Endothelial dysfunction in hemodialysis patients with failed renal transplants

Gorgulu N, Yelken B, Caliskan Y, Elitok A, Cimen AO, Yazici H, Oflaz H, Golcuk E, Ekmekci A, Turkmen A, Yildiz A, Sever MS. Endothelial dysfunction in hemodialysis patients with failed renal transplants.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01160.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Endothelial dysfunction (ED) is a common precursor and denominator of cardiovascular events including development of atherosclerosis. In this cross‐sectional study, we aimed to investigate ED, measured by coronary flow reserve (CFR) in hemodialysis (nHD) patients who were never transplanted and patients with failed renal transplants restarting hemodialysis (fTx‐HD). Methods: Forty nHD (24 males, mean age 39 ± 9 yr) and 43 fTx‐HD patients (27 males, mean age 36 ± 9 yr) were included in the study. Clinical and biochemical parameters, including high‐sensitive C‐reactive protein (hs‐CRP) levels were determined. Also, CFR measurements were used to evaluate ED. Results: There were no significant differences regarding age, gender, smoking status, systolic and diastolic blood pressure levels, mean duration of HD treatment as well as Kt/V_(urea) values between the two groups. Time spent on dialysis in the nHD group and dialysis duration following failure of renal allograft in the fTx‐HD group were similar. Serum creatinine, hemoglobin, hematocrit, calcium and phosphorus levels were similar between the two groups as well. When compared to nHD group, serum total cholesterol (139 ± 3 vs. 154 ± 3 mg/dL, p = 0.045), serum albumin (3.8 ± 0.3 g/dL vs. 4.1 ± 0.2 g/dL, p < 0.0001) and CFR (1.60 ± 0.2 vs. 1.75 ± 0.3, p = 0.028) levels were significantly lower, while serum hs‐CRP levels (11 ± 15 mg/L vs. 3 ± 4 mg/L, p = 0.001) were significantly higher in the fTx‐HD group. Serum hs‐CRP negatively correlated (r = ?0254, p = 0.021), while serum albumin positively correlated (r = 0402, p = 0.001) with CFR values. Conclusion: ED is more prominent in fTx‐HD than the nHD patients. Inflammation, caused by failed renal allograft can be responsible for this abnormality.     

The Association between Serum Adiponectin Levels and Nutritional Status of Hemodialysis Patients

Adiponectin plays an important role in the regulation of body weight, insulin sensitivity, lipid metabolism, and the inflammatory response. Adiponectin is elevated in hemodialysis patients. We investigated the association between altered serum adiponectin levels and the nutritional–inflammation status of hemodialysis patients. Forty-four hemodialysis patients (21 men and 23 women; mean age 53.9 ± 9.2 years) were enrolled and 32 healthy volunteers were included as the control group. Serum adiponectin was measured using a commercial radioimmunoassay kit. Serum albumin, cholesterol, triglyceride, high-sensitivity C-reactive protein, urea, creatinine, transferrin, lean body mass, fat mass, body mass index (BMI), the subjective global assessment (SGA) score, and the malnutrition–inflammation score (MIS) were measured in all patients. Adiponectin levels were significantly elevated in the hemodialysis patients compared with the healthy subjects (24.8 ± 10.4 μg/mL and 6.8 ± 4.2 μg/mL, respectively, p < 0.0001). Serum adiponectin correlated positively with SGA (r = 0.47) and MIS (r = 0.38), and negatively with BMI (r = ?0.34), triglyceride (r = ?0.53), and glucose levels (r = ?0.42). Serum adiponectin levels were significantly higher in malnourished patients than in well-nourished patients when assessed with SGA (20.5 ± 10.4 μg/mL and 29.0 ± 8.7 μg/mL, respectively, p = 0.005). In conclusion, serum adiponectin levels reflect the nutritional–inflammation status of hemodialysis patients. Adiponectin may also be associated with insulin resistance, dyslipidemia, and the inflammatory response in these patients.     

Beneficial effect of atorvastatin on erythropoietin responsiveness in maintenance haemodialysis patients

