Sclerostin as a new key player in arteriovenous fistula calcification.

BACKGROUND: The osteocyte-derived sclerostin has been shown to play a key inhibitor role in determining the normal extent of bone formation, and it consequently protects against the deleterious effects of uncontrolled bone growth. Sclerostin has been demonstrated to be upregulated during vascular smooth muscle cell calcification in vitro and has recently been identified in the human aorta at the protein level. Whether the effects of sclerostin on bone turnover and its vascular expression also translate into clinically significant changes in arteriovenous fistula patency is unknown. PATIENTS AND METHODS: The primary outcome was loss of unassisted arteriovenous fistula patency, defined as arteriovenous fistula thrombosis or need for intervention. In this prospective cohort study, 350 prevalent hemodialysis patients were followed up for 12 months. Serum sclerostin levels were measured and arteriovenous fistula calcification was detected using a 64-detector computerized tomographic scanner. RESULTS: Patients with calcified arteriovenous fistula had higher serum sclerostin levels than patients without. Overall, 26 % of the patients reached the outcome during the follow-up. The 12-month arteriovenous fistula survival was reduced in patients with calcified arteriovenous fistulas. Patients with serum sclerostin levels above median levels at the start of the observation period had a worse arteriovenous fistula survival. Multivariable-adjusted Cox regression analyses revealed that only presence of arteriovenous fistula calcification and serum C-reactive protein level independently predicted loss of unassisted arteriovenous fistula patency. CONCLUSION: Our study suggests that the detection of arteriovenous fistula calcification and serum C-reactive protein levels might be useful for identifying patients at an increased risk for loss of unassisted arteriovenous fistula patency.

Comparison of renal resistive index among patients with Type 2 diabetes with different levels of creatinine clearance and urinary albumin excretion.

AIM: To evaluate the prevalence of increased renal resistive index and related factors among patients with Type 2 diabetes with different levels of creatinine clearance and urinary albumin excretion. METHODS: Laboratory analyses, including calculation of 24-h urinary albumin excretion and 24-h creatinine clearance, and renal doppler ultrasonography to measure renal resistive index, were carried out for patients newly diagnosed with Type 2 diabetes mellitus. RESULTS: Participants were classified into four groups according to 24-h creatinine clearance and 24-h urinary albumin excretion levels. Group 1 was composed of 73 patients (54.1%) with normal 24-h creatinine clearance and 24-h urinary albumin excretion. Group 2 was composed of 34 (25.2%) patients with normal 24-h creatinine clearance and increased 24-h urinary albumin excretion. Group 3 was composed of 14 (10.4%) patients with decreased 24-h creatinine clearance and normal 24-h urinary albumin excretion. Group 4 was composed of 14 (10.4%) patients with both decreased 24-h creatinine clearance and increased 24-h urinary albumin excretion . In total, 41 patients (30.4%) had increased renal resistive index levels. Comparison of the four groups with respect to increased renal resistive index revealed: among group 1 patients, 10 (13.7%) had increased renal resistive index levels; among group 2 patients, 14 (41.2%) had increased renal resistive index levels; among group 3 patients, eight (57.1%) had increased renal resistive index levels; among group 4 patients, nine (64.3%) had increased renal resistive index levels (P<0.0001 for trend). In multivariate regression, 24-h creatinine clearance (P<0.0001), but not 24-h urinary albumin excretion, was related to increased renal resistive index levels. CONCLUSION: Renal resistive index levels were highest in patients with Type 2 diabetes with both decreased 24-h creatinine clearance and increased 24-h urinary albumin excretion, whereas they were lowest in patients with normal creatinine clearance and normal urinary albumin excretion.

Renin-angiotensin system and cancer: epidemiology, cell signaling, genetics and epigenetics.

Day by day, the health and economical burden of cancer increases globally. Indeed it can be considered that there is ''cancer pandemic''. Blocking the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors (ACEI) or angiotensin-receptor blockers (ARB) are widely used measures to treat hypertension and heart failure. It has been recently suggested the activation and blocking of RAS has been associated with various types of cancer in epidemiological and experimental studies. Various studies have shown that RAS blockage is protective in some cancers. However, although fewer, contradictory data also showed that RAS blockage is either not related or adversely related to cancer. Although the reasons for these findings are not exactly known, different types of receptors and effectors in RAS may account for these findings. In the current review, we summarize the different RAS receptors and cancer development with regard to epidemiology, and pathogenesis including cell signaling pathways, apoptosis, genetic and epigenetic factors.

Malnutrition inflammation score is associated with coronary artery disease in hepatitis C virus-infected hemodialysis patients.

