R Palla

Università di Pisa, Pisa, Tuscany, Italy

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Publications (90)210.24 Total impact

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    ABSTRACT: Mixed diffusive-convective dialysis therapies offer greater removal capabilities than conventional dialysis. The aim of this study was to compare two different on-line, post-dilution hemodiafiltration (HDF) treatments with regard to achieved convective volume and middle-molecule dialysis efficiency: standard volume control (sOL-HDF) and automated control of the transmembrane pressure (TMP) (UC-HDF). We enrolled 30 ESRD patients (55.9 ± 14.0 years, 20/10 M/F) in a randomized, prospective, cross-over study. The patients received a 3-month period of sOL-HDF followed by UC-HDF for a further 3 months, or vice versa, using the same dialysis machine. In sOL-HDF, fixed exchange volumes were set according to a filtration fraction greater than or equal to 25%. In UC-HDF therapy, the exchanged volume was driven by a biofeedback system controlling the TMP and its set point in a double loop. Patients maintained their treatment time, dialyzer, blood flow rate, and anticoagulant regimen unchanged throughout the study. Greater convective volumes were achieved in UC-HDF than in sOL-HDF (23.8 ± 3.9 vs.19.8 ± 4.8 L; p<0.001) with high pre-dialysis Ht value (sOL-HDF 34.0 ± 4.5% and UC-HDF 34.0 ± 4.4%; p = 0.91). The average clearance values of ß2m and P were higher in UC-HDF than in sOL-HDF (respectively 123 ± 24 vs. 111 ± 22 ml/min, p<0.002 and 158 ± 26 vs. 152 ± 25 ml/min, p<0.05). Moreover, the UC-HDF mode led to a significantly increased rate of call-free sessions from 88% to 97% (p<0.0001). This study showed that the biofeedback module, applied to the automatic control of TMP in on-line HDF, results in higher convective volumes and correspondingly higher ß2m and P clearances. By making the HDF treatment more automated and less complex to perform, it significantly reduced the staff workload.
    The International journal of artificial organs 06/2012; 35(6):435-43. DOI:10.5301/ijao.5000106 · 0.96 Impact Factor
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    ABSTRACT: 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 20 mL/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.
    Renal Failure 07/2009; 23(3-4):551-62. DOI:10.1081/JDI-100104737 · 0.94 Impact Factor
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    ABSTRACT: The 'RISchio CArdiovascolare nei pazienti afferenti all' Area Vasta In Dialisi' (RISCAVID) study is an observational and prospective trial including the whole chronic haemodialysis (HD) population in the northwest part of Tuscany (1.235 million people). The aim of the study was to elucidate the relevance of traditional and non-traditional risk factors of mortality and morbidity in HD patients as well as the impact of different HD modalities. A total of 757 HD patients (mean age 66 +/- 14 years, mean dialytic age 70 +/- 76 months, diabetes 19%) were prospectively followed up for 30 months and all-cause mortality, cardiovascular (CV) mortality and non-fatal CV events (acute myocardial infarction and stroke) were registered. At the time of the enrolment, demographic, clinical and laboratory data of the whole population were entered into a centralized database. Serum albumin, high-sensitive C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-8 (IL-8) were centrally determined at the start of the study. Patients were stratified into three groups according to the HD modality: standard bicarbonate HD (BHD) (n = 424), haemodiafiltration (HDF) with sterile bags (n = 204) and online HDF (n = 129). The Cox proportional hazards regression assessed adjusted differences in CV morbidity and mortality risk; a multivariate analysis was also performed. All-cause and CV mortality was 12.9%/year and 5.9%/year, respectively. Patients with combined high levels of CRP and pro-inflammatory cytokines showed an increased risk for CV (RR 1.9, P < 0.001) and all-cause mortality (RR 2.57, P < 0.001). Multivariate analysis adjusted for comorbidity and demographic showed CRP as the most powerful mortality predictor (P < 0.001) followed by IL-6. The Cox proportional hazards regression assessed that online HDF and HDF patients had a significantly increased adjusted cumulative survival than BHD (P < 0.01). Data at 30 months from this study showed the synergic effect of CRP and pro-inflammatory cytokines as the strong predictors of all-cause and CV mortality. HDF was associated with an improved cumulative survival independent of the dialysis dose.
