Giuseppe Cianciolo

Standard heparin versus low-molecular-weight heparin. A medium-term comparison in hemodialysis.

Background: To compare standard heparin (SH) and low molecular weight heparin (LMWH) in terms of anticoagulation, platelet activation and lipid metabolism, we selected 54 patients who had been on 4-hour hemodialysis three times weekly for at least 12 months, without bleeding disorders or dyslipidemic diseases. 28 were on hemodialysis with Polysulfone low-flux, 26 were on hemodiafiltration with Polysulfone high-flux. All patients underwent EPO. Methods: During the first 18 months, we administered SH 1,500 IU on starting dialysis and 1,500 ± 500 IU in continuous intradialytic infusion per session. In the following 18 months, we administered LMWH 64.6 IU/kg on starting dialysis in a single arterious bolus. We assessed aPTT, anti-factor Xa activity, TAT and FPA, β-TG and PF4. Blood samples were taken monthly at times 0, 30, 60, 180 and 240 min, as well as 1, 4 and 20 h after dialysis end. Predialysis cholesterol, HDL, LDL, triglycerides and lipoprotein(a) were checked monthly. Results: During both LMWH and SH sessions no clotting or major bleeding complications were observed. APTT with LMWH was lower than that found with SH (p < 0.001); aFXa using LMWH was higher than when using SH (p < 0.001); TAT and FPA were lower in LMWH sessions (p < 0.01) than in SH sessions. We also detected lower β-TG (p < 0.05) and PF4 levels (p < 0.05) using LMWH than using SH. As regards lipids, we only observed a significant decrease in triglycerides after 18 months of LMWH treatment. Conclusions: Routine use of LMWH during hemodialysis affords a safe and effective alternative to SH, and causes reduced platelet activation.

Importance of vascular calcification in kidney transplant recipients.

Background: Kidney transplantation is the treatment of choice for chronic kidney disease (CKD), but in kidney transplant recipients (KTRs) cardiovascular events are the first cause of death with a functioning graft, ranging from 36 to 55%. The impact of vascular calcification (VC) on morbidity and mortality of KTRs is not appreciated enough nowadays. Summary: This review summarizes 13 important studies on VC in KTRs, comparing the results with CKD and dialysis populations. We focused on VC evaluation and use of coronary artery calcification (CAC) and aorta calcification (AoC) scores. We also evaluated the influence of traditional and non-traditional progression risk factors. Key Messages: VC strongly predicts cardiovascular events and all-cause mortality in KTRs. VC assessment is important in KTRs and based essentially on multislice computed tomography or electron beam computed tomography recognition of lesions. Quantitative measurement of CAC and AoC scores is essential for a correct definition of the calcium burden before and after kidney transplant. Progression of CAC slows down but does not halt after kidney transplant. A variable association of both traditional and non-traditional risk factors is shown. There is a strong association between baseline CAC score and CAC progression. A significant improvement in secondary hyperparathyroidism after transplantation favorably affects the progression of CAC. Low 25(OH)D3 levels are an independent determinant of CAC progression. Diabetes is a risk factor for the presence of CAC in KTRs, but has not been independently associated with CAC progression. The data published on the use of immunosuppressive drugs as progression factors are few and inconclusive.

5-Methyltetrahydrofolate Administration Is Associated with Prolonged Survival and Reduced Inflammation in ESRD Patients

BACKGROUND Hemodialysis (HD) patients have a greatly increased risk of cardiovascular morbidity and mortality. For this reason, attempts are often made to normalize hyperhomocysteinemia. This randomized prospective study sought to determine which risk factors are predictors of mortality and whether high doses of folates or 5-methyltetrahydrofolate (5-MTHF) could improve hyperhomocysteinemia and survival in HD patients. METHODS 341 patients were divided into two groups: group A was treated with 50 mg i.v. 5-MTHF, and group B was treated with 5 mg/day oral folic acid. Both groups received i.v. vitamin B(6) and B(12). By dividing patients into C-reactive protein (CRP) quartiles, group A had the highest survival for CRP <12 mg/l, whereas no survival difference was found for group B. CRP was the only predictive risk factor for death (RR 1.17, range 1.04-1.30, p = 0.02). Dialysis age, hyperhomocysteinemia, methylenetetrahydrofolate reductase polymorphism, albumin, lipoprotein (a) and folate did not influence mortality risk. Survival in group A was higher than that in group B, namely 36.2 +/- 20.9 vs. 26.1 +/- 22.2 months (p = 0.003). RESULTS Our results suggest that CRP, but not hyperhomocysteinemia, is the main risk factor for mortality in HD patients receiving vitamin supplements. Intravenous 5-MTHF seems to improve survival in HD patients independent from homocysteine lowering.

