Increased risk of renal events in people with diabetic foot disease: A longitudinal observational study.

OBJECTIVE: Diabetic kidney disease favors diabetic foot ulcers, however we do not know whether the reverse relation exists. We investigated whether diabetic foot disease (DFD) related to an increased risk of developing renal events. RESEARCH DESIGN AND METHODS: We conducted a retrospective analysis of a cohort of patients hospitalized for type 2 diabetes mellitus (T2DM) between 2009 and 2017, stratified for the risk of diabetic foot ulcer grades 0 (no risk), 1 and 2 (at risk), and 3 (DFD) according to the International Work Group on Diabetic Foot (IWGDF) classification. We highlighted new renal events (end-stage renal disease or a doubling of serum creatinine) in their medical records until December 2020. The relationship between DFD and later renal events was analyzed by multivariable Cox regression model. RESULTS: Among 519 patients, 142 (27 %) had a DFD at baseline, and 159 (30 %) were classified as Grades 1 or 2. Thirty-six renal events occurred during the 54 ± 27 months of follow-up: 19 subjects started dialysis, 1 had a renal transplantation, and 16 had a doubling of serum creatinine: 15 each in subjects with DFD and subjects at risk, versus 6 in subjects with Grade 0 DFD (logrank: P = 0.001). Adjusted for i) age and sex; ii) hyperglycemic exposure; iii) conventional cardiovascular risk factors; iv) renal parameters: and v) new diabetic foot ulcers during follow-up, DFD (HR 2.7 to 5.9) and being at risk of DFD Grades 1-2 (HR 2.8 to 5.1) were significantly related to new renal events. CONCLUSION: The risk of renal events was increased in people with T2DM and DFD.

Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets.

Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.

Impact of dexamethasone in severe COVID-19-induced acute kidney injury: a multicenter cohort study.

BACKGROUND: Acute kidney injury (AKI) in intensive care unit (ICU) patients with severe COVID-19 is common (> 50%). A specific inflammatory process has been suggested in the pathogenesis of AKI, which could be improved by dexamethasone (DXM). In a small monocenter study (n = 100 patients), we reported a potential protective effect of DXM on the risk of AKI. This study aimed to investigate the preventive impact of DXM on AKI in a multicenter study of patients with severe COVID-19. METHODS: We conducted a multicenter study in three French ICUs from March 2020 to August 2021. All patients admitted to ICU for severe COVID-19 were included. Individuals with preexistent AKI or DXM administration before admission to ICU were excluded. While never used during the first wave, DXM was used subsequently at ICU entry, providing two treatment groups. Multivariate Cause-specific Cox models taking into account changes in ICU practices over time, were utilized to determine the association between DXM and occurrence of AKI. RESULTS: Seven hundred and ninety-eight patients were included. Mean age was 62.6 ± 12.1 years, 402/798 (50%) patients had hypertension, and 46/798 (6%) had previous chronic kidney disease. Median SOFA was 4 [3-6] and 420/798 (53%) required invasive mechanical ventilation. ICU mortality was 208/798 (26%). AKI was present in 598/798 (75%) patients: 266/598 (38%), 163/598 (27%), and 210/598 (35%) had, respectively, AKI KDIGO 1, 2, 3, and 61/598 (10%) patients required renal replacement therapy. Patients receiving DXM had a significantly decreased hazard of AKI occurrence compared to patients without DXM (HR 0.67; 95CI 0.55-0.81). These results were consistent in analyses that (1) excluded patients with DXM administration to AKI onset delay of less than 12 h, (2) incorporating the different 'waves' of the COVID-19 pandemic. CONCLUSIONS: DXM was associated with a decrease in the risk of AKI in severe COVID-19 patients admitted to ICU. This supports the hypothesis that the inflammatory injury of AKI may be preventable.

ROR2/PCP a New Pathway Controlling Endothelial Cell Polarity Under Flow Conditions.

