Clinical use of computational modeling for surgical planning of arteriovenous fistula for hemodialysis.

BACKGROUND: Autogenous arteriovenous fistula (AVF) is the best vascular access (VA) for hemodialysis, but its creation is still a critical procedure. Physical examination, vascular mapping and doppler ultrasound (DUS) evaluation are recommended for AVF planning, but they can not provide direct indication on AVF outcome. We recently developed and validated in a clinical trial a patient-specific computational model to predict pre-operatively the blood flow volume (BFV) in AVF for different surgical configuration on the basis of demographic, clinical and DUS data. In the present investigation we tested power of prediction and usability of the computational model in routine clinical setting. METHODS: We developed a web-based system (AVF.SIM) that integrates the computational model in a single procedure, including data collection and transfer, simulation management and data storage. A usability test on observational data was designed to compare predicted vs. measured BFV and evaluate the acceptance of the system in the clinical setting. Six Italian nephrology units were involved in the evaluation for a 6-month period that included all incident dialysis patients with indication for AVF surgery. RESULTS: Out of the 74 patients, complete data from 60 patients were included in the final dataset. Predicted brachial BFV at 40 days after surgery showed a good correlation with measured values (in average 787 ± 306 vs. 751 ± 267 mL/min, R = 0.81, p < 0.001). For distal AVFs the mean difference (±SD) between predicted vs. measured BFV was -2.0 ± 20.9%, with 50% of predicted values in the range of 86-121% of measured BFV. Feedbacks provided by clinicians indicate that AVF.SIM is easy to use and well accepted in clinical routine, with limited additional workload. CONCLUSIONS: Clinical use of computational modeling for AVF surgical planning can help the surgeon to select the best surgical strategy, reducing AVF early failures and complications. This approach allows individualization of VA care, with the aim to reduce the costs associated with VA dysfunction, and to improve AVF clinical outcome.

Wishful Thinking: The Surprisingly Sparse Evidence for a Relationship between Oxidative Stress and Cardiovascular Disease in Hemodialysis Patients.

The increased frequency of cardiovascular disease observed in hemodialysis patients is secondary to the combination of many traditional (age, male sex, hypertension, smoking, diabetes mellitus, and dyslipidemia) and novel and uremia-related (inflammation, uremic toxins, adipokine imbalance, coagulation disorders, protein-energy wasting, volume overload, endothelial dysfunction, hyperparathyroidism, and subclinical hypothyroidism) risk factors. Usually, in the latter group, oxidative stress is included. However, after decades of research, it remains essentially unknown if oxidative stress has a causative role in the development of cardiovascular disease in long-term hemodialysis patients because adequate longitudinal studies are lacking. Data deriving from cross-sectional studies suggest that biomarkers of oxidative stress are associated with cardiovascular disease prevalence. Conversely, conflicting and inconclusive results have been obtained on the association between oxidative stress and coronary artery calcification, atherosclerosis, and all-cause and cardiovascular disease-related outcome. It is desirable that further studies are conducted on this topic in the near future.

Fatigue is associated with serum interleukin-6 levels and symptoms of depression in patients on chronic hemodialysis.

CONTEXT: Little is known about activated immune-inflammatory pathways and interleukin-6 (IL-6) in the development of fatigue and/or depression in patients with end-stage renal disease on chronic hemodialysis (HD). OBJECTIVES: To evaluate the possible correlation between fatigue and serum levels of IL-6 in patients on chronic HD. METHODS: One hundred HD patients were assessed for the presence of fatigue using the SF-36 Vitality subscale and were administered the Beck Depression Inventory (BDI), the Hamilton Anxiety Rating Scale (HARS), the Mini-Mental State Examination (MMSE), the activities of daily living (ADL), and the instrumental activities of daily living (IADL). We also calculated the time of recovery after hemodialysis (TIRD) and the number/severity of comorbidities using the Charlson Comorbidity Index (CCI). Laboratory parameters were measured as well as serum IL-6. RESULTS: Forty-three patients constituted the fatigued group and 57 the nonfatigued group. Age, CCI, BDI, HARS, and TIRD were significantly higher in fatigued patients than in the nonfatigued patients. Conversely, the scores of ADL, IADL, and MMSE were significantly lower in fatigued than in nonfatigued patients. Serum IL-6 levels (pg/mL) were higher in the fatigued group (5.1 ± 3.4) than in the nonfatigued group (1.6 ± 1.5; P < 0.001); serum albumin and creatinine levels were significantly lower. Twenty-six patients (26%) had no symptoms of depression (BDI score <10), and 74 patients (74%) had symptoms of depression (BDI score >9). Patients with a BDI score >9 were older; had a higher CCI; a lower MMSE; a higher TIRD; lower serum albumin, creatinine, and urea levels; and higher serum IL-6 levels. The correlation analyses showed that the score of the SF-36 Vitality subscale was associated with age, dialytic age, TIRD, ADL, IADL, CCI, BDI, HARS, MMSE, serum urea, creatinine, albumin, and IL-6 levels. On multivariate general linear model analyses, with fatigue as the dependent variable and gender as a second factor, BDI and serum IL-6 levels were independently associated with the score of the SF-36 Vitality subscale. A canonical correlation analysis was performed including in the model fatigue, BDI, and biomarkers; the correlation was 0.679 (R(2) = 0.462). Fatigue, BDI, and IL-6 among biomarkers showed the strongest association with the underlying construct (standardized canonical coefficients = -0.989, 0.015, and 0.852, respectively), thus explaining a correlation of IL-6 with both depression and fatigue. CONCLUSION: Fatigue was significantly associated with symptoms of depression and serum IL-6 levels in patients receiving chronic HD.

