Association between serum iron markers, iron supplementation and cardiovascular morbidity in pre-dialysis chronic kidney disease.

BACKGROUND: The optimal range of serum iron markers and usefulness of iron supplementation are uncertain in patients with pre-dialysis chronic kidney disease (CKD). We investigated the association between serum iron indices and risk of cardiovascular disease (CVD) events and the effectiveness of iron supplementation using Chronic Kidney Disease Japan Cohort data. METHODS: We included 1416 patients ages 20-75 years with pre-dialysis CKD. The tested exposures were serum transferrin saturation and serum ferritin levels and the outcome measures were any cardiovascular event. Fine-Gray subdistribution hazard models were used to examine the association between serum iron indices and time to events. The multivariable fractional polynomial interaction approach was used to evaluate whether serum iron indices were effect modifiers of the association between iron supplementation and cardiovascular events. RESULTS: The overall incidence rate of CVD events for a median of 4.12 years was 26.7 events/1000 person-years. Patients with serum transferrin saturation <20% demonstrated an increased risk of CVD [subdistribution hazard ratio (HR) 2.13] and congestive heart failure (subdistribution HR 2.42). The magnitude of reduction in CVD risk with iron supplementation was greater in patients with lower transferrin saturations (P = .042). CONCLUSIONS: Maintaining transferrin saturation >20% and adequate iron supplementation may effectively reduce the risk of CVD events in patients with pre-dialysis CKD.

Association of single and serial measures of serum phosphorus with adverse outcomes in patients on peritoneal dialysis: results from the international PDOPPS.

BACKGROUND: While high serum phosphorus levels have been related to adverse outcomes in hemodialysis patients, further investigation is warranted in persons receiving peritoneal dialysis (PD). METHODS: Longitudinal data (2014-17) from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS), a prospective cohort study, were used to examine associations of serum phosphorus with all-cause mortality and major adverse cardiovascular events via Cox regression adjusted for confounders. Serum phosphorus levels were parameterized by four methods: (i) baseline serum phosphorus; (ii) mean 6-month serum phosphorus; (iii) number of months with serum phosphorus >4.5 mg/dL; and (iv) mean area-under-the-curve of 6-month serum phosphorus control. RESULTS: The study included 5847 PD patients from seven countries; 9% of patients had baseline serum phosphorus <3.5 mg/dL, 24% had serum phosphorus ≥3.5 to ≤4.5 mg/dL, 30% had serum phosphorus >4.5 to <5.5 mg/dL, 20% had serum phosphorus ≥5.5 to <6.5 mg/dL, and 17% had serum phosphorus ≥6.5 mg/dL. Compared with patients with baseline serum phosphorus ≥3.5 to ≤4.5 mg/dL, the adjusted all-cause mortality hazard ratio (HR) was 1.19 (0.92,1.53) for patients with baseline serum phosphorus ≥5.5 to <6.5 mg/dL and HR was 1.53 (1.14,2.05) for serum phosphorus ≥6.5 mg/dL. Associations between serum phosphorus measurements over 6 months and clinical outcomes were even stronger than for a single measurement. CONCLUSIONS: Serum phosphorus >5.5 mg/dL was highly prevalent (37%) in PD patients, and higher serum phosphorus levels were a strong predictor of morbidity and death, particularly when considering serial phosphorus measurements. This highlights the need for improved treatment strategies in this population. Serial serum phosphorus measurements should be considered when assessing patients' risks of adverse outcomes.

Impact of Transferrin Saturation on All-Cause Mortality in Patients on Maintenance Hemodialysis.