BACKGROUND: Endothelial cells (ECs) are sensitive to physical forces created by blood flow, especially to laminar shear stress. Among the cell responses to laminar flow, EC polarization against the flow direction emerges as a key event, particularly during the development and remodeling of the vascular network. EC adopt an elongated planar cell shape with an asymmetrical distribution of intracellular organelles along the axis of blood flow. This study aimed to investigate the involvement of planar cell polarity via the receptor ROR2 (receptor tyrosine kinase-like orphan receptor 2) in endothelial responses to laminar shear stress. METHODS: We generated a genetic mouse model with EC-specific deletion of Ror2, in combination with in vitro approaches involving loss- and gain-of-function experiments. RESULTS: During the first 2 weeks of life, the endothelium of the mouse aorta undergoes a rapid remodeling associated with a loss of EC polarization against the flow direction. Notably, we found a correlation between ROR2 expression and endothelial polarization levels. Our findings demonstrate that deletion of Ror2 in murine ECs impaired their polarization during the postnatal development of the aorta. In vitro experiments further validated the essential role of ROR2 in both EC collective polarization and directed migration under laminar flow conditions. Exposure to laminar shear stress triggered the relocalization of ROR2 to cell-cell junctions where it formed a complex with VE-Cadherin and ß-catenin, thereby regulating adherens junctions remodeling at the rear and front poles of ECs. Finally, we showed that adherens junctions remodeling and cell polarity induced by ROR2 were dependent on the activation of the small GTPase Cdc42. CONCLUSIONS: This study identified ROR2/planar cell polarity pathway as a new mechanism controlling and coordinating collective polarity patterns of EC during shear stress response.

Performance of real-time PCR in suspected haemodialysis catheter-related bloodstream infection: a proof-of-concept study.

Background: Catheter-related bloodstream infections (CRBIs) remain a major cause of mortality in haemodialysis (HD) patients with central venous catheters (CVCs), especially because of the non-specific symptomatology and the delay in microbiological diagnosis with possible use of non-optimal empiric antibiotics. Moreover, empiric broad-spectrum antibiotics increase antibiotic resistance development. This study aims to evaluate the diagnostic performance of real-time polymerase chain reaction (rt-PCR) in suspected HD CRBIs compared with blood cultures. Methods: A blood sample for rt-PCR was collected simultaneously with each pair of blood cultures for suspected HD CRBI. The rt-PCR was performed on the whole blood, without any enrichment stage and with specific DNA primers: 16S (universal bacterial), Staphylococcus spp., Staphylococcus aureus and mecA. Each successive patient with a suspected HD CRBI in the HD centre of Bordeaux University Hospital was included. Performance tests were used to compare the result obtained in each rt-PCR assay with its corresponding routine blood culture. Results: Eighty-four paired samples were collected and compared for 40 suspected HD CRBI events in 37 patients. Among these, 13 (32.5%) were diagnosed as HD CRBI. All rt-PCRs except mecA (insufficient number of positive samples) showed high diagnostic performances within 3.5 h: 16S (sensitivity 100%, specificity 78%), Staphylococcus spp. (sensitivity 100%, specificity 97%), S. aureus (sensitivity 100%, specificity 99%). Based on the rt-PCR results, antibiotics could be more appropriately targeted, thus cutting anti-cocci Gram-positive therapy from 77% to 29%. Conclusions: The performance of rt-PCR in suspected HD CRBI events showed fast and high diagnostic accuracy. Its use would improve HD CRBI management with an antibiotic consumption decrease.

Revisiting malignant hypertension: rationale and design of the 'HAMA cohort', on behalf of the ESH working group 'hypertension and the kidney'.

BACKGROUND: Malignant hypertension has not disappeared and is associated with a poor prognosis. Yet, so far, it has received limited attention from the medical community. Guidelines are mainly based on expert consensus and low quality evidences. METHOD: We set up a prospective, multicenter, observational cohort of patients with malignant hypertension. We collect at admission medical history, demographic data, ongoing treatment, clinical parameters, symptoms, care pathways, target organ status and at discharge and during follow up treatment administrated, adverse events, blood pressure level, target organ status. We aim to recruit 500 patients with malignant hypertension in 5 years, with a 5-year follow-up. Our primary objective is to assess the 5 years prognosis of these patients. DISCUSSION: The HAMA (Hypertension Arterielle MAligne, meaning malignant hypertension) registry aims to describe the epidemiology and to assess the prognosis of malignant hypertension in a contemporary multidisciplinary cohort, with emphasis on the diversity of current management and care pathway among the different medical specialties. It may help improving our pathophysiological knowledge, and pave the way to update the definition of this particular form of hypertension. The multidisciplinary network developed in the wake of this project is expected to facilitate the set up therapeutic trials, laying the ground for evidence-based recommendations.

Clinical trajectories and impact of acute kidney disease after acute kidney injury in the intensive care unit: a 5-year single-centre cohort study.

