Prospective validation of the EASL management algorithm for acute kidney injury in cirrhosis.

BACKGROUND & AIMS: The management of acute kidney injury (AKI) in cirrhosis is challenging. The EASL guidelines proposed an algorithm for the management of AKI, but this has never been validated. We aimed to prospectively evaluate this algorithm in clinical practice. METHODS: We performed a prospective cohort study in consecutive hospitalized patients with cirrhosis and AKI. The EASL management algorithm includes identification/treatment of precipitating factors, 2-day albumin infusion in patients with AKI ≥stage 1B, and treatment with terlipressin in patients with hepatorenal syndrome (HRS-AKI). The primary outcome was treatment response, which included both full and partial response. Secondary outcomes were survival and adverse events associated with terlipressin therapy. RESULTS: A total of 202 AKI episodes in 139 patients were included. Overall treatment response was 80%, while renal replacement therapy was required in only 8%. Response to albumin infusion was achieved in one-third of episodes. Of patients not responding to albumin, most (74%) did not meet the diagnostic criteria of HRS-AKI, with acute tubular necrosis (ATN) being the most common phenotype. The response rate in patients not meeting the criteria for HRS-AKI was 70%. Only 30 patients met the diagnostic criteria for HRS-AKI, and their response rate to terlipressin was 61%. Median time from AKI diagnosis to terlipressin initiation was only 2.5 days. While uNGAL (urinary neutrophil gelatinase-associated lipocalin) could differentiate ATN from other phenotypes (AUROC 0.78), it did not predict response to therapy in HRS-AKI. Ninety-day transplant-free survival was negatively associated with MELD-Na, ATN and HRS-AKI as well as uNGAL. Three patients treated with terlipressin developed pulmonary edema. CONCLUSIONS: The application of the EASL AKI algorithm is associated with very good response rates and does not significantly delay initiation of terlipressin therapy. IMPACT AND IMPLICATIONS: The occurrence of acute kidney injury (AKI) in patients with cirrhosis is associated with poor short-term mortality. Improving its rapid identification and prompt management was the focus of the recently proposed EASL AKI algorithm. This is the first prospective study demonstrating that high AKI response rates are achieved with the use of this algorithm, which includes identification of AKI, treatment of precipitating factors, a 2-day albumin challenge in patients with AKI ≥1B, and supportive therapy in patients with persistent AKI not meeting HRS-AKI criteria or terlipressin with albumin in those with HRS-AKI. These findings support the use of this algorithm in clinical practice.

Precise Targeting of Autoantigen-Specific B Cells in Lupus Nephritis with Chimeric Autoantibody Receptor T Cells.

Despite conventional therapy, lupus nephritis (LN) remains a significant contributor to short- and long-term morbidity and mortality. B cell abnormalities and the production of autoantibodies against nuclear complexes like anti-dsDNA are recognised as key players in the pathogenesis of LN. To address the challenges of chronic immunosuppression associated with current therapies, we have engineered T cells to express chimeric autoantibody receptors (DNA-CAART) for the precise targeting of B cells expressing anti-dsDNA autoantibodies. T cells from LN patients were transduced using six different CAAR vectors based on their antigen specificity, including alpha-actinin, histone-1, heparan sulphate, or C1q. The cytotoxicity, cytokine production, and cell-cell contact of DNA-CAART were thoroughly investigated in co-culture experiments with B cells isolated from patients, both with and without anti-dsDNA positivity. The therapeutic effects were further evaluated using an in vitro immune kidney LN organoid. Among the six proposed DNA-CAART, DNA4 and DNA6 demonstrated superior selectively cytotoxic activity against anti-dsDNA+ B cells. Notably, DNA4-CAART exhibited improvements in organoid morphology, apoptosis, and the inflammatory process in the presence of IFNα-stimulated anti-dsDNA+ B cells. Based on these findings, DNA4-CAART emerge as promising candidates for modulating autoimmunity and represent a novel approach for the treatment of LN.

Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS: We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS: Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION: Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

Organ dysfunction and failure in liver disease.