BACKGROUND: Transferrin saturation (TSAT) is an index that represents the iron-binding capacity of transferrin, which is the main transport protein for iron, and is widely used to evaluate iron status. OBJECTIVE: To evaluate the prognostic importance of TSAT in Japanese patients on maintenance hemodialysis (MHD). METHODS: A total of 398 patients on MHD were recruited and divided into 3 groups on the basis of their baseline TSAT levels (<20, 20-40, and >40%). RESULTS: There was no difference in the proportion of patients on erythropoiesis-stimulating agents or iron supplements between the 3 groups. During a mean follow-up period of 52.2 ± 1 6.3 months, 130 patients died of cardiovascular causes (n = 63, 15.8%) or infection (n = 47, 11.8%). Compared with the reference group (TSAT 20-40%), patients with a TSAT <20% had a significantly higher all-cause mortality rate (6.44 vs. 9.55 events per 100 patient-years, p = 0.0452). Kaplan-Meier analysis showed that all-cause mortality rate was significantly higher in patients with TSAT <20% than in the other 2 groups (p = 0.0353). CONCLUSIONS: Low TSAT was a significant independent risk factor for all-cause mortality in a cohort of Japanese patients on MHD. The findings of this study suggest that the adverse clinical outcomes in patients with low TSAT can be partly attributed to infection-related iron deficiency.

Recent Advances in the Management of Vascular Calcification in Patients with End-Stage Renal Disease.

BACKGROUND: Vascular calcification (VC) is common in patients with chronic kidney disease (CKD) including end-stage renal disease (ESRD). The pathogenesis of VC is complex, resulting in increased arterial stiffening, which is associated with cardiovascular mortality. In addition to traditional cardiovascular risk factors, CKD patients also have a number of non-traditional cardiovascular risk factors that may play an important role in the pathogenesis of VC. SUMMARY: Management of CKD-mineral bone disorder using conventional therapeutic approaches, which include restricting dietary phosphate, administering phosphate binders, and using active vitamin D and calcimimetics, may inhibit the progression of VC, but these approaches remain controversial because recommended biochemical targets are difficult to achieve. Current treatment strategies focus on correcting abnormal calcium, phosphate, parathyroid hormone, and vitamin D levels in ESRD patients. Novel therapies for addressing VC include magnesium and vitamin K supplementation, which are currently being investigated in randomized controlled trials. This review summarizes current treatment strategies and therapeutic targets for the management of VC in patients with ESRD. Key Messages: A better understanding of the potential therapeutic approaches to VC may lead to improved mortality rates among patients with CKD including those on dialysis. Fetuin-A inhibits VC by binding to the nanoparticles of calcium and phosphate, preventing mineral accretion. These particles are known as calciprotein particles and may provide an important pathway for mineral transport and clearance. This review article summarizes the current management of VC in patients with ESRD.

Serum Magnesium Levels and Mortality in Japanese Maintenance Hemodialysis Patients.

BACKGROUND/AIMS: Although hypomagnesemia was found to be a risk for cardiovascular diseases in the general population, the relationship between serum magnesium (Mg) levels and prognosis of patients on maintenance hemodialysis (MHD) has not been extensively studied. This study sought to determine the relationship of serum Mg levels with aortic arch calcification (AoAC) and mortality in Japanese MHD patients. METHODS: We measured serum Mg levels in a cohort of 392 patients on MHD, classified the patients into 3 groups according to these levels, and followed their course for 4 years. AoAC was assessed using chest-X-rays. RESULTS: During follow-up, there were 117 deaths. Kaplan-Meier analyses showed that the high serum Mg group tended to have better survival rates than the low and middle serum Mg groups but this did not reach statistical significance. We also found that patients in the high serum Mg group had better nutritional status associated with higher serum albumin, triglyceride, and phosphate levels and had a significantly lower serum C-reactive protein level. In total, 83 patients (59.3%) in the high serum Mg group had been prescribed Mg oxide (MgO). CONCLUSIONS: Hypermagnesemia tended to be associated with better survival and a higher prescription rate of MgO. Interventional studies are needed to clarify whether Mg supplementation is beneficial for improving patient prognosis.

Cell Sheet Engineering and Kidney Diseases.

Treatment using the cell sheet technology has been applied to various organs, including the cornea, heart, esophagus, periodontium, cartilage, middle ear, and lungs. It has been shown that the therapeutic efficacy of cell sheet transplantation involves 2 aspects, supplementation of cells and provision of cytokines to the affected organ. In addition, cell sheet transplantation also promotes repair of damage through the paracrine effects of cytokines derived from the transplanted cells. It is known that in cases of cell transplantation by injection, the transplanted cells are less likely to differentiate into renal tissue to supply cells, but repair is promoted by the actions of the transplanted cell-derived renotropic factors. Renal function requires functional conjugation of various tissues, including blood vessels, glomeruli, renal tubules, and collecting ducts. It is difficult to supply the necessary cells directly to the affected site of the renal tissue composed of complex structures. On the contrary, the 2-dimensional cell sheet can produce proteins such as erythropoietin, and is thus suitable for transplantation into the living body. It would be desirable to develop cell sheet therapy for the suppression of kidney damage in the future, taking advantage of the beneficial characteristics of cell sheets.