OBJECTIVE: Hepatitis C virus (HCV) infection exerts diverse effects on atherogenesis. We investigated whether malnutrition inflammation score (MIS) is associated with the presence of coronary artery disease (CAD) in anti-HCV-positive hemodialysis (HD) patients. SUBJECTS/METHODS: Twenty-two anti-HCV-positive HD patients with CAD and 61 anti-HCV-positive HD patients without CAD (as controls) were included. Data were obtained from hospital records, patients were evaluated for risk factors for CAD. The same physician performed MIS evaluation. RESULTS: MIS of anti-HCV-positive HD patients with CAD were significantly higher than patients without CAD (8.8+/-4.0 vs 6.5+/-2.6, P=0.02). In patients with CAD, basal (P=0.002) and peak C-reactive protein (P=0.03) and serum ferritin (P=0.01) concentrations were higher, serum albumin concentrations (P=0.003) were lower than those patients without CAD. MIS was positively correlated with age (r=+0.359, P=0.001) and viral load (r=+0.629, P<0.0001). In univariate logistic regression analysis, advanced age (odds ratios (OR)=1.093, confidence interval (CI): 1.039-1.150, P=0.001), hypertension (OR=3.143, CI: 1.084-9.116, P=0.035), diabetes mellitus (OR=5.344, CI: 1.343-21.269, P=0.017), low triglyceride (OR=0.992, CI: 0.984-0.999, P=0.026) and high MIS (OR=1.259, CI: 1.066-1.488, P=0.007) were associated with the presence of CAD. Multivariate logistic regression analysis identified age (OR=1.090, CI: 1.007-1.179, P=0.033) and MIS as the factors associated with the presence of CAD (OR=1.232, CI: 1.004-1.511, P=0.04). CONCLUSIONS: MIS may be associated with CAD in anti-HCV-positive HD patients.

Lipid profile during azathioprine or mycophenolate mofetil combinations with cyclosporine and steroids.

BACKGROUND: Immunosuppressive therapy is the major cause of hyperlipidemia after renal transplantation. We sought to compare the effects of an azathioprine (AZA) combination (n = 26) with corticosteroid and cyclosporine (CyA; group 1) with a mycophenolate mofetil (MMF) combination (n = 71; group 2) in the first year following renal transplantation. METHODS: Ninety-seven renal transplant patients (71 men, 26 women; aged 34.7 +/- 13.1 years; renal transplantation duration, 44.9 +/- 12.9 months) underwent serum lipid profiles--total cholesterol, triglyceride, high-density lipoprotein (HDL); low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) at the initiation of as well as 3-month intervals after grafting for 1 year retrospectively. Serum creatinine for each patient was recorded at 12 months. We evaluated possible risk factors for hyperlipidemia. RESULTS: For all patients, the prevalence of hypercholesterolemia (>200 mg/dL) was 36.1% during the pretransplant period, 60.8% at month 3, 50.5% at month 6, and 38.1% at month 12 after renal transplantation. Total cholesterol and triglyceride levels significantly increased in both groups in the first year (P = .001 and P = .02, respectively). Three-month values for total cholesterol were higher in group 2 than group 1 (P = .001). No significant difference was observed between the groups with respect to total cholesterol and triglyceride levels (P > .05). In both groups, HDL, LDL, and VLDL levels did not change during the 12-month study (P > .05 for all). CONCLUSIONS: Independent of hyperlipidemia risk factors, serum total cholesterol and triglyceride levels tended to increase during CyA and steroid therapy among patients undergoing renal transplantation. Combination with MMF or AZA showed no advantage over one another regarding their effects on the lipid profile.

Additional effect of hyperparathyroidism on inflammatory status and rHuEPO requirements in hemodialysis patients.

BACKGROUND: The aim of this study was to analyze the effects of elevated parathyroid hormone (iPTH) and C-reactive protein (CRP) on rHuEPO requirements and associated clinical and biochemical parameters of hemodialysis patients. METHODS: A total of 127 hemodialysis patients were included. Laboratory values from the previous 3 months (monthly measured CRP, iPTH, albumin, prealbumin, calcium, phosphorus, and hemoglobin) and clinical findings (rHuEPO requirements, iron supplements, Kt/V) were recorded retrospectively. Patients were subgrouped according to presence of hyperparathyroidism (mean iPTH > 350 pg/mL) and chronic inflammation (mean CRP > 8.5 mg/L) as group I (low iPTH, low CRP, n = 32), group II (high iPTH, low CRP, n = 32), group III (low iPTH, high CRP, n = 32), and group IV (high iPTH, high CRP, n = 31). RESULTS: We found that group IV had lowest hemoglobin (P < .0001, .0001, .01, respectively), albumin (P < .0001), prealbumin (P < .0001, .0001, .02, respectively), and highest rHuEPO requirements (P < .0001, .0001, .01, respectively) compared to other groups despite of similar iron indices. Group III also had lower albumin (P < .002, .0001, respectively), prealbumin (P < .001, .01, respectively), hemoglobin (P < .001, .005, respectively), but higher rHuEPO requirements (P < .01) compared to group I and group II. CONCLUSIONS: We propose that hyperparathyroidism increases rHuEPO requirements and aggravates the negative effects of chronic inflammation in hemodialysis patients.

