Discontinuation of continuous renal replacement therapy: A post hoc analysis of a prospective multicenter observational study

Objectives: To describe current practice for the discontinuation of continuous renal replacement therapy in a multinational setting and to identify variables associated with successful discontinuation. The approach to discontinue continuous renal replacement therapy may affect patient outcomes. However, there is lack of information on how and under what conditions continuous renal replacement therapy is discontinued. Design: Post hoc analysis of a prospective observational study. Setting. Fifty-four intensive care units in 23 countries. Patients: Five hundred twenty-nine patients (52.6%) who survived initial therapy among 1006 patients treated with continuous renal replacement therapy. Interventions: None. Measurements and Main Results., Three hundred thirteen patients were removed successfully from continuous renal replacement therapy and did not require any renal replacement therapy for at least 7 days and were classified as the ""success"" group and the rest (216 patients) were classified as the ""repeat-RRT"" (renal replacement therapy) group. Patients in the ""success"" group had lower hospital mortality (28.5% vs. 42.7%, p < .0001) compared with patients in the ""repeat-RRT"" group. They also had lower creatinine and urea concentrations and a higher urine output at the time of stopping continuous renal replacement therapy. Multivariate logistic regression analysis for successful discontinuation of continuous renal replacement therapy identified urine output (during the 24 hrs before stopping continuous renal replacement therapy: odds ratio, 1.078 per 100 mL/day increase) and creatinine (odds ratio, 0.996 per mu mol/L increase) as significant predictors of successful cessation. The area under the receiver operating characteristic curve to predict successful discontinuation of continuous renal replacement therapy was 0.808 for urine output and 0.635 for creatinine. The predictive ability of urine output was negatively affected by the use of diuretics (area under the receiver operating characteristic curve, 0.671 with diuretics and 0.845 without diuretics). Conclusions. We report on the current practice of discontinuing continuous renal replacement therapy in a multinational setting. Urine output at the time of initial cessation (if continuous renal replacement therapy was the most important predictor of successful discontinuation, especially if occurring without the administration of diuretics. (Crit Care Med 2009; 37:2576-2582)

Cardiac MRI for Detection of Unrecognized Myocardial Infarction in Patients With End-Stage Renal Disease: Comparison With ECG and Scintigraphy

OBJECTIVE. The purposes of this study were to use the myocardial delayed enhancement technique of cardiac MRI to investigate the frequency of unrecognized myocardial infarction (MI) in patients with end-stage renal disease, to compare the findings with those of ECG and SPECT, and to examine factors that may influence the utility of these methods in the detection of MI. SUBJECTS AND METHODS. We prospectively performed cardiac MRI, ECG, and SPECT to detect unrecognized MI in 72 patients with end-stage renal disease at high risk of coronary artery disease but without a clinical history of MI. RESULTS. Fifty-six patients (78%) were men ( mean age, 56.2 +/- 9.4 years) and 16 (22%) were women ( mean age, 55.8 +/- 11.4). The mean left ventricular mass index was 103.4 +/- 27.3 g/m(2), and the mean ejection fraction was 60.6% +/- 15.5%. Myocardial delayed enhancement imaging depicted unrecognized MI in 18 patients (25%). ECG findings were abnormal in five patients (7%), and SPECT findings were abnormal in 19 patients (26%). ECG findings were false-negative in 14 cases and false-positive in one case. The accuracy, sensitivity, and specificity of ECG were 79.2%, 22.2%, and 98.1% (p = 0.002). SPECT findings were false-negative in six cases and false-positive in seven cases. The accuracy, sensitivity, and specificity of SPECT were 81.9%, 66.7%, and 87.0% ( not significant). During a period of 4.9-77.9 months, 19 cardiac deaths were documented, but no statistical significance was found in survival analysis. CONCLUSION. Cardiac MRI with myocardial delayed enhancement can depict unrecognized MI in patients with end-stage renal disease. ECG and SPECT had low sensitivity in detection of MI. Infarct size and left ventricular mass can influence the utility of these methods in the detection of MI.