Renal Anemia and Iron Metabolism.

Normal iron metabolism is essential for effective hemoglobin (Hb) production in the management of renal anemia. Considering that studies regarding the optimal Hb levels predated the creation of the iron management indices found in the treatment guidelines for hemodialysis (HD) patients, an increase in the Hb levels caused by intravenous iron supplementation has been used as an iron management index. However, no consideration was given to iron metabolism or the long-term safety of intravenous iron supplementation. Although iron is a vital trace element in humans, it can also be toxic, and its metabolism is carefully controlled, with several factors affecting it. Considering that the details regarding the mechanisms underlying iron metabolism have been elucidated recently, a study regarding iron management that is safe and considers iron metabolism status effective for Hb production in patients with renal anemia is warranted. This study presents information regarding iron metabolism in patients on HD, the factors that influence iron metabolism in such patients, and the problems with existing treatment guidelines in Japan, apart from discussing the optimal iron levels and optimal Hb production indices.

Fibroblast growth factor 23 is upregulated in the kidney in a chronic kidney disease rat model.

The hormone fibroblast growth factor 23 (FGF23) is secreted from bone and is involved in phosphorus (P) metabolism. FGF23 mainly binds the FGF receptor, which interacts with αKlotho in the kidney or parathyroid and regulates Na-dependent phosphate co-transporter type IIa (NaPi-IIa) and type IIc (NaPi-IIc) expression, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity, and parathyroid hormone (PTH) secretion. In this study, we utilized hemi-nephrectomized rats fed a high-P diet (HP Nx), rats subjected to a partial nephrectomy (PN) and rats with doxorubicin-induced renal failure (DXR) as chronic kidney disease (CKD) animal models and analyzed the P metabolism and FGF23 expression in the kidneys in each CKD model. We cultured HK2 cells with a high level of P, 1,25(OH)2D3 or transforming growth factor-ß1 (TGFß1) to investigate the FGF23 expression mechanism. In both the HP Nx and PN rats, the blood FGF23 and PTH levels were increased. However, the 1,25(OH)2D3 level was increased in the HP Nx rats and decreased in the PN rats. In all three animal models, the mRNA expression of αKlotho, NaPi-IIa and NaPi-IIc was decreased, and the mRNA expression of TGFß1, collagen1a1, osteopontin and FGF23 was elevated in the kidney. FGF23 protein and mRNA were expressed at high levels in the extended tubule epithelium, which was an osteopontin-positive region in the HP and PN rats. FGF23 and osteopontin mRNAs were expressed in HK2 cells incubated with TGFß1; however, these levels were not altered in HK2 cells incubated with 1,25(OH)2D3 and high P levels in vitro. Altogether, FGF23 is expressed in the kidneys in CKD model rats. Following stimulation with TGFß1, the injured renal tubular epithelial cells are strongly suspected to express both FGF23 and osteopontin. FGF23 produced in the kidney might contribute to P metabolism in subjects with CKD.

The Renoprotective Effects of Docosahexaenoic Acid as an Add-on Therapy in Patients Receiving Eicosapentaenoic Acid as Treatment for IgA Nephropathy: A Pilot Uncontrolled Trial.

