HCV cirrhotic patients treated with direct-acting antivirals: Detection of tubular dysfunction and resolution after viral clearance.

BACKGROUND/AIMS: Hepatitis C virus (HCV) has been identified in tubular epithelial cells of infected patients; however, the presence of tubular dysfunction, which is a risk factor for chronic kidney disease (CKD), has never been examined in vivo. The present prospective longitudinal study aimed to estimate the prevalence of tubular dysfunction alone or with glomerular damage and its evolution after HCV clearance in cirrhotic patients. METHODS: One hundred and thirty-five consecutive Child-Pugh A cirrhotic patients were evaluated before antiviral treatment and 6 months after the end of therapy. Tubular dysfunction was evaluated by urinary alpha1-microglobulin to creatinine ratio (α1-MCR), and glomerular damage was assessed by urinary albumin to creatinine ratio (ACR). RESULTS: Almost all the patients (93.3%) showed a normal or mildly decreased e-GFR (KDIGO-G1/G2-categories). Tubular dysfunction was found in 23.7% (32/135) of patients, co-occurring with glomerular damage in 37.5% (12/32) of cases, while glomerular damage was found in 16.3% (22/135) of patients. In multiple logistic regression, glomerular damage and the concomitant presence of diabetes and hypertension were the only predictors significantly associated with tubular dysfunction. After HCV clearance, patients experienced a significant reduction of α1-MCR levels (21.0 vs 10.5 µg/mg, P = .009) and tubular dysfunction resolved in 57.1% of subjects. CONCLUSIONS: Tubular dysfunction is an unrecognized feature of HCV-related kidney disease in cirrhotic patients and its presence should be primarily investigated in subjects with glomerular damage, diabetes and hypertension, despite normal e-GFR. Tubular dysfunction resolves in the majority of cases after HCV clearance; however, it may persist after antiviral treatment and further studies should evaluate its long-term impact on kidney function.

Copeptin Kinetics in Acute Ischemic Stroke May Differ According to Revascularization Strategies: Pilot Data.

Background and Purpose- Prognostic value of copeptin in acute ischemic stroke has been widely reported. This study aimed to evaluate copeptin temporal profile according to revascularization strategies and the development of brain edema and hemorrhagic transformation. Methods- Plasma copeptin and brain edema and hemorrhagic transformation assessed by computed tomography/magnetic resonance imaging were evaluated upon admission (T0), at 24 hours (T1), and between the third and fifth day of hospitalization (T2) in 34 acute ischemic stroke patients. Results- Median copeptin concentration was 50.71 pmol/L at T0, 18.31 pmol/L at T1, and 10.92 pmol/L at T2. Copeptin at T1 was higher in patients with medium/severe brain edema at T2 (32.25 versus 13.67 pmol/L; P=0.038) and hemorrhagic transformation at T1 (93.10 versus 13.67 pmol/L; P<0.003) and T2 (85.70 versus 14.45 pmol/L; P=0.024). Copeptin level drop (CopΔT1-T0) was significantly steeper in patients receiving revascularization, particularly in those undergoing combined therapy (-129.34 versus -5.43 pmol/L; P=0.038). ΔT1-T0 also correlated with Thrombolysis in Cerebral Infarction score (P<0.001). Conclusions- Copeptin resulted associated with brain edema and hemorrhagic transformation in acute ischemic stroke, and its drop at 24 hours may mirror effective brain vessel recanalization.

Presepsin as a potential marker for bacterial infection relapse in critical care patients. A preliminary study.

BACKGROUND: Systemic bacterial infection carries a high risk of mortality in critical care patients. Improvements in diagnostic procedures are required for effective management of sepsis. Recently, the soluble CD14 subtype, or presepsin, has been suggested as a reliable marker of sepsis, and we set out to compare its diagnostic performance with that of procalcitonin (PCT). We focused on a cohort of septic patients who, during their hospitalization, relapsed after a period of clinical relief from symptoms. METHODS: In total 21 adult patients were studied during their hospitalization in the Critical Care Unit of Policlinico Umberto I hospital; 74 plasma samples were collected at multiple time points, and presepsin levels were measured using a PATHFAST analyzer. RESULTS: Presepsin and PCT were significantly lower in healthy controls than in sepsis or severe sepsis (p<0.001), both enabled a significant difference to be detected between systemic inflammatory response syndrome (SIRS) and severe sepsis (p<0.05). The area under the curve (AUC) calculated from the receiver operating characteristic (ROC) curve analysis was 0.888 for presepsin and 0.910 for PCT. In those patients in whom a clinical recurrence of sepsis was observed, while PCT levels normalized during the transient remission phase, presepsin levels (>1000 pg/mL) remained high. CONCLUSIONS: This study confirms the importance of monitoring a combination of several biomarkers in order to obtain a reliable diagnosis. Maximal presepsin levels could alert clinicians not to suspend antibiotic treatments and to carefully monitor septic patients' state of health, even after clinical symptoms have disappeared and PCT levels returned to normal.