    Nephrology Dialysis Transplantation 07/2008; 23(7):2337-43. DOI:10.1093/ndt/gfm951 · 3.58 Impact Factor
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    ABSTRACT: 131I-labelled Human Serum Albumin and 125I-sodium iodide were used to measure protein loss from the peritoneum and peritoneal clearance of iodide in a group of 8 uraemic patients, each one being studied after a different number of dialyses.Both albumin loss and iodide clearance reached a maximum at about the 10th dialytic treatment and then tended towards the initial levels.Protein loss as determined isotopically was markedly lower than indicated by direct radioimmunoassay measurements performed in three cases. Fitting experimental points by a model which assumes direct passage of protein from plasma to peritoneal cavity suggests the presence of a “delay” pool between plasma and the peritoneal cavity itself (extravascular sites adjacent to peritoneum?).The shorter retention time of the dialysis solution in the abdomen (4–8 minutes) seemed to us to cause lower protein losses than reported by authors using longer retention times.
    European Journal of Clinical Investigation 06/2008; 5(1):109 - 114. DOI:10.1111/j.1365-2362.1975.tb00435.x · 2.73 Impact Factor
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    ABSTRACT: HFR [double chamber haemodiafiltration (HDF) with reinfusion of regenerated ultrafiltrate] is a novel dialytic method which combines the processes of diffusion, convection and adsorbance. In this technique an adsorbent cartridge of resin and charcoal may regenerate the ultrafiltrate suggesting its use as an endogenous substitution fluid. The aim of this multicentre randomized cross-over study was to compare HFR to online HDF in terms of inflammatory and nutritional parameters. After a 1 month run-in period of standard bicarbonate dialysis (HD) with a synthetic membrane, 25 chronic dialytic patients were randomized (A-B or B-A) to be treated by HFR (A) with a two-chamber filter (SG 8 Plus - high permeability Polysulphone HF 0.7 m2 + SMC 1.95 sqm; Bellco, Mirandola, Italy) or by online sterile bicarbonate HDF. Each study period of 4 months was separated by 1 month of HD and the entire length of the study was 10 months. CRP levels were measured by a highly sensitive nephelometric assay (Dade, Behring) with a sensitivity of 0.1 microg/ml. Cytokine concentrations were determined by EIA [Interleukin (IL) 6, Biosource, USA and IL-10 Bender MED-Systems, Vienna]. The sensitivity thresholds were < 5 pg/ml for IL-6 and < 8 pg/ml for IL-10. Serum leptin was determined with a ELISA method (Biosource, USA). All parameters were determined monthly in patients starting a midweek dialytic session. Plasma CRP and IL-6 were significantly reduced during the 4 months of HFR and HDF: CRP from 8.0 +/- 3.2 to 5.6 +/- 3.4 mg/l with HFR (P < 0.05) and from 9.4 +/- 4.3 to 5.9 +/- 3.9 mg/l with HDF (P < 0.05). IL-6 decreased from 14.8 +/- 6.3 to 10.1 +/- 3.2 with HFR (P < 0.02) and from 12.1 +/- 4.2 to 9.6 +/- 3.7 with HDF (P = ns) with a percentage decrease after 4 months of 32% with HFR vs 21% with HDF. During the 1 month wash-out period with HD, CRP increased from 5.7 +/- 3.6 to 8.7 +/- 3.9 mg/l (P < 0.01) and IL-6 from 10 +/- 3.4 to 13.5 +/- 5.2 pg/ml (P < 0.01). A significant increase in IL-10 was detected either in HFR (from 4.8 +/- 2.1 to 6.89 +/- 1.7 pg/ml) and in HDF (from 3.3 +/- 1.7 to 8.95 +/- 4.3 pg/ml; P < 0.05) after 4 months. No significant variation in serum leptin levels were observed during the study. CRP and IL-6 were highly correlated (r = 0.54; P < 0.001) as was serum albumin and prealbumin (r = 0.39; P < 0.001). Serum albumin was negatively correlated with CRP (r = -0.26; P < 0.01) and IL-6 (r = -0.19; P < 0.05); serum prealbumin was correlated with IL-6 (r = 0.37; P < 0.001) and with CRP (r = 0.24; P < 0.01). Haemodiafiltration with online regeneration of ultrafiltrate and online HDF are highly biocompatible techniques and no significant difference between HFR and online HDF was observed in terms of reduction of inflammatory markers. Further studies with a longer follow-up are needed to evaluate the clinical relevance of the online endogenous reinfusion to counteract the chronic inflammatory state of the uraemic patient.