Objective Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been reported to have beneficial effects in patients with IgA nephropathy (IgAN). Although DHA and EPA have different mechanisms of action, no study to date has assessed their individual actions in patients with IgAN. This study therefore analyzed the effects administering DHA in addition to EPA for the treatment of IgAN. Methods Twenty-one IgAN patients who were being treated with EPA (1,800 mg/day) were switched to EPA (1,860 mg/day) and DHA (1,500 mg/day). The changes in their clinical parameters from 6 months before to 6 months after switching treatment were analyzed. Results The triglyceride levels did not change during treatment with EPA alone, but tended to decrease-although not to a statistically significant extent-after the switch. The patients' low-density-lipoprotein cholesterol, blood pressure, proteinuria, and hematuria levels were similar before and after switching. The estimated glomerular filtration rate (eGFR) tended to decrease during EPA therapy, but became stable after switching and the median %⊿eGFR changed from -7.354% during EPA therapy to +1.26% during the 6 months after switching to EPA and DHA therapy (p=0.00132), and renal the function remained stable for another 6 months. Moreover, the median %⊿eGFR during the 6 months after switching was significantly higher in comparison to IgAN patients who were treated with EPA alone as a control (-3.26%, p=0.0361). No clinical parameters were independently associated with a stable renal function without switching to DHA/EPA. Conclusion The addition of DHA to EPA stabilized the renal function of IgAN patients, and it seemed that there were pleiotropic effects beyond the improvement of the clinical parameters.

Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients.

Approximately 5-10% of patients with end-stage renal disease (ESRD) exhibit hyporesponsiveness to erythropoiesis-stimulating agents (ESAs), defined as a continued need for higher than 300 IU/kg/week doses of epoetin or a 1.5 mg/kg/week dose of darbepoetin. ESA hyporesponsiveness contributes to the morbidity, mortality and health-care economic burden of ESRD patients. The most common causes of ESA resistance are absolute or functional iron deficiency and inflammation. Maintaining adequate iron stores is clearly accepted as the most important strategy for reducing the ESA requirement and for enhancing ESA efficacy. Recent clinical studies have shown that iron administration to ESRD patients is associated with an increased risk of infection and atherosclerosis. ESA hyporesponsiveness due to chronic inflammation in ESRD patients has been reported to be improved by a number of interventions, including the use of biocompatible hemodialysis membranes, ultrapure dialysate, ascorbic acid therapy, vitamin E supplementation, and statin therapy. Other causes of ESA hyporesponsiveness include inadequate dialysis, hyperparathyroidism, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, primary bone marrow disorders, myelosuppressive agents, hemoglobinopathies, hemolysis, and hypersplenism. This article summarizes the common causes of ESA hyporesponsiveness and the proposed therapeutic interventions.

Impact of lanthanum carbonate on cortical bone in dialysis patients with adynamic bone disease.

Among the most serious problems in patients with chronic kidney disease (CKD) is fragility of cortical bone caused by cortical thinning and increased cortical porosity; the cortical fragility is sometimes irreversible, with fractures generally initiating from cortical bone. Therefore, development of treatments for problems of cortical bone is urgently desired. Cortical bone has the three surfaces, including the periosteal surface, intracortical spaces and endocortical surface. Bone turnover at the endocortical surface and intracortical resorption spaces are increased as compared with that at cancellous surface. Bone growth sometimes depends on apposition at the periosteal surface. We treated hyperphosphatemia in two hemodialysis patients with adynamic bone disease with 750-1500 mg/day of lanthanum carbonate, which is a non-calcium containing phosphate binder; the treatment resulted in a decrease of the serum phosphorus levels (P levels), without significant change of the serum intact parathyroid hormone levels. We now report that treatment of these patients with lanthanum carbonate increased mineralization of the periosteal surface, increased bone mass within the intracortical resorption spaces and increased mineralization of the minimodeling surface at the endocortical surface. In addition, woven bone volume in cortical bone was decreased and mineralization of bone units, namely, osteons, was increased. Although these findings were not observed across all surfaces of the cortical bone in the patients, it is expected that lanthanum carbonate would increase the cortical stability in CKD patients, with consequent reduction in the fracture rate in these patients.

Additional reduction in serum phosphorus levels by pulverized lanthanum carbonate chewable in hemodialysis patients.

