PTFE grafts versus tunneled cuffed catheters for hemodialysis: which is the second choice when arteriovenous fistula is not feasible?

Vascular access-related complications are still one of the leading causes of morbidity in hemodialysis patients. The aim of this study was to compare polytetrafluoroethylene (PTFE) grafts versus tunneled cuffed permanent catheters (TCCs) in terms of vascular access and patients' survival. An observational study was carried out with a 2-year follow-up. Eighty-seven chronic hemodialysis patients were enrolled: 31 with a PTFE graft as vascular access for hemodialysis versus 56 with a TCC. Patients' mean age was 63.8 ± 14.6 (grafts) versus 73.5 ± 11.3 years (TCCs), P = 0.001. Significantly more patients with TCC had atrial fibrillation than patients with grafts (30.3% versus 6.5%, P = 0.01). In an unadjusted Kaplan-Meier analysis, median TCC survival at 24 months was 5.4 months longer than that of PTFE grafts but not significantly (log-rank test = 1.3, P = ns). In a Cox regression analysis adjusted for age, gender, number of previous vascular accesses, diabetes, atrial fibrillation, smoking, and any complication, this lack of significant difference in survival of the vascular access between TCC and PTFE groups was confirmed and diabetes proved to be an independent risk factor for the survival of both vascular accesses considered (P = 0.02). In an unadjusted Kaplan-Meier analysis, a higher mortality was found in the TCC group than in the PTFE group at 24 months (log-rank test = 10.07, P < 0.01). The adjusted Cox regression analysis showed that patients with TCC had a 3.2 times higher risk of death than patients with PTFE grafts. When an arteriovenous fistula (AVF) is not possible, PTFE grafts can be considered the vascular access of second choice, whereas TCCs can be used when an AVF or PTFE graft are not feasible or as a bridge to AVF or PTFE graft creation.

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.

Neutrophil gelatinase-associated lipocalin increases HLA-G(+)/FoxP3(+) T-regulatory cell population in an in vitro model of PBMC.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is emerging as a mediator of various biological and pathological states. However, the specific biological role of this molecule remains unclear, as it serves as a biomarker for many conditions. The high sensitivity of NGAL as a biomarker coupled with relatively low specificity may hide important biological roles. Data point toward an acute compensatory, protective role for NGAL in response to adverse cellular stresses, including inflammatory and oxidative stress. The aim of this study was to understand whether NGAL modulates the T-cell response through regulation of the human leukocyte antigen G (HLA-G) complex, which is a mediator of tolerance. METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood mononuclear cells (PBMCs) were obtained from eight healthy donors and isolated by centrifugation on a Ficoll gradient. All donors gave informed consent. PBMCs were treated with four different concentrations of NGAL (40-320 ng/ml) in an iron-loaded or iron-free form. Changes in cell phenotype were analyzed by flow cytometry. NGAL stimulated expression of HLA-G on CD4+ T cells in a dose- and iron-dependent manner. Iron deficiency prevented NGAL-mediated effects, such that HLA-G expression was unaltered. Furthermore, NGAL treatment affected stimulation of regulatory T cells and in vitro expansion of CD4(+) CD25(+) FoxP3(+) cells. An NGAL neutralizing antibody limited HLA-G expression and significantly decreased the percentage of CD4(+) CD25(+) FoxP3(+) cells. CONCLUSIONS/SIGNIFICANCE: We provide in vitro evidence that NGAL is involved in cellular immunity. The potential role of NGAL as an immunomodulatory molecule is based on its ability to induce immune tolerance by upregulating HLA-G expression and expansion of T-regulatory cells in healthy donors. Future studies should further evaluate the role of NGAL in immunology and immunomodulation and its possible relationship to immunosuppressive therapy efficacy, tolerance induction in transplant patients, and other immunological disorders.

The efficacy and safety of cyclosporine reduction in de novo renal allograft patients receiving sirolimus and corticosteroids: results from an open-label comparative study.

