A dual model of normal vs isogenic Nrf2-depleted murine epithelial cells to explore oxidative stress involvement.

Cancer-derived cell lines are useful tools for studying cellular metabolism and xenobiotic toxicity, but they are not suitable for modeling the biological effects of food contaminants or natural biomolecules on healthy colonic epithelial cells in a normal genetic context. The toxicological properties of such compounds may rely on their oxidative properties. Therefore, it appears to be necessary to develop a dual-cell model in a normal genetic context that allows to define the importance of oxidative stress in the observed toxicity. Given that the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is considered to be the master regulator of antioxidant defenses, our aim was to develop a cellular model comparing normal and Nrf2-depleted isogenic cells to qualify oxidative stress-related toxicity. We generated these cells by using the CRISPR/Cas9 technique. Whole-genome sequencing enabled us to confirm that our cell lines were free of cancer-related mutations. We used 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product closely related to oxidative stress, as a model molecule. Here we report significant differences between the two cell lines in glutathione levels, gene regulation, and cell viability after HNE treatment. The results support the ability of our dual-cell model to study the role of oxidative stress in xenobiotic toxicity.

Sepsis-trained macrophages promote antitumoral tissue-resident T cells.

Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.

Successful Treatment of SIADH after Removal of Ruptured Breast Implants.

Local adverse reactions to breast implants and systemic reactions, mostly autoinflammatory, are numerously described in the literature. A patient presented at our institution with severe neurologic symptoms, including confusion and phasic troubles due to severe hyponatremia as part of syndrome of inappropriate antidiuretic hormone secretion (SIADH). Common etiologies for SIADH, primarily malignancy and central nervous system disturbances, have been ruled out by imaging. On the computed tomography scan of the thorax and abdomen, several masses were found in the pectoral region, inferior to the sternum and in the left axilla that were biopsied and verified as silicone. While evaluating the patient's medical history, the patient remembered having undergone breast augmentation with silicone implants several decades ago. The only explanation left for the persisting SIADH was her ruptured silicone implants, causing an inflammatory systemic reaction. Literature was searched, and one abstract was found, in which a woman presenting with SIADH was treated successfully after removal of her silicone breast implants. We offered the same treatment to our patient, and siliconomas were removed through a bilateral inframammary approach as well as axillary on the left. There were no complications encountered. Postoperatively, the patient's hyponatremia improved and normalized 1 month later even without hydric restriction. This potential form of etiology and treatment of SIADH is a novelty in the medical literature. Surgical removal of dispersed silicone is presumed to be the cure for this syndrome. It represents a diagnosis of exclusion after more life-threatening causes, such as central nervous system disturbances and malignancies, have been ruled out.

Adjuvant Docetaxel in Node-Negative Breast Cancer Patients: A Randomized Trial of AGO-Breast Study Group, German Breast Group, and EORTC-Pathobiology Group.

BACKGROUND: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. METHODS: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m2 (FEC-Doc). Primary endpoint was disease-free survival (DFS). RESULTS: In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC. CONCLUSIONS: With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

Association of Low Handgrip Strength with Chemotherapy Toxicity in Digestive Cancer Patients: A Comprehensive Observational Cohort Study (FIGHTDIGOTOX).

In the FIGHTDIGO study, digestive cancer patients with dynapenia experienced more chemotherapy-induced neurotoxicities. FIGHTDIGOTOX aimed to evaluate the relationship between pre-therapeutic handgrip strength (HGS) and chemotherapy-induced dose-limiting toxicity (DLT) or all-grade toxicity in digestive cancer patients. HGS measurement was performed with a Jamar dynamometer. Dynapenia was defined according to EWGSOP2 criteria (<27 kg (men); <16 kg (women)). DLT was defined as any toxicity leading to dose reduction, treatment delay, or permanent discontinuation. We also performed an exploratory analysis in patients below the included population's median HGS. A total of 244 patients were included. According to EWGSOP2 criteria, 23 patients had pre-therapeutic dynapenia (9.4%). With our exploratory median-based threshold (34 kg for men; 22 kg for women), 107 patients were dynapenic (43.8%). For each threshold, dynapenia was not an independent predictive factor of overall DLT and neurotoxicity. Dynapenic patients according to EWGSOP2 definition experienced more hand-foot syndrome (p = 0.007). Low HGS according to our exploratory threshold was associated with more all-grade asthenia (p = 0.014), anemia (p = 0.006), and asthenia with DLT (p = 0.029). Pre-therapeutic dynapenia was not a predictive factor for overall DLT and neurotoxicity in digestive cancer patients but could be a predictive factor of chemotherapy-induced anemia and asthenia. There is a need to better define the threshold of dynapenia in cancer patients.

