Sodium thiosulphate and progression of vascular calcification in end-stage renal disease patients: a double-blind, randomized, placebo-controlled study.

BACKGROUND: Sodium thiosulphate (NaTS) is mostly used in haemodialysis (HD) patients with calcific uraemic arteriolopathy. This double-blind, randomized, placebo-controlled study assessed the effect of NaTS on progression of cardiovascular calcifications in HD patients. METHODS: From 65 screened patients, we recruited 60 patients with an abdominal aorta Agatston calcification score ≥100. Thirty patients were randomized to receive NaTS 25 g/1.73 m2 and 30 patients to receive 100 mL of 0.9% sodium chloride intravenously during the last 15 min of HD over a period of 6 months. The primary endpoint was the absolute change of the abdominal aortic calcification score. RESULTS: The abdominal aortic calcification score and calcification volume of the abdominal aorta increased similarly in both treatment groups during the trial. As compared with the saline group, patients receiving NaTS exhibited a reduction of their iliac artery calcification score (-137 ± 641 versus 245 ± 755; P = 0.049), reduced pulse wave velocity (9.6 ± 2.7 versus 11.4 ± 3.6; P = 0.000) and a lower carotid intima-media thickness (0.77 ± 0.1 versus 0.83 ± 00.17; P = 0.033) and had better preservation of echocardiographic parameters of left ventricular hypertrophy. No patient of the NaTS group developed new cardiac valve calcifications during the trial as compared with 8 of 29 patients in the saline group. By univariate analysis, NaTS therapy was the only predictor of not developing new valvular calcifications. No adverse events possibly related to NaTS infusion were noted. CONCLUSIONS: While NaTS failed to retard abdominal aortic calcification progress, it positively affected calcification progress in iliac arteries and heart valves as well as several other cardiovascular functional parameters.

Prognostic value of cardiovascular calcifications in hemodialysis patients: a longitudinal study.

PURPOSE: Cardiovascular calcifications (CVC) are present in up to 70% of non-diabetic dialysis patients. Sparse data are available on predictors of very long-term outcomes of such patients. The Belgrade Aachen Study on Calcification in Hemodialysis patients (BASCH study) aimed to study this using a comprehensive CVC assessment. METHODS: We prospectively analyzed 220 hemodialysis patients followed for a mean of 76 months (median 73 months, range 6-160 months). We compared patients deceased from cardiovascular diseases (CVD) and survivors. Analyses included composite calcification scores (determined by combining ultrasound and X-ray analyses), demographic, clinical and laboratory data and pulse wave velocity (PWV). For survival analysis, patients were divided into group according to quartiles (Q). RESULTS: Compared to survivors, deceased patients from CVD were significantly older, more frequently hypertensive, had shorter dialysis times per week and lower Kt/V values, and they exhibited lower serum fetuin A, osteoprotegerin and hemoglobin as well as higher CRP levels. Composite calcification and Adragao scores were significantly higher in deceased patients from CVD as was PWV. Mean survival was 101 ± 47 months (Q1), 87 ± 51 month (Q2), 66 ± 48 (Q3) and 54 ± 45 months (Q4), p = 0.000. Cox multivariate regression analysis showed that independent predictors for cardiovascular mortality were composite calcification score in the range of third and fourth quartiles. CONCLUSION: Composite calcification score emerged as significant predictors of long-term survival in our group of largely non-diabetic dialysis patient population, finding that should be confirmed by intervention studies.

Calcification in arteriovenous fistula blood vessels may predict arteriovenous fistula failure: a 5-year follow-up study.

PURPOSE: Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. The impact of vascular calcification process on AVF survival remains unclear and results of several studies about this issue are controversial. In the light of the new knowledge about the different susceptibility for calcification process in different blood vessels, the aim of our study was to analyze whether the calcification of AVF-blood vessels may have an impact on AVF longevity. METHODS: The study included 90 patients, 49 males and 41 females, all of them Caucasians, with a mean age 62 ± 11 years, on regular hemodialysis for more than 1 year with patent primary AVFs. Vascular calcification in AVF-blood vessels or in the anastomotic region was detected using X-ray examination. RESULTS: Calcification in AVF-blood vessels was found in 62% of patients. Binary logistic regression analysis demonstrated that male gender, presence of diabetes mellitus and longer duration of AVF before calcification determination were associated with calcification of AVF-blood vessels. Using a Cox proportional hazard model adjusted for these standardized predicted values revealed that patients with present AVF-blood vessels calcification had increased risk to develop AVF failure with a hazard rate of 3.42 (95% confidence interval 1.00-11.67; P = 0.049). CONCLUSIONS: Calcifications of AVF-blood vessels are found frequently among dialysis patients and may jeopardize the survival of native AVF. We suggested the local X-ray as simple and valid method for detection of patients that are at risk for AVFs failure which should be monitored more closely.