BACKGROUND: Patients suffering from acute kidney injury(AKI) in the intensive care unit (ICU) can have various renal trajectories and outcomes. Aims were to assess the various clinical trajectories after AKI in the ICU and to determine risk factors for developing chronic kidney disease (CKD). METHODS: We conducted a prospective 5-year follow-up study in a medical ICU at Bordeaux University Hospital (France). The patients who received invasive mechanical ventilation, catecholamine infusion or both and developed an AKI from September 2013 to May 2015 were included. In the Cox analysis, the violation of the proportional hazard assumption for AKD was handled using appropriate interaction terms with time, resulting in a time-dependent hazard ratio (HR). RESULTS: A total of 232 patients were enrolled, with an age of 62 ± 16 years and a median follow-up of 52 days (interquartile range 6-1553). On day 7, 109/232 (47%) patients progressed to acute kidney disease (AKD) and 66/232 (28%) recovered. A linear trajectory (AKI, AKD to CKD) was followed by 44/63 (70%) of the CKD patients. The cumulative incidence of CKD was 30% [95% confidence interval (CI) 24-36] at the 5-year follow-up. In a multivariable Cox model, in the 6 months following AKI, the HR for CKD was higher in AKD patients [HR 29.2 (95% CI 8.5-100.7); P < 0.0001). After 6 months, the HR for CKD was 2.2 (95% CI 0.6-7.9; P = 0.21; n = 172 patients). CONCLUSION: There were several clinical trajectories of kidney disease after ICU-acquired AKI. CKD risk was higher in AKD patients only in the first 6 months. Lack of renal recovery rather than AKD per se was associated with the risk of CKD.

Impact of Albumin Assays in the Diagnosis of Malnutrition in Hemodialysis Patients: A Cohort Study.

OBJECTIVE: In hemodialysis (HD) patients, malnutrition should be diagnosed by several assessment tools including a plasma albumin concentration of less than 3.8 g/dL or 3.5 g/dL using bromocresol green or immunonephelometry (IN), respectively. However, albumin measurement is not yet standardized and two alternative methods are also commonly used in laboratories: bromocresol purple (BCP) and immunoturbidimetry (IT). This study aimed to revisit the hypoalbuminemia thresholds for BCP and IT, in HD patients. METHODS: Plasma albumin was measured by the four analytical methods during the monthly HD nutritional assessment of 103 prospectively included patients. RESULTS: Significant differences in albumin levels were observed in HD patients depending on the method used. Using BCP or IT with the cut-off at 3.5 g/dL (determined for the general population) we obtained 33% and 9.7% of false hypoalbuminemia in comparison to IN (mean bias of -0.4 g/dL and -0.065 g/dL, respectively). The best hypoalbuminemia threshold for BCP was 3.05 g/dL and 3.4 g/dL for IT. Twenty percent of HD patients were classified as malnourished when albumin was determined by IN. Similar rates were obtained using the new hypoalbuminemia cut-offs for BCP (18.5%) and IT (19.5%). CONCLUSION: To avoid nutritional misclassification of HD patients, we should adjust hypoalbuminemia thresholds when BCP or IT methods are used in laboratories.

Impact of previous REnal TRansplantation on the mid-term renal Outcome after CARdiac surgery: the RETROCAR trial.

BACKGROUND: Acute kidney injury (AKI) is one of the most common complications after cardiac surgery with cardiopulmonary bypass (CPB). Renal transplant recipients (RTRs) have a higher risk of cardiac surgery-associated AKI (CSA-AKI). A relationship has been strongly suggested between AKI and poor long-term graft survival. The main objective was to evaluate the impact of on-pump cardiac surgery on the 1-year renal allograft survival rate. METHODS: The study population consisted of 37 RTRs and 56 non-RTRs who underwent cardiac surgery between 1 January 2010 and 31 December 2019. They were matched according to age, sex, preoperative glomerular function, diabetes and type of surgery. The primary composite outcome was renal survival, defined as patient survival without the requirement for permanent dialysis or new kidney transplantation at 1 year after surgery. RESULTS: The renal survival rate was significantly lower in the RTR group than in the non-RTR group [81% versus 96%; odds ratio 0.16 (95% confidence interval 0.03-0.82), P = .03]. The proportion of patients who returned to permanent dialysis was higher in the RTR group than in the non-RTR group (12% versus 0%; P = .02). The proportion of patients with severe AKI was also higher in the RTR group. At 1 year after surgery, serum creatinine level, glomerular filtration rate and all-cause mortality rates were comparable between both groups. CONCLUSION: Patients with a functional renal allograft have a low 1-year renal allograft survival rate after cardiac surgery with CPB. In addition, these patients have significant risks of AKI and acute kidney disease after open-heart surgery.