Coronary Calcifications in End-Stage Renal Disease Patients: A New Link between Osteoprotegerin, Diabetes and Body Mass Index?

The aim of the study was to assess the factors potentially involved in coronary artery calcifications (CAC) in end-stage renal disease patients. 253 hemodialysis (HD) patients (92 females, 161 males), aged 62.5 ± 13.5, who had been on HD treatment for at least 6 months, were enrolled in a cross-sectional study. Calcium-phosphate product (Ca × P), body mass index (BMI), fetuin-A, osteoprotegerin (OPG), osteopontin, transforming growth factor-β1 (TGF-β1), fibroblast growth factor-23 (FGF-23) and matrix Gla protein (MGP) were considered. CAC was assessed using multislice spiral computed tomography and calcium score was quantified by means of the Agatston score. The median calcium score was 364 Agatston (range 0–7,336). CAC was detected in 228/253 patients (90.1%). Multivariate regression analysis, adjusted for age and for dialysis vintage, showed that TGF-β1, OPG and days with Ca × P >55 mg/dl are independent predictors of CAC, while MGP was shown to be a protective factor. Surprisingly, results showed that BMI was a protective factor too: the interpolation with cubic spline function revealed a significant reduction in calcium score in patients with a high BMI (>28). However, when diabetes was considered in the regression analysis, only OPG emerged as a predictor of a high CAC score. The interpolation with spline function continued to show a significant reduction in CAC score in nondiabetic and in diabetic patients with the highest BMI quartile. The protective effect of a high BMI on CAC might represent another example of inverse biology in dialysis patients but it needs to be further addressed in larger longitudinal studies.

VDR Expression on Circulating Endothelial Progenitor Cells in Dialysis Patients Is Modulated by 25(OH)D Serum Levels and Calcitriol Therapy

Background/Aims: Vitamin D deficiency is associated with endothelial dysfunction in uremic patients, possibly by the impairment in the number and function of endothelial progenitor cells (EPCs). In 89 hemodialysis patients, we investigated the factors associated with the number of circulating EPCs (CD34⁺/CD133⁺/KDR⁺ and CD34⁺/CD133^–/KDR⁺ cells), the presence of VDR and the determinants of VDR expression on EPCs, in particular in calcitriol therapy. Methods: EPC counts, percentages of VDR-positive EPCs and VDR expression were assessed by flow cytometry. Cells isolated from a subgroup of patients were cultured to analyze colony-forming units, specific markers expression and a capillary-like structure formation. Results/Conclusions: Our study demonstrates the presence of VDR on EPCs. In our dialysis patients, the parameters studied on both CD34⁺/CD133⁺/KDR⁺ and CD34⁺/CD133^–/KDR⁺ cells, in particular VDR expression, seem to be influenced by uremia-related factors, including anemia, inflammation, diabetes, 25(OH)D serum levels and calcitriol therapy.

Role of the hemodialysis vascular access type in inflammation status and monocyte activation

Purpose The aim of this study was to ascertain the role of different vascular access types in inflammatory status, monocyte activation, and senescence in hemodialysis patients. Methods We recruited 126 hemodialysis patients, including 51 with arterovenous fistula (AVF), 32 with arterovenous graft (AVG), and 43 with tunneled cuffed catheters (TCC). In dialysis patients enrolled in the study and in a control group of 40 healthy subjects, we measured the serum levels of albumin, CRP, IL-6, and TNF-α, the expression of CD14, CD44, and CD32 on monocyte surface, and the percentage of monocytes exhibiting a senescent phenotype (CD14+CD32+). Results The patients with AVG compared to those with AVF had: a) higher levels of CRP and TNF-α; b) increased expression of CD14 and CD32 on monocyte surface, with no difference in CD44 expression; c) no difference in the percentage of CD14+CD32+ monocytes. In the comparison of TCC vs. AVF group, we observed significantly higher values of: a) circulating inflammatory markers (CRP, IL-6, TNF-α); b) monocyte surface expression of cellular activation markers (CD14, CD44 and CD32); c) relative count of CD14+CD32+ monocytes. When comparing TCC vs. AVG group, we found: a) no difference in serum levels of CRP, IL-6, and TNF-α; b) no difference in the expression of CD14, CD44, and CD32 on monocyte surface; c) no difference in the percentage of CD14+CD32+ monocytes. Conclusions These results suggest that the use of AVG and TCC for dialysis vascular access is associated with serological and cellular indexes of inflammatory reaction, also resulting in a higher degree of monocyte activation and senescence.