Acute-on-chronic liver failure (ACLF) is a complex syndrome defined by the existence of different organ failures (OFs) in patients with chronic liver disease, mainly cirrhosis. Several definitions have been proposed to define the syndrome, varying in the grade of the subjacent liver disease, the type of precipitants and the organs considered in the definition. Liver, coagulation, brain, kidney, circulatory and pulmonary are the six types of OFs proposed in the different classifications, with different prevalence worldwide. Irrespective of the definition used, patients who develop ACLF present a hyperactive immune system, profound haemodynamic disturbances and several metabolic alterations that finally lead to organ dysfunction. These disturbances are triggered by different factors such as bacterial infections, alcoholic hepatitis, gastrointestinal bleeding or hepatitis B virus flare, among others. Because patients with ACLF present high short-term mortality, a prompt recognition is needed to start treatment of the trigger event and specific organ support. Liver transplantation is also feasible in carefully selected patients and should be evaluated.

Small-Extracellular-Vesicle-Derived miRNA Profile Identifies miR-483-3p and miR-326 as Regulators in the Pathogenesis of Antiphospholipid Syndrome (APS).

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disease associated with recurrent thrombosis and/or obstetric morbidity with persistent antiphospholipid antibodies (aPL). Although these antibodies drive endothelial injury and thrombophilia, the underlying molecular mechanism is still unclear. Small extracellular vesicles (sEVs) contain miRNAs, key players in intercellular communication. To date, the effects of miRNA-derived sEVs in PAPS are not well understood. We characterised the quantity, cellular origin and miRNA profile of sEVs isolated from thrombotic APS patients (PAPS, n = 50), aPL-carrier patients (aPL, n = 30) and healthy donors (HD, n = 30). We found higher circulating sEVs mainly of activated platelet origin in PAPS and aPL patients compared to HD, that were highly engulfed by HUVECs and monocyte. Through miRNA-sequencing analysis, we identified miR-483-3p to be differentially upregulated in sEVs from patients with PAPS and aPL, and miR-326 to be downregulated only in PAPS sEVs. In vitro studies showed that miR-483-3p overexpression in endothelial cells induced an upregulation of the PI3K-AKT pathway that led to endothelial proliferation/dysfunction. MiR-326 downregulation induced NOTCH pathway activation in monocytes with the upregulation of NFKB1, tissue factor and cytokine production. These results provide evidence that miRNA-derived sEVs contribute to APS pathogenesis by producing endothelial cell proliferation, monocyte activation and adhesion/procoagulant factors.

Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Decompensated cirrhosis (DC) is associated with high mortality, mainly owing to the development of acute-on-chronic liver failure (ACLF). Identifying the patients with DC who are at high risk of mortality and ACLF development is an unmet clinical need. Liver fatty acid-binding protein (L-FABP) is expressed in several organs and correlates with liver and systemic inflammation. Herein, we aimed to assess the prognostic value of L-FABP in patients with DC. METHODS: A prospective series of 444 patients hospitalized for DC was divided into 2 cohorts: study cohort (305 patients) and validation cohort (139 patients). L-FABP was measured in urine and plasma samples collected at admission. Neutrophil gelatinase-associated lipocalin (NGAL) was also measured in urine samples for comparison. RESULTS: Urine but not plasma L-FABP correlated with 3-month survival on univariate analysis. On multivariate analysis, urine L-FABP and model for end-stage liver disease (MELD)-Na were the only independent predictors of prognosis. Urine L-FABP levels were higher in patients with ACLF than in those without and also predicted the development of ACLF, together with MELD-Na, during follow-up. In patients with ACLF, urine L-FABP correlated with liver, coagulation, and circulatory failure. Urine L-FABP levels were also increased in patients with acute kidney injury, particularly in those with acute tubular necrosis. The ability of urinary L-FABP to predict survival and ACLF development was confirmed in the validation cohort. Urine NGAL predicted outcome on univariate but not multivariate analysis. CONCLUSIONS: Urinary L-FABP levels are independently associated with the 3-month clinical course in patients with DC, in terms of mortality and ACLF development. Urinary L-FABP is a promising prognostic biomarker for patients with DC. LAY SUMMARY: Increased levels of liver fatty acid-binding protein (L-FABP), a protein related to lipid metabolism, have been associated with liver-related diseases. The present study analyzed urinary L-FABP levels in 2 independent groups of patients with decompensated cirrhosis and showed that higher urinary L-FABP levels correlated with increased mortality and risk of acute-on-chronic liver failure development. Therefore, urinary L-FABP levels could be useful as a new tool to predict complications in patients with decompensated cirrhosis.