Expected and Observed Glomerular Filtration Rates in Kidney Transplant Patients Converted to Once Daily Tacrolimus: 10 Years of Follow-up.

The decline of allograft kidney function in the long term remains a significant issue in renal transplantation, with drug nephrotoxicity and cardiovascular complications as important risk factors. Our study aimed to evaluate the estimated glomerular filtration rate (eGFR) trend and metabolic cardiovascular risk factors over 10 years in a cohort of kidney transplant (KT) recipients converted from twice-daily (TD) tacrolimus (Tac) to once-daily (OD)-Tac. We enrolled 55 consecutive KT recipients who had been at the outpatient clinic between 2009 and 2011. Thirty-seven reached the 10-year follow-up. We compared the observed eGFR with the expected eGFR trend described in KT-recipients and monitored blood pressure and metabolic cardiovascular risk factors. The observed eGFR remained stable throughout the complete follow-up (P = .188). The observed decline of eGFR was significantly lower compared with the expected decline for KT patients (P < .001). The blood pressure was maintained within target values. The monitoring of plasma glucose levels demonstrated the stability of median values (P = .686), as well as cholesterol level (P = .250), high-density lipoprotein (HDL) cholesterol (P = .294), and triglycerides (P = .592) throughout the follow-up. The monitoring of tacrolimus plasma level demonstrated that median trough levels remained constant (median values 4.4-5.5 ng/mL) throughout the entire follow-up period (P = .149). We suggest that the reasonable control of metabolic risk factors for cardiovascular disease over long-term follow-up may significantly contribute to the preservation of eGFR compared with the decline expected in KT recipients.

Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study.

INTRODUCTION: Recent clinical data suggest that early administration of vasopressin analogues may be advantageous compared to a last resort therapy. However, it is still unknown whether vasopressin and terlipressin are equally effective for hemodynamic support in septic shock. The aim of the present prospective, randomized, controlled pilot trial study was, therefore, to compare the impact of continuous infusions of either vasopressin or terlipressin, when given as first-line therapy in septic shock patients, on open-label norepinephrine requirements. METHODS: We enrolled septic shock patients (n = 45) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomized to receive continuous infusions of either terlipressin (1.3 microg.kg-1.h-1), vasopressin (.03 U.min-1) or norepinephrine (15 microg.min-1; n = 15 per group). In all groups, open-label norepinephrine was added to achieve a mean arterial pressure between 65 and 75 mmHg, if necessary. Data from right heart and thermo-dye dilution catheterization, gastric tonometry, as well as laboratory variables of organ function were obtained at baseline, 12, 24, 36 and 48 hours after randomization. Differences within and between groups were analyzed using a two-way ANOVA for repeated measurements with group and time as factors. Time-independent variables were compared with one-way ANOVA. RESULTS: There were no differences among groups in terms of systemic and regional hemodynamics. Compared with infusion of .03 U of vasopressin or 15 microg.min-1 of norepinephrine, 1.3 microg.kg-1.h-1 of terlipressin allowed a marked reduction in catecholamine requirements (0.8 +/- 1.3 and 1.2 +/- 1.4 vs. 0.2 +/- 0.4 microg.kg-1.min-1 at 48 hours; each P < 0.05) and was associated with less rebound hypotension (P < 0.05). At the end of the 48-hour intervention period, bilirubin concentrations were higher in the vasopressin and norepinephrine groups as compared with the terlipressin group (2.3 +/- 2.8 and 2.8 +/- 2.5 vs. 0.9 +/- 0.3 mg.dL-1; each P < 0.05). A time-dependent decrease in platelet count was only observed in the terlipressin group (P < 0.001 48 hours vs. BL). CONCLUSIONS: The present study provides evidence that continuous infusion of low-dose terlipressin--when given as first-line vasopressor agent in septic shock--is effective in reversing sepsis-induced arterial hypotension and in reducing norepinephrine requirements.

