A clinical model to predict successful renal replacement therapy (RRT) discontinuation in patients with Acute Kidney Injury (AKI).

INTRODUCTION: Ideal timing of Renal Replacement Therapy (RRT) discontinuation in Acute Kidney Injury (AKI) is still unknown. We aimed to study the role of creatinine-related variables in predicting RRT successful discontinuation and to propose a clinical predictive score. METHODS: In this single-centre retrospective study, we evaluated all AKI patients in whom RRT was interrupted for at least 48 hours. Patients who were still RRT-independent 7 days after initial RRT cessation were included in the "Success" group and opposed to the "Failure" group. We evaluated baseline characteristics and variables collected at the time of RRT interruption, as well as the Kinetic estimated Glomerular Filtration Rate (KeGFR), the simple variation in serum Creatinine (ΔsCr), and the incremental creatinine ratio on the first three days after RRT interruption. Multivariable analysis was performed to evaluate prediction of success. Internal validation using a simple binomial generalized regression model with Lasso estimation and 5-fold cross validation method was performed. RESULTS: We included 124 patients, 49 in the "Failure" group and 75 in the "Success" group. All creatinine-related variables predicted success in simple and multiple logistic regression models. The best model generated a clinical score based on the odds ratio obtained for each variable and included urine output, non-renal SOFA score, fluid balance, serum urea, serum potassium, blood pH, and the variation in sCr values after RRT discontinuation. The score presented an area under the ROC of 0.86 (95% CI 0.76‒1.00). CONCLUSION: Creatinine variation between the first 2 consecutive days after RRT discontinuation might predict success in RRT discontinuation. The developed clinical score based on these variables might be a useful clinical decision tool to guide hemodialysis catheter safe removal.

TREATMENT WITH HUMAN UMBILICAL CORD-DERIVED MESENCHYMAL STEM CELLS IN A PIG MODEL OF SEPSIS-INDUCED ACUTE KIDNEY INJURY: EFFECTS ON MICROVASCULAR ENDOTHELIAL CELLS AND TUBULAR CELLS IN THE KIDNEY.

ABSTRACT: Background: Approximately 50% of patients with sepsis develop acute kidney injury (AKI), which is predictive of poor outcomes, with mortality rates of up to 70%. The endothelium is a major target for treatments aimed at preventing the complications of sepsis. We hypothesized that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could attenuate tubular and endothelial injury in a porcine model of sepsis-induced AKI. Methods: Anesthetized pigs were induced to fecal peritonitis, resulting in septic shock, and were randomized to treatment with fluids, vasopressors, and antibiotics (sepsis group; n = 11) or to that same treatment plus infusion of 1 × 10 6 cells/kg of hUC-MSCs (sepsis+MSC group; n = 11). Results: At 24 h after sepsis induction, changes in serum creatinine and mean arterial pressure were comparable between the two groups, as was mortality. However, the sepsis+MSC group showed some significant differences in comparison with the sepsis group: lower fractional excretions of sodium and potassium; greater epithelial sodium channel protein expression; and lower protein expression of the Na-K-2Cl cotransporter and aquaporin 2 in the renal medulla. Expression of P-selectin, thrombomodulin, and vascular endothelial growth factor was significantly lower in the sepsis+MSC group than in the sepsis group, whereas that of Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) was lower in the former. Conclusion: Treatment with hUC-MSCs seems to protect endothelial and tubular cells in sepsis-induced AKI, possibly via the TLR4/NF-κB signaling pathway. Therefore, it might be an effective treatment for sepsis-induced AKI.

Definitions, phenotypes, and subphenotypes in acute kidney injury-Moving towards precision medicine.

The current definition of acute kidney injury (AKI) is generic and, based only on markers of function, is unsuitable for guiding individualized treatment. AKI is a complex syndrome with multiple presentations and causes. Targeted AKI management will only be possible if different phenotypes and subphenotypes of AKI are recognised, based on causation and related pathophysiology. Molecular signatures to identify subphenotypes are being recognised, as specific biomarkers reveal activated pathways. Assessment of individual clinical risk needs wider dissemination to allow identification of patients at high risk of AKI. New and more timely markers for glomerular filtration rate (GFR) are available. However, AKI diagnosis and classification should not be limited to GFR, but include tubular function and damage. Combining damage and stress biomarkers with functional markers enhances risk prediction, and identifies a population enriched for clinical trials targeting AKI. We review novel developments and aim to encourage implementation of these new techniques into clinical practice as a strategy for individualizing AKI treatment akin to a precision medicine-based approach.