Persistent hypercalcemia is a significant risk factor for graft dysfunction in renal transplantation recipients.

Hypercalcemia is a common problem in renal transplant recipients, although in most cases, spontaneous resolution occurs within 1 year after renal transplantation. This condition may persist in some patients producing effects on renal function which are not well understood. In this study, we sought to analyze the effect of persistent hypercalcemia in the posttransplantation period on the function of renal transplants. A total of 121 recipients (31 women, 90 men; mean age, 34.1 +/- 9.9 years) underwent renal transplantation between 1999 and 2002. All patients underwent prospective evaluation of their serum calcium levels at 6-month intervals. A sustained corrected mean serum calcium level higher than 10.2 mg/dL was defined as "persistent hypercalcemia." Patients who had a gradual increase in their serum creatinine levels to >2 mg/dL or a 50% rise above the baseline were considered to display chronic allograft dysfunction (CAD). Among 121 recipients, 52 patients (43%) developed CAD and 37 patients (30.6%) had persistent hypercalcemia. Among the CAD patients, 22 suffered persistent hypercalcemia, while the other 15 patients were without CAD, a difference that was statistically significant (42.3% vs 21.7%, P = .01). The mean calcium levels were lower among patients without than with CAD, a difference that did not reach statistical significance (9.9 +/- 0.4 mg/dL vs 10.1 +/- 0.6 mg/dL, P = .1). In conclusion, persistent hypercalcemia in the posttransplantation period may significantly contribute to the development of chronic allograft nephropathy.

Subjective global assessment is a useful method to detect malnutrition in renal transplant patients.

Adequate nutrition is essential for the well-being of renal transplant patients. While body weight gain is a common widely investigated finding, a considerable fraction of patients exhibit poor nutritional status after successful kidney transplantation. In the present study, the prevalence association with nutritional parameters and clinical data of malnutrition among kidney transplant patients were determined based upon a subjective global assessment. This cross-sectional study in the transplant outpatient clinic included 47 patients (10 women, 37 men) of mean age 37.6 +/- 10.2 years. The same dietitian performed the assessment on all patients, including anthropometric measurements of body mass index (BMI), mid-arm circumference, and triceps skinfold thickness. The patient data including medications, number of hospitalizations in the preceding year, and presence of chronic allograft failure were collected from medical records. The mean laboratory values during the last 6 months included hemoglobin, creatinine, albumin, phosphorus, C-reactive protein levels, and lipid profile. The patients were classified into 3 groups defined as A (n = 31, 66%), B (n = 11, 23.4%), and C (n = 5, 10.6%), namely, A, no malnutrition versus B/C, moderate or severe malnutrition. Comparison of the 2 groups revealed the serum albumin (P < .0001), body mass index (P = .02), and mid-arm circumference (P = .02) to be higher in group A than groups B/C. Group B/C patients showed higher levels of C-reactive protein (P < .0001). When compared to the pretransplantation period, the 31 patients in group A included 26 who had increased body mass index after transplantation versus only 3 of 16 patients in groups B/C had (P < .0001). The hospitalization rates were significantly lower in group A (P = .02). Additionally, the patients in group A tended to have a lower frequency of chronic allograft rejection when compared to group B/C subjects (P = .13). In conclusion, assessment of nutritional status of renal transplant patients combined with intervention in the nutritional intake may decrease the morbidity rates in this patient group.

Hepatitis C infection in hemodialysis patients: Protective against oxidative stress?

Hepatitis C virus (HCV) infection is a common problem that increases morbidity and mortality in hemodialysis patients. These patients are also at risk of increased oxidative stress. The aim of this study was to evaluate possible interactions between HCV infection and oxidative stress indicators in a group of hemodialysis patients awaiting transplantation. We evaluated 73 patients (29 women, 44 men; ages, 49.3 +/- 13.3 years; dialysis duration, 81.7 +/- 48.8 months; Kt/V > or = 1.3). Indicators of plasma oxidative status were monitored at the beginning of a clinically stable hemodialysis session. Measurements were performed for plasma superoxide dismutase (SOD), glutathione peroxidase (GPX), and malonyldialdehyde (MDA) by spectrophotometric methods. We retrospectively recorded the prior year's monthly laboratory values for alanine aminotransferase (ALT), C-reactive protein (CRP), albumin, lipids, homocysteine, Lp(a), calcium, phosphorus, intact parathyroid hormone, and predialysis blood urea nitrogen (BUN) creatinine, as well as clinical findings of body mass index and pre- and postdialysis blood pressures. We excluded patients with chronic inflammation (mean CRP levels > or = 10 mg/L) or HCV infection of duration <12 months or clinically advanced liver failure. Twenty-six patients had HCV. The sex distribution, mean age, and dialysis duration were similar between groups. HCV-infected patients showed significantly lower levels of MDA, albumin, total cholesterol, triglyceride, predialysis creatinine, and phosphorus. Antioxidative indicator levels were also higher in the HCV group, but they were not statistically significant. In conclusion, HCV infection in dialysis patients is associated with decreased levels of plasma oxidative load.