Short-term effects of phenylephrine on systemic and regional hemodynamics in patients with septic shock: a crossover pilot study.

Clinical studies evaluating the use of phenylephrine in septic shock are lacking. The present study was designed as a prospective, crossover pilot study to compare the effects of norepinephrine (NE) and phenylephrine on systemic and regional hemodynamics in patients with catecholamine-dependent septic shock. In 15 septic shock patients, NE (0.82 +/- 0.689 microg x kg(-1) x min(-1)) was replaced with phenylephrine (4.39 +/- 5.23 microg x kg(-1) x min(-1)) titrated to maintain MAP between 65 and 75 mmHg. After 8 h of phenylephrine infusion treatment was switched back to NE. Data from right heart catheterization, acid-base balance, thermo-dye dilution catheter, gastric tonometry, and renal function were obtained before, during, and after replacing NE with phenylephrine. Variables of systemic hemodynamics, global oxygen transport, and acid-base balance remained unchanged after replacing NE with phenylephrine except for a significant decrease in heart rate (phenylephrine, 89 +/- 18 vs. NE, 93 +/- 18 bpm; P < 0.05). However, plasma disappearance rate (phenylephrine, 13.5 +/- 7.1 vs. NE, 16.4 +/- 8.7% x min(-1)) and clearance of indocyanine green (phenylephrine, 330 +/- 197 vs. NE, 380 +/- 227 mL x min(-1) x m(-2)), as well as creatinine clearance (phenylephrine, 81.3 +/- 78.4 vs. NE, 94.3 +/- 93.5 mL x min(-1)) were significantly decreased by phenylephrine infusion (each P < 0.05). In addition, phenylephrine increased arterial lactate concentrations as compared with NE infusion (1.7 +/- 1.0 vs. 1.4 +/- 1.1 mM; P < 0.05). After switching back to NE, all variables returned to values obtained before phenylephrine infusion except creatinine clearance and gastric tonometry values. Our results suggest that for the same MAP, phenylephrine causes a more pronounced hepatosplanchnic vasoconstriction as compared with NE.

Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial.

INTRODUCTION: Previous findings suggest that a delayed administration of phenylephrine replacing norepinephrine in septic shock patients causes a more pronounced hepatosplanchnic vasoconstriction as compared with norepinephrine. Nevertheless, a direct comparison between the two study drugs has not yet been performed. The aim of the present study was, therefore, to investigate the effects of a first-line therapy with either phenylephrine or norepinephrine on systemic and regional hemodynamics in patients with septic shock. METHODS: We performed a prospective, randomized, controlled trial in a multidisciplinary intensive care unit in a university hospital. We enrolled septic shock patients (n = 32) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomly allocated to treatment with either norepinephrine or phenylephrine infusion (n = 16 each) titrated to achieve a mean arterial pressure between 65 and 75 mmHg. Data from right heart catheterization, a thermodye dilution catheter, gastric tonometry, acid-base homeostasis, as well as creatinine clearance and cardiac troponin were obtained at baseline and after 12 hours. Differences within and between groups were analyzed using a two-way analysis of variance for repeated measurements with group and time as factors. Time-independent variables were compared with one-way analysis of variance. RESULTS: No differences were found in any of the investigated parameters. CONCLUSIONS: The present study suggests there are no differences in terms of cardiopulmonary performance, global oxygen transport, and regional hemodynamics when phenylephrine was administered instead of norepinephrine in the initial hemodynamic support of septic shock. TRIAL REGISTRATION: ClinicalTrial.gov NCT00639015.

Glibenclamide dose response in patients with septic shock: effects on norepinephrine requirements, cardiopulmonary performance, and global oxygen transport.

Adenosine triphosphate-sensitive potassium channels are important regulators of arterial vascular smooth muscle tone and are implicated in the pathophysiology of catecholamine tachyphylaxis in septic shock. The present study was designed as a prospective, randomized, double-blinded, clinical pilot study to determine whether different doses of glibenclamide have any effects on norepinephrine requirements, cardiopulmonary hemodynamics, and global oxygen transport in patients with septic shock. We enrolled 30 patients with septic shock requiring invasive hemodynamic monitoring and norepinephrine infusion of 0.5 microg.kg-1.min-1 or greater to maintain MAP between 65 and 75 mmHg. In addition to standard therapy, patients were randomized to receive either 10, 20, or 30 mg of enteral glibenclamide. Systemic hemodynamics, global oxygen transport including arterial lactate concentrations, gas exchange, plasma glucose concentrations, and electrolytes were determined at baseline and after 3, 6, and 12 h after administration of the study drug. Glibenclamide decreased plasma glucose concentrations in a dose-dependent manner but failed to reduce norepinephrine requirements. None of the doses had any effects on cardiopulmonary hemodynamics, global oxygen transport, gas exchange, or electrolytes. These data suggest that oral glibenclamide in doses from 10 to 30 mg fails to counteract arterial hypotension and thus to reduce norepinephrine requirements in catecholamine-dependent human septic shock.