A clinical model to predict successful renal replacement therapy (RRT) discontinuation in patients with Acute Kidney Injury (AKI)

Abstract Introduction Ideal timing of Renal Replacement Therapy (RRT) discontinuation in Acute Kidney Injury (AKI) is still unknown. We aimed to study the role of creatinine-related variables in predicting RRT successful discontinuation and to propose a clinical predictive score. Methods In this single-centre retrospective study, we evaluated all AKI patients in whom RRT was interrupted for at least 48 hours. Patients who were still RRT-independent 7 days after initial RRT cessation were included in the "Success" group and opposed to the "Failure" group. We evaluated baseline characteristics and variables collected at the time of RRT interruption, as well as the Kinetic estimated Glomerular Filtration Rate (KeGFR), the simple variation in serum Creatinine (ΔsCr), and the incremental creatinine ratio on the first three days after RRT interruption. Multivariable analysis was performed to evaluate prediction of success. Internal validation using a simple binomial generalized regression model with Lasso estimation and 5-fold cross validation method was performed. Results We included 124 patients, 49 in the "Failure" group and 75 in the "Success" group. All creatinine-related variables predicted success in simple and multiple logistic regression models. The best model generated a clinical score based on the odds ratio obtained for each variable and included urine output, non-renal SOFA score, fluid balance, serum urea, serum potassium, blood pH, and the variation in sCr values after RRT discontinuation. The score presented an area under the ROC of 0.86 (95% CI 0.76‒1.00). Conclusion Creatinine variation between the first 2 consecutive days after RRT discontinuation might predict success in RRT discontinuation. The developed clinical score based on these variables might be a useful clinical decision tool to guide hemodialysis catheter safe removal.

Risk Factors for Acute Kidney Injury and Death in Patients Infected With the Yellow Fever Virus During the 2018 Outbreak in São Paulo, Brazil.

Introduction: There have been few studies investigating acute kidney injury (AKI) in patients with yellow fever (YF). The objective of this study was to identify the risk factors for AKI and death in such patients. Methods: We evaluated 95 consecutive critically ill adult patients with the sylvatic form of YF, as confirmed by reverse-transcriptase polymerase chain reaction, in Brazil. The outcome measures were AKI (as defined by Kidney Disease: Improving Global Outcomes [KDIGO] criteria) and in-hospital death. Results: Of the 95 patients, 73 (76.8%) had AKI and 59 (62.1%) died from it. A total of 70 patients (73.7%) required dialysis because of AKI. After adjusting for age, sex, and the Simplified Acute Physiology Score 3 (SAPS 3), we found that elevated fractional excretion of sodium and requiring dialysis were independent risk factors for in-hospital mortality and that proteinuria correlated with AKI-associated mortality. Conclusion: Our findings indicate that, in patients with sylvatic YF, AKI is common and is associated with significant mortality. The data presented here could prove useful for improving understanding of the pathogenesis of AKI in YF and informing decisions regarding the care of the affected patients.

Urinary sodium excretion is low prior to acute kidney injury in patients in the intensive care unit.