Survival Benefit of Hemodiafiltration Compared With Prolonged High-flux Hemodialysis.

INTRODUCTION:  Patients on dialysis have a high rate of death, mainly of cardiovascular cause. Nephrologists are actively looking for ways to improve patients' outcomes, and alternative dialysis strategies, such as long conventional hemodialysis and hemodiafiltration, are currently being investigated. The aim of this study was to compare anemia, nutrition, inflammation, mineral metabolism, and 3-year survival rates between patients treated with hemodiafiltration and prolonged high-flux hemodialysis (HFH). MATERIALS AND METHODS:  A total of 58 dialysis patients were divided into 2 groups to undergo hemodiafiltration 3 times weekly, 12 hours in total per week, or prolonged duration of HFH (≥ 15 h/w). One-year biochemical parameters were collected retrospectively, together with 36 months patients' survival (prospectively). RESULTS: Patients in the HFH group had longer dialysis vintage; significantly higher levels of hemoglobin (despite less frequent use of erythropoietin-stimulating agents), serum albumin, serum calcium, and serum bicarbonate; and a lower in-tact parathyroid hormone level. Survival rates were comparable between the two groups. The Cox proportional hazard model showed that patients treated with longer HFH had a 32% relative risk reduction of mortality compared to patients treated with hemodiafiltration, but without statistical significance (hazard ratio, 0.68; 95% confidence interval, 0.21 to 2.20; adjusted for diabetes mellitus). CONCLUSIONS: Longer duration of hemodialysis with high-flux membranes had beneficial effects on anemia indexes, mineral metabolism, nutrition parameters, and acidosis in comparison with hemodiafiltration. However, hemodiafiltration did not offer a 36-months survival benefit over prolonged HFH.

Association between Hemodialysis Patient Outcomes and Compliance with KDOQI and KDIGO Targets for Mineral and Bone Metabolism.

BACKGROUND: Increased mortality of hemodialysis (HD) patients is associated with chronic kidney disease-mineral and bone disorders (CKD-MBD), and therefore, their correction may improve patient survival. Differences in targets recommended by KDOQI and KDIGO CKD-MBD guidelines directed us to compare the relative numbers of patients achieving these targets and to examine possible associations between compliance with the targets and patient outcome. METHODS: A total of 1,744 patients (61.2% males, aged 58.7 ± 12.5 years) dialyzed in 20 HD centers in Serbia were monitored for 3 years. The number of participants achieving KDOQI/KDIGO guideline targets for serum phosphorus, calcium, and iPTH was determined. The Cox proportional hazards model was used to select variables significantly associated with risk of time to death. RESULTS: A majority of patients were dialyzed thrice weekly for 4 h; 86.3% of them used phosphate binders and 49.3% vitamin D3. Proportions of patients achieving KDOQI and KDIGO targets were 49.5 and 44.4% for phosphorus, 53.2 and 76.7% for calcium, 21 and 42.8% for iPTH. Multivariate Cox analysis selected serum phosphorus level outside the KDIGO target, as well as serum iPTH levels outside KDOQI and KDIGO targets as significant mortality predictors. Areas under the receiver operating characteristic curves showed that achievement of both guideline targets for iPTH had similar survival predictive values. CONCLUSION: Serum phosphorus levels outside KDIGO targets and iPTH levels outside both KDOQI and KDIGO targets were associated with a significantly higher risk of death. These findings may be useful in the management of CKD-MBD and for establishing local guidelines.

Compliance with guidelines and predictors of mortality in hemodialysis. Learning from Serbia patients.