Phosphorus overload and PTH induce aortic expression of Runx2 in experimental uraemia

Background. Vascular calcification (VC) is commonly seen in patients with chronic kidney disease (CKD). Elevated levels of phosphate and parathormone (PTH) are considered nontraditional risk factors for VC. It has been shown that, in vitro, phosphate transforms vascular smooth muscle cells (VSMCs) into calcifying cells, evidenced by upregulated expression of runt-related transcription factor 2 (Runx2), whereas PTH is protective against VC. In addition, Runx2 has been detected in calcified arteries of CKD patients. However, the in vivo effect of phosphate and PTH on Runx2 expression remains unknown. Methods. Wistar rats were submitted to parathyroidectomy, 5/6 nephrectomy (Nx) and continuous infusion of 1-34 rat PTH (at physiological or supraphysiological rates) or were sham-operated. Diets varied only in phosphate content, which was low (0.2%) or high (1.2%). Biochemical, histological, immunohistochemistry and immunofluorescence analyses were performed. Results. Nephrectomized animals receiving high-PTH infusion presented VC, regardless of the phosphate intake level. However, phosphate overload and normal PTH infusion induced phenotypic changes in VSMCs, as evidenced by upregulated aortic expression of Runx2. High-PTH infusion promoted histological changes in the expression of osteoprotegerin and type I collagen in calcified arteries. Conclusions. Phosphate, by itself is a potential pathogenic factor for VC. It is of note that phosphate overload, even without VC, was associated with overexpression of Runx2 in VSMCs. The mineral imbalance often seen in patients with CKD should be corrected.

Effect of hypothalamo-pituitary disconnection on the development of anterior pituitary cells in late gestation ovine fetuses

The specific role of the hypothalamus in regulating the developmental profile of anterior pituitary (AP) cells remains largely unknown. The present study evaluated hypothalamic contributions to AP cell development, utilizing the technique of hypothalamo-pituitary disconnection (HPD). HPD of fetal sheep or sham surgery was performed at 110 days gestation (d) (n=6 each group; term ~ 147d). Fetuses were removed and pituitaries collected at 110d (no surgery; n=6) or 141d (sham and HPD groups). The impact of HPD on AP cell development was assessed by single-labeled immunofluorescence for five hormones to identify proportions of AP cells expressing each hormone. HPD was associated with a 70% increase (P

Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury

Purpose: The aim of this study is to evaluate the relationship between timing of renal replacement therapy (RRT) in severe acute kidney injury and clinical outcomes. Methods: This was a prospective multicenter observational study conducted at 54 intensive care units (ICUs) in 23 countries enrolling 1238 patients. Results: Timing of RRT was stratified into ""early"" and ""late"" by median urea and creatinine at the time RRT was started. Timing was also categorized temporally from ICU admission into early (<2 days), delayed (2-5 days), and late (>5 days). Renal replacement therapy timing by serum urea showed no significant difference in crude (63.4% for urea <= 24.2 mmol/L vs 61.4% for urea >24.2 mmol/L; odds ratio [OR], 0.92; 95% confidence interval [CI], 0.73-1.15; P = .48) or covariate-adjusted mortality (OR, 1.25; 95% CI, 0.91-1.70; P = .16). When stratified by creatinine, late RRT was associated with lower crude (53.4% for creatinine >309 mu mol/L vs 71.4% for creatinine <= 309 mu mol/L; OR, 0.46; 95% CI, 0.36-0.58; P < .0001) and covariate-adjusted mortality (OR, 0.51; 95% CI, 0.37-0.69; P < .001).However, for timing relative to ICU admission, late RRT was associated with greater crude (72.8% vs 62.3% vs 59%, P < .001) and covariate-adjusted mortality (OR, 1.95; 95% CI, 1.30-2.92; P = .001). Overall, late RRT was associated with a longer duration of RRT and stay in hospital and greater dialysis dependence. Conclusion: Timing of RRT, a potentially modifiable factor, might exert an important influence on patient survival. However, this largely depended on its definition. Late RRT (days from admission) was associated with a longer duration of RRT, longer hospital stay, and higher dialysis dependence. (C) 2009 Elsevier Inc. All rights reserved.