ADD10 protects renal cells from cold injuries by improving energy metabolism.

Static cold storage (SCS) is currently the most widely used method for organ preservation, but a number of limitations are associated including tissue damage and restricted opportunity for organ repair. Thus, the development of improved hypothermic storage solutions is an urgent need. Herein, using a renal epithelial cell model (LLC-PK1), we tested the benefits of ADD10, a novel clinical grade antioxidant product, in reducing damages associated with ischemia-reperfusion (IR). Cells were stored up to 24h at 4 °C in University of Wisconsin (UW) solution without or in the presence of 1% ADD10 with following reperfusion up to 24h at 37 °C. The presence of ADD10 significantly decreased cells damages, cell death, and the level of reactive oxygen species (ROS) (P < 0.05). Concomitantly, ADD10 supplementation also favored an increased oxygen consumption rate (OCR) and improved bioenergetics of LLC-PK1 cells (P < 0.05). Finally, preliminary in vivo studies suggested a benefit of ADD10 on the renal function post-transplantation. In conclusion, these results demonstrate that the addition of ADD10 to the preservation solution not only efficiently protects renal cells during SCS, but also improves the functionality of cold-stored organs during transplantation.

Analgesic and preventive effects of donepezil in animal models of chemotherapy-induced peripheral neuropathy: Involvement of spinal muscarinic acetylcholine M2 receptors.

BACKGROUND: Donepezil, a cholinesterase inhibitor approved in Alzheimer's disease, has demonstrated analgesic and preventive effects in animal models of oxaliplatin-induced neuropathy. To improve the clinical interest of donepezil for the management and prevention of chemotherapy-induced peripheral neuropathy (CIPN), a broader validation is required in different animal models of CIPN. METHODS: using rat models of CIPN (bortezomib, paclitaxel, and vincristine), the analgesic and preventive efficacies of donepezil were evaluated on tactile, cold and heat hypersensitivities. The involvement of muscarinic M2 acetylcholine receptors (m2AChRs) in analgesic effects was investigated at the spinal level. The absence of interference of donepezil with the cytotoxic effect of chemotherapy has been controlled in cancer cell lines. RESULTS: the analgesic efficacy of donepezil was demonstrated for all CIPN models, mainly on tactile hypersensitivity (maximal efficacy at 60 min, p < 0.05 vs. vehicle group). This effect was suppressed by an intrathecal injection of methoctramine (m2AChR antagonist). Regarding preventive effects, donepezil limited tactile hypersensitivity induced by paclitaxel, but not for other CIPN models. Donepezil did not modify the viability of cancer cells or the efficacy of anticancer drugs. CONCLUSIONS: donepezil had a broad analgesic effect on animal models of CIPN and this effect involved spinal m2AChRs. This work validates the repositioning of donepezil in the management of CIPN.

Pathogenic Variants in ZSWIM7 Cause Primary Ovarian Insufficiency.

CONTEXT: Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers. OBJECTIVE: We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis. SETTING: Study subjects were recruited at academic centers. PATIENTS OR OTHER PARTICIPANTS: Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected. RESEARCH DESIGN: Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene. MAIN OUTCOME MEASURE(S): Rare deleterious variants in known and candidate genes associated with POI. RESULTS: Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function. CONCLUSIONS: Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.

