparesis due to arterial blood flow insufficiency may arise because of false-positive or false-negative errors. By performing controlled intraoperative awakening during aneurysm clipping, we compared patients' voluntary movements with simultaneous MEP. METHODS: Four patients with anterior choroidal artery aneurysms and one patient with a dorsal internal carotid artery aneurysm were included in this study. MEP and intraoperative voluntary movements under awake craniotomy were assessed simultaneously during and after the clipping procedure. RESULTS: Aneurysms were safely and successfully clipped in all patients, with no evidence of postoperative neurological deficits. Voluntary movements and MEP findings did not differ from the control state in three patients. In the other two patients, we observed a discrepancy between MEP amplitudes and voluntary movements. In one patient, deterioration and subsequent improvement in voluntary movements were preceded by MEP amplitude reduction during clipping. In the other patient, MEP amplitude did not change although voluntary movement deteriorated during temporary occlusion of the internal carotid artery. CONCLUSIONS: Intraoperative neurological assessment during aneurysmal clipping under awake craniotomy is feasible and safe, and should be valuable for the assessment of ischemia, especially in the anterior choroidal artery. From a neurophysiologic viewpoint, MEP may be insufficiently sensitive for evaluating voluntary movement under ischemia.

The modulation of rolandic oscillation induced by digital nerve stimulation and self-paced movement of the finger: a MEG study.

BACKGROUND: The rolandic cortex exhibits spontaneous rhythmic activity. This oscillation can be modulated by somatosensory stimulation and voluntary movement. The purpose of this study is to elucidate the influence of sensory input on the rolandic oscillation in comparison with movement-related oscillation. METHODS: Magnetic brain rhythms were recorded in nine healthy subjects in two sessions: electrical stimulation (STIM) of the digital nerve and self-paced movement (SPM) of the right index finger. Thereafter, 10 and 20 Hz oscillatory activities were compared between the two sessions with temporal spectral evolution analysis. RESULTS: Sensory input altered the rolandic oscillations even under no movement conditions. As for 10 Hz ERD in the STIM session, three subjects showed a contralateral dominant pattern, whereas the remaining subjects showed a bilateral pattern. In spite of this individual variability, ERD showed comparable amplitude in both sessions. However, ERSs in the SPM session were larger than that in the STIM session. These findings might reflect the activation of neural networks common to sensory and motor systems followed by the inhibition of the other surrounding cortical areas. CONCLUSIONS: Our results suggest that rolandic oscillations may reflect the coordination of sensory and motor systems in the neural networks including both sensory and motor systems.

The leptomeningeal ivy sign on fluid-attenuated inversion recovery images in moyamoya disease: positron emission tomography study.

BACKGROUND: The ivy sign is sometimes seen on fluid-attenuated inversion recovery (FLAIR) images in moyamoya disease (MMD). In recent studies using single-photon emission computed tomography, ivy sign proliferation correlated with decreases in cerebrovascular reserve. However, a decreased vascular reserve is not concrete. The purpose of this study was to evaluate the correlation between ivy sign proliferation and the findings of 15O gas positron emission tomography (PET). METHODS: In 19 MMD patients (12 women, age 31-69 years) with ischemic symptoms, FLAIR magnetic resonance imaging and 15O gas PET were performed. We classified the middle cerebral artery (MCA) territory into 2 regions in each hemisphere, and the degree of the ivy sign (ivy sign score) in each region was classified into 3 grades (0-2), where grade 0 indicated an absence of the ivy sign, grade 1 indicated that the ivy sign was seen on less than half of the cortical surface in each region, and grade 2 indicated that the ivy sign was seen on more than half of the cortical surface. We examined the relationship among the ivy sign score, the severity of ischemic symptoms and PET parameters in 76 MCA regions of 19 patients. RESULTS: Ivy sign scores of the regions were 0 (n = 19), 1 (n = 40), and 2 (n = 17). Total ivy sign score of a hemisphere increased as clinical symptoms became more severe. Cerebral blood flow (CBF) values were lower, cerebral blood volume (CBV) values were higher, and CBF/CBV values were lower than those of controls as symptoms became severe (p < 0.05). CBF and CBF/CBV values decreased and CBV values increased as the ivy sign score increased, and were significantly higher and lower, respectively, than control values (p < 0.05). No significant differences in cerebral metabolic rate of oxygen and oxygen extraction fraction were found between the 3 ivy sign scores. A positive correlation was found between ivy sign score and increases in CBV (p < 0.01), and a more obvious negative correlation was found between ivy sign score and decreases in CBF/CBV (p < 0.001). CONCLUSIONS: We evaluated the correlation between ivy sign proliferation and the findings of 15O gas PET. We suggested that ivy sign proliferation was associated with both dilated pial vasculature and the slow flow of developed leptomeningeal collaterals in patients with MMD.