Lanthanum carbonate (LC) is one of the relatively new phosphate binders. The general LC dosage form is a chewable pharmaceutical preparation. This investigation was targeted to subjects who do not chew LC chewable preparations adequately, for the purpose of studying the clinical efficacy of changing to pulverized prescriptions, such as changes in serum phosphorus levels (P levels). The study took place at Minamisenju Hospital in October 2011, with 41 subjects on maintenance hemodialysis. We pulverized all of the LC chewable medicines of the LC insufficient mastication group (non-chewing: NC group, n = 18) using a crusher, and changed them to pulverized prescriptions. The testing period was set at 10 weeks. In the NC group, there was a significant lowering of P levels from 5.86 ± 1.31 mg/dL before pulverization of the LC chewable preparation (week 0) to 5.38 ± 1.26 mg/dL after 2 weeks of administration of the pulverized medication (P = 0.0310), 5.20 ± 1.25 mg/dL after 4 weeks (P = 0.0077), and 5.12 ± 1.34 mg/dL after 6 weeks (P = 0.0167). P levels in other patients than NC group showed no significant change. In this study, the P levels in the NC group was lowered significantly by changing the LC chewable to the pulverized prescription, and the residual LC images on the abdominal X-rays disappeared to the point where they could barely be confirmed.

Hepcidin is a potential regulator of iron status in chronic kidney disease.

Hepcidin is a small defensin-like peptide produced primarily by hepatocytes, but also by other cells, including macrophages. In addition to hepcidin's antimicrobial properties, it is the main regulator of iron metabolism and controls both the amount of dietary iron absorbed in the duodenum and the iron release by reticuloendothelial cells. Hepcidin expression is upregulated by a variety of stimuli, including inflammation and iron overload, and downregulated by anemia, hypoxia, and iron deficiency. Chronic kidney disease (CKD) is associated with increased serum hepcidin levels, and the increased levels may contribute to the development and severity of anemia and to resistance to erythropoiesis-stimulating agents (ESAs). Elevated serum hepcidin levels contribute to the dysregulation of iron homeostasis in CKD patients. Although parenteral iron supplementation can bypass some of the iron-blocking effects of hepcidin in CKD patients with anemia, and free iron and iron stores increase as a result, the anemia is only partially corrected, and the ESA dose requirements remain significantly higher than needed for physiological replacement. Treatment with agents that lower serum hepcidin levels or inhibit its actions may be an effective strategy for restoring normal iron homeostasis and improving anemia in CKD patients. The aim of this article was to review the regulation of hepcidin levels and the role of hepcidin in CKD-related anemia, and to discuss hepcidin's potential as a clinical biomarker and several investigational treatments designed to lower serum hepcidin levels.

Vitamin D receptor agonist supplementation and suppression of inflammation may have advantage for all-cause mortality in hemodialysis patients.

BACKGROUND: Vitamin D deficiency is common in hemodialysis (HD) patients. The aim of this study was to determine whether HD patients with low 25-hydroxyvitamin D [25(OH)D] levels are at increased risk of mortality. METHODS: This was a prospective cohort study of Japanese HD patients. We selected all patients with measured serum 25(OH)D levels at the time of entry. We assessed the impact of low serum 25(OH)D levels on the long-term mortality of HD patients by performing Cox regression analyses. Associations between serum 25(OH)D levels and all-cause mortality were also investigated. RESULTS: Data from 100 patients (mean age 61.0 ± 11.8 years, 64 % males) were available. There was a high prevalence (55 %) of 25(OH)D insufficiency < 20 ng/ml, and 51 % of study subjects were treated with alfacalcidol. Twenty-four patients died during a follow-up period of 4.6 years. There were no significant associations between serum 25(OH)D levels and all-cause mortality (p = 0.777). After adjustments for possible confounders, the hazard ratio (with 95 % CI) for all-cause mortality was 1.091 (1.024-1.167) for age, 0.734 (0.566-1.167) for dialysis vintage, 1.012 (0.995-1.031) for serum total cholesterol values, 2.028 (1.093-3.701) for serum phosphate levels, and 0.291 (0.088-0.855) for treatment with alfacalcidol. A survival advantage of alfacalcidol treatment was observed (log-rank, p = 0.0150). The group of subjects whose serum (25(OH)D level was <20 ng/ml and who were not treated with alfacalcidol had the highest mortality rate. CONCLUSION: Vitamin D deficiency in HD patients who had not taken vitamin D receptor agonist (VDRA) is associated with an increased risk of all-cause mortality. VDRA supplementation may suppress chronic inflammation and have some advantage for mortality of HD patients with vitamin D deficiency.