Xerostomia is associated with old age and poor appetite in patients on chronic hemodialysis.

OBJECTIVE: The objective of this study was to assess variables associated with xerostomia in patients on chronic hemodialysis (HD). DESIGN AND METHODS: This was a cross-sectional study of 75 HD patients at an outpatient HD service. Demographic, clinical (renal disease, HD regimen/duration, Charlson comorbidity index, activities of daily living, instrumental activities of daily living [IADL], body mass index), and laboratory (hemoglobin, albumin, interleukin-6 [IL-6], and parathyroid hormone) parameters were recorded. We assessed the appetite through the Hemodialysis Study Appetite questionnaire and xerostomia through the Xerostomia Inventory (XI). A single question ("How often does your mouth feel dry?"; never = Class 1, almost never = Class 2, occasionally = Class 3, often = Class 4, very often = Class 5) was also included in the study questionnaire. MAIN OUTCOME MEASURE: The main outcome measure was factors correlated with XI. RESULTS: The median XI score was 18 (min-max = 11-33). Forty patients had an XI score of 18 or less (Group 1) and between 18 and 35 (Group 2). In Group 2, age, Charlson comorbidity index score, and number of patients with poor/very poor appetite were significantly higher. At the univariate analysis, the score of the XI was significantly associated with age, appetite, IADL, Charlson comorbidity index, and serum IL-6 levels. Multiple linear regression analysis showed that the XI was independently associated with age and appetite. Thirty-one patients were in Class 1 to 2, 23 were in Class 3, and 21 were in Class 4 to 5. In Classes 4 to 5, age and the number of patients with poor/very poor appetite were higher (P = .012 and .09, respectively). CONCLUSION: Xerostomia is associated with old age and poor appetite in patients on chronic HD.

Histology and immunohistochemistry of the parathyroid glands in renal secondary hyperparathyroidism refractory to vitamin D or cinacalcet therapy.

BACKGROUND: Cinacalcet is a new effective treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients (HP), but the alterations of parathyroid gland (PTG) hyperplasia determined by cinacalcet and vitamin D have not been extensively investigated in humans. METHODS: We performed histological analyses of 94 PTGs removed from 25 HP who underwent parathyroidectomy (PTx) because of SHPT refractory to therapy with vitamin D alone (group A=13 HP and 46 PTGs) or associated with cinacalcet (group B=12 HP and 48 PTGs). The number, weight, the macroscopic cystic/hemorrhagic changes, and type of hyperplasia of PTG (nodular=NH, diffuse=DH) were assessed. In randomly selected HP of group A (4 HP and 14 PTGs) and group B (4 HP and 15 PTGs), the labeling index of cells positive to Ki-67 and TUNEL and the semiquantitative score of immunohistochemistry staining of vitamin D receptor, calcium-sensing receptor, and vascular endothelial growth factor-α (VEGF-α) were measured in the entire PTGs and in the areas with DH or NH. RESULTS: The number and weight of single and total PTG of each HP were similar in the two groups as well as the number of PTG with macroscopic cystic/hemorrhagic areas. TUNEL, Ki-67, and VEGF-α scores were higher in NH than in DH areas. CONCLUSION: This observational study of a highly selected population of HP, submitted to PTx because SHPT refractory to therapy, shows that the macroscopic, microscopic, and immunochemistry characteristics of PTG in HP who received or did not receive cinacalcet before PTx did not differ significantly.