    Nephrology Dialysis Transplantation 03/2006; 21(3):756-62. DOI:10.1093/ndt/gfi189 · 3.58 Impact Factor
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    ABSTRACT: Despite the well known association between interleukin-6 (IL-6) and cardiovascular mortality, no study has so far verified whether IL-6 adds prognostic information to that provided by C-reactive protein (CRP). A cohort of 218 haemodialysis patients from four different dialytic centres was followed-up retrospectively. Plasma IL-6 and CRP concentrations were determined. Full information on co-morbidities was available in 162 patients. With respect to the lowest quartile (< 3.6 pg/ml for IL-6, and < 2.2 mg/l for CRP), the crude relative risk (RR) of death from all causes of the upper quartile (> 13.9 pg/ml for IL-6, and > 12.8 mg/l for CRP) was 5.20 (95% confidence interval 2.06-13.011) for IL-6 and 3.16 (1.41-7.12) for CRP. When both variables were included, the estimates were 4.10 (1.30-12.96) for IL-6 and 1.29 (0.47-3.57) for CRP. As to continuous variables, the relationship between both variables and mortality tended to level off for the highest values, but became fairly linear after log transformation of the variables. For one unit SD of the log (variable), the RR was 2.09 (1.52-2.88) for IL-6 and 1.66 (1.23-2.24) for CRP. When they were included in the same model, the estimates were 1.90 (1.18-2.82) for IL-6 and 1.16 (0.81-1.66) for CRP. IL-6 has a stronger predictive value than CRP for cardiovascular mortality and provides independent prognostic information, while conveying most of that provided by CRP.
    Nephrology Dialysis Transplantation 05/2004; 19(5):1154-60. DOI:10.1093/ndt/gfh052 · 3.58 Impact Factor
  • Nephron 10/2002; 92(2):498-498. · 13.26 Impact Factor
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    ABSTRACT: Several studies have provided convincing evidence that in apparently healthy subjects elevated serum levels of plasma C-reactive protein (CRP) are associated with an increased risk of experiencing myocardial infarction and sudden cardiac death. It has been claimed that, in dialytic patients, the hepatic synthesis of this 'acute phase response' plasma protein is primarily induced by the macrophage-derived interleukin 6 (IL-6). Little information is available, however, regarding CRP and IL-6 plasma levels in pre-dialytic renal failure. Plasma CRP by a modification of the laser nephelometry technique, IL-6 and serum albumin were determined in 103 chronic pre-dialytic patients (mean age 50 +/- 6.3 years; creatinine clearance (Cr.cl.) 36.3 +/- 23.1 ml/min). CRP was >5 mg/l (normal upper range) in 42% of the global population. CRP and IL-6 were significantly related (r = 0.35, p < 0.0004). CRP and IL-6 were related to renal function (CRP vs. Cr.cl., r = -0.56, p < 0.0001; IL-6 vs. Cr.cl., r = -0.55, p < 0.0001, Spearman correlation coefficient). When patients were divided in tertiles according to renal function, CRP median value resulted 7.9 mg/l (interquartile interval: 5-12) in the first tertile (Cr.cl. <18.5 ml/min), 4.0 mg/l (3-6) in the second tertile (Cr.cl. 18.5-45 ml/min) and 3.2 mg/l (2.7-4.0) in the last tertile (Cr.cl. >45 ml/min) (p < 0.0001). A negative correlation between CRP and S-albumin was also found (r = -0.52, p < 0.0001, Spearman correlation coefficient). IL-6 and CRP were increased and were inversely related to creatinine clearance in our population of 103 chronic predialytic patients. The possibility of a decreased renal clearance of CRP and/or cytokines as a cause of an activated acute-phase response is discussed. A negative correlation between CRP and S-albumin was found confirming the link between chronic inflammation and malnutrition in chronic renal patients.