Characteristics of body composition and nutritional status in patients receiving hemodialysis therapy for more than 30 years.

BACKGROUND/AIMS: We investigated the body composition and nutritional status of extremely long-term (more than 30 years) hemodialysis patients. METHODS: Eighty outpatients receiving maintenance hemodialysis (including 18 for more than 30 years) were enrolled. We classified the patients according to the duration of hemodialysis therapy (less than 10 years, 10-20 years, 20-30 years, or over 30 years) and compared the laboratory and anthropometric data. RESULTS: No significant differences in age or the total protein, albumin, total cholesterol, triglyceride or CRP levels were observed. The corrected body mass index (BMI) was significantly lower in the more than 30 years than in the less than 10 years group. The corrected arm muscle area (AMA) was significantly lower in the more than 30 years group than in the other groups. CONCLUSION: In extremely long-term hemodialysis outpatients, the BMI and AMA were reduced, whereas nutritional markers were relatively preserved.

The use of H1-receptor antagonists and left ventricular remodeling in patients on chronic hemodialysis.

Suppression of left ventricular (LV) remodeling secondary to heart failure seems critical to improve the prognosis of hemodialysis (HD) patients. This is a retrospective study on the relationship of an antiallergic drug and antihistamines with LV hypertrophy. A total of 149 patients (88 males and 61 females) were entered in the study. Mean age was 66.7 years and mean duration of dialysis 14.4 years. Twenty-three patients received oral treatment with an antiallergic drug or second-generation antihistamines, 3 with the antiallergic drug and 20 with antihistamines. The multivariate analysis using LV mass index (LVMI) as the objective variable extracted the following independent factors: male sex, erythropoietin (EPO)/w, uric acid (UA), total cholesterol, antihistamines, antiallergic drug, and calcium channel blocker (CCB), with a standard regression coefficient of 0.187, 0.196, 0.212, -0.262, -0.215, -0.149 and -0.173, respectively. This study suggests a suppressive role of second-generation antihistamines on LV remodeling. Male sex, high-dose EPO/w, and elevated UA were considered as aggravating factors, and CCB as a suppressive factor.

Different effects of L/N-type and L-type calcium channel blockers on the renin-angiotensin-aldosterone system in SHR/Izm.

BACKGROUND: The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress sympathetic nerve activity. In the present study, we investigated the effects of cilnidipine on the renin-angiotensin-aldosterone system (RAAS) in SHR/Izm rats to confirm differences from the effects of L-type CCB. METHODS: Male SHR/Izm rats received vehicle, cilnidipine (0.3, 3 mg/kg) or amlodipine (0.3, 3 mg/kg) by gavage for systolic blood pressure (SBP) measurement. For biochemical analyses, the experiments were performed under anesthesia. RESULTS: Low doses of cilnidipine or amlodipine had no effect on SBP or RAAS parameters. A high dose of either drug produced similar effects on SBP levels. Although cilnidipine had no effect on plasma renin activity or the plasma angiotensin II level, amlodipine significantly increased these parameters as compared to levels in the vehicle group. The cilnidipine group had a significantly lower plasma aldosterone level and renal cortical tissue norepinephrine level than the vehicle group. CONCLUSIONS: Cilnidipine had effects different from those of L-type CCB on the RAAS in SHR/Izm rats. Our results indicate that suppression of RAAS hyperactivity by cilnidipine can be partly explained by its sympatholytic action.

Arterial stiffness in patients with non-diabetic chronic kidney disease (CKD).