Diffusion-magnetic resonance imaging predicts decline of kidney function in chronic kidney disease and in patients with a kidney allograft.

Kidney cortical interstitial fibrosis is highly predictive of kidney prognosis and is currently assessed by evaluation of a biopsy. Diffusion-weighted magnetic resonance imaging is a promising non-invasive tool to evaluate kidney fibrosis. We recently adapted diffusion-weighted imaging sequence for discrimination between the kidney cortex and medulla and found that the cortico-medullary difference in apparent diffusion coefficient (ΔADC) correlated with histological interstitial fibrosis. Here, we assessed whether ΔADC as measured with diffusion-weighted magnetic resonance imaging is predictive of kidney function decline and dialysis initiation in chronic kidney disease (CKD) and patients with a kidney allograft in a prospective study encompassing 197 patients. We measured ΔADC in 43 patients with CKD (estimated GFR (eGFR) 55ml/min/1.73m2) and 154 patients with a kidney allograft (eGFR 53ml/min/1.73m2). Patients underwent a kidney biopsy and diffusion-weighted magnetic resonance imaging within one week of biopsy; median follow-up of 2.2 years with measured laboratory parameters. The primary outcome was a rapid decline of kidney function (eGFR decline over 30% or dialysis initiation) during follow up. Significantly, patients with a negative ΔADC had 5.4 times more risk of rapid decline of kidney function or dialysis (95% confidence interval: 2.29-12.58). After correction for kidney function at baseline and proteinuria, low ADC still predicted significant kidney function loss with a hazard ratio of 4.62 (95% confidence interval 1.56-13.67) independent of baseline age, sex, eGFR and proteinuria. Thus, low ΔADC can be a predictor of kidney function decline and dialysis initiation in patients with native kidney disease or kidney allograft, independent of baseline kidney function and proteinuria.

[Living donor nephrectomy]. / Prélèvement de rein chez le donneur vivant.

Kidney living donor is the best treatment of terminal kidney failure. Donors are remarkably altruistic. The first concern of the medical team is not to harm the donor and respect their will to give their kidney. The technological evolution towards mini-invasive approaches has largely contributed to a better post-operative recovery. The evolution of this trend has led us to use laparoscopic robot-assisted kidney harvesting as the optimal standard. This work describes our pathway to this option.

Recevoir un rein par un donneur vivant est à ce jour le meilleur traitement de l'insuffisance rénale terminale. Les donneurs font un geste remarquablement altruiste. Le but primaire de l'équipe médicale est de pouvoir soigner un patient insuffisant rénal grâce au don d'organe sans nuire au donneur. Les avancées technologiques vers des approches mini-invasives ont contribué à l'amélioration de la prise en charge des donneurs en augmentant considérablement leur confort postopératoire et en réduisant drastiquement les durées moyennes d'hospitalisation. La procédure standard aux HUG à ce jour est la laparoscopie robot-assistée. Cet article retrace l'évolution mini-invasive du don de rein dans le service.

Relationship between renal function and blood pressure dipping status in renal transplant recipients: a longitudinal study.

BACKGROUND: Hypertension (HT) is associated with adverse outcomes in kidney transplant (KTX) recipients. Blunting of physiological decrease in nighttime compared to daytime blood pressure (non-dipping status) is frequent in this setting. However, weather non-dipping is independently associated with renal function decline in KTX patients is unknown. METHODS: We retrospectively screened KTX outpatients attending for a routine ambulatory blood pressure monitoring (ABPM) (T1) at a single tertiary hospital. Patients had two successive follow-up visits, 1 (T2) and 2 (T3) years later respectively. Routine clinical and laboratory data were collected at each visit. Mixed linear regression models were used with estimated glomerular filtration rate (eGFR) as the dependent variable. RESULTS: A total of 123 patients were included with a mean follow-up of 2.12 ± 0.45 years after ABPM. Mean age and eGFR at T1 were 56.0 ± 15.1 and 54.9 ± 20.0 mL/min/1.73m2 respectively. 61 patients (50.4%) had sustained HT and 81 (65.8%) were non-dippers. In multivariate analysis, systolic dipping status was positively associated with eGFR (p = 0.009) and compared to non-dippers, dippers had a 10.4 mL/min/1.73m2 higher eGFR. HT was negatively associated with eGFR (p = 0.003). CONCLUSIONS: We confirm a high prevalence of non-dippers in KTX recipients. We suggest that preserved systolic dipping is associated with improved renal function in this setting independently of potential confounders, including HT and proteinuria. Whether modification of dipping status by chronotherapy would preserve renal function remains to be tested in clinical trials.