Alterations in Gut Microbiome in Cirrhosis as Assessed by Quantitative Metagenomics: Relationship With Acute-on-Chronic Liver Failure and Prognosis.

BACKGROUND AND AIMS: Cirrhosis is associated with changes in gut microbiome composition. Although acute-on-chronic liver failure (ACLF) is the most severe clinical stage of cirrhosis, there is lack of information about gut microbiome alterations in ACLF using quantitative metagenomics. We investigated the gut microbiome in patients with cirrhosis encompassing the whole spectrum of disease (compensated, acutely decompensated without ACLF, and ACLF). A group of healthy subjects was used as control subjects. METHODS: Stool samples were collected prospectively in 182 patients with cirrhosis. DNA library construction and sequencing were performed using the Ion Proton Sequencer (ThermoFisher Scientific, Waltham, MA). Microbial genes were grouped into clusters, denoted as metagenomic species. RESULTS: Cirrhosis was associated with a remarkable reduction in gene and metagenomic species richness compared with healthy subjects. This loss of richness correlated with disease stages and was particularly marked in patients with ACLF and persisted after adjustment for antibiotic therapy. ACLF was associated with a significant increase of Enterococcus and Peptostreptococcus sp and a reduction of some autochthonous bacteria. Gut microbiome alterations correlated with model for end-stage liver disease and Child-Pugh scores and organ failure and was associated with some complications, particularly hepatic encephalopathy and infections. Interestingly, gut microbiome predicted 3-month survival with good stable predictors. Functional analysis showed that patients with cirrhosis had enriched pathways related to ethanol production, γ-aminobutyric acid metabolism, and endotoxin biosynthesis, among others. CONCLUSIONS: Cirrhosis is characterized by marked alterations in gut microbiome that parallel disease stages with maximal changes in ACLF. Altered gut microbiome was associated with complications of cirrhosis and survival. Gut microbiome may contribute to disease progression and poor prognosis. These results should be confirmed in future studies.

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. METHODS: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. LAY SUMMARY: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.

Late bedtime is associated with lower weight loss in patients with severe obesity after sleeve gastrectomy.

BACKGROUND: Previous research has shown that sleep can play a role in obesity and weight loss. However, the association of sleep with weight loss in patients with severe obesity after bariatric surgery remains unexplored. We aimed to evaluate the role of sleep in weight loss evolution in a cohort of patients who underwent sleeve gastrectomy. METHODS: A cohort of 252 patients with severe obesity (75.7% women; age [mean ± SD] 47.7 ± 10.8 years; BMI 44.2 ± 5.9 kg/m2) was followed for 1 year after surgery. Anthropometric, biochemical, physical activity, sleep (bedtime, wakeup time, and sleep duration) and dietary intake variables were collected pre- and post-surgery (1 year). Linear and non-linear regression models were used to examine the associations between sleep variables and weight loss. Participants were grouped into 'early' and 'late' sleepers according to a bedtime threshold (before or after 24:00 h), and the differences in weight loss, physical activity, meal timing, and dietary intake between groups were studied. RESULTS: 1-h increments in bedtime were linearly associated with less excess weight loss (EWL) [-2.23%; 95%CI: -3.37; -0.70; p = 0.005] 1 year after the sleeve gastrectomy. Late sleepers lost less weight (-5.64% of EWL [95%CI: -10.11; -1.17]; p = 0.014) when compared to early sleepers and showed a higher energy intake after 21:00 h (8.66% of total energy intake [95% CI: 4.87; 12.46]; p < 0.001). CONCLUSIONS: Late bedtime is associated with less success of weight loss 1 year after the sleeve gastrectomy. Late sleepers consumed more of their calories closer to bedtime. Our results highlight the relevance of considering recommendations on bedtime and meal timing for patients after bariatric surgery.

Sequential changes in urinary biomarker levels in patients with cirrhosis and severe hepatorenal syndrome.