BACKGROUND: Patients with chronic kidney disease (CKD) have a high prevalence of cardiovascular disease (CVD). Arterial stiffness plays an important role in the pathogenesis of CVD; however, to date, there have been no reports of the assessment of arterial stiffness in patients at different stages of non-diabetic CKD. METHODS: We studied 50 patients with non-diabetic CKD (stages 1-5, 5D) receiving medical treatment at Tokyo Women's Medical University. Pulse wave velocity (PWV) was assessed using an applanation tonometer to determine arterial compliance. All current medications were recorded and biochemical parameters were analyzed. RESULTS: Non-diabetic CKD stage 5D patients had a higher PWV, and higher serum levels of C-reactive protein (CRP), Ca, P and intact parathyroid hormone (iPTH) than non-diabetic CKD stage 1-5 patients (p=0.03, p=0.009, p=0.006, p=0.00005, and p=0.002, respectably). As compared to non-diabetic CKD stage 1-2 patients, patients with non-diabetic CKD stage 3-5 were older, and had higher serum levels of P and iPTH and a higher PWV (p=0.0002, p=0.009, p=0.03, and p=0.004). Nephrosclerosis was associated with a higher PWV, higher serum levels of CRP, and a higher prevalence of CVD than patients with CKD of other origins. CONCLUSION: We showed a stepwise increase of arterial stiffness with increasing disease severity stage in patients with CKD not associated with diabetes mellitus. CKD caused by nephrosclerosis was found to be associated with increased arterial stiffness and to be a risk factor for CVD.

Effects of sevelamer on the progression of vascular calcification in patients on chronic haemodialysis.

BACKGROUND/AIM: Vascular calcification is thought to be associated with a high cardiovascular mortality rate in patients with end-stage renal disease. Control of hyperphosphataemia is important for the treatment of the vascular calcification. The aim of the present study was to evaluate the effects of sevelamer hydrochloride on the progression of aortic calcification in haemodialysis (HD) patients. METHODS: 42 HD patients were studied in this study and divided into two groups (sevelamer vs. calcium). Sevelamer was added and titrated up to achieve serum P control for 6 months. The estimations of aortic calcification index (ACI) by abdominal computed tomography scans were performed twice in each patient. We compared the changes in serum calcium, phosphorus, intact parathyroid hormone, and lipids in two groups. RESULTS: Serum phosphorus levels decreased significantly from 6.7 +/- 0.7 to 6.2 +/- 0.5 mg/dl with no changes in serum intact parathyroid hormone levels in the sevelamer group (p < 0.01), and increased from 6.5 +/- 1.0 to 6.7 +/- 1.1 mg/dl in the calcium group (p < 0.05). Serum calcium levels did not change in the sevelamer group and calcium group. The serum levels of total cholesterol decreased significantly from 158.5 +/- 20.7 to 146.2 +/- 24.1 mg/dl (p = 0.024) and the low-density lipoprotein cholesterol level from 65.3 +/- 14.4 to 54.7 +/- 11.6 mg/dl (p = 0.014) in the sevelamer group. Serum C-reactive protein decreased significantly from 0.14 +/- 0.13 to 0.08 +/- 0.11 mg/dl in the sevelamer group (p = 0.038) and significantly increased (0.18 +/- 0.09 vs. 0.22 +/- 0.12 mg/dl) in the calcium group (p = 0.042). The mean changes in ACI (DeltaACI) were 3.6 +/- 1.5% in the sevelamer group and 8.2 +/- 3.1% in the calcium group. CONCLUSIONS: Sevelamer allows a better serum phosphorus control compared with calcium-based phosphate binder and suppresses the progression of aortic calcification in HD patients.

[Pathogenesis and therapy for vascular calcification in patients on chronic hemodialysis].

Vascular calcification is a common complication of end-stage renal disease (ESRD) and is likely related to the high incidence of cardiovascular disease in patients with ESRD. Vascular calcification occurs both in the vascular intima and in the tunica media. Intimal calcification is disseminated and is associated with damaged endothelium and macrophage. On the contrary, medial calcification occurs in patchy distribution and the most frequent cells types found in its vicinity are smooth muscle cells (SMC). The uremic state is associated with numerous metabolic abnormalities and endocrine disturbances primarily involving calcium and phosphorus metabolism. In addition, ESRD is considered state of active inflammatory response. These dysfunctions likely contribute to the development and progression of vascular calcification. Recent reports have shown that this is a highly regulated process governed by factors that closely resemble calcium deposition in bone tissue. Vascular calcification requires changes in the phenotype of SMC and the expression of several bone-associated proteins normally involved in bone metabolism. This review is focused on the role of phosphorus in the pathogenesis of vascular calcification and the therapeutic approaches currently available to slow its progression in patients with ESRD.