P-selectin, E-selectin, and CD40L over time in chronic hemodialysis patients.

The aim of this study was to measure P-selectin, E-selectin, and CD-4L levels over time in chronic hemodialysis (HD) patients. Thirty stable patients with end-stage renal failure undergoing chronic HD were included in the study. Blood samples were obtained before HD for measurement of P-selectin, E-selectin, and CD-40L. Measurements were performed at month 0 (T0), 3 (T2), 8 (T3), and 13 (T4). The levels of P-selectin, E-selectin, and CD40L were also analyzed according to the occurrence of cardiovascular disease (CVD) and to CVD-related mortality. The levels of CD40L and P-selectin changed significantly over time, decreasing at month 3 and 6 and returning at the T0 levels at month 13. Conversely, E-selectin levels did not. The levels of CD40L, P-selectin and E-selectin over time did not differ significantly between patients with age ≤ 65 or > 65 years, between patients with or without CVD, or between patients who died or who survived during the follow-up. In end-stage renal failure patients undergoing chronic HD, CD40L and P-selectin, but not E-selectin, showed a transient decrease over time, and the serum levels of these molecules were not associated with CVD or with CVD-related mortality.

Anorexia, fatigue, and plasma interleukin-6 levels in chronic hemodialysis patients.

This study aimed at evaluating the possible relationship between anorexia and fatigue in hemodialysis (HD) patients and at measuring the plasma levels of interleukin-6 (IL-6) and C-reactive protein (CRP) in HD patients with or without anorexia and/or fatigue. The first question of the Hemodialysis Study Appetite questionnaire was used to assess the appetite of the HD patients and the vitality scale of the SF-36 to assess fatigue. The Charlson Comorbidity Index was assessed in each patient. Seventy-six HD patients were studied. Forty-four were males and 32 females. Thirty-two were classified as not-anorexic and not-fatigued, 12 as not-anorexic but fatigued, 6 as anorexic and not-fatigued, and 26 as anorexic and fatigued. Plasma IL-6 levels (pg/mL) were significantly higher in anorexic and fatigued patients (10.9 ± 11.9) than in not-anorexic and not-fatigued (1.6 ± 0.6) (p < 0.001) and in anorexic but not-fatigued patients (1.8 ± 1.7) (p < 0.01). With respect to not-anorexic but fatigued patients (3.1 ± 1.5), the difference was not statistically significant (p = 0.058). The plasma CRP levels (mg/dL) also were significantly higher in anorexic and fatigued patients (9.2 ± 6.3) than in not-anorexic and not-fatigued patients (4.1 ± 4.5), in anorexic but not-fatigued patients (2.5 ± 1.6), and in not-anorexic but fatigued patients (4.1 ± 4.4) (p = 0.001). The presence of both anorexia and fatigue in chronic HD patients is associated with significantly higher levels of plasma IL-6 and CRP and a higher frequency of comorbidities.

Fatigue and its correlates in chronic hemodialysis patients.

BACKGROUND: The present study aimed at evaluating the possible correlation between fatigue and demographic, clinical and laboratory variables in chronic HD patients. METHODS: Sixty-two chronic HD patients were assessed for the presence of fatigue through the SF-36 Vitality subscale and were administered the Beck Depression Inventory (BDI), the Hamilton Anxiety Rating Scale (HARS), and the Mini-Mental State Examination. In all, the number/severity of comorbidities was assessed through the Charlson Comorbidity Index and laboratory parameters were measured. RESULTS: Correlations among the SF-36 Vitality subscale and age, dialytic age, BDI, HARS and the Charlson Comorbidity Index were statistically significant. Correlations between the SF-36 vitality score and the serum creatinine, albumin and IL-6 levels were also significant. Twenty-six and 36 patients constituted the fatigued and nonfatigued groups, respectively. The age and the scores of the Charlson Comorbidity Index, BDI and HARS of fatigued patients were significantly higher than those of nonfatigued subjects. Serum IL-6 levels were significantly higher in the fatigued than in the nonfatigued group, whereas serum albumin and creatinine levels were significantly lower. CONCLUSIONS: We found that depression, anxiety, number and severity of comorbidities and IL-6 levels are significantly correlated with fatigue in end-stage renal disease patients receiving chronic hemodialysis.

Circulating bacterial-derived DNA fragments and markers of inflammation in chronic hemodialysis patients.