    Nephron 08/2002; 91(4):594-600. DOI:10.1159/000065018 · 13.26 Impact Factor
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    ABSTRACT: 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D3, is a potent immunomodulatory agent on several cell types such as monocytes and mesangial cells. Recruitment of inflammatory cells, as well as stimulation of resident cells and mesangial matrix accumulation are key features of various experimental and human glomerular diseases. Here we show that 1,25(OH)2D3 attenuates the morphologic and functional alterations in anti-Thy-1.1. nephritis, an experimental model of mesangial proliferative glomerulonephritis. The anti-Thy-1.1 group (group I) comprised 24 rats that at day 0 received 0.5 mL of saline containing 400 microg of monoclonal antibodies (mAb) anti-Thy-1.1 IgG. The anti-Thy-1.1 treated with 1,25(OH)2D3 group (group II) were 24 rats given 1,25(OH)2D3 at the dose of 25 ng/100 g body wt/day, from day -3 to day 14. At day 0, the rats received 400 microg of anti-Thy-1.1 monoclonal IgG. The control group (group III) comprised 12 rats injected with vehicle alone; the control group treated with 1,25(OH)2D3 (group IV)-12 rats were given 1,25(OH)2D3 as in group II without mAb administration. Proteinuria and urinary interleukin-6 excretion were measured daily. Blood urea nitrogen and creatinine, creatinine clearance, calcium, and phosphate were measured at days 0, 4, 7, and 14. In addition to conventional periodic acid-Schiff staining, binding of anti-Thy-1.1 IgG and C3b complement fraction, His48- and ED1-positive cells were studied by immunofluorescence. Mesangial proliferation was studied by the proliferating cell nuclear antigen (PCNA) technique. Apoptosis was evaluated by the TUNEL assay. The anti-Thy-1.1 treated with 1,25(OH)2D3 group versus the anti-Thy-1.1 alone group showed a significant reduction in urinary protein (at day 7, 424 +/- 228 vs. 66 +/- 30 mg/mg urinary creatinine, P = 0.02) and interleukin-6 excretion (at day 3, 537 +/- 360 pg/mL vs. 110 +/- 34 pg/mg urinary creatinine, P = 0.015), reduced glomerular diameters (at day 7, 283 +/- 38 vs. 261 +/- 48 microm, P < 0.01), decreased neutrophil (at day 4, 20 +/- 12 His48-positive cells/glomerulus vs. 3.7 +/- 1.3 His48-positive cells/glomerulus, P < 0.001), and monocyte accumulation (day 7, 4.9 +/- 2.9 ED1-positive cells/glomerulus vs. 2.8 +/- 2.9 ED1-positive cells/glomerulus, P < 0.05), and attenuated glomerular cells proliferation (day 7, 13 +/- 3.2 PCNA-positive cells/glomerulus vs. 9.4 +/- 3 PCNA-positive cells/glomerulus, P < 0.01). Apoptosis showed a biphasic behavior with an early peak at day 4 in the anti-Thy-1.1 group (2.3 +/- 2.2 TUNEL-positive cells/glom) related to cellular lysis and a late peak at day 14 related to the recovery phase. 1,25(OH)2D3 can reduce glomerular hypercellularity, inflammatory infiltration in anti-Thy-1.1 nephritis, preserving the apoptotic response of the reparative phase.