This study evaluated the safety and efficacy of a sirolimus, corticosteroid, and cyclosporine reduction regimen in an open-label, 12-month trial of 420 de novo renal allograft recipients at 49 European transplant centers. One month post-transplantation, 357 patients were randomized to receive standard-dose cyclosporine (sCsA, n = 179) or reduced-dose cyclosporine (rCsA, n = 178). All patients also received sirolimus and corticosteroids. The primary end points were the rate of biopsy-confirmed acute rejection (BCAR) and renal function, as measured by serum creatinine. Baseline demographic and donor characteristics were similar between groups. BCAR rates at 12 months were not significantly different: 11.2% for rCsA patients and 16.2% for sCsA patients. Mean serum creatinine (±SEM) was significantly lower (1.75 ± 0.10 vs. 1.97 ± 0.07 mg/dl, P < 0.001), and creatinine clearance (±SEM; Nankivell method) was significantly higher (57.8 ± 1.78 vs. 49.5 ± 2.46 ml/min, P < 0.001) in patients receiving rCsA versus sCsA at 1 year, respectively. Patient and graft survival exceeded 98% in both groups. No significant differences in infection or malignancy were noted between groups. The rCsA with sirolimus and corticosteroid regimen resulted in excellent 12-month patient and graft survival, a low incidence of BCAR, and improved renal function in renal allograft recipients. Sirolimus administered with rCsA and corticosteroids provided adequate immunosuppression while reducing the potential for the nephrotoxic effects of cyclosporine. These findings may help to improve long-term renal allograft outcomes.

Incidence and predictors of postoperative atrial fibrillation in kidney transplant recipients.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a complication of cardiothoracic and noncardiothoracic surgery. Kidney transplant recipients bear several known risk factors and may have a higher incidence of POAF. We retrospectively studied kidney and kidney/liver transplant recipients to estimate their POAF incidence and identify relevant risk factors. We also adapted a clinical score originally designed to predict thromboembolic risk in atrial fibrillation (AF; CHA2DS2-VASc) for assessing transplant patients. METHODS: We reviewed the clinical charts of kidney or kidney/liver transplant recipients from January 2005 to December 2008 at St. Orsola University Hospital Kidney Transplant Centre. Patients with and without POAF were compared on a number of clinical, laboratory, and instrumental data. RESULTS: The POAF incidence in kidney transplant recipients was 8.2%. Risk factors for POAF identified in univariate analyses included older recipient age, history of myocardial infarction, history of AF, liver/kidney transplantation, arterial stiffness, atherosclerotic plaques in the aorta or lower limbs, and diabetes mellitus. In a multivariate analysis, age, myocardial infarction history and combined liver/kidney transplantation were significant independent predictors of POAF. The modified CHA2DS2-VASc score proved to have a better predictive validity that the original CHA2DS2-VASc (area under the curve=0.71, 95% confidence interval=0.63-0.79 vs. area under the curve=0.62, 95% confidence interval=0.52-0.73, respectively). CONCLUSION: AF is a notable complication of kidney, and particularly simultaneous liver/kidney, transplant surgery. Age, previous myocardial infarction, and simultaneous liver/kidney transplant independently predicted POAF. The modified CHA2DS2-VASc score could be useful to predict POAF risk in kidney transplant candidates.

The impact of apoptosis and inflammation gene polymorphisms on transplanted kidney function.

BACKGROUND: The progressive deterioration of kidney allograft function leads in most cases to transplant failure. Polymorphisms in genes encoding for inflammatory and apoptosis molecules may be one possible explanation for interindividual differences in kidney transplant outcomes. The objective of our work was to identify the possible effect of interleukin 6 (IL-6), transforming growth factor beta 1 (TGFB1), and Fas on graft function. MATERIAL AND METHODS: A case-control study was carried out to assess potential associations between polymorphisms in inflammation- and apoptosis-related genes and the risk for chronic impairment of kidney graft function. The study included 376 cadaveric kidney recipients, 256 of them with stable graft function and 120 who experienced renal deterioration during the follow-up period of 2.6 ± 1.4 years. Genotyping of IL-6/G-174C, TGFB1/L10P, TGFB1/R25P, and Fas/G-670A polymorphisms was performed by PCR-RFLP and direct sequencing. RESULTS: Considering the single IL-6, TGFB1, and Fas polymorphisms, we found similar allelic and genotype frequencies between the 2 groups. To test the hypothesis of mutual effects of polymorphisms, multiple logistic regression was performed incorporating data for all the possible dual genotypic associations. The association of IL-6 high producer and Fas low producer genotype resulted in a protective effect against graft dysfunction (OR=0.79; 95% C.I.=0.72-0.86). CONCLUSIONS: This study did not find significant associations of apoptosis and inflammation gene polymorphisms with transplanted kidney function in Italian renal transplant recipients. However, our data seem to indicate that the carriage of IL-6 high producer/Fas low producer genotype has a protective effect against graft function loss.