BACKGROUND AND OBJECTIVES: Bacterial-derived DNA fragments (BDNAs) have been shown to be present in dialysis fluid, to pass through dialyzer membranes, and to induce IL-6 (IL-6) in mononuclear cells. The present study aimed at assessing the eventual presence of BDNAs in the blood of hemodialysis (HD) patients and if this is associated with markers of chronic inflammation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-eight HD patients and 30 controls were included in the study. A blood sample was collected from a peripheral vein and from the central venous catheter (CVC) or the arteriovenous fistula (AVF) and examined for presence of BDNAs by 16S rRNA gene PCR amplification, bacterial growth, and measurement of C-reactive protein and IL-6. Thirty minutes after the start of HD, a sample of dialysis fluid was collected before the entry into and at the exit of the dialyzer and examined for presence of BDNAs. RESULTS: Controls had negative blood cultures and absence of blood BDNAs. All HD patients had negative blood cultures, but in 12 (20.7%), BDNAs were present in the whole blood. In five of the latter, BDNAs were also found in the dialysis fluid. C-reactive protein serum levels (mg/L) were significantly higher in patients with than in those without BDNAs. Likewise, IL-6 serum levels (pg/ml) were significantly higher in patients with BDNA than in those without. CONCLUSIONS: Circulating BDNAs are associated with higher levels of C-reactive protein and IL-6 in HD patients.

Mechanisms and treatment of anorexia in end-stage renal disease patients on hemodialysis.

Anorexia, defined as the loss of the desire to eat, is relatively common in hemodialysis patients, occurring in one third of such cases. The pathogenesis is essentially unknown. It has been proposed that uremic toxins such as middle molecules, inflammation, altered amino acid pattern, leptin, ghrelin, and neuropeptide Y are involved. Anorexia reduces oral energy and protein intakes, thus contributing to the development of malnutrition and cachexia. Unquestionably, it contributes to poor quality of life. The clinical relevance of anorexia as an independent prognostic factor in hemodialysis is debated. The treatment of this debilitating condition is based on a therapeutic strategy that may include daily dialysis sessions and nutritional counseling. Normalization of plasma branched chain amino acids through branched chain amino acid supplementation may decrease anorexia and improve energy and protein intake. The role of megestrol acetate as an appetite stimulant needs to be validated through adequate randomized trials. Subcutaneous ghrelin administration and melanocortin-receptor antagonists appear to be promising therapeutic interventions.

Body mass index and cardiovascular risk factors and biomarkers in hemodialysis patients.

BACKGROUND: Being overweight and obesity are associated with improved survival in hemodialysis (HD) patients, based on mechanisms that are presently uncertain. We compared traditional and uremia-related cardiovascular risk factors in HD patients stratified according to their body mass index (BMI). METHODS: One hundred sixteen HD patients were stratified into 4 groups according to the BMI: underweight (<18.5), normal weight (18.5-24.9), overweight (25.0-29.9) and obese (> or =30). Blood samples were obtained before the HD session to measure serum albumin, high-sensitivity C-reactive protein, fibrinogen, ferritin, total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein A-I and apolipoprotein B-100, apolipoprotein B (apoB) to apolipoprotein A (apoA) ratio and Lp(a) lipoprotein. RESULTS: There were 3 underweight (excluded from the analysis), 58 normal weight, 35 overweight and 20 obese patients. Their mean age was 62.1 +/- 14.1 years. There were 68 men and 45 women. Mean dialytic age was 5.32 +/- 3.2 years. The mean BMI of the study population was 25.2 +/- 4.1. The prevalence of smoking habit was similar in the 3 groups (17.2%, 8.5% and 25%, respectively; p=0.28). The prevalence of hypertension was higher in overweight (77.1%) and obese (65%) patients than in leaner counterparts (53.4%), although the difference was not significant. Conversely, diabetes prevalence was significantly higher in overweight and obese patients (22.8% and 30%, respectively) than in normal weight patients (6.9%; p=0.02). The serum levels of total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a) lipoprotein, apolipoprotein A-I, apolipoprotein B-100, and apoA/apoB ratio were similar in the 3 BMI groups. Triglycerides levels were significantly higher in obese (221.2 +/- 132.7 mg/dL) and overweight (230.5 +/- 119.3 mg/dL) patients than in those of normal weight (154.6 +/- 78.8 mg/dL; p=0.02). Most of the uremia-related cardiovascular risk factors (anemia, hyperparathyroidism, chronic inflammation) were comparable among BMI categories as well as the levels of C-reactive protein, fibrinogen and ferritin. CONCLUSION: The present study suggests that almost all traditional and uremia-related cardiovascular risk factors do not differ significantly among different categories of BMI in hemodialysis patients.

