Pro-Apoptotic Effects of Plasma from Patients with Cardiorenal Syndrome on Human Tubular Cells.

BACKGROUND: The pathophysiology of Cardiorenal Syndrome Type 1 (CRS1) is widely studied, although the mechanisms by which renal tubular epithelial cells (TECs) cease to proliferate and embark upon terminal differentiation, following the initial insult of heart failure (HF), remain a key target. This study seeks to provide insight into the pathophysiological pathways in CRS1; we evaluated in vitro the effects of CRS1 plasma on TECs. METHODS: We enrolled 40 acute HF patients and 15 controls (CTR) without HF or acute kidney injury (AKI). Ten out of 40 HF patients exhibited AKI at the time of admission for HF or developed AKI during hospitalization and were classified as CRS1. In vitro, cell viability, DNA fragmentation and caspase-3 levels were investigated in TECs incubated with HF, CRS1, and CTR plasma. We assessed inflammatory cytokines and NGAL expression at the gene and protein levels. RESULTS: We observed a marked pro-apoptotic activity and a significantly increased in vitro level of apoptosis in TECs incubated with plasma from CRS1 patients compared to HF and CTR (p < 0.01). In the CRS1 group, the mRNA expression of IL-6, IL-18 and NGAL resulted significantly higher in TECs incubated with CRS1 plasma compared with those incubated with plasma from HF and CTR (p < 0.01). IL-6, IL-18, NGAL, and RANTES levels were significantly higher in TECs supernatant incubated with CRS1 plasma compared with HF patients and CTR plasma (p < 0.01). CONCLUSION: In vitro exposure to plasma from CRS1 patients altered the expression profile of TECs characterized by increases in proinflammatory mediators, release of tubular damage markers, and apoptosis.

Oxidative stress: dual pathway induction in cardiorenal syndrome type 1 pathogenesis.

Cardiorenal Syndrome Type 1 (Type 1) is a specific condition which is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Even though its pathophysiology is complex and not still completely understood, oxidative stress seems to play a pivotal role. In this study, we examined the putative role of oxidative stress in the pathogenesis of CRS Type 1. Twenty-three patients with acute heart failure (AHF) were included in the study. Subsequently, 11 patients who developed AKI due to AHF were classified as CRS Type 1. Quantitative determinations for IL-6, myeloperoxidase (MPO), nitric oxide (NO), copper/zinc superoxide dismutase (Cu/ZnSOD), and endogenous peroxidase activity (EPA) were performed. CRS Type 1 patients displayed significant augmentation in circulating ROS and RNS, as well as expression of IL-6. Quantitative analysis of all oxidative stress markers showed significantly lower oxidative stress levels in controls and AHF compared to CRS Type 1 patients (P < 0.05). This pilot study demonstrates the significantly heightened presence of dual oxidative stress pathway induction in CRS Type 1 compared to AHF patients. Our findings indicate that oxidative stress is a potential therapeutic target, as it promotes inflammation by ROS/RNS-linked pathogenesis.

Pharmacokinetic analysis of antibiotic adsorption (vancomycin and teicoplanin) by the Lixelle extracorporeal unit.