Incidence and prevalence of cancer in kidney transplantation waiting list patients: an Italian experience.

INTRODUCTION: Evaluation of kidney transplant candidates is based on strict exclusion of major pathologies, such as neoplastic disease. The aim of this study is to evaluate epidemiological and clinical impact of tumor disease in an Italian renal transplant waiting list and to propose a screening schedule for neoplastic detection.
 MATERIALS AND METHODS: We retrospectively observed data of patients enrolled on the Emilia-Romagna kidney transplant waiting list between 1st August 2008 and 31st December 2010, evaluating the different causes of getting out from the list, the histologic type and incidence of cancer and the correlation between cancer onset and clinical features. The ratio of observed to expected cancer numbers (standardized incidence ratio, SIR), was estimated. RESULTS: We observed 2345 patients; 1297 got out from the waiting list; 57 of them (4,4%) got out because the onset of tumor. The overall incidence rate of cancer was 1354.8 (x 100,000 person-year) (1045.9 person-year in patients awaiting for first transplant(FT), 1851.5 person-year in patients awaiting for second transplant(ST)). The overall prevalence of cancer was 2,43% (2.2% in FT, 3.4% in ST) with a SIR of 1.8; In our population the prevalence of cancers related to ESKD was 52.6% with a SIR of 15.8.
 CONCLUSION: Kidney transplant waiting list patients present a higher incidence and prevalence of cancer compared to general population; it could be important to evaluate them for ESKD related malignancies because of their high incidence.

Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial.

BACKGROUND: Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. METHODS: This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. RESULTS: Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. CONCLUSION: Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

Mesenchymal stem cells and islet cotransplantation in diabetic rats: improved islet graft revascularization and function by human adipose tissue-derived stem cells preconditioned with natural molecules.

Hypoxia plays an important role in limiting the engraftment, survival, and function of intrahepatically transplanted islets. Mesenchymal stem cells (MSCs) were recently used in animal models of islet transplantation not only to reduce allograft rejection but also to promote revascularization. Among different possible origins, adipose tissue represents a novel and good source of MSCs. Moreover, the capability of adipose tissue-derived stem cells (ASCs) to improve islet graft revascularization was recently reported after hybrid transplantation in mice. Within this context, we have previously shown that hyaluronan esters of butyric and retinoic acids can significantly enhance the rescuing potential of human MSCs (hMSCs). Here we evaluated whether ex vivo preconditioning of human ASCs (hASCs) with a mixture of hyaluronic (HA), butyric (BU), and retinoic (RA) acids may result in optimization of graft revascularization after islet/stem cell intrahepatic cotransplantation in syngeneic diabetic rats. We demonstrated that hASCs exposed to the mixture of molecules are able to increase the secretion of vascular endothelial growth factor (VEGF) as well as the transcription of angiogenic genes, including VEGF, KDR (kinase insert domain receptor), and hepatocyte growth factor (HGF). Rats transplanted with islets cocultured with preconditioned hASCs exhibited a better glycemic control than rats transplanted with an equal volume of islets and control hASCs. Cotransplantation with preconditioned hASCs was also associated with enhanced islet revascularization in vivo, as highlighted by graft morphological analysis. The observed increase in islet graft revascularization and function suggests that our method of stem cell preconditioning may represent a novel strategy to remarkably improve the efficacy of islets-hMSCs cotransplantation.

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-a, 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-a; 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-a); 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-a; 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.