Aim: To evaluate the effect of atorvastatin on erythropoietin responsiveness and whether this effect is mediated by C‐reactive protein (CRP) reduction in prevalent dyslipidemic, haemodialysis patients. Methods: We studied prospectively 33 stable, iron‐repleted haemodialysis patients with low‐density lipoprotein cholesterol (LDL) ≥2.58 mmol/L, who received 20 mg atorvastatin aiming to achieve the target of LDL <2.58 mmol/L, over a period of 9 months. Twenty‐five patients completed the study, 15 men, with mean age 66.1 ± 8.2 years. The duration of haemodialysis was 56.6 ± 63.1 months and 5/25 patients were diabetics. Total serum cholesterol, triglycerides, high‐density lipoprotein cholesterol, LDL, haemoglobin, albumin, intact parathyroid hormone, serum iron, ferritin, total iron binding capacity, CRP and weekly dose of erythropoietin/body weight/haemoglobin were analysed. Results: Twenty of the 25 patients (80%) achieved the goal of LDL <2.58 mmol/L. There was a significant decrease in total cholesterol (5.77 ± 0.88 to 4.16 ± 0.96 mmol/L, P < 0.001) and LDL (3.59 ± 0.77 to 1.94 ± 0.77 mmol/L, P < 0.001). Haemoglobin increased from 121 ± 11 to 126 ± 7 g/L (P < 0.05), while weekly dose of erythropoietin/body weight/haemoglobin decreased significantly from 8.34 ± 3.70 to 7.87 ± 3.11 IU/kg per haemoglobin (P < 0.05). CRP decreased not significantly from 7.0 ± 6.1 to 4.5 ± 2.2 mg/L. Conclusion: Dyslipidemia of haemodialysis patients was treated safely and effectively with atorvastatin, but a fifth of the patients failed to achieve the therapeutic target. Statin therapy resulted in a significant increase of haemoglobin levels and improvement of erythropoietin responsiveness without a significant reduction in CRP levels, suggesting that the beneficial effect of statins on erythropoietin responsiveness may be driven by a mechanism other than CRP reduction.     

Reduced Plasma Zinc Levels,Lipid Peroxidation,and Inflammation Biomarkers Levels in Hemodialysis Patients: Implications to Cardiovascular Mortality

Despite the fact that low plasma zinc (Zn) levels play important roles in the oxidative stress, the relationships between lipid peroxidation and inflammation biomarkers with low plasma Zn levels have not been investigated in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the Zn plasma levels, electronegative LDL [LDL(–)] levels, and inflammation markers as predictors of cardiovascular (CV) mortality in hemodialysis (HD) patients. Forty-five HD patients (28 men, 54.2 ± 12.7 years, 62.2 ± 51.4 months on dialysis and BMI 24.3 ± 4.1 kg/m²) were studied and compared to 20 healthy individuals (9 men, 51.6 ± 15.6 years, BMI 25.2 ± 3.9 kg/m²) and followed for 24 months to investigate the risks for CV mortality. LDL(–) levels were measured by ELISA, plasma Zn levels by atomic absorption spectrophotometry, C-reactive protein (CRP) level by immunoturbidimetric method, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) levels by a multiplex assay kit. HD patients presented low plasma Zn levels (54.9 ± 16.1 μg/dL) and high-LDL(–) (0.18 ± 0.12 U/L) and TNF-α (5.5 ± 2.2 pg/mL) levels when compared to healthy subjects (78.8 ± 9.4μ g/dL, 0.10 ± 0.08U/L, 2.4 ± 1.1 pg/mL, respectively, p < 0.05). Zn plasma levels were negatively correlated to TNF-α (r = –0.49; p = 0.0001) and LDL(–) (r = –0.33; p = 0.008). During the 2 years, 24.4% of the patients died, all due to CV disease. Analysis by the Cox model showed that high CRP, TNF-α, IL-6 levels, and long duration of HD were significant predictors of mortality. In conclusion, reduced Zn levels were associated with lipid peroxidation and inflammation, and we confirm here in a Brazilian cohort of HD patients that inflammation markers are strong predictors of CV death.     

Donkey Pericardium as an Alternative Bioprosthetic Heart Valve Material

This study comparatively evaluates the characteristics of glutaraldehyde‐treated acellular bovine and donkey pericardium using histological and electronic microscopic observation techniques, shrinkage temperature, and mechanical properties, as well as determining calcium and phosphorus content at 4 and 8 weeks after the subcutaneous implantation of donkey and bovine pericardium in Wistar rats. Donkey pericardium was significantly thinner compared with bovine pericardium (1.622 ± 0.161 mm vs. 4.027 ± 0.401 mm, P < 0.0001) and was associated with significantly greater tensile strength (14.21 ± 3.81 MPa vs. 3.78 ± 1.20 MPa, P = 0.001) and elastic modulus (81.67 ± 20.41 MPa vs. 21.67 ± 11.69 MPa, P < 0.0001) over bovine pericardium. Shrinkage temperature of donkey pericardium was similar to that of bovine pericardium (87.43 ± 0.55°C vs. 87.50 ± 0.36°C, P = 0.810). No differences between groups were observed for maximum load (donkey: 21.64 ± 7.02 KN/m vs. bovine: 15.05 ± 4.50 KN/m, P = 0.082) and tear strength (donkey: 11.54 ± 5.33 MPa vs. bovine: 10.69 ± 3.77 MPa, P = 0.757). Calcium content was significantly lower in donkey pericardium compared with bovine pericardium at 4 weeks (690.15 ± 191.27 µg/g vs. 1381.73 ± 62.52 µg/g, P = 0.001) and 8 weeks (205.24 ± 62.40 µg/g vs. 910.48 ± 398.29 µg/g, P = 0.037). This preliminary study has confirmed that glutaraldehyde‐tanned donkey pericardium, demonstrating reduced calcification and increased tensile strength, may provide a suitable bioprosthetic valve substitute.     