    Kidney International 08/2001; 60(1):87-95. DOI:10.1046/j.1523-1755.2001.00775.x · 8.56 Impact Factor
  • Transplantation Proceedings 06/2001; 33(3):2366-8. DOI:10.1016/S0041-1345(01)02023-1 · 0.98 Impact Factor
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    ABSTRACT: Recent studies suggest that chronic inflammation plays a role in the pathogenesis of cardiovascular disease. Cytokines released from jeopardized tissues stimulate the liver to synthesize acute phase proteins, including C-reactive protein (CRP). Baseline levels of CRP in apparently healthy persons or in persons with unstable angina constitute an independent risk factor for cardiovascular events. More recently, it has been suggested that CRP is useful not only as a marker of the acute phase response, but is also involved in the pathogenesis of the disease. CRP may, in fact, directly interact with the atherosclerotic vessels or ischemic myocardium by activation of the complement system, thereby promoting inflammation and thrombosis. Several studies in uremic patients have implicated CRP as a marker of malnutrition, resistance to erythropoietin, and chronic stimulation in hemodialysis. An increased cytokine production secondary to blood interaction with bioincompatible dialysis components has been reported by several studies; interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and mainly IL-6 are the three proinflammatory cytokines involved in the pathogenesis of hemodialysis-related disease. We have provided evidence for the occurrence of high CRP and IL-6 levels in chronic dialytic patients exposed to contaminate dialysate and suggest that backfiltration may induce a chronic, slowly developing inflammatory state that may be abrogated by avoiding backfiltration of contaminate dialysate. Therefore, CRP is implicated as a marker linking bioincompatibility associated with backfiltration and increased cytokine production with a clinical state of chronic inflammation.
    Kidney international. Supplement 09/2000; 76(Suppl. 76):S96-103. DOI:10.1046/j.1523-1755.2000.07612.x
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    ABSTRACT: BACKGROUND. Anti-neutrophil cytoplasmic autoantibodies (ANCA) have been described in patients suffering from systemic vasculitis such as Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and other pathological conditions. In this paper we report a greater incidence of ANCA in hemodialysis patients as compared to peritoneal dialysis patients, pre-dialytic uremic patients and non-renal patients; a possible role for dialysis bioincompatibility in ANCA generation was also investigated. A total of 335 uremics in substitutive treatment (176 in hemodialytic treatment and 159 in peritoneal dialysis) were examined for ANCA positivity. A total of 189 patients with advanced renal failure in conservative treatment and 100 healthy subjects were used as control. The dialysis techniques were standard hemodialysis (n = 119), low volume hemodiafiltration (n = 26) and hemofiltration (n = 31). ANCA positivity was examined by immunofluorescence (IF): diffuse finely granular staining was considered as classical positive reaction (C-ANCA) and P-ANCA was diagnosed if a perinuclear staining was observed. EIA for proteinase-3 (anti PR-3) and myeloperoxidase-antibodies (anti-MPO) were also performed. In non-renal patients and in patients with pre-dialytic renal insufficiency none were found ANCA positive. In peritoneal dialysis patients all but one were ANCA negative with IF, with all EIA test resulting negative. In hemodialytic patients, a positive IF test was found in 26 (14.7%) for P-ANCA and in 5 (2.8%) for C-ANCA; using the EIA test 23 (13%) patients were positive for MPO and 12 (6.8%) for PR-3. No correlation with age, primary renal diseases, dialytic age, dialysis membrane materials was found; regarding the different extracorporeal dialytic techniques a higher incidence (p < 0.02) was detected in patients undergoing HDF Backfiltration of contaminated dialysate may induce ANCA via an increased cytokine generation.