Background: The incidence of acute kidney injury (AKI) is high in intensive care units (ICUs), and a better understanding of AKI is needed. Early chronic kidney disease is associated with urinary concentration inability and AKI recovery with increased urinary solutes in humans. Whether the inability of the kidneys to concentrate urine and excrete solutes at appropriate levels could occur prior to the diagnosis of AKI is still uncertain, and the associated mechanisms have not been studied. Methods: In this single-center prospective observational study, high AKI risk in ICU patients was followed up for 7 days or until ICU discharge. They were grouped as "AKI" or "No AKI" according to their AKI status throughout admission. We collected daily urine samples to measure solute concentrations and osmolality. Data were analyzed 1 day before AKI, or from the first to the fifth day of admission in the "No AKI" group. We used logistic regression models to evaluate the influence of the variables on future AKI diagnosis. The expression of kidney transporters in urine was evaluated by Western blotting. Results: We identified 29 patients as "No AKI" and 23 patients as "AKI," the latter being mostly low severity AKI. Urinary sodium excretion was lower in "AKI" patients prior to AKI diagnosis, particularly in septic patients. The expression of Na+/H+ exchanger (NHE3), a urinary sodium transporter, was higher in "AKI" patients. Conclusions: Urinary sodium excretion is low before an AKI episode in ICU patients, and high expressions of proximal tubule sodium transporters might contribute to this.

Continuous renal replacement therapy in COVID-19-associated AKI: adding heparin to citrate to extend filter life-a retrospective cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) may predispose patients to thrombotic events. The best anticoagulation strategy for continuous renal replacement therapy (CRRT) in such patients is still under debate. The purpose of this study was to evaluate the impact that different anticoagulation protocols have on filter clotting risk. METHODS: This was a retrospective observational study comparing two different anticoagulation strategies (citrate only and citrate plus intravenous infusion of unfractionated heparin) in patients with acute kidney injury (AKI), associated or not with COVID-19 (COV + AKI and COV - AKI, respectively), who were submitted to CRRT. Filter clotting risks were compared among groups. RESULTS: Between January 2019 and July 2020, 238 patients were evaluated: 188 in the COV + AKI group and 50 in the COV - AKI group. Filter clotting during the first filter use occurred in 111 patients (46.6%). Heparin use conferred protection against filter clotting (HR = 0.37, 95% CI 0.25-0.55), resulting in longer filter survival. Bleeding events and the need for blood transfusion were similar between the citrate only and citrate plus unfractionated heparin strategies. In-hospital mortality was higher among the COV + AKI patients than among the COV - AKI patients, although it was similar between the COV + AKI patients who received heparin and those who did not. Filter clotting was more common in patients with D-dimer levels above the median (5990 ng/ml). In the multivariate analysis, heparin was associated with a lower risk of filter clotting (HR = 0.28, 95% CI 0.18-0.43), whereas an elevated D-dimer level and high hemoglobin were found to be risk factors for circuit clotting. A diagnosis of COVID-19 was marginally associated with an increased risk of circuit clotting (HR = 2.15, 95% CI 0.99-4.68). CONCLUSIONS: In COV + AKI patients, adding systemic heparin to standard regional citrate anticoagulation may prolong CRRT filter patency by reducing clotting risk with a low risk of complications.