Reticulocyte hemoglobin equivalent: an indicator of reduced iron availability in chronic kidney diseases during erythropoietin therapy.

Anemia is a common complication of chronic kidney disease (CKD), particularly in dialysis patients. Correction of anemia in CKD patients includes the administration of both recombinant human erythropoietin and intravenous iron. An optimization of iron treatment requires obtaining a target hemoglobin level and avoiding an excessive body-iron overload. The reticulocyte hemoglobin content (CHr) has been shown to be an early indicator of iron-restricted erythropoiesis. The recent European guidelines for anemia treatment in CKD assessed the value for CHr >29 pg/cell as the reticulocyte parameter to evaluate a patient's iron needs. The reticulocyte hemoglobin equivalent (RET-He), recently introduced to determine the forward scatter of fluorescence-labeled reticulocytes, seems to be a sensitive indicator of iron-deficiency anemia. This study evaluates the concordance between the CHr parameter, used as a reference, and the new RET-He in a cohort of 57 dialysis patients referred to the Nephrology Unit of our hospital. All patients received erythropoietin, and iron was administered intravenously to maintain the hemoglobin level between 10 and 12 mg/dL. A total of 285 determinations were performed with both instruments. In the dialysis population, the 95% central range for CHr of 24.8 to 36.3 pg corresponds to a range for RET-He of 23.3 to 40.1 pg, with a mean bias of 1.12 pg between the 2 parameters. In comparison with CHr, the value of 30.5 pg for RET-He appeared to be the best cut-off point with a very good sensitivity and specificity to determine patients needing iron supplementation. Our study showed an excellent diagnostic efficiency of RET-He to evaluate patients needing iron support and demonstrated a strict correspondence between the classic CHr and the new Ret-He. This correspondence was independent of clinical changes, frequently occurring in dialysis patients. Both parameters could be used soon to guide and monitor iron treatment in dialysis patients.

Parathyroid carcinoma in a chronic hemodialysis patient: case report and review of the literature.

Parathyroid carcinoma is a rare disease in normal population as well as in patients with end-stage renal disease. Approximately 700 cases have been reported and, of these, 20 occurred in patients receiving chronic hemodialysis. We describe a case of parathyroid carcinoma in a 59-year-old female patient with end-stage renal disease secondary to membranous glomerulonephritis treated by hemodialysis since 1995. In September 1998, the calcium level was 12.4 mg/dl and intact parathyroid hormone serum levels were 1366 pg/ml (normal range, 25-65). A routine ultrasonographic examination of the neck revealed enlargement of two parathyroid glands, the left inferior gland being the largest and measuring 2x3x2 cm. In October 1998, resection of two parathyroid glands was performed. On the basis of histology, which documented the presence of proliferating cells arranged in sheets or in a trabecular pattern, numerous mitosis and vascular invasion, a diagnosis of parathyroid carcinoma was made.

Muscle ubiquitin m-rNA levels in patients with end-stage renal disease on maintenance hemodialysis.

BACKGROUND: Loss of lean body mass is frequently reported in patients with end-stage renal disease (ES-RD). Inadequate nutrient intake, superimposed illnesses, endocrine disorders, uremia and acidosis are some of the potential causes of muscle depletion. Previous reports on experimental models show that lean body mass depletion results from enhancement of muscle tissue protein catabolism, mainly associated with activation of ATP-ubiquitin-dependent proteolysis. Little is known, however, about the affects on this proteolytic system in ESRD patients on maintenance hemodialysis (HD). The present study was designed to investigate the expression of ubiquitin mRNAs in skeletal muscle of patients with ESRD on maintenance HD. METHODS: Biopsies from the rectus abdominis muscle were obtained from eight ESRD patients and from six control subjects undergoing surgery for benign disease. Ubiquitin mRNA levels were measured by Northern blotting analysis. RESULTS: Patients with ESRD had mild metabolic acidosis, as a result of chronic intermittent HD. There were no significant differences between HD patients and controls with regard to the 1.2kb polyubiquitin mRNA species (332.9+/-139 vs 324.2+/-60; ns), but the levels of the 2.4 kb mRNA species were significantly lower in HD patients than in controls (1687+/-542 vs 2529.9+/-325, p=0.01). No correlation was observed between ubiquitin mRNA levels and nutritional parameters and degree of acidosis. CONCLUSIONS: The present study found that the ubiquitin mRNA levels were not increased in the muscle of stable, mildly acidotic hemodialysis patients.