Pentoxifylline improves haemoglobin and interleukin‐6 levels in chronic kidney disease

Aim: To assess whether pentoxifylline improves anaemia of chronic kidney disease (CKD) via suppression of interleukin‐6 (IL‐6) and improved iron mobilization. Background: CKD patients may have elevated IL‐6 and tumour necrosis factor alpha levels. These cytokines can increase hepcidin production, which in turn reduces iron release from macrophages resulting in reduced availability of iron for erythropoiesis. In experimental models, pentoxifylline was shown to reduce IL‐6 expression. Methods: We studied 14 patients with stages 4–5 CKD (glomerular filtration rate <30mL/min per 1.73 m²) due to non‐inflammatory renal diseases. None of the patients had received immunosuppressive or erythropoietin‐stimulating agents or parenteral iron. Patients had weekly blood tests for iron studies and cytokines during a control run‐in period of 3 weeks and during 4 weeks of pentoxifylline treatment. Results: Ten patients (eGFR 23 ± 6 mL/min) completed the study. At the end of the run‐in period average haemoglobin was 111 ± 5 g/L, ferritin 92 ± 26 µg/L, transferrin saturation 15 ± 3% and circulating IL‐6 10.6 ± 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL‐6 (6.6 ± 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 ± 5%, P < 0.003) and decreased serum ferritin (81 ± 25 µg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 ± 6 g/L by week 4 (P < 0.001). Conclusions: Pentoxifylline reduces circulating IL‐6 and improves haemoglobin in non‐inflammatory moderate to severe CKD. These changes are associated with changes in circulating transferrin saturation and ferritin, suggesting improved iron release. It is hypothesized that pentoxifylline improves iron disposition possibly through modulation of hepcidin.     

Impact of Dry Weight Determined by Calf Bioimpedance Ratio on Carotid Stiffness and Left Ventricular Hypertrophy in Hemodialysis Patients

Our previous study has shown that modification of bioimpedance technique by the measurement of bioimpedance ratio in the calf (calf‐BR) was a simple and practical method in assessing fluid status in hemodialysis patients. However, the consequences of periodical dry weight (DW) adjustment under the guidance of calf‐BR on target organ damage have not been investigated. One hundred fifteen hemodialysis patients were enrolled in this pilot trial. Patients were divided into bioimpedance group and control group according to their dialysis schedule. In the bioimpedance group, DW was routinely adjusted under the guidance of calf‐BR every 3 months. In the control group, the assessment of DW remained a clinical judgment. Carotid stiffness, left ventricular mass index (LVMI), and calf‐BR were measured at baseline and at the 12th month in both groups. Home blood pressure (BP) was monitored monthly. Episodes of dialysis‐related adverse events were recorded. No significant differences were observed in parameters between the two groups at baseline. Compared with the control group, the bioimpedance group had significantly lower values in terms of the annual averages of systolic home BP (147.4 ± 15.3 mm Hg vs. 152.6 ± 16.9 mm Hg, P = 0.019), carotid stiffness index β (10.7 ± 3.3 vs. 12.2 ± 3.1, P = 0.003), LVMI (155.21 ± 15.64 g/m² vs. 165.17 ± 16.76 g/m², P < 0.001), and the percentage of individuals with calf‐BR over target range (P = 0.040) at month 12, with less annual averages of antihypertensive medications used and lower frequency of intradialytic hypotension, muscle cramps, or clotted angioaccess. Continued DW control achieved by periodical calf‐BR measurement improved arterial stiffness and left ventricular hypertrophy with good tolerability in hemodialysis patients.     

Vitamin D deficiency, CD4+CD28null cells and accelerated atherosclerosis in chronic kidney disease

Aim: Cardiovascular disease (CVD) is the leading cause of death among chronic kidney disease (CKD) patients. The role of vitamin D remains controversial in this process. We evaluated the relationship between 25‐hydroxyvitamin D, abnormal T helper cells (CD4+CD28null cells), systemic inflammation and atherosclerosis in CKD patients. Methods: A total of 101 stage 4–5 non‐dialysis CKD patients and 40 healthy controls were studied. Common carotid artery intima media thickness (CCA‐IMT) was measured with an ultrasound system. 25(OH) vitamin D and highly sensitive C‐reactive protein (hsCRP) were measured in serum by enzyme linked immunosorbent assay. The frequency of circulating CD4+CD28null cells was evaluated by flowcytometry. Results: CKD subjects exhibited higher CCA‐IMT (0.71 ± 0.01 vs 0.56 ± 0.01 mm, P < 0.0001), hsCRP (90.7 ± 5.8 vs 50.1 ± 8.6 µg/mL, P < 0.0001), CD4+CD28null cell frequency (9.1 ± 0.9 vs 3.6 ± 0.5%, P < 0.0001) and lower 25(OH) vitamin D levels (17.9 ± 1.9 vs 26.9 ± 3.5 ng/mL, P < 0.0001). In CKD subjects, serum 25 (OH) vitamin D level showed a strong inverse correlation with CCA‐IMT (r = ?0.729, P < 0.0001) and correlated with CD4+CD28null cell frequency (r = ?0.249, P = 0.01) and hsCRP (r = ?0.2, P = 0.047). We also noted correlation of IMT with patient age (r = 0.291, P = 0.004) and CD4+CD28null cells (r = 0.34, P = 0.001). On multiple regression analysis, 25(OH) vitamin D level, diabetic status and CD4+CD28null cell frequency exhibited independent association with IMT in CKD subjects. Conclusions: Vitamin D deficiency, inflammatory activation and higher frequency of CD4+CD28null T lymphocyte population correlate with preclinical atherosclerotic changes in CKD population. These findings suggest possible linkage between vitamin D metabolism and T cell modulation – abnormalities that may contribute to development of atherosclerosis in CKD.     