OBJECTIVES: The aims of the study were to determine the percentage of patients on regular hemodialysis (HD) in Serbia failing to meet KDOQI guidelines targets and find out factors associated with the risk of time to death and the association between guidelines adherence and patient outcome. METHODS: A cohort of 2153 patients on regular HD in 24 centers (55.7% of overall HD population) in Serbia were followed from January 2010 to December 2012. The percentage of patients failing to meet KDOQI guidelines targets of dialysis dose (Kt/V>1.2), hemoglobin (>110g/L), serum phosphorus (1.1-1.8mmol/L), calcium (2.1-2.4mmol/L) and iPTH (150-300pg/mL) was determined. Cox proportional hazards analysis was used to select variables significantly associated with the risk of time to death. RESULTS: The patients were on regular HD for 5.3±5.3 years, dialyzed 11.8±1.9h/week. Kt/V<1.2 had 42.4% of patients, hemoglobin <110g/L had 66.1%, s-phosphorus <1.1mmol/L had 21.7% and >1.8mmol/L 28.6%, s-calcium <2.1mmol/L had 11.7% and >2.4mmol/L 25.3%, iPTH <150pg/mL had 40% and >300pg/mL 39.7% of patients. Using Cox model (adjustment for patient age, gender, duration of HD treatment) age, duration of HD treatment, hemoglobin, iPTH and diabetic nephropathy were selected as significant independent predictors of time to death. When targets of five examined parameters were included in Cox model, target for KtV, hemoglobin and iPTH were found to be significant independent predictors of time to death. CONCLUSION: Substantial proportion of patients examined failed to meet KDOQI guidelines targets. The relative risk of time to death was associated with being outside the targets for Kt/V, hemoglobin and iPTH.

Achievement of guideline targets in elderly patients on hemodialysis: a multicenter study.

OBJECTIVES: Advanced age is associated with shorter survival on dialysis. The aim of the present study was to compare the adherence with KDOQI guideline targets and the association between mortality and satisfying the guidelines targets between hemodialysis patients aged 65 years and over and those younger than 65 years. METHODS: Data were collected using a questionnaire sent to all 46 HD centers in Serbia with totally 3868 HD patients. The 24 centers responded and sent the data on all patients aged 18 years or older that were on regular HD for more than 3 months (2153 patients, 1320 males, aged 18-90 years). Data are presented in two groups: a group of patients younger than 65 years (1438, 66.8 %) and a group of patients aged 65 years and over (715, 33.2 %). The percentage of patients whose values failed to meet the targets recommended by KDOQI Clinical Practice Guidelines was calculated for dialysis dose (spKt/V), hemoglobin, serum phosphorus, serum calcium and plasma iPTH (150-300 pg/mL). Patients were followed from enrollment until their death, kidney transplantation, departure from the center or the end of the study. RESULTS: Elderly patients were more likely to have hypertension, significantly lower systolic and diastolic blood pressure and smaller dialysis vintage than younger patients. They were less frequently treated with high-flux membranes and hemodiafiltration and they had significantly lower number of dialysis hours per week and significantly lower interdialytic weight gain. They used ESA and phosphate binders less frequently than younger patients (p < 0.001 and p = 0.002). Older patients had similar Kt/V as younger ones but they had significantly more frequent Hb level outside the target range than younger patients. During the year follow-up period, by using a Cox proportional hazards model it has been confirmed that age, dialysis vintage, weekly dialysis time and target values for Kt/V were significant independent predictors of time to death for younger patients and gender, dialysis vintage and iPTH were independent predictor of time to death for older patients. CONCLUSION: Despite less favorable dialysis prescription, older patients had similar Kt/V and less frequent deviations from the target values proposed by KDOQI for serum phosphorus and iPTH but more frequent deviation for Hb value as compared with younger patients. Risk factors for mortality differ between older and younger patients; out of five KDOQI targets, only Kt/V proved to be a significant risk factor for mortality for younger and iPTH for older patients.

Impact of vascular calcifications on arteriovenous fistula survival in hemodialysis patients: a five-year follow-up.

BACKGROUND/AIMS: Vascular calcifications are frequently found among dialysis patients, and the calcification process may influence the patient's outcome. The aim of the present study was to determine the role that vascular calcifications may have on autologous arteriovenous fistula (AVF) survival. METHODS: This study included 90 patients (49 males, mean age 62 ± 11) with a native AVF treated by chronic hemodialysis (HD) for more than one year. The overall vascular calcification scores ranged from 0-11 (Adragao score + vascular access calcification score); patients were categorized into mild (score 0-3; n = 36), moderate (score 4-7; n = 24) and severe (score 8-11; n = 30) calcification groups. AVF survival was then followed for 5 years after calcification measurement or until the patient's death/transplantation. RESULTS: Patients with more pronounced vascular calcifications were more frequently diabetic and male. Multiple linear regression analysis showed a significant relationship between calcification score and male gender, diabetes mellitus, previous duration of AVF, low dialysis flow rate and intact parathormone (iPTH) values. After multivariate adjustment for basal differences, Cox proportional analysis revealed a graded impact of calcification scores on AVF failure: moderate scores (were associated with a hazard rate (HR) of 3.82 (95% confidence interval (CI) 1.10-13.23) and severe scores with an HR of 4.65 (CI 0.97-22.38). CONCLUSION: Vascular calcifications are associated with worse survival of native arteriovenous hemodialysis fistulas.