Cov-hep study: heparin in standard anticoagulation based on citrate for continuous veno-venous hemodialysis in patients with COVID-19: a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: The primary objective is to test if heparin added to a standard regional anticoagulation protocol based on citrate is able to reduce dialysis circuit losses by clotting without increasing the risk of thrombocytopenia or bleeding, in patients with COVID-19 with acute kidney injury requiring dialysis. TRIAL DESIGN: Randomized, parallel-group, open-label trial, with two arms (ratio 1:1) comparing different continuous renal replacement therapy anticoagulation strategies. PARTICIPANTS: Eligibility conditions: All ICU patients of University of Sao Paulo General Hospital (Hospital das Clínicas), Brazil will be screened for eligibility conditions. Adults (> 18 years old) with confirmed COVID-19 and acute kidney injury requiring dialysis with agreement between ICU and nephrology teams for the introduction of renal continuous replacement therapy in daily ICU rounds. Continuous renal replacement therapy will be prescribed by consulting nephrologists based on standard clinical guidelines, including acute kidney injury with hemodynamic instability plus hyperkalemia, severe acidosis, volume overload, respiratory distress, multiorgan failure or some combination of these factors. DATA COLLECTION: Patients demographics and associated clinical data and comorbidities will be recorded at ICU entry. Demographic information will include the patient's age, sex, and admission dates. Clinical data comprise comorbidities, APACHE 2, SAPS 3, need for mechanical ventilation, and use of vasopressor drugs. Physiological data collected by the day of CRRT start will be vital signs, the arterial oxygen tension/fraction of inspired oxygen (PaO2/FiO2) index, and serum creatinine, blood urea nitrogen, bilirubin, hemoglobin, hematocrit, platelets, white blood cell count levels and Peak D-dimer levels. Patients will be analyzed for the first 72h of CRRT, and they will be evaluated regarding clinical variables, filter patency and any adverse events that could be related to the anticoagulation choice, as bleeding (mild or major) or low platelets counts (<100.000 ui/uL) during treatment period. Mild and major bleeding will be defined by hemorrhagic event without clinical impact or hemoglobin (Hb) fall lesser than 1g/dL and hemorrhagic event with clinical impact or Hb fall higher than 1g/dL, respectively. EXCLUSION CRITERIA: Hypersensitivity to any of the substances going to be used in the study (Citric acid dextrosol 2.2% and unfractionated heparin); Previous diagnosis of coagulopathy or thrombophilia; Contraindication to the use of unfractionated heparin; Risk of citrate poisoning - (Lactate> 30 mg/dL, international normalized ratio > 2.5, Total bilirubin> 15 mg/dL); Pregnancy; Patients unlikely to survive for more than 24 hours. The trial is being undertaken at the University of Sao Paulo General Hospital (Hospital das Clinicas), Brazil. INTERVENTION AND COMPARATOR: Group A (control) - Patients on continuous renal replacement therapy (blood flow 150 ml/min, dose of 30 mL/Kg/h) receiving anticoagulation with sodium citrate at 4 mmol/L Group B (experiment): Patients on continuous hemodialysis (blood flow 150 mL/min, dose of 30 mL/Kg/h) receiving anticoagulation with sodium citrate at 4 mmol/L associated with unfractionated heparin at 10 U/Kg/h. MAIN OUTCOMES: The percentage of clotted dialyzers within 72 hours in each of the studied groups (Primary outcome) Secondary outcomes: Number of dialyzers used in the first 72 hours of dialysis protocol, Mortality in the first 72 h of dialysis protocol, Bleeding events (Major or minor) in the first 72 h of dialysis protocol, Thrombocytopenia (less than 50.000 platelets) proportion in the first 72 h of dialysis protocol, Dialysis efficiency (Urea sieving) - variation in urea sieving between the first, second and third days of dialysis protocol, Continuous renal replacement therapy pressures (Arterial, Venous, dialysate and pre-filter pressure) in the first 72 h of dialysis protocol, in-hospital mortality. RANDOMIZATION: RedCap→ randomization - 2 blocks randomization by D-dimer level (5000ng/dL cut-off) and catheter site (Right Internal Jugular versus other sites) with 1:1 allocation ratio. BLINDING (MASKING): No blinding - Open label format NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Total number of patients 90 (45 per group) TRIAL STATUS: Trial version 2.0 - ongoing recruitment. First recruitment: June 29, 2020 Estimated date for last recruitment: December 31, 2020 TRIAL REGISTRATION: Responsible Party: University of Sao Paulo General Hospital (Hospital das Clinicas) ClinicalTrials.gov Identifier: NCT04487990 , registered July 27, 2020, ReBec www.ensaiosclinicos.gov.br/rg/RBR-45kf9p/ Other Study ID Numbers: U1111-1252-0194 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1) In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Wharton's jelly-derived mesenchymal stem cells attenuate sepsis-induced organ injury partially via cholinergic anti-inflammatory pathway activation.