Efficacy of low‐dose i.v. iron therapy in haemodialysis patients

Aim: i.v. iron therapy is more effective in maintaining adequate iron status in haemodialysis (HD) patients than oral iron therapy (OIT). However, data on lower doses of i.v. iron therapy are insufficient. Methods: A non‐randomized, open‐label study was performed to compare the efficacy of low‐dose (≤50 mg/week of iron sucrose) i.v. iron therapy (LD‐IVIT) with OIT in HD patients with 100–800 µg/L serum ferritin levels over 4 months. Results: Eighty‐nine patients in the LD‐IVIT group (40 men, 49 women; aged 61 ± 13 years) and 30 patients in the oral iron therapy group (17 men, 13 women; aged 59 ± 7 years) were evaluated. After 4 months of each treatment, serum ferritin levels increased from 398 ± 137 to 529 ± 234 µg/L in the LD‐IVIT group (P < 0.01) but decreased from 351 ± 190 to 294 ± 175 µg/L in the OIT group (P < 0.01). In the LD‐IVIT group, transferrin saturation (from 28% ± 11% to 30% ± 14%, P = 0.49), weekly doses of recombinant human erythropoietin (from 5822 ± 2354 to 5636 ± 2306 IU/week, P = 0.48) and haemoglobin (from 101 ± 9 to 103 ± 9 g/L, P = 0.15) levels remained stable. Conclusion: LD‐IVIT may be one of the regimens that may be considered for maintaining iron status in HD patients. However, efficacy of LD‐IVIT should be verified by further randomized study.     

Dialysis and Patient Factors Which Determine Convective Volume Exchange in Patients Treated by Postdilution Online Hemodiafiltration

Recent reports suggest a survival advantage for dialysis patients treated by postdilutional online hemodiafiltration (OL‐HDF) who achieve higher volume convective exchanges. As such, the factors associated with achieving higher convective volume exchange were determined. The convective exchange volumes during the midweek OL‐HDF session in a cohort of 653 patients with corresponding bio‐impedance measurements of volume status and sessional electronic records were audited. Mean patient age was 64.9 ± 14.9 years, 65.3% male, 47.7% diabetes, with 81.6% dialyzing using fistula access. Sessional substitution volume exchanged was 17.0 ± 3.5 L (83.8 ± 13.9 mL/min), with a filtration fraction of 23.3 ± 4.6%, sessional time of 3.8 ± 0.5 h, and blood flow 321 ± 28 mL/min. As expected, convection exchange volume achieved was associated with sessional time (β 3.24, P < 0.001), blood flow (β 0.03, P < 0.001), dialysate flow (β 0.03, P < 0.001), but also patient factors: postsessional intracellular water (ICW) (β 0.07, P = 0.002), and serum albumin (β 0.71, P = 0.011). In addition convective exchange was lower for diabetics (16.6 ± 3.0 vs. 17.3 ± 3.8 L, P < 0.01), and for patients with higher Davies co‐morbidity grades ( 16.6 ± 2.8 vs. 17.0 ± 3.6 vs. 17.9 ± 4.0 L), P = 0.01 respectively. As expected the convective volume exchanged with OL‐HDF was associated with sessional time and blood and dialysate flows. However, the convective volume exchange achieved was also associated with patient factors, including ICW, which is related to body cell mass and also co‐morbidity. Although some center practices can be modified to increase convective exchange, patient factors are not so readily remediable. As such, highly comorbid patients may not be able to achieve the higher volume convective exchanges reported to be associated with improved patient survival.     