Urinary neutrophil gelatinase-associated lipocalin at birth predicts early renal function in very low birth weight infants.

Preterm infants are exposed to conditions that can impair renal function. We evaluated the ability of serum and urinary neutrophil gelatinase-associated lipocalin (sNGAL and uNGAL) to predict renal function in the first weeks of life. From September 2008 to July 2009, infants weighing ≤1500 g at birth with no major congenital anomalies or sepsis were eligible. We measured sNGAL and uNGAL levels at birth. To evaluate renal function, we determined changes in serum creatinine (sCreat) and estimated GFR (eGFR) from birth to d 21. Forty neonates (mean GA, 27 ± 2 wk) completed the study. Renal function improved in 32 of 40 (80%) infants (normal renal function, NRF group) (sCreat, from 0.97 ± 0.2 to 0.53 ± 0.13 mg/dL; eGFR, from 15.3 ± 4.1 to 28.6 ± 7.9 mL/min), whereas renal function worsened in 8 of 40 (20%) infants (impaired renal function, IRF group) (sCreat, from 0.71 ± 0.27 to 0.98 ± 0.43 mg/dL; eGFR from 23 ± 14.7 to 16.4 ± 9.1 mL/min). The uNGAL/urinary creatinine (uCreat) ratio at birth was higher in the IRF group (31.05 ng/mg) than the NRF group (6.0 ng/mg), and uNGAL was significantly higher in IRF group, detecting IRF with a cutoff of 100 ng/mL. uNGAL levels at birth may have a predictive role in very LBW (VLBW) infants.

[Physical activity and renal transplantation]. / Attivita' fisica nei pazienti con trapianto di rene.

A sedentary lifestyle is an important risk factor leading to cardiovascular disease. Cardiovascular disease is particularly frequent in kidney transplant recipients, with a mortality rate of 38%. In this population, besides the classic risk factors (genetics, age, smoking, etc.) and disease-related factors (chronic renal failure, dialysis vintage) there are the side effects of immunosuppressive therapy such as diabetes and metabolic syndrome. Despite the general advice given on an appropriate lifestyle, most transplanted patients lead a sedentary life which may result in overweight. In this study the physiopathological effects of a sedentary lifestyle were analyzed with reference to the recent literature regarding the efficacy of physical activity in transplanted patients. Studies in the general population have demonstrated the beneficial effect of physical activity on the prevention of cardiovascular disease. There are only few studies within the kidney transplant population regarding regular physical activity and these studies were performed with heterogeneous protocols and different observation periods, and are therefore difficult to compare. Overall, positive results in terms of maximal aerobic capacity, muscle strength and perception of well-being have been obtained in the short and medium term (1 year). Further studies are necessary to verify the effect of physical activity on long-term patient and graft survival. In order to enhance physical activity in transplanted patients, local programs in collaboration with sports rehabilitation centers are to be recommended.

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-1ß, 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-1ß, 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-1ß, 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.

Mesenchymal stem cells in renal function recovery after acute kidney injury: use of a differentiating agent in a rat model.

Acute kidney injury (AKI) is a major health care condition with limited current treatment options. Within this context, stem cells may provide a clinical approach for AKI. Moreover, a synthetic compound previously developed, hyaluronan monoesters with butyric acid (HB), able to induce metanephric differentiation, formation of capillary-like structures, and secretion of angiogenic cytokines, was tested in vitro. Thereafter, we investigated the effects of human mesenchymal stem cells from fetal membranes (FMhMSCs), both treated and untreated with HB, after induction of ischemic AKI in a rat model. At reperfusion following 45-min clamping of renal pedicles, each rat was randomly assigned to one of four groups: CTR, PBS, MSC, and MSC-HB. Renal function at 1, 3, 5, and 7 days was assessed. Histological samples were analyzed by light and electron microscopy and renal injury was graded. Cytokine analysis on serum samples was performed. FMhMSCs induced an accelerated renal functional recovery, demonstrated by biochemical parameters and confirmed by histology showing that histopathological alterations associated with ischemic injury were less severe in cell-treated kidneys. HB-treated rats showed a minor degree of inflammation, both at cytokine and TEM analyses. Better functional and morphological recovery were not associated to stem cells' regenerative processes, but possibly suggest paracrine effects on microenvironment that induce retrieval of renal damaged tissues. These results suggest that FMhMSCs could be useful in the treatment of AKI and the utilization of synthetic compounds could enhance the recovery induction ability of cells.