Emerging effects of sevelamer in chronic kidney disease.

Sevelamer, a non-absorbable anion exchange resin, is used to control hyperphosphatemia in chronic kidney disease (CKD) by binding to dietary phosphate in the gastrointestinal tract. Lipid-lowering effect is a widely recognized pleiotropic effect of sevelamer. In addition, many studies have reported that sevelamer leads to reduced vascular calcification compared with calcium-containing phosphate binders, which is attributed to the improved lipid profiles and decreased calcium load. In addition, recent studies have suggested novel pleiotropic effects on bone structure, inflammation, oxidative stress, anemia, fetuin-A, and trace element metabolism in CKD patients. All of these effects have the potential to suppress the development/progression of cardiovascular lesions and reduce mortality. This review summarizes novel findings from recent studies and discusses the potential pleiotropic effects of sevelamer on non-traditional cardiovascular risk factors in CKD patients.

Notch signaling regulates nucleocytoplasmic Olig2 translocation in reactive astrocytes differentiation after ischemic stroke.

Treatment with DAPT, an inhibitor of the Notch-activating enzyme, γ-secretase is known to reduce damage to ischemic brain. However, the molecular mechanisms supporting this therapeutic effect are not fully understood. Here we demonstrated that Notch/RBP-J signaling is activated in NG2(+) glial progenitors and reactive astrocytes such as GFAP(+) cells, Nestin(+) cells and RC2(+) cells, using Notch/RBP-J signaling reporter mice. 3-day DAPT treatment reduced the number of reactive astrocytes but not NG2(+) glial progenitors. BrdU labeling experiments have shown that this reduction was due to decreased proliferation of reactive astrocytes. DAPT inhibited nuclear-translocation of Olig2, which is indispensable for proliferation and differentiation of reactive astrocytes. These findings suggest that Notch signaling might promote proliferation and differentiation of reactive astrocytes through the regulation of nucleo-cytoplasmic translocation of Olig2.

Hybrid operating room for the treatment of complex neurovascular and brachiocephalic lesions.

BACKGROUND: We examine the impact of the installation of integrated hybrid operating rooms (ORs) that allow both surgical and endovascular procedures and are designed for less invasive and 1-stage treatment of complex neurovascular lesions. METHODS: We retrospectively analyzed our experience in the treatment of complex neurovascular lesions in a hybrid OR. RESULTS: Three patients with distal middle cerebral artery (MCA) aneurysms underwent a proximal clip occlusion or endovascular trapping with a superficial temporal artery-MCA bypass after correct localization of the recipient branch distal to the aneurysm using superselective intra-arterial infusion of indocyanine green under an operating microscope. Two patients with innominate artery stenosis were treated with retrograde stenting from the common carotid artery (CCA) with distal protection of the internal carotid artery (ICA) alone, and with antegrade stenting with dual protection of the ipsilateral ICA and the vertebral artery. Two patients with tandem stenosis of the proximal CCA and carotid bifurcation underwent 1-stage retrograde stenting combined with a carotid endarterectomy. A patient with the innominate artery and the proximal CCA stenosis underwent staged percutaneous antegrade angioplasty of the innominate artery followed by retrograde stenting of both lesions. A patient with tandem stenosis of the subclavian and innominate arteries underwent 1-stage retrograde stenting. In 2 patients with carotid stenosis that was difficult to access via the endovascular route, carotid stenting was performed by direct puncture of the proximal CCA. No patients suffered from new postoperative neurologic deficits. CONCLUSIONS: The integration of a high-end hybrid OR enables combined endovascular and surgical procedures for complex neurovascular and brachiocephalic lesions in a 1-stage treatment.

Clinical factors associated with serum copper levels and potential effect of sevelamer in hemodialysis patients.

OBJECTIVE: Copper is an essential mineral nutrient for humans. Serum copper levels of hemodialysis patients are higher than those of healthy subjects, but it remains to be elucidated whether increased serum copper may have harmful effects. In addition, a recent in vitro study has shown that sevelamer can adsorb copper. In the present study, we searched for clinical factors associated with serum copper levels in hemodialysis patients. METHODS: This cross-sectional study included patients undergoing hemodialysis for more than 6 months. In these patients, we statistically tested associations between serum copper levels and other parameters, including nutritional markers, lipid profiles, oxidative stress, inflammation, and sevelamer administration. RESULTS: Among 48 patients (male/female = 28:20, age 71 ± 10 years, hemodialysis duration 84 ± 72 months), sevelamer hydrochloride was administered in 39 patients (81.3 %). In univariate analysis, serum copper levels showed significant positive correlations with serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde modified-LDL and negative correlations with plasma total homocysteine levels and the administered dose of sevelamer. In multivariate analysis, serum levels of LDL-cholesterol and hs-CRP were found to be independent determinants of serum copper levels. CONCLUSION: We found that serum copper levels were independently associated with dyslipidemia and inflammation in hemodialysis patients, but the pathogenic roles of copper remain to be elucidated. In addition, potential effect of sevelamer on serum copper levels should be examined in appropriately designed studies.