    The International journal of artificial organs 03/2000; 23(2):97-103. · 0.96 Impact Factor
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    ABSTRACT: Cardiovascular complications caused by an accelerated atherosclerotic disease represent the largest single cause of mortality in chronic renal failure patients. The rapidly developing atherosclerosis of the uremic syndrome appears to be caused by a synergism of different mechanisms, such as malnutrition, oxidative stress and genetic factors. Recent studies provide evidence that chronic inflammation plays an important role in the pathogenesis of cardiovascular diseases. Elevated serum levels of plasma C-reactive protein (CRP) are associated with an increased risk of experiencing myocardial infarction and sudden cardiac death in apparently healthy subjects. Several recently published papers have confirmed this strong association between CRP and the extent and severity of the atherosclerotic processes. In patients affected by predialytic renal failure, increased levels of CRP and interleukin (IL)-6 were recorded in 25% of our population; CRP and IL-6 were inversely related with renal function. These data suggest the activation - even in the predialytic phase of renal failure - of mechanisms known to contribute to the enhanced cardiovascular morbidity and mortality of the uremic syndrome. In recent years we have investigated the hypothesis that the chronic inflammatory state of the uremic patient could at least in part be due to the dialytic technique. We provide evidence suggesting that the increase of CRP in stable dialytic patients may be due to the stimulation of monocyte/macrophage by backfiltration of dialysate contaminants.
    Blood Purification 02/2000; 18(3):183-90. DOI:10.1159/000014417 · 1.28 Impact Factor
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    ABSTRACT: In hemodialysis patients, C-reactive protein (CRP), an acute-phase reactant, is a sensitive and independent marker of malnutrition, anemia, and amyloidosis. The aim of the present studies was to evaluate CRP and interleukin 6 levels in plasma samples from long-term hemodialysis patients on different extracorporeal modalities associated with or without backfiltration. Two hundred and forty-seven patients were recruited in eight hospital-based centers. All patients had been on their dialytic modality for at least 6 months. At enrollment, 46 hemodialysis patients out of 247 (18.6%) had clinical evidence of pathologies known to be associated with high CRP values. The 201 remaining patients were defined as clinically stable and were on conventional hemodialysis (34%), hemodiafiltration with infusion volumes <10 liters/session (10%), hemodiafiltration with infusion volumes <20 liters/session (32%), and double-chamber hemodiafiltration with infusion volumes <10 liters/session (22%). Analysis of CRP values in the clinically stable patients showed that an unexpectedly high proportion (47%) of the patients had CRP values higher than 5 mg/l (taken as the upper limit in normal human subjects). The values of CRP and interleukin 6 were significantly higher in hemodiafiltration with infusion volumes <10 liters/session than in hemodiafiltration with infusion volumes >20 liters/session, in hemodialysis and in double-chamber hemodiafiltration. The same pattern occurred after 6 months of follow-up in 171 out of 201 clinically stable patients. Hemodialytic conditions that expose to the risk of backfiltration such as low exchange volume hemodiafiltration may induce a chronic inflammatory state as reflected by increased plasma values of both CRP and interleukin 6, thus suggesting the need for hemodialytic strategies that reduce (hemodialysis with low-permeability membranes or hemodiafiltration with infusion volumes >20 liters) or eliminate (double-chamber hemodiafiltration) backfiltration of bacteria-derived contaminants.