Cardiovascular disease in kidney transplant recipients: the prognostic value of inflammatory cytokine genotypes.

BACKGROUND: Cardiovascular disease (CVD) represents the main cause of morbidity and mortality after renal transplantation. In view of the modern paradigm of atherosclerosis as an inflammatory disease, this study investigated the impact of inflammatory cytokine polymorphisms on posttransplant CVD. METHODS: The association between cytokine polymorphisms and CVD was assessed in a case-control study to identify the differences in genotype distributions between kidney allografts with or without posttransplant CVD. To validate our results in two independent groups, we divided a cohort of 798 renal transplant recipients according to geographic area: an evaluation cohort of 478 patients from Emilia-Romagna and a validation cohort of 320 patients from the rest of Italy. Tumor necrosis factor (TNF)-alpha, transforming growth factor-beta1, interleukin (IL)-10, IL-6, interferon-gamma, and IL-8 polymorphisms were analyzed, and thereafter, the cytokine production genotype was assigned. RESULTS: In the evaluation cohort, the patients in the CVD and no-CVD groups differed significantly in TNF-alpha and IL-10 genotype frequencies. Using multivariate analyses to test the association with CVD, the TNF-alpha high-producer genotype was associated with a significantly increased cardiovascular risk (odds ratio [OR]=4.41, 95% confidence interval (CI)=2.53-7.67). Conversely, the IL-10 high-producer genotype resulted protective against CVD (OR=0.07, 95% CI=0.02-0.29). These findings were confirmed in the validation cohort where the carriers of the TNF-alpha high-producer genotype proved to be at 2.45-fold increased cardiovascular risk (OR=2.45, 95% CI=1.29-4.63), whereas the IL-10 high-producer genotype was associated with a 0.08-fold reduced risk (OR=0.08, 95% CI=0.02-0.36). CONCLUSIONS: This work suggests a prognostic value of TNF-alpha and IL-10 genotypes, which might represent cardiovascular risk markers in renal transplant.

Tacrolimus combined with two different corticosteroid-free regimens compared with a standard triple regimen in renal transplantation: one year observational results.

Side effects of steroid use have led to efforts to minimize their use in transplantation. Two corticosteroid-free regimens were compared with a triple immunosuppressive therapy. Data from the original intent-to-treat (ITT) population (153 tacrolimus/basiliximab [Tac/Bas], 151 tacrolimus/MMF [Tac/MMF], and 147 tacrolimus/MMF/steroids [control]) were analyzed in a 12-month follow-up. Percentage of graft survival were 92.8%, 95.4%, and 95.9% (KM estimates 89.9%, 95.3%, 95.9%), percentage of surviving patients were 98.7%, 98.0%, and 100% (KM estimates 95.9%, 92.8%, and 100%). During months 7-12, graft loss occurred in 3 Tac/Bas, 2 Tac/MMF, and zero control patients, patient deaths in 1 Tac/Bas, 2 Tac/MMF, and zero control, and biopsy-proven acute rejection episodes in 4 Tac/Bas, 3 Tac/MMF, and zero control. Mean serum creatinine at month 12 was 141.9 +/- 69.6 microM, 144.0 +/- 82.1 microM, and 134.5 +/- 71.2 microM (ns). New-onset insulin use in previously non-diabetic patients at month 12 was 1/138, 6/127, and 4/126. Patient and graft survival as well as renal function at 12 months were not different between patient groups, despite considerably higher rates of acute rejection occurring within the first six months after transplantation in both steroid-free patient groups. Tac/Bas therapy might offer benefits in terms of a trend for a more favorable cardiovascular risk profile.

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 x P), body mass index (BMI), fetuin-A, osteoprotegerin (OPG), osteopontin, transforming growth factor-beta1 (TGF-beta1), 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-beta1, OPG and days with Ca x 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.