Sepsis induces organ dysfunction due to overexpression of the inflammatory host response, resulting in cardiopulmonary and autonomic dysfunction, thus increasing the associated morbidity and mortality. Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) express genes and secrete factors with anti-inflammatory properties, neurological and immunological protection, as well as improve survival in experimental sepsis. The cholinergic anti-inflammatory pathway (CAP) is mediated by α7-nicotinic acetylcholine receptors (α7nAChRs), which play an important role in the control of systemic inflammation. We hypothesized that WJ-MSCs attenuate sepsis-induced organ injury in the presence of an activated CAP pathway. To confirm our hypothesis, we evaluated the effects of WJ-MSCs as a treatment for cardiopulmonary injury and on neuroimmunomodulation. Male Wistar rats were randomly divided into four groups: control (sham-operated); cecal ligation and puncture (CLP) alone; CLP+WJ-MSCs (1 × 106 cells, at 6 h post-CLP); and CLP+methyllycaconitine (MLA)+WJ-MSCs (5 mg/kg body wt, at 5.5 h post-CLP, and 1 × 106 cells, at 6 h post-CLP, respectively). All experiments, including the assessment of echocardiographic parameters and heart rate variability, were performed 24 h after CLP. WJ-MSC treatment attenuated diastolic dysfunction and restored baroreflex sensitivity. WJ-MSCs also increased cardiac sympathetic and cardiovagal activity. WJ-MSCs reduced leukocyte infiltration and proinflammatory cytokines, effects that were abolished by administration of a selective α7nAChR antagonist (MLA). In addition, WJ-MSC treatment also diminished apoptosis in the lungs and spleen. In cardiac and splenic tissue, WJ-MSCs downregulated α7nAChR expression, as well as reduced the phospho-STAT3-to-total STAT3 ratio in the spleen. WJ-MSCs appear to protect against sepsis-induced organ injury by reducing systemic inflammation, at least in part, via a mechanism that is dependent on an activated CAP.

Effects of Brazilian green propolis on proteinuria and renal function in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Chronic kidney disease (CKD) is a public health problem worldwide, and proteinuria is a well-established marker of disease progression in CKD patients. Propolis, a natural resin produced by bees from plant materials, has anti-inflammatory, immunomodulatory, and anti-oxidant properties, as well as having been shown to have an antiproteinuric effect in experimental CKD. The aim of this study was to evaluate the impact of Brazilian green propolis extract on proteinuria reduction and the changes in the estimated glomerular filtration rate (eGFR). METHODS: This was a randomized, double-blind, placebo-controlled study including patients with CKD caused by diabetes or of another etiology, 18-90 years of age, with an eGFR of 25-70 ml/min per 1.73 m2 and proteinuria (urinary protein excretion > 300 mg/day) or micro- or macro-albuminuria (urinary albumin-to-creatinine ratio > 30 mg/g or > 300 mg/g, respectively). We screened 148 patients and selected 32, randomly assigning them to receive 12 months of Brazilian green propolis extract at a dose of 500 mg/day (n = 18) or 12 months of a placebo (n = 14). RESULTS: At the end of treatment, proteinuria was significantly lower in the propolis group than in the placebo group-695 mg/24 h (95% CI, 483 to 999) vs. 1403 mg/24 h (95% CI, 1031 to 1909); P = 0.004-independent of variations in eGFR and blood pressure, which did not differ between the groups during follow-up. Urinary monocyte chemoattractant protein-1 was also significantly lower in the propolis group than in the placebo group-58 pg/mg creatinine (95% CI, 36 to 95) vs. 98 pg/mg creatinine (95% CI, 62 to 155); P = 0.038. CONCLUSIONS: Brazilian green propolis extract was found to be safe and well tolerated, as well as to reduce proteinuria significantly in patients with diabetic and non-diabetic CKD. TRIAL REGISTRATION: ( ClinicalTrials.gov number NCT02766036. Registered: May 9, 2016).

Chronic Hyponatremia Due to the Syndrome of Inappropriate Antidiuresis (SIAD) in an Adult Woman with Corpus Callosum Agenesis (CCA).