    Blood Purification 02/2000; 18(1):30-6. DOI:10.1159/000014405 · 1.28 Impact Factor
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    ABSTRACT: Recombinant human erythropoietin (rHuEpo) is the treatment of choice in anemia associated with end-stage renal disease. Its major side effect is hypertension, which occurs in 8-30% of uremic patients. The exact mechanism of rHuEpo-induced hypertension has not been fully elucidated, and several possibilities have been proposed, such as a direct vascular effect of the drug with a shift in the balance of constrictor and relaxing endothelial factors (endothelins and nitric oxide (NO)). Recent papers suggested an enhanced rather than reduced activity of endogenous NO system in rats with normal renal function and rHuEpo-induced hypertension. Our study was designed to verify whether, in spite of enhanced activity of the renal NO system, rHuEpo may affect endothelium-dependent (acetylcholine-induced) and/or endothelium-independent (sodium nitroprusside-induced) vasorelaxation and to evaluate basal NO release by the infusion of NG-nitro-L-arginine methyl ester (L-NAME) in an isolated and perfused rat kidney model. To investigate this hypothesis, we have determined systemic and renal NO activity in Wistar rats treated with a hypertensive dose of rHuEpo (150 IU/kg b.w. every other day for 2 weeks) by measuring stable NO metabolites (NO2+NO3) in the urine and have also evaluated variations in renal vascular resistance after the injection of Ach, SNP and the infusion of L-NAME. Hematocrit, hemoglobin concentration and arterial blood pressure were significantly increased in the treated group as compared with the controls. Urinary excretion of NO2+NO3 was significantly higher in treated than in the controls (438+/-66 vs. 294+/-36 nM/ml/min, p<0.01, respectively). There were no significant differences in the dose-response curves to Ach and SNP between the two groups. The renal vasoconstriction following the infusion of L-NAME was also similar in the two groups. The analysis of our results seems to indicate that the endogenous NO system activity was enhanced in rHuEpo-induced hypertension in rats with normal renal function and a resistance to NO was not developed in renal circulation. Further studies seem to be necessary to better clarify the exact mechanisms underlying the development of rHuEpo-induced hypertension.
    Kidney and Blood Pressure Research 06/1999; 22(3):140-5. DOI:10.1159/000025920 · 2.12 Impact Factor
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    ABSTRACT: In recent years, acute phase reactants have been reevaluated as not merely biochemical markers of inflammation but also as active modulators of the inflammatory response. C-reactive protein - which is normally present in serum in only trace amounts, but whose concentration may rise markedly with inflammatory stimuli - was the first human acute phase protein discovered. It is now clear that cytokines are the major mediators of acute phase protein induction: interleukin-6 currently is felt to be the principal cytokine influencing C-reactive protein acute changes. Several studies have provided convincing evidence that among normal men, base-line serum levels of C-reactive protein are predictive of future myocardial infarction and ischemic stroke. The relevance of acute phase reactants in morbidity and mortality of haemodialysis patients has not been fully elucidated until now: in fact a few studies have implicated C-reactive protein in malnutrition, EPO-resistance, as a cardiovascular risk factor and as a marker of chronic stimulation in haemodialysis. The authors suggest the hypothesis of the occurrence of long-term complications in patients exposed to contaminated dialysate and suggest that back-filtration may induce a chronic, slowly developing inflammatory state that may be abrogated by avoiding backfiltration of contaminated dialysate.
    Blood Purification 02/1999; 17(2-3):142-8. DOI:10.1159/000014386 · 1.28 Impact Factor