Increased Capillary Permeability in Heart Induces Diastolic Dysfunction Independently of Inflammation, Fibrosis, or Cardiomyocyte Dysfunction.

BACKGROUND: While endothelial dysfunction is suggested to contribute to heart failure with preserved ejection fraction pathophysiology, understanding the importance of the endothelium alone, in the pathogenesis of diastolic abnormalities has not yet been fully elucidated. Here, we investigated the consequences of specific endothelial dysfunction on cardiac function, independently of any comorbidity or risk factor (diabetes or obesity) and their potential effect on cardiomyocyte. METHODS: The ubiquitine ligase Pdzrn3, expressed in endothelial cells (ECs), was shown to destabilize tight junction. A genetic mouse model in which Pdzrn3 is overexpressed in EC (iEC-Pdzrn3) in adults was developed. RESULTS: EC-specific Pdzrn3 expression increased cardiac leakage of IgG and fibrinogen blood-born molecules. The induced edema demonstrated features of diastolic dysfunction, with increased end-diastolic pressure, alteration of dP/dt min, increased natriuretic peptides, in addition to limited exercise capacity, without major signs of cardiac fibrosis and inflammation. Electron microscopic images showed edema with disrupted EC-cardiomyocyte interactions. RNA sequencing analysis of gene expression in cardiac EC demonstrated a decrease in genes coding for endothelial extracellular matrix proteins, which could be related to the fragile blood vessel phenotype. Irregularly shaped capillaries with hemorrhages were found in heart sections of iEC-Pdzrn3 mice. We also found that a high-fat diet was not sufficient to provoke diastolic dysfunction; high-fat diet aggravated cardiac inflammation, associated with an altered cardiac metabolic signature in EC-Pdzrn3 mice, reminiscent of heart failure with preserved ejection fraction features. CONCLUSIONS: An increase of endothelial permeability is responsible for mediating diastolic dysfunction pathophysiology and for aggravating detrimental effects of a high-fat diet on cardiac inflammation and metabolism.

PHACTR-1 (Phosphatase and Actin Regulator 1) Deficiency in Either Endothelial or Smooth Muscle Cells Does Not Predispose Mice to Nonatherosclerotic Arteriopathies in 3 Transgenic Mice.

BACKGROUND: Genome-wide association studies have revealed robust associations of common genetic polymorphisms in an intron of the PHACTR-1 (phosphatase and actin regulator 1) gene (chr6p24), with cervical artery dissection, spontaneous coronary artery dissection, and fibromuscular dysplasia. The aim was to assess its role in the pathogenesis of cervical artery dissection or fibromuscular dysplasia. METHODS: Using various tissue-specific Cre-driver mouse lines, Phactr1 was deleted either in endothelial cells using 2 tissue-specific Cre-driver (PDGFB [platelet-derived growth factor B]-CreERT2 mice and Tie2 [tyrosine kinase with immunoglobulin and EGF homology domains]-Cre) and smooth muscle cells (smooth muscle actin-CreERT2) with a third tissue-specific Cre-driver. RESULTS: To test the efficacy of the Phactr1 deletion after cre-induction, we confirmed first, a decrease in Phactr1 transcription and Phactr1 expression in endothelial cell and smooth muscle cell isolated from Phactr1iPDGFB and Phactr1iSMA mice. Irrespective to the tissue or the duration of the deletion, mice did not spontaneously display pathological phenotype or vascular impairment: mouse survival, growth, blood pressure, large vessel morphology, or actin organization were not different in knockout mice than their comparatives littermates. Challenging vascular function and repair either by angiotensin II-induced hypertension or limb ischemia did not lead to vascular morphology or function impairment in Phactr1-deleted mice. Similarly, there were no more consequences of Phactr1 deletion during embryogenesis in endothelial cells. CONCLUSIONS: Loss of PHACTR-1 function in the cells involved in vascular physiology does not appear to induce a pathological vascular phenotype. The in vivo effect of the intronic variation described in genome-wide association studies is unlikely to involve downregulation in PHACTR-1 expression.

Urine Protein/Creatinine Ratio in Thrombotic Microangiopathies: A Simple Test to Facilitate Thrombotic Thrombocytopenic Purpura and Hemolytic and Uremic Syndrome Diagnosis.