Association between pentosidine and arteriosclerosis in patients receiving hemodialysis

Background It has been suggested that advanced glycation endproducts (AGEs) accumulate in arteriosclerotic lesions, playing an important role in the development and progression of arteriosclerosis. A chemical quantification method using high-performance liquid chromatography (HPLC) has been established to determine pentosidine levels in these products. Some studies reported that the abdominal aorta calcification index (ACI), obtained by computed tomography (CT), was useful for noninvasively diagnosing arteriosclerosis and determining its severity. In the present study, we measured the ACI and plasma pentosidine in patients receiving maintenance hemodialysis, and investigated the association between arteriosclerosis and pentosidine.Methods In 73 patients receiving maintenance hemodialysis (43 men; 30 women), we determined the ACI, and investigated the association of the ACI with plasma total pentosidine, total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, serum creatinine, and parathyroid hormone (PTH), as well as the product of serum calcium and serum phosphorus, duration of dialysis, and age.Results The ACI did not correlate with total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, serum creatinine, PTH, or the product of serum calcium and serum phosphorus. Age, duration of dialysis, and plasma total pentosidine correlated with the ACI: (y = –33.12 + 0.913x; r = 0.407; P 0.01), (y = 13.94 + 0.403x; r = 0.488; P 0.01), and (y = 14.13 + 0.630x; r = 0.365; P 0.01), respectively.Conclusions It is suggested that pentosidine may be associated with arteriosclerotic development in hemodialysis patients.     

Influence of Hemodialysis Procedure on HCV RNA Detection in Serum and Peripheral Blood Mononuclear Cells

Aim. To assess whether hemodialysis procedure induces qualitative or quantitative changes in hepatitis C virus (HCV) RNA. Methods. We obtained blood samples in the 10 HCV RNA‐positive patients of our hemodialysis unit before (sample I) and 5 min after a dialysis session (sample II), and before the next dialysis session (sample III). HCV RNA was tested by PCR in serum and peripheral blood mononuclear cells (PBMC). Serum viral load was measured by branched‐DNA assay. Results. Serum HCV RNA was positive in samples I, II and III of the 10 patients. PBMC HCV RNA was detected in samples I, II and III of seven patients. Mean viral load was 1.43 ± 0.99 Meq genome/mL in sample I, 0.86 ± 0.40 Meq genome/mL in sample II and 1.27 ± 0.56 Meq genome/mL in sample III. Conclusions. HCV load was low in most HCV RNA‐positive patients. It had a downward trend during dialysis procedure but HCV RNA remained detectable in all serum samples and in most PBMC samples. Therefore, qualitative HCV RNA seems to be better than viral load to assess HCV infection in hemodialysis patients.     

Albumin dialysis without anticoagulation in high-risk patients: an observational study

Severe liver failure causes coagulopathy and high bleeding risk. Albumin dialysis with Molecular Adsorbent Recirculating System (MARS) (Gambro, Lund, Sweden) is useful for treatment. However, anticoagulation during its use is of uncertain value. We omitted heparin‐saline priming and intradialytic heparin and examined its effects. Albumin dialysis was performed in critically ill patients with intermittent circuit saline flushes (2664 ± 2420 mL per treatment). A total of 12 patients (M : F = 10:2; age 49 ± 9 years) were thus treated: 6 for fulminant hepatic failure and 6 for acute‐on‐chronic liver failure. The overall hospitalization duration was 31 ± 30 days. A total of 44 treatment sessions were performed (average 8 ± 7 sessions per patient). Prescribed versus achieved MARS duration were 13 ± 3 versus 11 ± 4 h, P < 0.05. Twenty‐three percent (10/44) of MARS sessions clotted, 11% (5/44) of treatments were electively terminated, and 2% (1/44) developed vascular catheter occlusion. Spontaneous bleeding occurred in 9% (4/44). Pre‐ versus post‐MARS systemic and blood circuit transmembrane pressures (mm Hg), and albumin dialysate afferent and efferent pressures were all stable. Coagulation indices were (pre‐ vs. post‐MARS): (i) prothrombin time (seconds): 36 ± 30 versus 42 ± 33, P = 0.143; (ii) activated partial thromboplastin time (seconds): 78 ± 43 versus 88 ± 45, P = 0.117; and (iii) platelet count (×10³/µL): 87 ± 40 versus 76 ± 48, P = 0.004. Systemic blood solute concentrations pre‐ versus post‐MARS were: (i) serum urea (mg/dL): 22.4 ± 19.6 versus 14.0 ± 8.4, P < 0.05; (ii) serum creatinine (mg/dL): 2.8 ± 2.3 versus 1.9 ± 1.5, P < 0.05; (iii) total bilirubin (mg/dL): 29.5 ± 8.8 versus 20.5 ± 5.1, P < 0.05; and (iv) plasma ammonia (µg/dL): 186 ± 85 versus 129 ± 66, P < 0.05. Anticoagulant‐free albumin dialysis remained effective despite frequent circuit clotting. This led to significant exacerbation of thrombocytopenia although bleeding risk remained low.     