Whether tubular injury develops in patients with acute kidney injury owing to hepatorenal syndrome (AKI-HRS) is controversial. We performed repeated measurements of biomarkers of tubular injury during a 14-day period in 60 patients with cirrhosis and AKI (34 with AKI-HRS meeting the classical definition of type 1 HRS and 26 with AKI owing to acute tubular necrosis, AKI-ATN). Nineteen of 34 patients had resolution of AKI-HRS, while the remainder had persistent AKI-HRS. The persistence of AKI-HRS was associated with remarkably high short-term mortality. There were no significant differences in urinary NGAL or IL-18 between patients with resolution vs those with persistent AKI-HRS throughout the 14-day period. By contrast, biomarker levels were significantly lower in AKI-HRS, even if persistent, compared to AKI-ATN. These findings are highly suggestive of lack of significant tubular injury in AKI-HRS and could be of value in the clinical decision between combined liver-kidney or liver transplantation alone in patients with cirrhosis and AKI candidates to transplantation.

Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes.

BACKGROUND & AIMS: Acute kidney injury (AKI) is common in cirrhosis and is associated with poor prognosis. In patients who survive after AKI, it is not known whether the acute injury leads to chronic impairment of kidney function (chronic kidney disease [CKD]). The aim of the study was to determine the frequency of CKD at 3 months after an AKI episode and its effects on patient outcomes. METHODS: Patients admitted for complications of cirrhosis during a 6.5-year period were evaluated using the same protocol, with assessment of kidney function at regular intervals during and after hospitalization. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 at 3 months after AKI. RESULTS: A total of 409 patients (168 with AKI and 241 without AKI) were included. After 3 months, 97 patients with AKI and 188 patients without AKI had survived. Of the 97 patients with AKI, 24 had developed CKD at 3 months compared to only 2 of the 188 patients without AKI (25% vs. 1%, odds ratio 31; p <0.0001). Risk factors independently associated with CKD were nosocomial AKI and severity of AKI (stage ≥1B). At diagnosis of CKD, all patients had stage 3A CKD and one-quarter of them progressed to stages 3B and 4 after 1 year. The transition from AKI to CKD was associated with an increased rate of 3-month hospital readmission, increased frequency of AKI, bacterial infections, ascites, and refractory ascites and a trend towards a higher need for liver transplantation. Transplant-free survival was not impaired. CONCLUSIONS: CKD frequently develops in patients with cirrhosis who survive AKI and has a negative impact on relevant clinical outcomes. The transition from AKI to CKD is common and should be considered a high-risk condition in patients with cirrhosis. LAY SUMMARY: Episodes of acute impairment of kidney function are common in patients with cirrhosis. This study shows that the development of chronic impairment of kidney function is frequent in patients surviving these acute episodes and that it is associated with a higher risk of developing other complications of cirrhosis and to a higher rate of 3-month hospital readmissions.

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. METHODS: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. RESULTS: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). CONCLUSIONS: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. GOV NUMBER: NCT03056612. LAY SUMMARY: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.

Neutrophil Gelatinase-Associated Lipocalin for Assessment of Acute Kidney Injury in Cirrhosis: A Prospective Study.

Kidney biomarkers appear to be useful in differential diagnosis between acute tubular necrosis (ATN) and other types of acute kidney injury (AKI) in cirrhosis, particularly hepatorenal syndrome (HRS-AKI). Distinction is important because treatment is different. However, kidney biomarkers are still not used in clinical practice. The aim of the current study was to investigate the accuracy of several biomarkers in differential diagnosis of AKI and in predicting kidney outcome and patient survival. This was a prospective study of 320 consecutive cases of AKI in patients hospitalized for decompensated cirrhosis. Evaluation of AKI was made with a diagnostic algorithm that included identification and removal/treatment of precipitating factors and albumin administration (1 g/kg for 2 days) to patients with AKI stage 1B or greater. Urinary neutrophil gelatinase-associated lipocalin (NGAL), monomeric NGAL (mNGAL), interleukin-18, and standard biomarkers were measured at diagnosis and on days 3, 7, and 14. Of the 320 cases, 153 were hypovolemia-induced AKI (48%), 93 were HRS-AKI (29%), 39 were ATN (12%), and 35 were due to miscellaneous causes (11%). Among all biomarkers, urinary NGAL measured at day 3 had the greatest accuracy for differential diagnosis between ATN and other types of AKI (area under the receiver operating characteristic curve, 0.87; 95% confidence interval, 0.78-0.95). The cutoff with the best predictive accuracy for ATN diagnosis was 220 µg/g creatinine. Progression of AKI during hospitalization was associated with persistently high NGAL levels, and NGAL was an independent predictive factor of AKI progression. Likewise, NGAL was also an independent predictive factor of 28-day mortality together with Model for End-Stage Liver Disease score. Conclusion: These results support the use of NGAL in clinical practice within the context of a diagnostic algorithm for differential diagnosis of AKI and outcome prediction in cirrhosis.