[IgA nephropathy : update]. / Nouveautés dans la néphropathie à IgA.

IgA nephropathy is the most common primary glomerulopathy worldwide. However, it remains underdiagnosed because of its clinical heterogeneity. Its diagnosis is currently based on kidney biopsy and there are no clinically validated serological tests. Its pathogenesis is based on an anomaly in the glycosylation of type A immunoglobulins and a progression punctuated by multiple triggering events (hits). The conservative approach of using corticosteroid therapy and/or more selective immunosuppression in certain clinical situations remains the state-of-the-art treatment. New therapeutic perspectives seem promising but must be validated.

La néphropathie à immunoglobulines A est la glomérulopathie primaire la plus fréquente dans le monde. Elle reste néanmoins sous-diagnostiquée de par son hétérogénéité clinique. Son diagnostic repose actuellement sur la biopsie rénale et il n'existe pas de tests sérologiques cliniquement validés. Sa pathogenèse repose sur une anomalie de la glycosylation des immunoglobulines de type A et une progression rythmée par des événements déclencheurs multiples. L'approche conservatrice reste la pierre angulaire du traitement avec recours à la corticothérapie et/ou une immunosuppression plus sélective dans certaines situations cliniques. De nouvelles perspectives thérapeutiques semblent prometteuses, mais doivent être validées.

Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population.

Next-generation sequencing strategies have resulted in mutation detection rates of 21% to 61% in small cohorts of patients with microphthalmia, anophthalmia and coloboma (MAC), but despite progress in identifying novel causative genes, many patients remain without a genetic diagnosis. We studied a cohort of 19 patients with MAC who were ascertained from a population with high rates of consanguinity. Using single nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES), we identified one pathogenic variant in TENM3 in a patient with cataracts in addition to MAC. We also detected novel variants of unknown significance in genes that have previously been associated with MAC, including KIF26B, MICU1 and CDON, and identified variants in candidate genes for MAC from the Wnt signaling pathway, comprising LRP6, WNT2B and IQGAP1, but our findings do not prove causality. Plausible variants were not found for many of the cases, indicating that our current understanding of the pathogenesis of MAC, a highly heterogeneous group of ocular defects, remains incomplete.

[Ethylene glycol intoxication requires a multidisciplinary approach]. / L'intoxication à l'éthylène glycol nécessite une approche multidisciplinaire.

Cheap and easy to access, ethylene glycol is used in the synthesis of antifreezes. Intoxication has potentially irreversible morbid consequences. Ingestion of a small amount can lead to death. Due to its ubiquitous distribution and potential complications, it is of paramount importance for the practitioner to recognize its manifestations and metabolic complications in order to implement its therapy in partnership with the nephrologist and the intensivist. A successful treatment depends on rapid and multidisciplinary management, as reviewed in this article.

L'éthylène glycol (EG), bon marché et facile d'accès, est notamment utilisé dans la synthèse des antigels. Une intoxication à l'EG a des conséquences morbides potentiellement irréversibles et est associée à une mortalité non négligeable. Du fait des complications et de sa distribution en libre-service, il convient pour le praticien des urgences d'en reconnaître les manifestations, notamment métaboliques, afin d'en assumer le traitement en partenariat avec l'intensiviste et le néphrologue. Le succès dépend d'une reconnaissance rapide et d'une prise en charge multidisciplinaire dont une approche est suggérée dans cet article.