Vitamin D in Kidney Transplant Recipients: Mechanisms and Therapy.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is common in kidney transplant recipients (KTRs), where secondary hyperparathyroidism (HPTH) and post-transplantation bone disease (PTBD) are potential effectors of both graft and vascular aging. Reduced 25(OH)D levels are highly prevalent in KTRs. Experimental and clinical evidence support the direct involvement of deranged vitamin D metabolism in CKD-MBD among KTRs. This review analyzes the pathophysiology of vitamin D derangement in KTRs and its fall out on patient and graft outcome, highlighting the roles of both nutritional and active vitamin D compounds to treat PTBD, cardiovascular disease (CVD) and graft dysfunction. Fibroblast growth factor-23-parathyroid hormone (PTH)-vitamin D axis, immunosuppressive therapy and previous bone status have been associated with PTBD. Although several studies reported reduced PTH levels in KTRs receiving nutritional vitamin D, its effects on bone mineral density (BMD) remain controversial. Active vitamin D reduced PTH levels and increased BMD after transplantation, but paricalcitol treatment was not accompanied by benefits on osteopenia. Vitamin D is considered protective against CVD due to the widespread pleiotropic effects, but data among KTRs remain scanty. Although vitamin deficiency is associated with lower glomerular filtration rate (GFR) and faster estimated GFR decline and data on the anti-proteinuric effects of vitamin D receptor activation (VDRA) in KTRs sound encouraging, reports on related improvement on graft survival are still lacking. Clinical data support the efficacy of VDRA against HPTH and show promising evidence of VDRAs effect in counteracting post-transplant proteinuria. New insights are mandatory to establish if the improvement of surrogate outcomes will translate into better patient and graft outcome.

Effects of unfractioned heparin and low-molecular-weight heparin on osteoprotegerin and RANKL plasma levels in haemodialysis patients

BACKGROUND This randomized crossover study investigated the effects of unfractioned heparin (UFH) and low-molecular-weight heparin (LMWH) on intra- and post-dialytic blood levels of osteoprotegerin (OPG), receptor activator of nuclear factor kappa B ligand (RANKL) and inflammatory cytokines. METHODS Forty patients on haemodialysis for at least 12 months were selected. UFH or LMWH was randomly assigned and maintained for 1 month, and then, in the following month, each patient was switched to the other form of heparin. In the mid-week session, we determined the changes in anti-Xa activity, OPG, RANKL, IL-1β, IL-6 and TNF-α values before heparin administration and after 15 min, 4, 8 and 24 h (T0, T1, T2, T3 and T4 respectively). Since these parameters at the various experimental times showed a non-normal distribution, log transformation was applied in order to run parametric ANOVA, with Bonferroni correction for multiple comparisons. RESULTS The changes in anti-Xa activity over time were similar but not the same for the UFH and LMWH. A highly significant (P<0.001) increase in anti-Xa activity was detected at T1, regardless of the type of heparin, as confirmed in the comparison of T0 vs T1 using one-way ANOVA. Moreover, with both heparins, significant differences were found in the comparisons of anti-Xa activity at T1 vs T2 (both P<0.001) and at T2 vs T3 (P=0.0003 with UFH; P<0.001 with LMWH). Conversely, the difference in anti-Xa activity at T3 vs T4 was still significant with UFH (P=0.0186) but not significant with LMWH (P=0.728). When comparing anti-Xa activity at T4 vs T0, no significant differences were found either with UFH (P=0.1996) or with LMWH (P=0.7470), thus indicating that 24 h after heparin infusion, anti-Xa activity returned back to the pre-infusion values. When we analysed the changes in OPG levels over time, we found that the administration of heparin, regardless of the type, determined an increase in circulating OPG with a zenith at 15 min (T1), with a return back to the baseline levels within the 24th hour post-infusion. One-way ANOVA revealed significant differences in OPG blood levels at T0 vs T1 with both UFH (P=0.0112) and LMWH (P=0.0288), whereas no significant difference was observed in the comparisons of OPG levels at T1 vs T2, T2 vs T3, T3 vs T4 and T4 vs T0, either with UFH or with LMWH. The circulating levels of RANKL, IL-1β, IL-6 and TNF-α at the different intra- and post-dialytic times did not show significant variations following heparin administration, either with UFH or with LMWH. One-way ANOVA performed on the log-transformed values of RANKL, IL-1β, IL-6 and TNF-α at the various experimental times (T0 vs T1, T1 vs T2, T2 vs T2, T3 vs T4 and T4 vs T0) revealed no significant intra- and post-dialytic changes in their blood levels, thus confirming that heparin infusion did not affect their blood levels. CONCLUSIONS These results suggest that heparin-regulated cyclic increases of OPG might play a role in the vascular pathology of haemodialysis patients.