Arteriovenous fistula aneurysm in patients on regular hemodialysis: prevalence and risk factors.

BACKGROUND/AIMS: Compared to all other complications, literature data about vascular access aneurysm (VAA) are the scarcest. The aim of this cross-sectional study was to evaluate the prevalence of arteriovenous fistula (AVF) aneurysms and to confirm the risk factors for their appearance. METHODS: The presence, number and morphological characteristics of AVF aneurysms were confirmed, and according to the score of AVF aneurysm (the sum of the length and width in cm), patients were classified into group 1 (score ≤12) and group 2 (score >12). Analysis included the last data from the medical records including vascular calcifications score. RESULTS: Out of 181 patients, 150 with native fistula were included in this study. Aneurysmatic changes were detected in 90 (60%) patients, and the majority had two or more aneurysms. VAA were more frequent in patients with adult polycystic kidney disease (ADPKD) than in other diagnostic categories. By using forward stepwise logistic regression, we confirmed that patients on high-flux hemodialysis (HD) had 5.3-fold higher risk, and patients with diabetes mellitus had 5.8-fold less risk for developing AVF aneurysm. While vascular calcification score did not influence the incidence of VAA, higher PWV had significant negative influence on formation of AVF aneurysm (OR 1.25, 95% CI 1.003-1.56, p = 0.047). By ROC curve analysis, it was determined that patients who were longer than 5.7 years on HD had greater risk for developing VAA (area = 0.741, p = 0.000). CONCLUSION: This single-center study confirmed the very high prevalence of VAA (60%). Aneurysms were more frequent in patients with ADPKD and in those who had longer dialysis vintage on high-flux membranes with higher blood flow rate.

Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD.

The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 age-matched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r = 0.62, P < 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P = 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study.

Screening of vascular calcifications in patients with end-stage renal diseases.

Vascular calcifications (VC) are a major contributor to the massively increased mortality in hemodialysis (HD) patients. The present study aimed to detect arterial media and intima calcifications in HD patients and to evaluate potential risk factors. 214 patients aged 59.0 +/- 11.0 years on HD for 6.39 +/- 4.59 years were studied. VC were scored based on to plain radiographs. Potential risk factors were assessed. Out of the 214 patients studied, only 14% did not display any detectable VC. Using plain radiographs calcifications could be detected in 136 (63.6%) patients. Calcified plaques on carotid arteries were detected in 168 (78.4%) patients. There was the highest frequency of patients with the most pronounced calcifications. Calcifications of heart valves were detected in 89 (44.1%) patients. Univariante analysis indicate that risk to develop VC is present in older patients, patients with longer dialysis vintage, thicker intima media, higher lumen diameter and mitral valve calcifications. Multivariate multinomial logistic regression analysis revealed these factors as independent predictors of VC in dialysis patients. Our data confirm a high prevalence of VC in HD patients, their association with older ages, longer dialysis vintage, and presence of valvular calcifications and early markers of atherosclerosis.

Risk factors for cardiovascular calcifications in non-diabetic Caucasian haemodialysis patients.

BACKGROUND/AIMS: Dialysis patients display an increased mortality which is associated with cardiovascular calcifications. Diabetes mellitus and ethnicity are known factors that affect the extent of cardiovascular calcifications. However, most studies have investigated mixed cohorts with diabetics and/or mixed ethnicity. METHODS: Cardiovascular calcifications were assessed in non-diabetic Caucasian haemodialysis patients by the semiquantitative Adragao calcification score (X-ray pelvis and hands) and a novel composite calcification score encompassing the Adragao score as well as calcifications detected by X-ray of the fistula arm, echocardiography of heart valves and carotid ultrasound. RESULTS: Using multivariate analysis, age, male gender, dialysis vintage, lower Kt/V, calcium-phosphate product, smoking and high-sensitivity CRP were independent risk factors for cardiovascular calcifications as assessed by the Adragao or the composite score. Pulse wave velocity was independently related to both calcification scores. Body mass index, cholesterol, triglycerides, iPTH and serum levels of fetuin-A and uncarboxylated matrix Gla protein were not associated with cardiovascular calcifications. CONCLUSIONS: In our cohort of non-diabetic Caucasian haemodialysis patients, age, male gender, dialysis vintage, smoking, calcium-phosphate product, high-sensitivity CRP and lower Kt/V were independent risk factors for cardiovascular calcifications. Whether lowering the calcium-phosphate product and increasing dialysis efficiency can reduce cardiovascular calcifications in dialysis patients remains to be determined.