PURPOSE: The pharmacokinetic properties of vancomycin (VAN) and teicoplanin (TEC) may be affected by adsorption during hemofiltration as well as hemoperfusion therapies. The aim of this in vitro study was to investigate VAN and TEC removal adsorption kinetics with mass balance analysis by direct hemoperfusion (DHP) with the Lixelle S-35 cartridge (Lixelle, Kaneka Corporation, Tokyo). METHODS: Mock DHP was performed for 120 min using VAN and TEC solutions (46.08 ± 0.81 and 74.79 ± 1.24 mg/l per N = 6). Clinical plasma antibiotic concentrations were circulated in a closed circuit simulating DHP using an adsorption column (Lixelle S-35) at flow rate of 250 ml/min. Samples were collected at 10, 60, and 120 min through both arterial and venous ports; drug levels were measured with particle enhanced turbidimetric inhibition immunoassay and fluorescence polarization immunoassay. All tests were performed in triplicate. RESULTS: Results subsequent to DHP at the primary assessment interval for VAN mass was 49.06 ± 1.47 mg, indicating a significant reduction of the starting mass (94.74 ± 1.63 mg). The observed reduction of TEC levels greatly exceeded that of VAN at the first interval (10 min). At 120 min of DHP, the estimated mass adsorption of VAN was 45.68 ± 2.26 mg, while the mesured total TEC mass adsorbed was 126.86 ± 0.91 mg. CONCLUSIONS: A VAN adsorption plateau indicating the VAN loading dose may be required in patients receiving DHP with the Lixelle S-35. The total TEC mass was adsorbed subsequent to 60 min of circulation, so the loading dose should be closely considered. In addition, the Lixelle S-35 may represent an option as a rescue therapy in accidental overdose of TEC.

The Role of NGAL in Peritoneal Dialysis Effluent in Early Diagnosis of Peritonitis: Case-Control Study in Peritoneal Dialysis Patients.

BACKGROUND: Peritoneal dialysis (PD) is frequently complicated by high rates of peritonitis, which result in hospitalization, technique failure, transfer to hemodialysis, and increased mortality. Early diagnosis, and identification of contributing factors are essential components to increasing effectiveness of care. In previous reports, neutrophil gelatinase-associated lipocalin (NGAL), a lipocalin which is a key player in innate immunity and rapidly detectable in peritoneal dialysis effluent (PDE), has been demonstrated to be a useful tool in the early diagnosis of peritonitis. This study investigates predictive value of PDE NGAL concentration as a prognostic indicator for PD-related peritonitis. METHODS: A case-control study with 182 PD patients was conducted. Plasma and PDE were analyzed for the following biomarkers: C-reactive protein (CRP), blood procalcitonin (PCT), leucocytes and NGAL in PDE. The cases consisted of patients with suspected peritonitis, while controls were the patients who came to our ambulatory clinic for routine visits without any sign of peritonitis. The episodes of peritonitis were defined in agreement with International Society for Peritoneal Dialysis guidelines. Continuous variables were presented as the median values and interquartile range (IQR). Mann-Whitney U test was used to compare continuous variables. Univariate and multivariate logistic regression were used to evaluate the association of biomarkers with peritonitis. Receiver operating characteristic (ROC) curve analysis was used to calculate area under curve (AUC) for biomarkers. Finally we evaluated sensitivity, and specificity for each biomarker. All statistical analyses were performed with SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). RESULTS: During the 19-month study, of the 182 patients, 80 had a clinical diagnosis of peritonitis. C-reactive protein levels (p < 0.001), PCT (p < 0.001), NGAL in PDE (p < 0.001), and white blood cells (WBC) in PDE (p < 0.001) were all significantly different in patients with and without peritonitis. In univariate analysis, CRP (odds ratio [OR] 1,339; p = 0.001), PCT (OR 2,473; p < 0,001), WBC in PDE (OR 3,986; p < 0,001), and NGAL in PDE (OR 36.75 p < 0.001) were significantly associated with episodes of peritonitis. In multivariate regression analysis, only WBC (OR 24.84; p = 0,012), and peritoneal NGAL levels (OR 136.6; p = 0,01) were independent predictors of peritonitis events. Moreover, AUC for NGAL in peritoneal effluent was 0,936 (p < 0.001) while AUC for CRP, PCT, and WBC count in peritoneal effluent were 0,704 (p = 0.001), 0.762 (p = 0.039), 0,975 (p < 0.001), respectively. Finally, combined WBC and peritoneal NGAL test increased the specificity (= 96%) of the single test. CONCLUSIONS: These results identify NGAL in peritoneal effluent as a reliable marker of peritonitis episodes in PD patients. Collectively, our findings demonstrate that the use of peritoneal NGAL cooperatively with current clinical diagnostic tools as a prognostic indicator, presents a valuable diagnostic tool in PD-associated peritonitis.