Serum α1-Antitrypsin But Not Complement C3 and C4 Predicts Chronic Inflammation in Hemodialysis Patients

Background.?We studied whether predialysis serum levels of positive acute phase markers such as α₁-antitrypsin (AT), and complement components C3 and C4 could identify the presence of chronic inflammation in maintenance hemodialysis (HD) patients. Methods/Results.?In 103 stable HD patients, AT directly correlated with C-reactive protein (CRP) (P<0.005), α₁ acid-glycoprotein (P<0.005), fibrinogen (P<0.05), lipoprotein (a) (P<0.01) and von Willebrand factor antigen (P<0.05), while C3 and C4 were not related to any of these inflammatory markers. In the patients with elevated CRP and hypoalbuminemia, the mean AT value of 1.74 ± 0.50 g/L was higher (P = 0.008) than that of 1.38 ± 0.27 g/L in the subjects with normal CRP and albumin. Using the above cut-off levels, the positive and negative predictive values of AT on the presence of severe inflammation were 0.86 and 0.62, respectively, and the sensitivity and specificity were 86% and 73%, respectively. Conclusion. Serum AT levels above 1.74 g/L and below 1.38 g/L may select the HD patients with severe inflammation from those without. Measurements of C3 and C4 are not helpful in this situation.     

Tuberculin Skin Test Results and the Booster Phenomenon in Two-Step Tuberculin Skin Testing in Hemodialysis Patients

Background. Angiotensin II (ang II) receptor subtype I binding sites has been recently demonstrated on bone cell precursors. Ang II stimulates DNA and collagen synthesis in human adult bone cells. The aim of this study is to evaluate the role of renin angiotensin system in the bone metabolism and to address the genetic influence of angiotensin converting enzyme (ACE) gene polymorphism on bone mass in hemodialysis patients. Methods. Forty‐eight end‐stage renal disease patients (28 male, 20 female mean age 42 ± 13 years,) on maintenance hemodialysis were included in the study. Bone mineral density (BMD) was estimated at lumbar spine and T score worse than ? 1.5 were considered as osteopenia. Serum parathyroid hormone (iPTH) and osteocalcin (OC), bone alkaline phosphatase (bAP) and carboxy terminal propeptide type 1 collagen (PICP) levels were measured as markers of bone metabolism. Plasma renin activity (PRA), serum ACE activity and ACE gene polymorphism (II, ID, DD) were determined. Results. Bone mineral density and T score of the hemodialysis patients were 0.92 ± 0.17 g/cm² and ? 1.36 ± 1.50, respectively. Twenty‐one patients (43,7%) were osteopenic (T score worse than ? 1.5) and mean T score of osteopenic patients was ? 2.72 ± 0.72. T score of nonosteopenic group was ? 0.29 ± 0.99. Serum calcium, serum, phosphorus, serum OC, serum bAP, serum PCIP, serum PTH levels were similar in osteopenics and nonosteopenics. No difference was observed in predialysis PRA and in both pre‐ and postdialysis serum ACE activity of patients in both groups. PRA after hemodialysis in nonosteopenic group was higher than osteopenics (p < 0.05). Percent increment in PRA in hemodialysis patients was correlated with T score (R = 0.48 p < 0.05). Serum ACE activity was positively correlated with serum iPTH (R = 0.29, p = 0.02), serum OC (R = 0.35, p = 0.01), serum bAP (R = 0.34, p = 0.01), serum PCIP (R = 0.36, p = 0.01). T score (? 0.7 ± 1.5, vs ? 1.7 ± 1.3 p < 0.05) was higher in DD group (n = 19) compared to II + ID group (n = 29). Conclusions. Association of biochemical and radiological signs of increased bone formation with activated RAS in hemodialysis patients might be an evidence for the involvement of this system in the regulation of bone metabolism.     

Is splenectomy a dyslipidemic intervention? Experimental response of serum lipids to different diets and operations

Spleen removal may be recommended during organ transplantation in ABO‐incompatible recipients as well as for hypoperfusion of the grafted liver, besides conventional surgical indications, but elevation of serum lipids has been observed in certain contexts. Aiming to analyze the influence of two dietary regimens on lipid profile, an experimental study was conducted. Methods: Male Wistar rats (n = 86, 333.0 ± 32.2 g) were divided in four groups: group 1: controls; group 2: sham operation; group 3: total splenectomy; group 4: subtotal splenectomy with upper pole preservation; subgroups A (cholesterol reducing chow) and B (cholesterol‐rich mixture) were established, and diet was given during 90 days. Total cholesterol (Tchol), high‐density lipoprotein (HDL), low‐density lipoprotein (LDL), very‐low‐density lipoprotein (VLDL), and triglycerides were documented. Results: After total splenectomy, hyperlipidemia ensued with cholesterol‐reducing chow. Tchol, LDL, VLDL, triglycerides, and HDL changed from 56.4 ± 9.2, 24.6 ± 4.7, 9.7 ± 2.2, 48.6 ± 11.1, and 22.4 ± 4.3 mg/dL to 66.9 ± 11.4, 29.9 ± 5.9, 10.9 ± 2.3, 54.3 ± 11.4, and 26.1 ± 5.1 mg/dL, respectively. Upper pole preservation inhibited abnormalities of Tchol, HDL, VLDL, and triglycerides, and LDL decreased (23.6 ± 4.9 vs. 22.1 ± 5.1, P = 0.002). Higher concentrations were triggered by splenectomy and cholesterol‐enriched diet (Tchol 59.4 ± 10.1 vs. 83.9 ± 14.3 mg/dL, P = 0.000), and upper‐pole preservation diminished without abolishing hyperlipidemia (Tchol 55.9 ± 10.0 vs. 62.3 ± 7.8, P = 0.002). Conclusions: After splenectomy, hyperlipidemia occurred with both diets. Preservation of the upper pole tended to correct dyslipidemia in modality A and to attenuate it in subgroup B. © 2008 Wiley‐Liss, Inc. Microsurgery, 2009.     