Serum Ferritin Level Remains a Reliable Marker of Bone Marrow Iron Stores Evaluated by Histomorphometry in Hemodialysis Patients

Background and objectives: As well as being a marker of body iron stores, serum ferritin (sFerritin) has also been shown to be a marker of inflammation in hemodialysis (HD) patients. The aim of this study was to analyze whether sFerritin is a reliable marker of the iron stores present in bone marrow of HD patients. Design: Histomorphometric analysis of stored transiliac bone biopsies was used to assess iron stores by determining the number of iron-stained cells per square millimeter of bone marrow. Results: In 96 patients, the laboratory parameters were hemoglobin = 11.3 +/- 1.6 g/dl, hematocrit = 34.3 +/- 5%, sFerritin 609 +/- 305 ng/ml, transferrin saturation = 32.7 +/- 22.5%, and C-reactive protein (CRP) = 0.9 +/- 1.4 mg/dl. sFerritin correlated significantly with CRP, bone marrow iron, and time on HD treatment W = 0.006, 0.001, and 0.048, respectively). The independent determinants of sFerritin were CRP (beta-coef = 0.26; 95% CI = 24.6 to 132.3) and bone marrow iron (beta-coef = 0.32; 95% CI = 0.54 to 2.09). Bone marrow iron was higher in patients with sFerritin >500 ng/ml than in those with sFerritin :5500 ng/ml. In the group of patients with sFerritin :5500 ng/ml, the independent determinant of sFerritin was bone marrow iron (beta-coef = 0.48, 95% CI = 0.48 to 1.78), but in the group of patients with sFerritin >500 ng/ml, no independent determinant of sFerritin was found. Conclusions: sFerritin adequately reflects iron stores in bone marrow of HD patients.

Urine Volume in Acute Kidney Injury: How Much Is Enough?

Eight hundred and seventy-nine patients with acute kidney injury were retrospectively studied over year and eleven months for evaluation of urine volume as a risk factor for death. They were divided into five groups, according to the 24 h urine volume (UV): anuric (UV <= 50 mL/24 h, group 1), oliguric (UV > 50 mL/24 h and < 400 mL/24 h, group 2), and non-oliguric (UV >= 400 mL/24 h). Nonoliguric group was subdivided in three subgroups: UV > 400 mL/24 h and <= 1000 mL/24 h (group 3, reference group), UV > 1000 mL/24 h and <= 2000 mL/24 h (group 4), and UV > 2000 mL/24 h (group 5). Linear tendency test (Mantel extension) pointed out a significant increase in mortality with UV decrease (p < 0.001), confirmed by multivariate analysis. Anuric and oliguric patients had increased risk of respectively 95% and 76% times for death compared to controls (p < 0.05). Patients from groups 4 and 5 presented a reduced risk for death of 50% and 70%, respectively, p = 0.004 and p = 0.001. In conclusion, urine volume was a strong independent factor for mortality in this cohort of AKI patients.

A quantitative and morphometric study of mast cells in cutaneous leishmaniasis

Background Mast cells (MCs) are related with healing process in chronic inflammatory diseases, although in cutaneous leishmaniasis (CL) its importance is unknown. The aim of this study was to determine the correlation of MC with clinical findings in patients with the localized form of CL. Methods A cohort of 85 patients with CL was evaluated. MCs count was performed in pre-treatment biopsies and correlation with clinical findings and Leishmania species determined by PCR were performed. Results The MCs count in patients with CL caused by Leishmania (V.) braziliensis was 14.3 +/- 9.8 cells/mm(2), and 7.0 +/- 6.5 cells/mm(2) in patients with L. (L.) amazonensis (P < 0.05). The linear regression of MCs count with the age showed a tendency of cell number decreasing, according to ageing of the patient (r(2) = 0.05; P < 0.05). The association of disease`s duration and MCs count was positive (r(2) = 0.11; P < 0.05). There was not any association of MCs count with number of lesions neither with Leishmania antigen expression. The MCs count was higher in patients with earlier healing after treatment (P < 0.05). Conclusion MC can be important in CL and related with healing lesion.