BACKGROUND Corpus callosum agenesis (CCA) is one of the most common congenital brain abnormalities, and is associated with neurodevelopmental and neuropsychiatric disorders. In CCA, defects in osmoregulation have been reported. This report presents a rare case of chronic hyponatremia associated with the syndrome of inappropriate antidiuresis (SIAD) in a woman with CCA. CASE REPORT A 41-year-old woman presented to the renal unit with symptomatic hyponatremia. In her past medical history, she had a four-year history of systemic arterial hypertension and Sjögren's syndrome, and a three-year history of systemic lupus erythematosus (SLE), which was treated with cyclophosphamide. She had CCA but with irregular neurological follow-up. During the previous eight years, her plasma sodium levels ranged from between 118-134 mEq/L. On this hospital admission, she had plasma hypo-osmolality, measured in milli-osmoles per kilogram of H2O (mOsm/kg H2O), of 251 mOsm/Kg H2O, and a urinary hyper-osmolality of 545 mOsm/Kg H2O, and increased level of plasma antidiuretic hormone (ADH) (1.8 pg/ml). Bone densitometry was consistent with osteoporosis. The patient remained asymptomatic during her hospital stay. Chronic hyponatremia associated with the SIAD was diagnosed. Water restriction and increased protein intake resulted in a partial improvement in the serum sodium level (128-134 mEq/L). The patient was discharged from the hospital with outpatient follow-up. CONCLUSIONS A rare case of chronic hyponatremia due to the SIAD associated with CCA is reported that demonstrates the importance of correct diagnosis, management, and clinical follow-up of the SIAD, including bone densitometry.

Human umbilical cord-derived mesenchymal stromal cells protect against premature renal senescence resulting from oxidative stress in rats with acute kidney injury.

BACKGROUND: Mesenchymal stromal cells (MSCs) represent an option for the treatment of acute kidney injury (AKI). It is known that young stem cells are better than are aged stem cells at reducing the incidence of the senescent phenotype in the kidneys. The objective of this study was to determine whether AKI leads to premature, stress-induced senescence, as well as whether human umbilical cord-derived MSCs (huMSCs) can prevent ischaemia/reperfusion injury (IRI)-induced renal senescence in rats. METHODS: By clamping both renal arteries for 45 min, we induced IRI in male rats. Six hours later, some rats received 1 × 106 huMSCs or human adipose-derived MSCs (aMSCs) intraperitoneally. Rats were euthanised and studied on post-IRI days 2, 7 and 49. RESULTS: On post-IRI day 2, the kidneys of huMSC-treated rats showed improved glomerular filtration, better tubular function and higher expression of aquaporin 2, as well as less macrophage infiltration. Senescence-related proteins (ß-galactosidase, p21Waf1/Cip1, p16INK4a and transforming growth factor beta 1) and microRNAs (miR-29a and miR-34a) were overexpressed after IRI and subsequently downregulated by the treatment. The IRI-induced pro-oxidative state and reduction in Klotho expression were both reversed by the treatment. In comparison with huMSC treatment, the treatment with aMSCs improved renal function to a lesser degree, as well as resulting in a less pronounced increase in the renal expression of Klotho and manganese superoxide dismutase. Treatment with huMSCs ameliorated long-term kidney function after IRI, minimised renal fibrosis, decreased ß-galactosidase expression and increased the expression of Klotho. CONCLUSIONS: Our data demonstrate that huMSCs attenuate the inflammatory and oxidative stress responses occurring in AKI, as well as reducing the expression of senescence-related proteins and microRNAs. Our findings broaden perspectives for the treatment of AKI.

Hemodiafiltration Decreases Serum Levels of Inflammatory Mediators in Severe Leptospirosis: A Prospective Study.