Evaluation of intradialytic solute and fluid kinetics. Setting Up a predictive mathematical model.

A mathematical model of solute kinetics for the improvement of hemodialysis treatment is presented. It includes a two-compartment description of the main solutes and a three-compartment model of body fluids (plasma, interstitial and intracellular). The main model parameters can be individually assigned a priori, on the basis of body weight and plasma concentration values measured before beginning the session. Model predictions are compared with clinical data obtained in vivo during 11 different hemodialysis sessions performed on 6 patients with a profiled sodium concentration in the dialysate and a profiled ultrafiltration rate. In all cases, the agreement between the time pattern of model solute concentrations in plasma and the in vivo data proves fairly good as to urea, sodium, chloride, potassium and bicarbonate kinetics. Only in two sessions was blood volume directly measured in the patient, and in both cases the agreement with model predictions was good. In conclusion, the model allows a priori computation of the amount of sodium removed during hemodialysis, and makes it possible to predict the plasma volume changes and plasma osmolarity changes induced by a given sodium concentration profile in the dialysate and by a given ultrafiltration profile. Hence, it can be used to improve clinical tolerance to the dialysis session taking the characteristics of individual patients into account, in order to minimize intradialytic hypotension.

Thrombosis of Tunneled-Cuffed Hemodialysis Catheters: Treatment With High-Dose Urokinase Lock Therapy

Thrombosis-related malfunction of tunneled-cuffed central venous catheters (TCC) for hemodialysis (HD) currently leads to a high rate of untimely catheter removal. Urokinase (UK) therapy is used for TCC thrombosis/malfunction, but no consensus exists on the adequate dose to obtain thrombolysis. We selected 72 HD patients with TCC and a mean age and HD vintage of 74 years (range 65-87) and 36 months (range 12-61), respectively. All patients received warfarin therapy with a target international normalized ratio (INR) of 1.8-2.5. Coagulative assessment of the patients was obtained by checking the INR, activated partial thromboplastin time, fibrinogen, hemoglobin, and platelets. Sixty-five thrombotic events were recorded during a 3-year follow-up (median 0.3 events/patient/year). The patients selected were randomized into two groups according to a different thrombolytic therapy. Group A comprised 29 thrombotic events in 32 patients who received UK 25,000 IU in both arterial and venous lines of the TCC for each event. UK restored an adequate blood flow rate (BFR) for HD (≥ 250 mL/min) in 4/29 events (13.7%), whereas addition of 50,000 IU to both arterial and venous lines was required in 25/29 events (86.3%). For the same 25 events in the second HD session, a further 75,000 IU of UK was needed for each TCC lumen. Group B comprised 36 thrombotic events in 40 patients who received 100 000 IU of UK in the arterial and venous lumen of the TCC for each event. An adequate BFR was recovered in all events. In 12/36 events (33.3%), 100,000 IU UK for both lumens were needed in the second HD. In conclusion, group B patients obtained (i) a significantly better TCC patency than group A patients; (ii) a low UK administration in the following HD sessions; and (iii) no bleeding complications.