Efficacy of Thalidomide in Discoid Lupus Erythematosus: Insights into the Molecular Mechanisms.

BACKGROUND: Thalidomide has been used successfully in a variety of chronic refractory inflammatory dermatological conditions with underlying autoimmune or infectious pathogenesis. It was first used for refractory discoid lupus erythematosus (DLE) in 1983 and has steadily grown since then. METHOD: In this review, we describe the therapeutic benefits of thalidomide for DLE treatment and its biological properties. We explain how new discoveries in DLE pathogenesis are relevant to understand thalidomide's mechanism of action and the need to find an alternative safe drug with similar therapeutic effects. SUMMARY: Thalidomide's efficacy in DLE patients is significant, with 80-90% reaching clinical remission according to different studies. However, thalidomide's use is still limited by serious adverse effects such as teratogenicity, neurotoxicity, and thrombosis. In addition, there is a frequent rate of relapse and many patients require a long-term low dose of thalidomide as maintenance. The achievement of clinical response within weeks is key to avoid irreversible DLE fibrotic sequelae, making it critical to introduce thalidomide earlier in the DLE treatment algorithm. Recently, microarray and miRNA screenings demonstrated a significant CD4+ T enrichment and T-helper 1 response predom-inance with a dysregulation of regulatory T cell (Treg) expression in DLE lesions that induced high levels of proinflammatory, chemotaxis, and apoptotic proteins that induce the chronic inflammation response. Thalidomide's anti-inflammatory, antiangiogenic, and T-cell co-stimulatory effects may be beneficial for DLE since it promotes cytokine inhibition, inhibits macrophage activation, regulates Treg responses, inhibits angiogenesis, modulates T cells, and promotes NK cell-mediated cytotoxicity.

Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial.

Background: The potential role of new oral anticoagulants in antiphospholipid antibody syndrome (APS) remains uncertain. Objective: To determine whether rivaroxaban is noninferior to dose-adjusted vitamin K antagonists (VKAs) for thrombotic APS. Design: 3-year, open-label, randomized noninferiority trial. (EU Clinical Trials Register: EUDRA [European Union Drug Regulatory Authorities] code 2010-019764-36). Setting: 6 university hospitals in Spain. Participants: 190 adults (aged 18 to 75 years) with thrombotic APS. Intervention: Rivaroxaban (20 mg/d or 15 mg/d, according to renal function) versus dose-adjusted VKAs (target international normalized ratio, 2.0 to 3.0, or 3.1 to 4.0 in patients with a history of recurrent thrombosis). Measurements: The primary efficacy outcome was the proportion of patients with new thrombotic events; the primary safety outcome was major bleeding. The prespecified noninferiority margin for risk ratio (RR) was 1.40. Secondary outcomes included time to thrombosis, type of thrombosis, changes in biomarker levels, cardiovascular death, and nonmajor bleeding. Results: After 3 years of follow-up, recurrent thrombosis occurred in 11 patients (11.6%) in the rivaroxaban group and 6 (6.3%) in the VKA group (RR in the rivaroxaban group, 1.83 [95% CI, 0.71 to 4.76]). Stroke occurred more commonly in patients receiving rivaroxaban (9 events) than in those receiving VKAs (0 events) (corrected RR, 19.00 [CI, 1.12 to 321.9]). Major bleeding occurred in 6 patients (6.3%) in the rivaroxaban group and 7 (7.4%) in the VKA group (RR, 0.86 [CI, 0.30 to 2.46]). Post hoc analysis suggested an increased risk for recurrent thrombosis in rivaroxaban-treated patients with previous arterial thrombosis, livedo racemosa, or APS-related cardiac valvular disease. Limitation: Anticoagulation intensity was not measured in the rivaroxaban group. Conclusion: Rivaroxaban did not show noninferiority to dose-adjusted VKAs for thrombotic APS and, in fact, showed a non-statistically significant near doubling of the risk for recurrent thrombosis. Primary Funding Source: Bayer Hispania.

The Urinary Exosomal miRNA Expression Profile is Predictive of Clinical Response in Lupus Nephritis.