Solute removal during continuous renal replacement therapy in critically ill patients: convection versus diffusion.

INTRODUCTION: The best modality, for continuous renal replacement therapy (CRRT) is currently uncertain and it is poorly understood how transport of different solutes, whether convective or diffusive, changes over time. METHODS: We conducted a prospective cross over study in a cohort of critically ill patients, comparing small (urea and creatinine) and middle (beta2 microglobulin) molecular weight solute clearance, filter lifespan and membrane performance over a period of 72 hours, during 15 continuous veno-venous dialysis (CVVHD) and 15 continuous veno-venous hemofiltration (CVVH)sessions. Both modalities were administered based on a prescription of 35 ml/kg/h and using polyacrylonitrile filters. RESULTS: Median filter lifespan was significantly longer during CVVHD (37 hours, interquartile range (IQR) 19.5 to 72.5) than CVVH (19 hours, IQR 12.5 to 28) (p = 0.03). Median urea time weighted average (TWA) clearances were not significantly different during CVVH (31.6 ml/minute, IQR 23.2 to 38.9) and CVVHD (35.7 ml/minute, IQR 30.1 to 41.5) (p = 0.213). Similar results were found for creatinine: 38.1 ml/minute, IQR 28.5 to 39, and 35.6 ml/minute, IQR 26 to 43 (p = 0.917), respectively. Median beta2m TWA clearance was higher during convective (16.3 ml/minute, IQR 10.9 to 23) than diffusive (6.27 ml/minute, IQR 1.6 to 14.9) therapy; nonetheless this difference did not reach statistical significance (p = 0.055). Median TWA adsorptive clearance of beta2m appeared to have scarce impact on overall solute removal (0.012 ml/minute, IQR -0.09 to 0.1, during hemofiltration versus -0.016 ml/minute, IQR -0.08 to 0.1 during dialysis; p = 0.79). Analysis of clearance modification over time did not show significant modifications of urea, creatinine and beta2m clearance in the first 48 hours during both treatments. In the CVVHD group, the only significant difference was found for beta2m between 72 hours and baseline clearance. CONCLUSION: Polyacrylonitrile filters during continuous hemofiltration and continuous hemodialysis delivered at 35 ml/kg/h are comparable in little and middle size solute removal. CVVHD appears to warrant longer CRRT sessions. The capacity of both modalities for removing such molecules is maintained up to 48 hours.

Diltiazem impairs maturation and functions of human dendritic cells.

The aim of this study was to define the effects of diltiazem, a calcium antagonist drug used in cardiology and in clinical transplantation, on the differentiation and maturation of human dendritic cells (DC). Herein, we demonstrate that diltiazem, in association with granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), induces monocytes to differentiate into cells with many of the characteristic of DC. However, diltiazem-induced DC express high levels of mannose receptor and Fc gamma RII and, consequently, manifest a higher endocytic activity compared with GM-CSF+IL-4-induced DC. Importantly, diltiazem-induced DCs have an impaired responsiveness to lipopolysaccharide and CD40 ligand because they produce decreased levels of IL-12 and reveal a reduced ability to stimulate alloreactive T-cell responses as well as in inducing interferon-gamma producing Th1 cells. These effects may contribute to a decreased DC-dependent T-cell activation and may help to explain the immunoregulatory function of diltiazem and its effectiveness in preventing transplant rejection.

Falsely elevated tacrolimus concentrations measured using the ACMIA method due to circulating endogenous antibodies in a kidney transplant recipient.