Implantable left ventricular assist devices and the kidney.

The use of left ventricular assist devices (LVADs) in treating patients with advanced heart failure restores cardiac output resulting in improved perfusion to multiple organ systems with important clinical benefits. Renal pathophysiology during LVAD support remains an evolving, poorly understood, and potentially dynamic problem. Changes in renal function after LVAD placement have been investigated in multiple studies with contradictory results. Renal dysfunction is common prior to LVAD placement, which complicates postoperative clinical outcomes. The purpose of this review is to assess the latest information regarding the effects of LVADs on renal function with regard to hemodynamics, physiology, pathology and clinical issues prior to and after placement of the devices. The review should then aid in identifying patients best suited to benefit from this technology and to refine the therapy to reduce associated risks.

Heart-kidney crosstalk and role of humoral signaling in critical illness.

Organ failure in the heart or kidney can initiate various complex metabolic, cell-mediated and humoral pathways affecting distant organs, contributing to the high therapeutic costs and significantly higher morbidity and mortality. The universal outreach of cells in an injured state has myriad consequences to distant organ cells and their milieu. Heart performance and kidney function are closely interconnected and communication between these organs occurs through a variety of bidirectional pathways. The term cardiorenal syndrome (CRS) is often used to describe this condition and represents an important model for exploring the pathophysiology of cardiac and renal dysfunction. Clinical evidence suggests that tissue injury in both acute kidney injury and heart failure has immune-mediated inflammatory consequences that can initiate remote organ dysfunction. Acute cardiorenal syndrome (CRS type 1) and acute renocardiac syndrome (CRS type 3) are particularly relevant in high-acuity medical units. This review briefly summarizes relevant research and focuses on the role of signaling in heart-kidney crosstalk in the critical care setting.

Fluid management in the intensive care unit: bioelectrical impedance vector analysis as a tool to assess hydration status and optimal fluid balance in critically ill patients.

BACKGROUND: Fluid balance disorders are a relevant risk factor for morbidity and mortality in critically ill patients. Volume assessment in the intensive care unit (ICU) is thus of great importance, but there are currently few methods to obtain an accurate and timely assessment of hydration status. Our aim was to evaluate the hydration status of ICU patients via bioelectric impedance vector analysis (BIVA) and to investigate the relationship between hydration and mortality. METHODS: We evaluated 280 BIVA measurements of 64 patients performed daily in the 5 days following their ICU admission. The observation period ranged from a minimum of 72 h up to a maximum of 120 h. We observed the evolution of the hydration status during the ICU stay in this population, and analyzed the relationship between mean and maximum hydration reached and mortality--both in the ICU and at 60 days--using logistic regression. RESULTS: A state of overhydration was observed in the majority of patients (70%) on admission, which persisted during the ICU stay. Patients who required continuous renal replacement therapy (CRRT) were more likely to be overhydrated starting from the 2nd day of observation. Logistic regression showed a strong and significant correlation between mean/maximum hydration reached and mortality, both independently and correcting for severity of prognosis. CONCLUSIONS: Fluid overload measured by BIVA is a frequent condition in critically ill patients--whether or not they undergo CRRT--and a significant predictor of mortality. Hence, hydration status should be considered as an additional prognosticator in the clinical management of the critically ill patient. KEY MESSAGES: (i) On the day of ICU admittance, patients showed a marked tendency to overhydration (>70% of total). This tendency was more pronounced in patients on CRRT. (ii) Hyperhydration persisted during the ICU stay. Patients who underwent CRRT showed significantly higher hyperhydration from the 2nd day of hospitalization. (iii) Nonsurvivors showed worse hyperhydration patterns in comparison to survivors in logistic univariate analysis (p < 0.05). This relationship between hydration and mortality is confirmed even when controlling for the effect of a worse prognosis approximated by any of three ICU scoring systems (APACHE II, SAPS II and SOFA). Mean and maximum hydration levels present a stronger correlation with mortality than with mean and maximum cumulative fluid balance reached during the observation period.