Surgical treatment of Spetzler-Martin grade III to V cerebral arteriovenous malformations: 10 years experience in Kyoto University.

Cerebral arteriovenous malformations (AVMs) are abnormal connections between arteries and veins leading to arteriovenous shunting with nidus formation. This study reviewed the clinical outcomes of surgical treatment for AVMs of Spetzler-Martin grades III to V in our institute. In addition, we summarized the technical aspects of surgical treatment for cerebral AVMs. Our development of the surgical modality for high-grade AVMs included intraoperative digital subtraction cerebral angiography, non-stick bipolar forceps, magnetic resonance tractography, and indocyanine green videoangiography. Excellent outcomes were obtained, but about 40% of all patients with AVMs could not receive surgical treatment. Multimodality approach including Onyx embolization may extend the surgical indications.

Cerebral blood flow and metabolism of hyperperfusion after cerebral revascularization in patients with moyamoya disease.

In moyamoya disease (MMD), surgical revascularization may be complicated with postoperative hyperperfusion. We analyzed cerebral perfusion and metabolism using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) before and after bypass surgery on 42 sides of 34 adult patients with MMD. In seven cases (16.7%) with symptomatic hyperperfusion, diagnosed by qualitative (123)I-iodoamphetamine (IMP) SPECT, a subsequent PET study during postoperative subacute stages revealed significantly increased cerebral blood flow (CBF) from 34.1 ± 8.2 to 74.3 ± 12.8 mL/100 g per minute (P<0.01), a persistent increase in cerebral blood volume (CBV) from 5.77 ± 1.67 to 7.01 ± 1.44 mL/100 g and a significant decrease in oxygen extraction fraction (OEF) from 0.61 ± 0.09 to 0.40 ± 0.08 (P<0.01). Mean absolute CBF values during symptomatic hyperperfusion were more than the normal control +2 standard deviations, the predefined criteria of PET. Interestingly, two patients with markedly increased cerebral metabolic rate of oxygen (CMRO(2)) at hyperperfusion were complicated with postoperative seizure. Among preoperative PET parameters, increased OEF was the only significant risk factor for symptomatic hyperperfusion (P<0.05). This study revealed that symptomatic hyperperfusion in MMD is characterized by temporary increases in CBF >100% over preoperative values caused by prolonged recovery of increased CBV.

The natural course of unruptured cerebral aneurysms in a Japanese cohort.

BACKGROUND: The natural history of unruptured cerebral aneurysms has not been clearly defined. METHODS: From January 2001 through April 2004, we enrolled patients with newly identified, unruptured cerebral aneurysms in Japan. Information on the rupture of aneurysms, deaths, and the results of periodic follow-up examinations were recorded. We included 5720 patients 20 years of age or older (mean age, 62.5 years; 68% women) who had saccular aneurysms that were 3 mm or more in the largest dimension and who initially presented with no more than a slight disability. RESULTS: Of the 6697 aneurysms studied, 91% were discovered incidentally. Most aneurysms were in the middle cerebral arteries (36%) and the internal carotid arteries (34%). The mean (±SD) size of the aneurysms was 5.7±3.6 mm. During a follow-up period that included 11,660 aneurysm-years, ruptures were documented in 111 patients, with an annual rate of rupture of 0.95% (95% confidence interval [CI], 0.79 to 1.15). The risk of rupture increased with increasing size of the aneurysm. With aneurysms that were 3 to 4 mm in size as the reference, the hazard ratios for size categories were as follows: 5 to 6 mm, 1.13 (95% CI, 0.58 to 2.22); 7 to 9 mm, 3.35 (95% CI, 1.87 to 6.00); 10 to 24 mm, 9.09 (95% CI, 5.25 to 15.74); and 25 mm or larger, 76.26 (95% CI, 32.76 to 177.54). As compared with aneurysms in the middle cerebral arteries, those in the posterior and anterior communicating arteries were more likely to rupture (hazard ratio, 1.90 [95% CI, 1.12 to 3.21] and 2.02 [95% CI, 1.13 to 3.58], respectively). Aneurysms with a daughter sac (an irregular protrusion of the wall of the aneurysm) were also more likely to rupture (hazard ratio, 1.63; 95% CI, 1.08 to 2.48). CONCLUSIONS: This study showed that the natural course of unruptured cerebral aneurysms varies according to the size, location, and shape of the aneurysm. (Funded by the Ministry of Health, Labor, and Welfare in Japan and others; UCAS Japan UMIN-CTR number, C000000418.).