BACKGROUND: Therapeutic monitoring of whole-blood concentration of tacrolimus, a potent immunosuppressive drug used after organ transplantation, is essential to avoid toxic effects and to maintain the correct dosage. Although the reference method for the determination of tacrolimus concentrations is LC-MS/MS, several certified immunoassays are widely used for routine examinations. We report falsely elevated blood tacrolimus concentrations using the antibody-conjugated magnetic immunoassay (ACMIA) from Siemens Healthcare Diagnostics for the analysis of a patient who had undergone renal transplantation. METHODS: Whole-blood samples from a patient with elevated tacrolimus concentrations not consistent with the clinical picture were analysed with an alternative immunoassay and were investigated for interference by performing double dilution tests, by incubating in heterophilic blocking tubes and by evaluating plasmatic interfering factors. RESULTS: Double dilution tests showed a clear nonlinearity, suggesting that antibody interference not related to heterophilic antibodies had occurred; false-positive concentrations of cyclosporin obtained when using an antibody-conjugated to ß-galactosidase suggested the presence of endogenous antibodies directed against ß-galactosidase. CONCLUSION: In patients receiving tacrolimus, continued surveillance by laboratory staff and clinicians is necessary when using a method not requiring external pre-treatment, such as the Siemens ACMIA method.

Alterations in serum anti-alpha-galactosyl antibodies in patients with Crohn's disease and ulcerative colitis.

Anti-galactosyl alpha1-3-galactosyl (anti-Gal) is a natural serum antibody abundantly produced in humans in response to immune stimulation by enteric bacteria. Marked elevation of its titer has been detected in parasitic diseases and in some autoimmune disorders. Because persistent intestinal infection and defective mucosal barrier have been suggested as potential etiologic agents of inflammatory bowel disease, the aim of this study was to analyze the sera levels of anti-Gal antibodies in patients with Crohn's disease and ulcerative colitis. An ELISA assay was performed to analyze circulating antibody using the disaccharide Gal (alpha 1-3)Gal coupled to human serum albumin as antigen and alkaline phosphatase-conjugated rabbit anti-human immunoglobulin G, A, M as antibody. Immunoglobulin classes were assayed using class-specific antibodies. The optical densities of sera from Crohn's disease (1.83 +/- 0.63) and ulcerative colitis (1.45 +/- 0.7) were significantly higher (P < 0.0001 and P < 0.0005, respectively) than those of the control group (0.97 +/- 0.39). In Crohn's disease the increase was distributed among the three immunoglobulin classes; in ulcerative colitis a significant increase was observed only for immunoglobulin A. The increased levels of circulating antibodies against Gal (alpha 1-3)Gal in the presence of intestinal bacterial strains expressing antigenic epitopes and breakdown of mucosal barrier could contribute to the dysregulated immune response observed in inflammatory bowel disease.

Recovery of chronic renal impairment with sirolimus after lung transplantation.

BACKGROUND: Standard immunosuppression after lung transplantation includes calcineurin inhibitors, azathioprine, and steroids. Calcineurin inhibitor administration is associated with an increased renal impairment. Sirolimus shows no renal toxicity and could be used in selected patients. METHODS: We have prospectively administered sirolimus as an alternative to calcineurin inhibitors in 15 lung transplantation recipients with persistent drug nephrotoxicity. Eight patients had also bronchiolitis obliterans syndrome. The mean serum creatinine and azotemia were 2.7 +/- 1.1 mg/dL and 111 +/- 39 mg/dL. After starting sirolimus, azathioprine was reduced to 50%-25% of baseline, calcineurin inhibitors were gradually reduced and eventually stopped, and steroids were maintained stable. Patients started sirolimus with 2 to 5 mg/d orally; adjustments were made according to trough levels (4 to 12 ng/mL for combined sirolimus + calcineurin inhibitors; 12 to 20 ng/mL as monotherapy), toxicity, and perceived efficacy. Patients were monitored for renal and graft function and clinical status. RESULTS: A significant creatinine decrease was observed after 6 months of treatment (p < 0.02); azotemia decreased after 1 month and remained stable (p < 0.01). Pulmonary function tests did not show any significant modification from before sirolimus baseline in patients without bronchiolitis obliterans syndrome. There were eight infectious complications and 10 episodes of toxicity (4 dermatitis, 2 epistaxis, 1 headache, 1 diarrhea, 1 nausea, 1 laryngeal cancer). Moderate leukocytopenia (n = 3) and hypertriglyceridemia (n = 6) responded to dose reduction. One patient was lost to follow-up. Three patients died of complications related to bronchiolitis obliterans. One patient underwent transplantation again. CONCLUSIONS: Sirolimus administration allows amelioration of renal function with a relatively low morbidity and is useful for chronic renal impairment rescue after lung transplantation.