Effectiveness of the CAGE questionnaire, gamma-glutamyltransferase and mean corpuscular volume of red blood cells as markers for alcohol-related problems in the workplace

Objective: To evaluate the usefulness of gamma-glutamyltransferase (GGT) and mean corpuscular volume (MCV), as well as that of the CAGE questionnaire, in workplace screening for alcohol abuse/dependence. Methods: A total of 183 male employees were submitted to structured interviews (Structured Clinical Interview for DSM-IV 2.0 and CAGE questionnaire). Blood samples were collected. Diagnostic accuracy and odds ratio were determined for the CAGE, GGT and MCV. Results: The CAGE questionnaire presented the best sensitivity for alcohol dependence (91%; specificity, 87.8%) and for alcohol abuse (87.5%, specificity, 80.9%), which increased when the questionnaire was used in combination with GGT (sensitivity, 100% and 87.5%, respectively; specificity, 68% and 61.5, respectively). CAGE positive results and/or alterations in GGT were less likely to occur among employees not presenting alcohol abuse/ dependence than among those presenting such abuse (OR for CAGE = 13, p < 0.05; OR for CAGE-GGT = 11, p < 0.05) or dependence (OR for CAGE = 76, p < 0.0 1; OR for GGT = 5, p < 0.0 1). Employees not presenting alcohol abuse/dependence were also several times more likely to present negative CAGE or GGT results. Conclusions: The use short, simple questionnaires, combined with that of low-cost biochemical markers, such as GGT, can serve as an initial screening for alcohol-related problems, especially for employees in hazardous occupations. The data provided can serve to corroborate clinical findings. (C) 2008 Elsevier Ltd. All rights reserved.

IL-1 beta breaks tolerance through expansion of CD25(+) effector T cells

IL-1 is a key proinflammatory driver of several autoimmune diseases including juvenile inflammatory arthritis, diseases with mutations in the NALP/cryopyrin complex and Crohn's disease, and is genetically or clinically associated with many others. IL-1 is a pleiotropic proinflammatory cytokine; however the mechanisms by which increased IL-1 signaling promotes autoreactive T cell activity are not clear. Here we show that autoimmune-prone NOD and IL-1 receptor antagonist-deficient C57BL/6 mice both produce high levels of IL-1, which drives autoreactive effector cell expansion. IL-1 beta drives proliferation and cytokine production by CD4(+)CD25(+)FoxP3(-) effector/memory T cells, attenuates CD4(+)CD25(+)FoxP3(+) regulatory T cell function, and allows escape of CD4(+)CD25(-) autoreactive effectors from suppression. Thus, inflammation or constitutive overexpression of IL-1 beta in a genetically predisposed host can promote autoreactive effector T cell expansion and function, which attenuates the ability of regulatory T cells to maintain tolerance to self.

Effect of the immunosuppressants on hepatocyte cells proliferation and apoptosis during liver regeneration after hepatectomy - molecular studies