Data on exosomal-derived urinary miRNAs have identified several miRNAs associated with disease activity and fibrosis formation, but studies on prognosis are lacking. We conducted a qPCR array screening on urinary exosomes from 14 patients with biopsy-proven proliferative lupus glomerulonephritis with a renal outcome of clinical response (n = 7) and non-response (n = 7) following therapy. Validation studies were performed by qRT-PCR in a new lupus nephritis (LN) cohort (responders = 22 and non-responders = 21). Responder patients expressed significantly increased levels of miR-31, miR-107, and miR-135b-5p in urine and renal tissue compared to non-responders. MiR-135b exhibited the best predictive value to discriminate responder patients (area under the curve = 0.783). In vitro studies showed exosome-derived miR-31, miR-107, and miR-135b-5p expression to be mainly produced by tubular renal cells stimulated with inflammatory cytokines (e.g IL1, TNFα, IFNα and IL6). Uptake of urinary exosomes from responders by mesangial cells was superior compared to that from non-responders (90% vs. 50%, p < 0.0001). HIF1A was identified as a potential common target, and low protein levels were found in non-responder renal biopsies. HIF1A inhibition reduced mesangial proliferation and IL-8, CCL2, CCL3, and CXCL1 mesangial cell production and IL-6/VCAM-1 in endothelial cells. Urinary exosomal miR-135b-5p, miR-107, and miR-31 are promising novel markers for clinical outcomes, regulating LN renal recovery by HIF1A inhibition.

Characterization of inflammatory response in hepatorenal syndrome: Relationship with kidney outcome and survival.

BACKGROUND: Several lines of evidence indicate that decompensated cirrhosis is characterized by the presence of systemic inflammation. Hepatorenal syndrome (HRS-AKI) is a unique type of renal failure that occurs at late stages of cirrhosis. However, confirmation of the presence and significance of such inflammatory response in HRS-AKI is lacking. AIM AND METHODS: To characterize the systemic inflammatory response, as estimated by measuring a large number of cytokines, in 161 patients hospitalized for an acute decompensation of cirrhosis: 44 patients without acute kidney injury (AKI), 63 patients with hypovolaemia-induced AKI and 58 patients with HRS-AKI. RESULTS: HRS-AKI was characterized by an altered cytokine profile compared to the other two groups, particularly IL-6, IL-8, TNF-α, VCAM-1, fractalkine and MIP-1α. The inflammatory response was not related to presence of bacterial infection, concomitant acute-on-chronic liver failure or severity of renal dysfunction. Patients who responded to terlipressin and albumin had only a decrease in TNF-α and RANTES after treatment without changes in other cytokines. Interestingly, patients with persistent HRS-AKI had higher levels of IP-10 and VCAM-1 compared to those with resolution of HRS-AKI. VCAM-1 was also an independent predictor of 3-month mortality. A systems biology analysis approach showed that the inflammatory status of HRS-AKI was similar to that of chronic nonhepatic inflammatory conditions, such as lupus erythematosus or inflammatory bowel disease. CONCLUSION: Hepatorenal syndrome is characterized by a marked systemic inflammatory state, reminiscent of that of nonhepatic inflammatory diseases, that correlates with patient outcomes.

Urinary Neuropilin-1: A Predictive Biomarker for Renal Outcome in Lupus Nephritis.

At present, Lupus Nephritis (LN) is still awaiting a biomarker to better monitor disease activity, guide clinical treatment, and predict a patient's long-term outcome. In the last decade, novel biomarkers have been identified to monitor the disease, but none have been incorporated into clinical practice. The transmembrane receptor neuropilin-1 (NRP-1) is highly expressed by mesangial cells and its genetic deletion results in proteinuric disease and glomerulosclerosis. NRP-1 is increased in kidney biopsies of LN. In this work we were interested in determining whether urinary NRP-1 levels could be a biomarker of clinical response in LN. Our results show that patients with active LN have increased levels of urinary NRP-1. When patients were divided according to clinical response, responders displayed higher urinary and tissue NRP-1 levels at the time of renal biopsy. Areas under the receiver operating characteristic curve, comparing baseline creatinine, proteinuria, urinary NRP-1, and VEGFA protein levels, showed NRP-1 to be an independent predictor for clinical response. In addition, in vitro studies suggest that NRP-1could promote renal recovery through endothelial proliferation and migration, mesangial migration and local T cell cytotoxicity. Based on these results, NRP-1 may be used as an early prognostic biomarker in LN.

Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial.

BACKGROUND & AIMS: Patients with decompensated cirrhosis on the waiting list for liver transplantation (LT) commonly develop complications that may preclude them from reaching LT. Circulatory dysfunction leading to effective arterial hypovolemia and activation of vasoconstrictor systems is a key factor in the pathophysiology of complications of cirrhosis. The aim of this study was to investigate whether treatment with midodrine, an alpha-adrenergic vasoconstrictor, together with intravenous albumin improves circulatory dysfunction and prevents complications of cirrhosis in patients awaiting LT. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial (NCT00839358) was conducted, including 196 consecutive patients with cirrhosis and ascites awaiting LT. Patients were randomly assigned to receive midodrine (15-30 mg/day) and albumin (40 g/15 days) or matching placebos for one year, until LT or drop-off from inclusion on the waiting list. The primary endpoint was incidence of any complication (renal failure, hyponatremia, infections, hepatic encephalopathy or gastrointestinal bleeding). Secondary endpoints were mortality, activity of endogenous vasoconstrictor systems and plasma cytokine levels. RESULTS: There were no significant differences between both groups in the probability of developing complications of cirrhosis during follow-up (p = 0.402) or one-year mortality (p = 0.527). Treatment with midodrine and albumin was associated with a slight but significant decrease in plasma renin activity and aldosterone compared to placebo (renin -4.3 vs. 0.1 ng/ml.h, p < 0.001; aldosterone -38 vs. 6 ng/dl, p = 0.02, at week 48 vs. baseline). Plasma norepinephrine only decreased slightly at week 4. Neither arterial pressure nor plasma cytokine levels changed significantly. CONCLUSIONS: In patients with cirrhosis awaiting LT, treatment with midodrine and albumin, at the doses used in this study, slightly suppressed the activity of vasoconstrictor systems, but did not prevent complications of cirrhosis or improve survival. LAY SUMMARY: Patients with cirrhosis who are on the liver transplant waiting list often develop complications which prevent them from receiving a transplant. Circulatory dysfunction is a key factor behind a number of complications. This study was aimed at investigating whether treating patients with midodrine (a vasoconstrictor) and albumin would improve circulatory dysfunction and prevent complications. This combined treatment, at least at the doses administered in this study, did not prevent the complications of cirrhosis or improve the survival of these patients.

Association Between Grade of Acute on Chronic Liver Failure and Response to Terlipressin and Albumin in Patients With Hepatorenal Syndrome.

BACKGROUND & AIMS: Type 1 hepatorenal syndrome (HRS) is the most high-risk type of renal failure in patients with cirrhosis. Terlipressin and albumin are effective treatments for type 1 HRS. However, the effects of acute on chronic liver failure (ACLF) grade on response to treatment are not clear. We aimed to identify factors associated with response to treatment with terlipressin and albumin in patients with type 1 HRS (reduction in serum level of creatinine to below 1.5 mg/dL at the end of treatment) and factors associated with death within 90 days of HRS diagnosis (90-day mortality). METHODS: We performed a retrospective analysis of 4 different cohorts of consecutive patients with HRS treated with terlipressin and albumin from February 2007 through January 2016 at medical centers in Europe (total, 298 patients). We analyzed demographic, clinical, and laboratory data collected before and during treatment; patients were followed until death, liver transplantation, or 90 days after HRS diagnosis. RESULTS: Response to treatment was observed in 53% of patients. Of patients with grade 1 ACLF, 60% responded to treatment; among those with grade 2 ACLF, 48% responded, and among those with grade 3 ACLF, 29% responded (P < .001 for comparison between grades). In multivariate analysis, baseline serum level of creatinine (odds ratio, 0.23; P = .001) and ACLF grade (odds ratio, 0.63; P = .01) were independently associated with response to treatment. Patient age (hazard ratio [HR], 1.05; P < .001), white blood cell count (HR, 1.51; P = .006), ACLF grade (HR, 2.06; P < .001), and no response to treatment (HR, 0.41; P < .001) associated with 90-day mortality. CONCLUSION: In a retrospective analysis of data from 4 cohorts of patients treated for type 1 HRS, we found ACLF grade to be the largest determinant of response to terlipressin and albumin. ACLF grade affects survival independently of response to treatment. New therapeutic strategies should be developed for patients with type 1 HRS and extrarenal organ failure.