BACKGROUND: Early diagnosis of thrombotic thrombocytopenic purpura (TTP) versus hemolytic and uremic syndrome (HUS) is critical for the prompt initiation of specific therapies. OBJECTIVE: To evaluate the diagnostic performance of the proteinuria/creatininuria ratio (PU/CU) for TTP versus HUS. PATIENTS/METHODS: In a retrospective study, in association with the "French Score" (FS) (platelets < 30 G/L and serum creatinine level < 200 µmol/L), we assessed PU/CU for the diagnosis of TTP in patients above the age of 15 with thrombotic microangiopathy (TMA). Patients with a history of kidney disease or with on-going cancer, allograft or pregnancy were excluded from the analysis. RESULTS: Between February 2011 and April 2019, we identified 124 TMA. Fifty-six TMA patients for whom PU/CU were available, including 35 TTP and 21 HUS cases, were considered. Using receiver-operating characteristic curves (ROC), those with a threshold of 1.5 g/g for the PU/CU had a 77% sensitivity (95% CI (63, 94)) and a 90% specificity (95% CI (71, 100)) for TTP diagnosis compared with those having an 80% sensitivity (95% CI (66, 92)) and a 90% specificity (95% CI (76, 100) with a FS of 2. In comparison, a composite score, defined as a FS of 2 or a PU/CU ≤ 1.5 g/g, improved sensitivity to 99.6% (95% CI (93, 100)) for TTP diagnosis and enabled us to reclassify seven false-negative TTP patients. CONCLUSIONS: The addition of urinary PU/CU upon admission of patients with TMA is a fast and readily available test that can aid in the differential diagnosis of TTP versus HUS alongside traditional scoring.

[Diagnosis and treatment of catheter-related bloodstream infection in hemodialysis: 10 years later]. / Diagnostic et prise en charge des bactériémies liées au cathéter d'hémodialyse : 10 ans après les dernières recommandations.

Patients in hemodialysis on central venous catheter as vascular access are at risk of infections. Catheter-related bloodstream infection is one of the most serious catheter-complications in hemodialysis patients. Its clinical and microbiological diagnosis is challenging. The implementation of empiric antibiotic therapy is based on old recommendations proposing the combination of a molecule targeting methicillin-resistant Staphylococcus aureus and a betalactamin active on P. aeruginosa, and also adapting this probabilistic treatment by carrying out a microbiological register on a local scale, which is rarely done. In our hemodialysis center at Bordeaux University Hospital, an analysis of the microorganisms causing all catheter-related bloodstream infection over the period 2018-2020 enabled us to propose, in agreement with the infectious disease specialists, an adapted probabilistic antibiotic therapy protocol. This approach allowed us to observe a low incidence of meticillinoresistance of Staphylococcus. For catheters inserted more than 6 months ago, we observed no Staphylococcus, no multi-resistant Pseudomonas, and only 2% of Enterobacteria resistant to cephalosporins. A frequent updating of the microbiological epidemiology of catheter-related bloodstream infection, in partnership with the infectious diseases team in each hemodialysis center, allowing an adaptation of the probabilistic antibiotic therapy, and seems to have a good feasibility. This strategy might favor the preservation of microbial ecology on an individual and collective scale in maintenance hemodialysis patients.

Decrease of Pdzrn3 is required for heart maturation and protects against heart failure.

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes (CM) connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between CM. Yet no factor on its own is known to coordinate CM polarized organization. We have previously shown that PDZRN3, an ubiquitine ligase E3 expressed in various tissues including the heart, mediates a branch of the Planar cell polarity (PCP) signaling involved in tissue patterning, instructing cell polarity and cell polar organization within a tissue. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. A moderate CM overexpression of Pdzrn3 (Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. In models of pressure-overload stress heart failure, CM-specific Pdzrn3 knockout showed complete protection against degradation of heart function. We reported that Pdzrn3 signaling induced PKC ζ expression, c-Jun nuclear translocation and a reduced nuclear ß catenin level, consistent markers of the planar non-canonical Wnt signaling in CM. We then show that subcellular localization (intercalated disk) of junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn3 OE mice, which provides a molecular explanation for impaired CM polarization in these mice. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of CM, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

[Acute kidney injury in intensive care unit: A review]. / Insuffisance rénale aiguë en soins intensifs-réanimation et ses conséquences : mise au point.