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    ABSTRACT: Calcitriol modulates in vivoand in vitro cytokine production: A role for intracellular calcium. Background. Several immunomodulatory properties of calcitriol are currently known, however, only little information is available regarding the in vivo and in vitro effects of calcitriol on cytokine production in chronic renal failure. Methods. To study the in vitro effect of calcitriol on lipopolysaccharide (LPS)-induced cytokine production, peripheral blood mononuclear cells (PBMC, 2.5 ml/ml) from 12 chronic dialytic (HD), 15 undialyzed chronic renal failure (CRF) patients and 10 normal subjects (N) were incubated at 37 degrees for 12 hours with 100 ng of LPS (E. coli and P. maltofilia). Increasing doses of calcitriol from 10-10 to 10-9 M were added and cell associated TNF-alpha and IL-1beta were determined by immunoreactive tests after three freeze-thaw cycles. The intradialytic TNF-alpha and IL-1beta production were evaluated in vivo in 12 HD patients before and after three months of intravenous calcitriol treatment (6 microgram/week). Intracellular calcium [Ca++]i was determined on PBMC with a cytofluorimetric assay using FLUO-3 AM as the indicator. Results. In vitro, TNF-alpha increased from 3.6 +/- 1.9 pg/cell to 1797 +/- 337 in N, from 4.5 +/- 1.7 to 1724 +/- 232 in CRF and from 3.4 +/- 2.3 to 1244 +/- 553 in HD after the LPS stimulus. The production of TNF-alpha was inhibited by calcitriol in a dose-dependent manner [LPS + Vit.D3 100 ng, 2.9 +/- 2.1 in N, 3.7 +/- 1.9 in CRF and 3.4 +/- 1.7 in HD; LPS + Vit.D3 50 ng, 263 +/- 296 (N), 6.73 +/- 11 (CRF), 38 +/- 28 (HD); LPS + Vit.D3 25 ng = 873 +/- 583 (N), 325 +/- 483 (CRF), 588 +/- 507 (HD); LPS + Vit.D3 12.5 ng, 954 +/- 483 (N), 912 +/- 510 (CRF), 875 +/- 527 (HD)]. Comparable data were observed on IL-1beta production. In vivo, the intradialytic TNF-alpha increase (from 8.5 +/- 2.3 to 19 +/- 5.6 pg/2.5 x 106 cell) during hemodialysis was markedly reduced after calcitriol therapy (from 6.6 +/- 3.1 to 11 +/- 4.7). [Ca++]i decreased from 105 +/- 25 to 72 +/- 18 nM (P < 0.05) and a positive correlation between cytokine levels and [Ca++]i was found (r = 0.79; P < 0.001). Conclusions. The in vitro increase of cell-associated cytokine after LPS challenge was inhibited by calcitriol in a dose-dependent manner. These data suggest a possible in vivo modulatory effect of calcitriol therapy on cytokine production in hemodialysis.
    Kidney International 12/1998; 54(5):1463-9. DOI:10.1046/j.1523-1755.1998.00152.x · 8.56 Impact Factor
  • Transplantation Proceedings 09/1998; 30(5):2028-9. DOI:10.1016/S0041-1345(98)00520-X · 0.98 Impact Factor
  • Transplantation Proceedings 09/1998; 30(5):2026-7. DOI:10.1016/S0041-1345(98)00519-3 · 0.98 Impact Factor
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    ABSTRACT: Bacterial contamination of dialysate may enhance cytokine production in hemodialysis. The authors tested the hypothesis that C-reactive protein and interleukin-6 (IL-6) may be linked in a large group of patients exposed to backfiltration of dialysate over a long period of observation. Plasmas stored in a recently published multicenter study were reevaluated. Plasma C-reactive protein and IL-6 concentrations in patients with chronic uremia undergoing hemodiafiltration, which is known to be associated with backfiltration (Group II, 12 patients), were compared with those found in patients treated with a modified hemodiafiltration modality without backfiltration (Group I, 16 patients), and in patients shifted from one modality to the other (Group III, 27 patients), and in 10 patients on hemodialysis (Group IV) in a 1 year multicenter study. Plasma C-reactive and IL-6 both increased significantly (p<0.002), but slowly (after 8 months) in Group II compared with I, and during the 4 month period in hemodiafiltration with backfiltration in Group III. Backfiltration of dialysate with a moderate to low degree of contamination may enhance synthesis of cytokine and C-reactive protein in the long term. Thus, the relevance for dialytic strategies aiming at improving dialysate quality or at reducing backfiltration is highlighted. (C)1998Amercian Society of Artificial Internal Organs
    ASAIO Journal 08/1998; 44(5). DOI:10.1097/00002480-199809000-00018 · 1.52 Impact Factor

Publication Stats

1k Citations
210.24 Total Impact Points


  • 1975–2009
    • Università di Pisa
      • Department of Clinical and Experimental Medicine
      Pisa, Tuscany, Italy
  • 2004
    • Windsor Regional Hospital
      Windsor, Ontario, Canada
  • 1995–2001
    • University of Milan
      • Department of Pharmacology, Chemotherapy and Medical Toxicology
      Milano, Lombardy, Italy
  • 1998
    • Civil Protection Department of Italy
      Roma, Latium, Italy