Dialysis Complications in Acute Kidney Injury Patients Treated With Prolonged Intermittent Renal Replacement Therapy Sessions Lasting 10 Versus 6 Hours: Results of a Randomized Clinical Trial

Prolonged intermittent renal replacement therapy (PIRRT) has emerged as an alternative to continuous renal replacement therapy in the management of acute kidney injury (AKI) patients. This trial aimed to compare the dialysis complications occurring during different durations of PIRRT sessions in critically ill AKI patients. We included patients older than 18 years with AKI associated with sepsis admitted to the intensive care unit and using noradrenaline doses ranging from 0.3 to 0.7 µg/kg/min. Patients were divided into two groups randomly: in G1, 6‐h sessions were performed, and in G2, 10‐h sessions were performed. Seventy‐five patients were treated with 195 PIRRT sessions for 18 consecutive months. The prevalence of hypotension, filter clotting, hypokalemia, and hypophosphatemia was 82.6, 25.3, 20, and 10.6%, respectively. G1 was composed of 38 patients treated with 100 sessions, whereas G2 consisted of 37 patients treated with 95 sessions. G1 and G2 were similar in male predominance (65.7 vs. 75.6%, P = 0.34), age (63.6 ± 14 vs. 59.9 ± 15.5 years, P = 0.28) and Sequential Organ Failure Assessment score (SOFA; 13.1 ± 2.4 vs. 14.2 ± 3.0, P = 0.2). There was no significant difference between the two groups in hypotension (81.5 vs. 83.7%, P = 0.8), filter clotting (23.6 vs. 27%, P = 0.73), hypokalemia (13.1 vs. 8.1%, P = 0.71), and hypophosphatemia (18.4 vs. 21.6%, P = 0.72). However, the group treated with sessions of 10 h were refractory to clinical measures for hypotension, and dialysis sessions were interrupted more often (9.5 vs. 30.1%, P = 0.03). Metabolic control and fluid balance were similar between G1 and G2 (blood urea nitrogen [BUN]: 81 ± 30 vs. 73 ± 33 mg/dL, P = 1.0; delivered Kt/V: 1.09 ± 0.24 vs. 1.26 ± 0.26, P = 0.09; actual ultrafiltration: 1731 ± 818 vs. 2332 ± 947 mL, P = 0.13) and fluid balance (–731 ± 125 vs. ?652 ± 141 mL, respectively) . In conclusion, intradialysis hypotension was common in AKI patients treated with PIRRT. There was no difference in the prevalence of dialysis complications in patients undergoing different durations of PIRRT.     

Combined treatment of hypercholesterolemia of renal transplant allograft recipients with fluvastatin and gemfibrozil

Abstract The aim of this study was to investigate the safety and efficacy of combined treatment with fluvastatin (F) and gemfibrozil (G) in hypercholesterolemic renal transplant recipients (RTR). Ten hypercholesterolemic (total cholesterol [TC] > 220 mg/dl) RTR (7 men) with mean age 44 years (range 25‐56 years) who remained hypercholesterolemic after 3 months of treatment (period A) with fluvastatin (40 mg/d) continued taking the same dose of F plus G (600 mg/dl) for another 3‐month period (B). Serum total cholesterol, high density lipoprotein cholesterol (HDL‐C), LDL cholesterol (LDL‐C), triglyceride, serum creatinine (creatinine phosphokinase (CPK), serum glutamic‐oxaloacetic transaminase (SGOT), and serum glutamate pyruvate transaminase (SGPT) were measured before treatment and at the end of periods A and B. Mean TC levels were 360.30 ± 62.42 mg/dl, 324.10 ± 100.53 mg/dl, 270.80 ± 67.77 mg/dl; mean LDL‐C levels were 259.33 ± 71.43 mg/dl, 219.60 ± 81.31 mg/dl, 189.70 ± 65.51 mg/dl; mean HDL‐C levels were 37.10 ± 11.68 mg/dl, 39.80 ± 13.21 mg/dl, 41.00 ± 12.94 mg/dl; mean triglyceride levels were 354.60 ± 183.29 mg/dl, 349.30 ± 242.94 mg/dl, 207.00 ± 85.35 mg/dl before treatment and at the end of periods A and B, respectively. There was a statistically significant fall of serum TC (P = 0.002), LDL‐C (P = 0.016), and triglyceride (P = 0.029) levels at the end of periods A and B. Kidney and liver function did not change. F and G combined treatment is safe and useful in patients who do not respond satisfactorily to monotherapy with F. Gemfibrozil augments the effect of F on TC, LDL‐C, and triglyceride levels.     