Acute kidney injury is a common complication in intensive care unit. Its incidence is variable according to the studies. It is considered to occur in more than 50 % of patients. Acute kidney injury is responsible for an increase in morbidity (length of hospitalization, renal replacement therapy) but also for excess mortality. The commonly accepted definition of acute kidney injury comes from the collaborative workgroup named Kidney Disease: Improving Global Outcomes (KDIGO). It made it possible to standardize practices and raise awareness among practitioners about monitoring plasma creatinine and also diuresis. Acute kidney injury in intensive care unit is a systemic disease including circulatory, endothelial, epithelial and cellular function involvement and an acute kidney injury is not accompanied by ad integrum repair. After prolonged injury, inadequate repair begins with a fibrotic process. Several mechanisms are involved (cell cycle arrest, epithelial-mesenchymal transition, mitochondrial dysfunction) and result in improper repair. A continuum exists between acute kidney disease and chronic kidney disease, characterized by different renal recovery phenotypes. Thus, preventive measures to prevent the occurrence of kidney damage play a major role in management. The nephrologist must be involved at every stage, from the prevention of the first acute kidney injury (upon arrival in intensive care unit) to long-term follow-up and the care of a chronic kidney disease.

ANCA-Negative Pauci-immune Necrotizing Glomerulonephritis: A Case Series and a New Clinical Classification.

RATIONALE & OBJECTIVE: Pauci-immune necrotizing glomerulonephritis (PING) is usually associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). However, a minority (2%-3%) of patients with PING do not have detectable ANCA. We assessed the clinical spectrum and outcome of patients with ANCA-negative PING. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 74 patients with ANCA-negative PING diagnosed in 19 French nephrology centers between August 2006 and December 2018 were included in the series. Patients' medical files were reviewed, and kidney biopsies were centrally reexamined by pathologists who were masked to the diagnosis. FINDINGS: Median age at diagnosis was 69 (IQR, 61-76) years. The clinical and pathological features were remarkable for a high frequency of extrarenal manifestations (54%), nephrotic syndrome (32%), and endocapillary hypercellularity (31%). Three main subtypes of ANCA-negative PING were observed: infection-associated (n=9[12%]), malignancy-associated (n=6[8%]), and primary (n=57[77%]). For patients with primary PING, induction treatment included mainly corticosteroids (n=56[98%]), cyclophosphamide (n=37[65%]), and rituximab (n=5[9%]). Maintenance treatment consisted mainly of corticosteroids (n=42[74%]), azathioprine (n=18[32%]), and mycophenolate mofetil (n=11[19%]). After a median follow-up period of 28 months, 28 (38%) patients had died and 20 (27%) developed kidney failure (estimated glomerular filtration rate<15mL/min/1.73m2). Eleven (21%) patients (9 with primary and 2 with malignancy-associated PING) relapsed. LIMITATIONS: Retrospective study and limited number of patients; electron microscopy was not performed to confirm the absence of glomerular immune deposits. CONCLUSIONS: Within the spectrum of ANCA-negative PING, infection and malignancy-associated forms represent a distinct clinical subset. This new clinical classification may inform the management of ANCA-negative PING, which remains a severe form of vasculitis with high morbidity and mortality rates despite immunosuppressive treatments.

Targeting Pdzrn3 maintains adult blood-brain barrier and central nervous system homeostasis.

Blood brain barrier (BBB) disruption is a critical component of the pathophysiology of cognitive impairment of vascular etiology (VCI) and associated with Alzheimer's disease (AD). The Wnt pathway plays a crucial role in BBB maintenance, but there is limited data on its role in cognitive pathologies. The E3 ubiquitin ligase PDZRN3 is a regulator of the Wnt pathway. In a murine model of VCI, overexpressing Pdzrn3 in endothelial cell (EC) exacerbated BBB hyperpermeability and accelerated cognitive decline. We extended these observations, in both VCI and AD models, showing that EC-specific depletion of Pdzrn3, reinforced the BBB, with a decrease in vascular permeability and a subsequent spare in cognitive decline. We found that in cerebral vessels, Pdzrn3 depletion protects against AD-induced Wnt target gene alterations and enhances endothelial tight junctional proteins. Our results provide evidence that Wnt signaling could be a molecular link regulating BBB integrity and cognitive decline under VCI and AD pathologies.

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study.

BACKGROUND: The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80-85 mmHg) and a low-target period (65-70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. RESULTS: 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (- 10 (95% CI - 17, - 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine-plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. CONCLUSIONS: In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.