Expression and activation of STAT family proteins in cerebral arteriovenous malformations.

OBJECTIVE: Cerebral arteriovenous malformations (AVMs) do not seem to be static congenital vascular malformations but rather are dynamically changing pathologies. In this work, we investigated the expression and possible activation of different signal transducers and activators of transcription (STAT) family members in AVM nidus. METHODS: Immunohistochemical analysis was conducted on 25 AVM specimens from 24 patients using antibodies against STATs 1, 3, 5, and 6 as well as their phosphorylated forms. Analysis was also undertaken to determine if there is any correlation between STAT activation and different clinical parameters of AVM patients. RESULTS: Our studies revealed that both STATs 1 and 3 were highly expressed in cerebral AVM, mainly in the endothelium of AVM blood vessels and perivascular infiltrating inflammatory cells within the nidus. STAT3 showed the most intense level of expression within the endothelium and perivascular infiltrating inflammatory cells. It was intensely expressed in the endothelium of 25 (100%) specimens and in the infiltrating inflammatory cells of 24 (96%) specimens. The expression of the phospho-STATs 1 and 3 was also high in the endothelium and perivascular infiltrating inflammatory cells indicating activation of STATs 1 and 3 in AVM. We could not find any significant effect of hemorrhage or preoperative embolization, or other clinical parameters, on the activation of STATs 1 and 3 in cerebral AVMs. CONCLUSION: We obtained evidence for significant overexpression and activation of both STATs 1 and 3 in cerebral AVM, thus suggesting an important role for these proteins in mediating the pathophysiology of cerebral AVM.

Transplantation of telencephalic neural progenitors induced from embryonic stem cells into subacute phase of focal cerebral ischemia.

Cerebral ischemia causes neuronal death and disruption of neural circuits in the central nervous system. Various neurological disorders caused by cerebral infarction can severely impair quality of life and are potentially fatal. Functional recovery in the chronic stage mainly depends on physical treatment and rehabilitation. We aim to establish cell therapy for cerebral ischemia using embryonic stem (ES) cells, which have self-renewing and pluripotent capacities. We previously reported that the transplanted monkey and mouse ES cell-derived neural progenitors, by stromal cell-derived inducing activity method, could survive and differentiate into various types of neurons and glial cells, and form the neuronal network in basal ganglia. In this report, we induced the differentiation of the neural progenitors from mouse ES cells using the serum-free suspension culture method and confirmed the expression of various basal ganglial neuronal markers and neurotransmitter-related markers both in vitro and in vivo, which was thought to be suitable for replacing damaged striatum after middle cerebral artery occlusion. This is the first report that used selectively induced telencephalic neural progenitors into ischemia model. Furthermore, we purified the progenitors expressing the neural progenitor marker Sox1 by fluorescence-activated cell sorting and Sox1-positive neural progenitors prevented tumor formation in ischemic brain for 2 months. We also analyzed survival and differentiation of transplanted cells and functional recovery from ischemic damage.

Potential influence of sevelamer hydrochloride on responsiveness to erythropoiesis-stimulating agents in haemodialysis patients.

AIM: Vitamin D analogues, cinacalcet, and sevelamer play pivotal roles in the management of chronic kidney disease-mineral bone disorder, and are noted to have pleiotropic effects. We examined whether these agents might be associated with the responsiveness to erythropoiesis-stimulating agents (ESA). METHODS: In this cross-sectional study including haemodialysis patients treated with ESA, we searched for clinical parameters associated with the ESA resistance index, which was calculated as the weekly ESA dose divided by the patient's haemoglobin value. RESULTS: Among 45 patients (male: female = 28 : 17, age 68 ± 10 years, haemodialysis duration 84 ± 60 months), vitamin D analogue, cinacalcet, and sevelamer were used in 95.6%, 26.7%, and 84.4% of the patients, respectively. Univariate analysis showed significant association of the ESA resistance index with transferrin saturation rate (TSAT), vitamin D analogue dose, and sevelamer dose. In multivariate analysis, the sevelamer dose and TSAT were found to be independent determinants of the ESA resistance index. CONCLUSION: Our preliminary data showed an independent association between sevelamer dose and the responsiveness to ESA in haemodialysis patients. Further studies are required to investigate the causal relationship between sevelamer and ESA responsiveness.