[The kidneys†: possible victims of global warming†?] / Les reins†: cibles du réchauffement climatique†?

Over the last decades, an increasing number of cases of chronic and end-stage kidney disease has been observed in Central America and Asia. This kidney disease mainly affects young farmers without classic renal risk factors. The clinical presentation includes a progressive decrease of the glomerular filtration rate, minimal proteinuria and the presence of tubulo-interstitial nephritis at renal biopsy. A close link with global warming is suspected for this disease, called (according to its location) meso-american nephropathy, Sri Lanka nephropathy or chronic kidney disease of unknown etiology. Others have suggested that intake of water contaminated with pesticides may be responsible. This article provides an overview of this new kidney disease. Measures to prevent acute kidney injury during heat waves in Switzerland are also discussed.

Au cours des dernières décennies, on observe un nombre croissant de cas d'insuffisance rénale chronique et terminale en Amérique centrale et en Asie. Celle-ci touche surtout des jeunes agriculteurs sans autre facteur de risque rénal. La symptomatologie inclut une baisse progressive de la filtration glomérulaire, et une protéinurie minime, avec à la biopsie une néphrite tubulo-interstitielle. Un lien étroit avec le réchauffement climatique a été évoqué pour cette maladie nommée selon la région néphropathie mésoaméricaine, sri lankaise ou néphropathie d'étiologie inconnue. Une autre hypothèse est la consommation d'eau contaminée par des pesticides. Dans cet article, nous ferons le point sur cette nouvelle maladie rénale. La prévention de l'insuffisance rénale aiguë pendant les périodes de forte chaleur en Suisse est également discutée.

Validation of the corticomedullary difference in magnetic resonance imaging-derived apparent diffusion coefficient for kidney fibrosis detection: a cross-sectional study.

BACKGROUND: Kidney cortical interstitial fibrosis (IF) is highly predictive of renal prognosis and is currently assessed by the evaluation of a biopsy. Diffusion magnetic resonance imaging (MRI) is a promising tool to evaluate kidney fibrosis via the apparent diffusion coefficient (ADC), but suffers from inter-individual variability. We recently applied a novel MRI protocol to allow calculation of the corticomedullary ADC difference (ΔADC). We here present the validation of ΔADC for fibrosis assessment in a cohort of 164 patients undergoing biopsy and compare it with estimated glomerular filtration rate (eGFR) and other plasmatic parameters for the detection of fibrosis. METHODS: This monocentric cross-sectional study included 164 patients undergoing renal biopsy at the Nephrology Department of the University Hospital of Geneva between October 2014 and May 2018. Patients underwent diffusion-weighted imaging, and T1 and T2 mappings, within 1 week after biopsy. MRI results were compared with gold standard histology for fibrosis assessment. RESULTS: Absolute cortical ADC or cortical T1 values correlated poorly to IF assessed by the biopsy, whereas ΔADC was highly correlated to IF (r=-0.52, P < 0.001) and eGFR (r = 0.37, P < 0.01), in both native and allograft patients. ΔT1 displayed a lower, but significant, correlation to IF and eGFR, whereas T2 did not correlate to IF nor to eGFR. ΔADC, ΔT1 and eGFR were independently associated with kidney fibrosis, and their combination allowed detection of extensive fibrosis with good specificity. CONCLUSION: ΔADC is better correlated to IF than absolute cortical or medullary ADC values. ΔADC, ΔT1 and eGFR are independently associated to IF and allow the identification of patients with extensive IF.

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Dialysis initiation improves calcification propensity.