BACKGROUND: Leptospirosis is a health problem worldwide. Its most severe form is a classic model of sepsis, provoking acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), with associated mortality that remains unacceptably high. We previously demonstrated that early initiation of sustained low-efficiency dialysis (SLED) followed by daily SLED significantly decreases mortality. However, the mode of clearance can also affect dialysis patient outcomes. Therefore, the objective of this study was to compare the effects of SLED with traditional (diffusive) clearance, via hemodialysis, and SLED with convective clearance, via hemodiafiltration (SLEDf), in patients with severe leptospirosis. METHODS: In this prospective study, conducted in the intensive care unit (ICU) from 2009 through 2012, we compared two groups-SLED (n = 19) and SLEDf (n = 20)-evaluating demographic, clinical, and biochemical parameters, as well as serum levels of interleukins, up to the third day after admission. All patients received dialysis early and daily thereafter. RESULTS: During the study period, 138 patients were admitted to our ICU with a diagnosis of leptospirosis; 39 (36 males/3 females) met the criteria for ARDS and AKI. All patients were on mechanical ventilation and were comparable in terms of respiratory parameters. Mortality did not differ between the SLEDf and SLED groups. However, post-admission decreases in the serum levels of interleukin (IL)-17, IL-7, and monocyte chemoattractant protein-1 were significantly greater in the SLEDf group. Direct bilirubin and the arterial oxygen tension/fraction of inspired oxygen ratio were significantly higher in the SLED group. We identified the following risk factors (sensitivities/specificities) for mortality in severe leptospirosis: age ≥ 55 years (67%/91%); serum urea ≥ 204 mg/dl (100%/70%); creatinine ≥ 5.2 mg/dl (100%/58%); Acute Physiology and Chronic Health Evaluation II score ≥ 39.5 (67%/88%); Sequential Organ Failure Assessment score ≥ 20.5 (67%/85%); and inspiratory pressure ≥ 31 mmHg (84%/85%). CONCLUSIONS: The mode of dialysis clearance might not affect outcomes in severe leptospirosis.

Hemodiafiltration decreases serum levels of inflammatory mediators in severe leptospirosis: A prospective study

BACKGROUND: Leptospirosis is a health problem worldwide. Its most severe form is a classic model of sepsis, provoking acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), with associated mortality that remains unacceptably high. We previously demonstrated that early initiation of sustained low-efficiency dialysis (SLED) followed by daily SLED significantly decreases mortality. However, the mode of clearance can also affect dialysis patient outcomes. Therefore, the objective of this study was to compare the effects of SLED with traditional (diffusive) clearance, via hemodialysis, and SLED with convective clearance, via hemodiafiltration (SLEDf), in patients with severe leptospirosis. METHODS: In this prospective study, conducted in the intensive care unit (ICU) from 2009 through 2012, we compared two groups-SLED (n = 19) and SLEDf (n = 20)-evaluating demographic, clinical, and biochemical parameters, as well as serum levels of interleukins, up to the third day after admission. All patients received dialysis early and daily thereafter. RESULTS: During the study period, 138 patients were admitted to our ICU with a diagnosis of leptospirosis; 39 (36 males/3 females) met the criteria for ARDS and AKI. All patients were on mechanical ventilation and were comparable in terms of respiratory parameters. Mortality did not differ between the SLEDf and SLED groups. However, post-admission decreases in the serum levels of interleukin (IL)-17, IL-7, and monocyte chemoattractant protein-1 were significantly greater in the SLEDf group. Direct bilirubin and the arterial oxygen tension/fraction of inspired oxygen ratio were significantly higher in the SLED group. We identified the following risk factors (sensitivities/specificities) for mortality in severe leptospirosis: age ≥ 55 years (67%/91%); serum urea ≥ 204 mg/dl (100%/70%); creatinine ≥ 5.2 mg/dl (100%/58%); Acute Physiology and Chronic Health Evaluation II score ≥ 39.5 (67%/88%); Sequential Organ Failure Assessment score ≥ 20.5 (67%/85%); and inspiratory pressure ≥ 31 mmHg (84%/85%). CONCLUSIONS: The mode of dialysis clearance might not affect outcomes in severe leptospirosis

Endothelial progenitor cells in tumor angiogenesis: another brick in the wall.

Until 15 years ago, vasculogenesis, the formation of new blood vessels from undifferentiated cells, was thought to occur only during embryonic development. The discovery of circulating cells that are able to promote vascular regeneration and repair-the so-called endothelial progenitor cells (EPCs)-changed that, and EPCs have since been studied extensively. It is already known that EPCs include many subtypes of cells that play a variety of roles in promoting vascular growth. Some EPCs are destined to differentiate into endothelial cells, whereas others are capable of promoting and sustaining angiogenesis through paracrine mechanisms. Vasculogenesis and angiogenesis might constitute complementary mechanisms for postnatal neovascularization, and EPCs could be at the core of this process. Although the formation of new blood vessels from preexisting vasculature plays a beneficial role in many physiological processes, such as wound healing, it also contributes to tumor growth and metastasis. However, many aspects of the role played by EPCs in tumor angiogenesis remain unclear. This review aims to address the main aspects of EPCs differentiation and certain characteristics of their main function, especially in tumor angiogenesis, as well as the potential clinical applications.