The regeneration and remodeling of the transplanted liver is the result of hepatocyte proliferation and apoptosis (programmed cell death). The purpose of this study was to verify the influence of immunosuppressants on the expression levels of genes: IL-6 (regulator of hepatocyte proliferation), pro-apoptotic (Bak and Bax) and anti-apoptotic (Bcl-Xl and Bcl-2). 36 newborn suckling rats (age 5-7 days, weight 6-10 g) were divided into four groups: hepatectomy, hepatectomy plus methylprednisolone, hepatectomy plus CsA and hepatectomy plus Tac. The same experiments were performed in 24 weaning rats (age 21-23 days, weight 30-50 g). The animals were killed one day after the hepatectomy and the remnant livers were analyzed. The livers of all animals exhibited histological changes of liver regeneration. The immunosuppressants did not promote any alteration on IL-6 gene expression levels. Methylprednisolone and CsA increased the expression levels of Bak gene in newborn rats. However, methylprednisolone and Tac promoted increased expression levels of Bcl-2 in all groups. We hypothesize that these effects explain the efficacy of these drugs on the treatment of acute and chronic liver rejection as the expression of Bcl-2 in cholangiocytes is decreased as a consequence of bile duct lesions.

Could endogenous self-peptides presented by dendritic cells initiate rheumatoid arthritis?

The critical interaction initiating and perhaps perpetuating rheumatoid arthritis (RA) is the presentation of arthritogenic antigen to autoreactive T cells. In contrast to many organ-specific autoimmune diseases, no candidate autoantigens have yet been confirmed for RA. Here, Ranjeny Thomas and Peter Lipsky examine the role of dendritic cells in autoimmune disease, leading to the hypothesis that activation of T cells by endogenous self-peptides may be sufficient to initiate RA.

Influence of Lactic Acid on Endogenous and Viral RNA-Induced Immune Mediator Production by Vaginal Epithelial Cells

OBJECTIVE: To evaluate the influence of lactic acid on immune mediator release from vaginal epithelial cells. METHODS: The human vaginal epithelial cell line, VK2/E6E7, was cultured in the presence or absence of physiological concentrations of lactic acid, and in the presence or absence of the viral Toll-like receptor 3 agonist, poly (inosinic acid: cytidylic acid). Supernatants were assayed by enzyme-linked immunosorbent assay (ELISA) for interleukin (IL)-1 beta, IL-6, IL-8, IL-23, transforming growth factor (TGF)-beta and secretory leukocyte protease inhibitor. RESULTS: Vaginal epithelial cells spontaneously released IL-1 beta (25.9 pg/mL), IL-8 (1.0 ng/mL), TGF-beta (175 pg/mL), and secretory leukocyte protease inhibitor (33.8 ng/mL). Only TGF-beta production was marginally enhanced (49%) by addition of lactic acid alone. Poly (inosinic acid: cytidylic acid) by itself stimulated the release of IL-6 (305 pg/mL) and enhanced IL-8 production (2.8 ng/mL). The combination of poly (inosinic acid: cytidylic acid) and lactic acid markedly increased IL-8 production (5.0 ng/mL) and induced the release of IL-1 beta (96.2 pg/mL). The poly (inosinic acid: cytidylic acid)-mediated lactic acid effect on IL-1 beta and IL-8 release was abrogated when the lactic acid was neutralized or if acetic acid was substituted for lactic acid. CONCLUSION: Lactic acid enhances the release of selective mediators from vaginal epithelial cells and stimulates antiviral immune responses. (Obstet Gynecol 2011;118:840-6) DOI: 10.1097/AOG.0b013e31822da9e9

When Should Renal Replacement Therapy be Initiated for Acute Kidney Injury?

Acute kidney injury (AKI) is now well recognized as an independent risk factor for increased morbidity and mortality particularly when dialysis is needed. Although renal replacement therapy (RRT) has been used in AKI for more than five decades, there is no standard methodology to predict which AKI patients will need dialysis and who will recover renal function without requiring dialysis. The lack of consensus on what parameters should guide the decision to start dialysis has led to a wide variation in dialysis utilization. A contributing factor is the lack of studies in the modern era evaluating the relationship of timing of dialysis initiation and outcomes. Although listed as one of the top priorities in research on AKI, timing of dialysis initiation has not been included as a factor in large, randomized controlled trials in this area. In this review we will discuss the criteria that have been used to define early vs. late initiation in previous studies on dialysis initiation. In addition, we propose a patient-centered approach to define early and late initiation that could serve as framework for managing patients and for future studies in this area.