BACKGROUND: Cardiovascular morbidity and mortality is high in patients starting dialysis and could be related to modifications of calcification inducers and inhibitors by dialysis, promoting cardiovascular events. The impact of dialysis initiation on serum calcification propensity evolution and arterial stiffness is unknown. We therefore prospectively determined the evolution of the one-half maximal transition time (T50) value and its main determinants as well as pulse wave velocity over the first 3 months of dialysis initiation. METHODS: We analysed the evolution of T50, fetuin-A and mineral metabolism parameters before dialysis initiation (M0) and monthly until Month 3 (M3) in incident patients starting haemodialysis (HD) or peritoneal dialysis (PD) in two tertiary Swiss university hospitals. Arterial stiffness was assessed by pulse tonometry at M0 and M3 and biological parameters were compared between M0 and M3 and before/after HD. Linear mixed models were used to assess parameter evolution over time, taking into account repeated measures and other influencing variables. RESULTS: Forty-six patients on HD and 12 on PD were followed. Among them, 45 were male (78%) with a median age of 67 years (25th-75th quartile range 54-77). T50 significantly increased between M0 and M3 from 183 (120-266) to 246 min (175-330) (P < 0.001). Fetuin-A, calcium and magnesium also increased while phosphate decreased. Factors associated with T50 changes over time were fetuin-A, phosphate and magnesium (P < 0.001). Fetuin-A changes were associated with inflammation-related factors (albumin, C-reactive protein) but not calcium and phosphate levels. Arterial stiffness was not significantly modified over 3 months. PD and HD initiation showed similar trends. CONCLUSIONS: Dialysis initiation significantly improves calcification propensity and fetuin-A levels. These modifications do not explain the high mortality related to dialysis initiation. The clinical relevance of using T50 values to initiate dialysis awaits further studies.

Biomarkers for acute kidney injury in decompensated cirrhosis: A prospective study.

AIM: Acute kidney injury (AKI) is a frequent complication in cirrhotic patients. As serum creatinine is a poor marker of renal function in this population, we aimed to study the utility of several biomarkers in this context. METHODS: A prospective study was conducted in hospitalized patients with decompensated cirrhosis. Serum creatinine (SCr), Cystatin C (CystC), NGAL and urinary NGAL, KIM-1, protein, albumin and sodium were measured on three separate occasions. Renal resistive index (RRI) was obtained. We analyzed the value of these biomarkers to determine the presence of AKI, its aetiology [prerenal, acute tubular necrosis (ATN), or hepatorenal (HRS)], its severity and a composite clinical outcome at 30 days (death, dialysis and intensive care admission). RESULTS: We included 105 patients, of which 55 had AKI. SCr, CystC, NGAL (plasma and urinary), urinary sodium and RRI at inclusion were independently associated with the presence of AKI. SCr, CystC and plasma NGAL were able to predict the subsequent development of AKI. Pre-renal state showed lower levels of SCr, NGAL (plasma and urinary) and RRI. ATN patients had high levels of NGAL (plasma and urinary) as well as urinary protein and sodium. HRS patients presented an intermediate pattern. All biomarkers paralleled the severity of AKI. SCr, CystC and plasma NGAL predicted the development of the composite clinical outcome with the same performance as the MELD score. CONCLUSIONS: In patients with decompensated cirrhosis, early measurement of renal biomarkers provides valuable information on AKI aetiology. It could also improve AKI diagnosis and prognosis.

Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.

The number of leukocytes present in circulation varies throughout the day, reflecting bone marrow output and emigration from blood into tissues. Using an organism-wide circadian screening approach, we detected oscillations in pro-migratory factors that were distinct for specific vascular beds and individual leukocyte subsets. This rhythmic molecular signature governed time-of-day-dependent homing behavior of leukocyte subsets to specific organs. Ablation of BMAL1, a transcription factor central to circadian clock function, in endothelial cells or leukocyte subsets demonstrated that rhythmic recruitment is dependent on both microenvironmental and cell-autonomous oscillations. These oscillatory patterns defined leukocyte trafficking in both homeostasis and inflammation and determined detectable tumor burden in blood cancer models. Rhythms in the expression of pro-migratory factors and migration capacities were preserved in human primary leukocytes. The definition of spatial and temporal expression profiles of pro-migratory factors guiding leukocyte migration patterns to organs provides a resource for the further study of the impact of circadian rhythms in immunity.