Células-tronco provenientes de cordão umbilical humano atenuam a senescência renal induzida por injúria renal aguda secundária à lesão de isquemia e reperfusão em ratos

A injúria renal aguda representa um estado de senescência precoce induzida por estresse, e as células-tronco mesenquimais podem ser uma alternativa para seu tratamento. Células-tronco jovens reduzem o fenótipo de envelhecimento em rins quando comparadas a células idosas. O objetivo deste estudo foi avaliar se o tratamento com jovens células-tronco mesenquimais derivadas de cordão umbilical humano podem interferir na senescência renal induzida por lesão de isquemia-reperfusão em ratos. Ratos machos foram submetidos ao modelo de isquemia de artérias renais bilateralmente por 45 minutos, com reperfusão após, e alguns animais receberam 1 X 106 células por via intraperitoneal após 6 horas da indução da lesão. Os animais foram eutanasiados no segundo ou no sétimo dia pós-isquêmico. No segundo dia após a lesão de isquemia-reperfusão, o tratamento com as células melhorou a filtração glomerular e a função tubular, melhorou a expressão renal de aquaporina-2 e reduziu a infiltração de macrófagos nos rins. Proteínas relacionadas à senescência (-galactosidase, p21, p16 e fator de transformação do crescimento ) e microRNAs (mir-29a e miR-34a) estiveram com a expressão aumentada após a isquemia-reperfusão, e houve redução nesses parâmetros com o tratamento. A redução na expressão de Klotho e o estado pró-oxidativo gerados pela isquemia-reperfusão também foram revertidos pelo tratamento. A senescência induzida pela injúria renal aguda é um processo independente de telômeros. Ao sétimo dia pós-lesão, os ratos isquêmicos mantinham defeito de concentração urinária, que foi revertido nos animais tratados. Além disso, o tratamento reduziu o índice de necrose tubular aguda em tecido renal e reduziu o infiltrado macrofágico túbulo-intersticial. O marcador pró-senescência p16 foi completamente restabelecido nos animais tratados...

Acute kidney injury represents a status of premature stress-induced senescence, and mesenchymal stem cells are an alternative for treatment. Young stem cells reduce aging phenotype in kidneys when compared to old cells. The objective of this study was to evaluate if treatment with young human umbilical cord mesenchymal stem cells could interfere in kidney senescence induced by renal ischemia-reperfusion in rats. Male rats were induced to ischemia-reperfusion injury by 45-minutes clamping of both renal arteries; some rats received 1X106 cells intraperitonally six hours later. Rats were euthanatized on post-renal ischemia reperfusion days two and seven. At day 2 after ischemia-reperfusion injury, treatment with cells improved glomerular filtration, tubular function, improved renal expression of aquaporin 2 and decreased macrophage kidney infiltration. Senescence-related proteins (?-galactosidase, p21, p16 and transforming growth factor ?) and microRNAs (miR-29a and miRNA-34a) were overexpressed after ischemia-reperfusion, and reversed by the treatment. The Klotho reduced expression and the pro-oxidative status induced by ischemia-reperfusion were reversed by the treatment. Senescence induced acute kidney injury is a telomere-independent process. At day 7, ischemic rats maintained urinary concentrating defect, which is reversed in treated animals. Moreover, treatment decreased the index of acute tubular necrosis in kidney tissue and decreased macrophage kidney infiltration. Senescence marker p16 was completely restored in treated animals...

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase.

The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-κB activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP+EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-l-arginine methyl ester (l-NAME) simultaneously with EPO administration (CLP+EPO+l-NAME). A fifth group (CLP+EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP+EPO rats presented significantly higher inulin clearance than did CLP and CLP+EPO+l-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP+EPO rats; and inulin clearance was significantly higher in CLP+EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP+EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-α activation, NF-κB activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-κB downregulation.