Atherosclerotic risk factors and carotid stiffness in elderly asymptomatic HD patients

Several studies showed that carotid atherosclerosis and stiffness are independent prognostic factors of cardiovascular morbidity and mortality in the general population and in end-stage renal disease patients. However, the impact of established risk factors on carotid structural and elastic properties in non-diabetic elderly hemodialysis patients with negative history for cardiovascular disease has not been fully elucidated. In this paper, we investigated the effect of established and potential risk factors on carotid atherosclerosis and stiffness. Thirty stable, non-symptomatic, non-diabetic patients, aged 65-years and older (mean age 71.4 ± 4.15, range 65–79) on hemodialysis for more than 6 months, were included. All patients underwent B-mode ultrasonography of common carotid artery estimating intima-media wall thickness and wall-to-lumen ratio bilaterally and checking for the presence of plaques. Carotid elasticity was evaluated by compliance, distensibility, and the incremental elastic modulus (Einc), whereas systemic arterial stiffening was evaluated by the augmentation index provided by tonometry of radial artery. Our results showed that presence of carotid plaques and wall thickening were frequent findings in this population (76% and 73.3%, respectively) and they were positively associated with fibrinogen (P < 0.005), diastolic blood pressure (P < 0.004), visceral obesity (P < 0.001) and bio-intact PTH (i-PTH) (P = 0.03). Overall, systemic and carotid stiffness were strongly correlated with hs-CRP (P = 0.018), serum ferritin (P = 0.02) with age (P = 0.03), lipids (P = 0.03) and i-PTH (P = 0.05). In conclusion, our findings show that stiffening and atherosclerosis in non-symptomatic elderly HD patients are very common and they are related not only to hemodynamic changes (diastolic blood pressure), inflammation (hs-CRP, fibrinogen, ferritin) or metabolic dysfunction (increased i-PTH, abnormal lipid profile), but also to abnormal fat deposition (increased waist to hip ratio and waist circumference). Considering the high morbidity and mortality of elderly patients, close monitoring of these parameters could be useful to prevent cardiovascular events.     

C REACTIVE PROTEIN IN PATIENTS WITH CHRONIC RENAL DISEASES

Base-line serum levels of plasma C-reactive protein (CRP) are predictive of future myocardial infarction and sudden cardiac death in apparently healthy subjects, suggesting the hypothesis that chronic inflammation might be important in the pathogenesis of atherothrombosis. CRP production is mediated by several inflammatory mediators: interleukin 6 (IL-6) is currently felt to be the major cytokine influencing the acute phase response. CRP and other acute phase proteins are elevated in dialysis patients and cardiovascular diseases represent the single largest cause of mortality in chronic renal failure patients. Little information is available, however regarding CRP and IL-6 plasma levels in pre-dialysis renal failure. Plasma CRP was determined by a modification of the laser nephelometry technique; IL-6 by immunoassay (RD System); and fibrinogen, serum albumin, cholesterol, triglycerides, hematocrit, white blood cell count, erythrocytic sedimentation rate (ESR) and urinary protein levels by standard laboratory techniques. Results were obtained in 102 chronic pre-dialysis patients whose mean age was 53 ± 5.8 years with a mean creatinine clearance (C_Cr) of 52 ± 37 mL/min). CRP was greater than 5 mg/L in 25% of the global population. CRP and IL-6 were 4.0 ± 4.6 mg/L and 5.8 ± 5.6 pg/mL, respectively and were not significantly correlated (r = 0.11, p = n.s.). CRP and IL-6 were however related with renal function (CRP versus C_Cr r = ?0.40 p < 0.001; IL-6 versus C_Cr r = ?0.45; p < 0.001). When patients were divided in two groups according to renal function, CRP resulted 7.4 ± 6.3 mg/L in the group of patients with a C_Cr lower than 20 mL/min (n = 32) and 2.76 ± 4.35 in the group of patients with a C_Cr higher than 20mL/min (n = 70) (p < 0.0001). CRP and IL-6 were positively related with ESR (r = 0.32 and 0.46 respectively). Serum albumin levels were not significantly different in the two groups of patients (3.2 ± 0.4 versus 3.0 ± 0.5 g/dL). CRP and serum albumin were not significantly related (r = 0.17). CRP and IL-6 correlated positively with ESR (r = 0.32 and 0.46 respectively). In pre-dialysis patients we have demonstrated an increase in both CRP and IL-6 that occurs as renal function decreases. These data provided evidence of the activation – even in the predialysis phase of renal failure – of mechanisms known to contribute to the enhanced cardiovascular morbidity and mortality of the uremic syndrome.