Vascular access calcification predicts mortality in hemodialysis patients.

Vascular calcification is a recognized risk factor for cardiovascular mortality in patients with end-stage renal disease. The aim of this study was to identify risk factors for vascular access calcification and to determine if patients with this disorder are at increased risk of death. Vascular access calcification was found in 49 of 212 hemodialysis patients as measured by plain X-ray (arteriovenous fistula or synthetic graft) in two dimensions. Male gender, diabetes mellitus, and length of time on dialysis were independent predictors for access calcification determined by logistic regression multivariate analysis. Serum parameters were not independently related to access calcification. Kaplan-Meier analysis showed an increased mortality risk, and Cox regression analysis confirmed that vascular access calcification was an independent mortality predictor. Our study suggests that detection of vascular access calcification is a cost-effective method to identify patients at increased mortality risk.

Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes.

Glomerulonephritis (GN) is a major cause of renal failure. This study sought to determine whether intrarenal injection of rat mesenchymal stem cells (MSC) can preserve renal function in a progressive rat model of GN. Early in GN (day 10), fluorescently labeled rat MSC localized to more than 70% of glomeruli, ameliorated acute renal failure, and reduced glomerular adhesions. Fifty days later, proteinuria had progressed in controls to 40 +/- 25 mg/d but stayed low in MSC-treated rats (13 +/- 4 mg/d; P < 0.01). Renal function on day 60 in the MSC group was better than in medium controls. Kidneys of the MSC group as compared with controls on day 60 contained 11% more glomeruli per 1-mm(2) section of cortex but also significantly more collagen types I, III, and IV and alpha-smooth muscle actin. Approximately 20% of the glomeruli of MSC-treated rats contained single or clusters of large adipocytes with pronounced surrounding fibrosis. Adipocytes exhibited fluorescence in their cytoplasm and/or intracellular lipid droplets. Lipid composition in these adipocytes in vivo mirrored that of MSC that underwent adipogenic differentiation in vitro. Thus, in this GN model, the early beneficial effect of MSC of preserving damaged glomeruli and maintaining renal function was offset by a long-term partial maldifferentiation of intraglomerular MSC into adipocytes accompanied by glomerular sclerosis. These data suggest that MSC treatment can be a valuable therapeutic approach only if adipogenic maldifferentiation is prevented.

Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis.

Bone marrow-derived cells contribute to glomerular cell turnover and repair, but the cell types involved are unknown. Whether rat mesenchymal stem cells (MSC) can accelerate recovery from damage in rat mesangioproliferative anti-Thy1.1 glomerulonephritis was studied. After injection into the left renal artery on day 2 after disease induction, fluorescently labeled MSC were detected in 20 to 50% of glomeruli and rare intrarenal vessels but not in the tubulointerstitium, in contralateral kidneys, or in medium controls. In control experiments, injected mesangial cells were detected less frequently in glomeruli in comparison with injected MSC. In nephritic outbred Wistar rats, MSC injection led to an approximately 50% reduction of mesangiolysis on days 4 and 6 after disease induction, accompanied by three- to four-fold higher intraglomerular cell proliferation on day 4 and more rapid mesangial reconstitution as detected by alpha-smooth muscle actin expression. Injection of MSC into tail veins or intra-arterial injection of mesangial cells instead of MSC failed to reproduce any of these findings. In inbred Lewis rats, anti-Thy1.1 nephritis followed an aggravated course with transient acute renal failure. Acute renal failure was ameliorated by MSC injection into the left renal artery on day 2 after disease induction. Again, MSC led to more rapid recovery from mesangiolysis, increased glomerular cell proliferation, and reduction of proteinuria by 28%. Double immunostaining of 5-bromo-2'-deoxyuridine-labeled MSC for endothelial, mesangial, or monocyte/macrophage antigens showed that 85 to 95% of MSC that localized in glomeruli on day 6 failed to express these markers. In vitro, MSC secreted high amounts of vascular endothelial growth factor and TGF-beta1 but not PDGF-BB. In conclusion, even low numbers of MSC can markedly accelerate glomerular recovery from mesangiolytic damage possibly related to paracrine growth factor release and not to differentiation into resident glomerular cell types or monocytes/macrophages.