Predictors of vascular access thrombosis among patients on the cadaveric renal transplantation waiting list.

Acute thrombotic complications remain a constant, proportionally increasing complication before and after renal transplantation. We sought to investigate predictors for a prothrombotic state that increased the risk of vascular access thrombosis, among chronic renal failure patients during the waiting period prior to cadaveric renal transplantation. Chronic renal failure patients awaiting cadaveric renal transplantation and followed between January 2002 and January 2005 were included in this study. The 109 subjects including, 61 females and 48 males of mean age: 47.4 +/- 12.9 years; There were 36 continuous ambulatory peritoneal dialysis and 73 hemodialysis patients. Serum albumin, prealbumin, CRP, d-dimer, fibrinogen, antithrombin III, anticardiolipin antibodies (immunoglobulins G and M), homocystein, vitamin B12, folic acid, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total platelet count were measured in each patient. Factor V Leiden, prothrombin 20210, ACE and MTHFR gene mutations were studied in all patients. Vascular Access thrombosis was detected in 62 patients. During follow-up 31 of 109 patients died. Vascular access thrombosis occurred in 78 patients who survived and 31 who died. The patients who died showed a significantly higher rate of thrombosis than those who survived (P = .003, OR: 4.61, CI: 1.70 to 12.50). Among the above biochemical risk factors, multiple regression analysis and backward logistic analysis revealed that d-dimer was the strongest biochemical predictor of thrombosis (P = .013, RR: 17.8). Upon evaluation of genetic risk factors, only factor V Leiden mutation was related to vascular access thrombosis (P = .001). In conclusion, the presence of vascular access thrombosis is a risk factor for mortality during the waiting period for cadaveric renal transplantation. As patients with factor V Leiden mutation or high serum d-dimer levels are at high risk for vascular access thrombosis, we recommend close monitorizing of these patients and use of anticoagulant therapy during the waiting period prior to renal transplantation.

Morning blood pressure surge is associated with serum gamma-glutamyltransferase activity in essential hypertensive patients.

The phenomenon that blood pressure rises sharply in the morning is called 'Morning Blood Pressure Surge' (MBPS). Serum gamma-glutamyltransferase (GGT) is a proinflammatory marker involved in the pathogenesis of cardiovascular diseases. Although both are novel cardiovascular risk factors associated with inflammation and atherosclerosis, the specific relationship between MBPS and serum GGT is unknown. This study investigates the relationship between MBPS and serum GGT activity in essential hypertensive patients. Totally, 320 hypertensive patients were recruited. Mean MBPS was 17.0 ± 12.9 mm Hg. MBPS was positively correlated with age (r = +0.222, P < 0.0001), body mass index (r = +0.132, P = 0.018), GGT (r = +0.271, P < 0.0001), daytime augmentation index adjusted for heart rate (AIx@75) (r = +0.140, P=0.014), 24-h pulse wave velocity (PWV) (r = +0.143, P = 0.014) and daytime PWV (r = +0.158, P = 0.007). From the 25th to 75th quartile of serum GGT, MBPS increased significantly (Ptrend < 0.0001). In multivariate linear regression analysis, MBPS was independently associated with age (P = 0.002), dipping status (P < 0.0001) and logGGT (P < 0.0001). In conclusion, MBPS is independently associated serum GGT activity in essential hypertensive patients. This is the first study in the literature to demonstrate an independent and a dose-response relationship between the two novel cardiovascular risk factors, MBPS and serum GGT, in this patient population.

Renin-angiotensin system and cancer: epidemiology, cell signaling, genetics and epigenetics

Day by day, the health and economical burden of cancer increases globally. Indeed it can be considered that there is ‘’cancer pandemic’’. Blocking the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors (ACEI) or angiotensin-receptor blockers (ARB) are widely used measures to treat hypertension and heart failure. It has been recently suggested the activation and blocking of RAS has been associated with various types of cancer in epidemiological and experimental studies. Various studies have shown that RAS blockage is protective in some cancers. However, although fewer, contradictory data also showed that RAS blockage is either not related or adversely related to cancer. Although the reasons for these findings are not exactly known, different types of receptors and effectors in RAS may account for these findings. In the current review, we summarize the different RAS receptors and cancer development with regard to epidemiology, and pathogenesis including cell signaling pathways, apoptosis, genetic and epigenetic factors (AU)